Before Treatment	After Treatment

This web site is constantly being updated and evolving as new pain related research is reviewed.  To avoid constantly re-reading the same material, the visitor is encouraged to make a note of the number of references cited at the end of the article.  New versions will have more references.

As this site was hastened to be posted in August 2003 at the request of numerous patients, the visitor is requested to appreciate that grammatical corrections and redundancy will be corrected, and addition of pending references will be forthcoming.  The authors apologize and anticipate prompt refinement to this site.

The material herein is notarized, copyright Aaron S. Geller, M.D. DBA Nashua Pain Management.  All rights reserved.  

The material herein reflects the extensive research and experience of the author.  Any medication discussed herein must be prescribed and consumed in accord with the prescribing information released from the manufacturer.
 

OBJECTIVES:

The clinician will appreciate;

Different mechanisms of action of different analgesic classes act via excitatory and inhibitory neurotransmitters, distinct sites and circuits in the peripheral and central nervous system, and different combinations of sodium, calcium, and potassium ion effects to achieve pain relief.  This is reflected in pain management by embracement of a polymodal treatment strategy utilizing agents of several classes to maximize analgesia and limit side effects.

Individual medications of analgesic classes of antidepressants, NSAID’s, opioids, anticonvulsants, anti-arrhythmics, and spasmolytics have structural distinctiveness such that different trials within each class can be pursued to effect antinociception in accord with each patient’s unique biophysiology.

The efficacy of the spectrum of topical medications, a limited number of systemic agents, and injections are often employed to limit cognitive and other side effects in the management of pain.  Topical medications may include sodium or calcium antagonists, NMDA blockers, opioids, and anticonvulsants.

Novel analgesics may be employed to attenuate pain, including T/N calcium channel blockers, substance P inhibitors, oral cannaboid receptor agonists, and NMDA antagonists.

Co-prescription of combinations of analgesics may potentiate pain relief in a supra-additive manner with limitation of side effects limited to simple additivity.

Treatment of mood depression, anxiety, obesity, fatigue, insomnia, and other comorbid conditions must be integral to comprehensive pain management to maximally reduce pain and enhance function.

Opioids are narcotic analgesics written by clinicians, not DEA, state police, FBI, Board of Medicine, or Board of Pharmacy.  Clinicians who elect to prescribe such medications must embrace the responsibility of screening for addiction and diversion.  Strategies will be presented.  

Opioids are safe and effective for chronic use for the patient truly suffering in pain.  Tolerance is a rare event, but addiction and criminal diversion are not rare nor are they victimless crimes.
 
 
 

OUTLINE OF CHAPTERS
EPIDEMIOLOGY OF PAIN – SCOPE OF THE CONDITION
CLASSIFICATION OF PAIN
PAIN MANAGEMENT TREATMENT GOALS

MECHANISMS OF PAIN – PHYSIOLOGY
PATHOPHYSIOLOGIC MECHANISMS OF ACUTE AND CHRONIC PAIN
MECHANISMS – PHYSIOLOGY – CALCIUM CHANNELS
MECHANISMS – PHYSIOLOGY – CALCIUM CHANNEL BLOCKING ANALGESICS
MECHANISMS – PHYSIOLOGY – SODIUM CHANNELS
MECHANISMS – PHYSIOLOGY – SODIUM CHANNEL BLOCKING ANALGESICS
MECHANISMS – PHYSIOLOGY – POTASSIUM CHANNELS
MECHANISMS – PHYSIOLOGY – POTASSIUM CHANNEL BLOCKING ANALGESICS

MEASUREMENT OF PAIN
DIAGNOSIS
EMERGENCIES
TREATMENT OF PAIN

COMORBID CONDITIONS
COMORBID CONDITIONS – MOOD DEPRESSION
COMORBID CONDITIONS – ANXIETY
COMORBID CONDITIONS – OBESITY
COMORBID OBESITY – TREATMENT – IMPAIRING FAT ABSORPTION
COMORBID OBESITY – TREATMENT – SUPPRESSING APPETITE
COMORBID CONDITIONS – MYOFASCIAL PAIN / FIBROMYALGIA
COMORBID CONDITIONS – SMOKING TOBACCO
COMORBID CONDITIONS – INSOMNIA
COMORBID CONDITIONS – RESTLESS LEGS SYNDROME
COMORBID CONDITIONS – ERECTILE DYSFUNCTION
COMORBID CONDITIONS – CHRONIC FATIGUE
COMORBID CHRONIC FATIGUE – TREATMENT– MODAFINIL
COMORBID CHRONIC FATIGUE – TREATMENT– ADDITIONAL OPTIONS

MEDICATION INDUCED SIDE EFFECTS
MEDICATION INDUCED SIDE EFFECTS – ORTHOSTATIC HYPOTENSION
MEDICATION INDUCED SIDE EFFECTS – XEROSTOMIA
MEDICATION INDUCED SIDE EFFECTS – CONSTIPATION
MEDICATION INDUCED SIDE EFFECTS – URINARY RETENTION

NON-ANALGESIC MEDICATIONS

ANALGESIC MEDICATIONS
MEDICATIONS – SYNERGISM OF COMBINATIONS OF ANALGESICS
MEDICATIONS – ANTAGONISM OF COMBINATIONS OF ANALGESICS
MEDICATIONS – GLUCOSAMINE AND CHONDROITIN

MEDICATIONS – ANTI-INFLAMMATORIES – STEROIDS
MEDICATIONS – ANTI-INFLAMMATORIES – ORAL STEROIDS
MEDICATIONS – ANTI-INFLAMMATORIES – INTRA-ARTICULAR STEROIDS
MEDICATIONS – INTRA-ARTICULAR STEROIDS – SACRO-ILIAC JOINTS
MEDICATIONS – INTRA-ARTICULAR STEROIDS – EPIDURAL STEROIDS
MEDICATIONS - ANTI-INFLAMMATORIES – LIPOXYGENASE ANTAGONISTS
MEDICATIONS - ANTI-INFLAMMATORIES – CYCLOOXYGENASE (COX) ANTAGONISTS
MEDICATIONS – NSAID’S – STRUCTURAL CLASSES
MEDICATIONS – NSAID’S – ASPIRIN
MEDICATIONS –NSAID’S – NEGATIVE GI CONSIDERATIONS 
MEDICATIONS – COX-2 SELECTIVE NSAID’S 
MEDICATIONS – NONSELECTIVE NSAID BLEEDING CONSIDERATIONS OTHER 
THAN COX-2 RELATED ISSUES
MEDICATIONS – NSAID’S – PRESCRIBING RECOMMENDATIONS
MEDICATIONS – NSAID’S –GI CONSIDERATIONS – PPI’s
MEDICATIONS – COX BLOCKING NSAID’s – NEGATIVE RENAL CONSIDERATIONS
MEDICATIONS – COX INHIBITING NSAID’s – CHRONIC PAIN

MEDICATIONS – ACETAMINOPHEN
MEDICATIONS – TOPICAL MEDICATIONS
MEDICATIONS – MUSCLE RELAXANTS
MEDICATIONS – MUSCLE RELAXANTS – SPECIFIC AGENTS
MEDICATIONS – ANTIDEPRESSANTS
MEDICATIONS – TRICYCLIC ANTIDEPRESSANTS
MEDICATIONS – DOPAMINERGIC ANTIDEPRESSANTS
MEDICATIONS – SEROTONERGIC ANTIDEPRESSANTS
MEDICATIONS – ANTIHISTAMINES 
MEDICATIONS – ANTICONVULSANTS
MEDICATIONS – ANTI-ARRHYTHMICS 
MEDICATIONS – PERIPHERAL ALPHA BLOCKING ANTIHYPERTENSIVES
MEDICATIONS – SUBSTANCE P INHIBITORS
MEDICATIONS – BISPHOSPHONATES
MEDICATIONS – CALCITONIN
MEDICATIONS – DOPAMINE RECEPTOR BLOCKING MOOD STABILIZERS 
MEDICATIONS – NARCOTICS
MEDICATIONS – NMDA BLOCKERS
MEDICATIONS – CANNABINOID RECEPTOR AGONISTS
MARIJUANA
MEDICATIONS – PSYCHOSTIMULANTS

MEDICATIONS – OPIOIDS
MEDICATIONS – OPIOIDS – CURING PAIN
MEDICATIONS – OPIOIDS – SUPRA-ADDITIVITY
MEDICATIONS – OPIOIDS – OPIOID RECEPTOR SUBTYPES
MEDICATIONS – OPIOIDS – OPIOID TYPES
REALITY, OPIOID RECEPTORS, AND OPIOID TYPE
MEDICATIONS – OPIOIDS - PSEUDOADDICTION
MEDICATIONS – OPIOIDS – DEPENDENCE – PATIENT CONCERNS
MEDICATIONS – OPIOIDS - ADDICTION
MEDICATIONS – OPIOIDS – ADDICTION – PATIENT CONCERNS
MEDICATIONS – OPIOIDS – ADDICTION – PHYSICIAN CONCERNS
OPIOID DIVERSION - CRIMINALS
OPIOIDS – INSIGHTS INTO WORKER’S COMPENSATION
OPIOIDS – PRACTICE POLICIES TO LIMIT DIVERSION
OPIOID – PRACTICE POLICIES TO LIMIT DIVERSION – OPIOID CONTRACT

MEDICATIONS – SHORT LASTING OPIOIDS – BENEFICIAL USES
MEDICATIONS – SHORT LASTING OPIOIDS – DETRIMENTAL CONSIDERATIONS
MEDICATIONS – OPIOIDS – SPECIFIC SHORT LASTING PURE AGONISTS
MEDICATIONS – SHORT LASTING OPIOIDS – TRAMODOL
MEDICATIONS – SHORT LASTING OPIOIDS – MEPERIDINE
MEDICATIONS – SHORT LASTING OPIOIDS – PROPOXYPHENE
MEDICATIONS – OPIOIDS – SPECIFIC AGONISTS/ANTAGONISTS
MEDICATIONS – OPIOIDS –AGONIST/ANTAGONIST COMBINED WITH PURE ANTAGONISTS
MEDICATIONS – LONG LASTING OPIOIDS
MEDICATIONS – LONG LASTING OPIOIDS – WHEN TO USE TWO AGENTS
MEDICATIONS – LONG LASTING OPIOIDS – OXYCONTIN
MEDICATIONS – LONG LASTING OPIOIDS – OXYMORPHONE
MEDICATIONS – LONG LASTING OPIOIDS - MORPHINE
MEDICATIONS – LONG LASTING OPIOIDS – METHADONE
MEDICATIONS – LONG LASTING OPIOIDS – METHADONE – NEGATIVE ASPECTS
MEDICATIONS – LONG LASTING OPIOIDS – LEVORPHANOL
MEDICATIONS – LONG LASTING OPIOIDS – FENTANYL
MEDICATIONS – OPIOIDS –TOLERANCE, A RARE HUMAN PHENOMENON
MEDICATIONS – OPIOIDS – PSEUDOTOLERANCE
MEDICATIONS – OPIOIDS – MANAGEMENT OF TRUE TOLERANCE

OPIOID INDUCED SIDE EFFECTS
OPIOID INDUCED SIDE EFFECTS – NAUSEA
OPIOID INDUCED SIDE EFFECTS – PRURITUS
OPIOID INDUCED SIDE EFFECTS – HYPERALGESIA
OPIOID INDUCED SIDE EFFECTS – DYSPHORIA

INTERVENTIONAL STRATEGIES
INTERVENTIONAL STRATEGIES – TRIGGER POINT INJECTIONS
INTERVENTIONAL STRATEGIES – PERIPHERAL / REGIONAL NERVE BLOCK
INTERVENTIONAL STRATEGIES – SPINAL ACCESSORY NERVE BLOCK
INTERVENTIONAL STRATEGIES – SUPRASCAPULAR NERVE BLOCK
INTERVENTIONAL STRATEGIES – AXILLARY NERVE BLOCK 
INTERVENTIONAL STRATEGIES – OCCIPITAL NERVE BLOCK
INTERVENTIONAL STRATEGIES – INTERCOSTAL NERVE BLOCK
INTERVENTIONAL STRATEGIES – SCIATIC NERVE BLOCK
INTERVENTIONAL STRATEGIES – GENITOFEMORAL NERVE BLOCK
INTERVENTIONAL STRATEGIES – ILIOINGUINAL NERVE BLOCK
INTERVENTIONAL STRATEGIES –  SAPHENOUS NERVE BLOCK
INTERVENTIONAL STRATEGIES – LATERAL FEMORAL CUTANEOUS NERVE BLOCK
INTERVENTIONAL STRATEGIES – SUPRAORBITAL NERVE BLOCK
INTERVENTIONAL STRATEGIES – MEDIAN NERVE BLOCK
INTERVENTIONAL STRATEGIES – SYMPATHETIC NERVE BLOCK

RADIOPHARMACEUTICALS
HYALURONAN KNEE INJECTIONS
NON-PHARMACOLOGIC TREATMENTS
NON-PHARMACOLOGIC TREATMENTS – PHYSICAL AND OCCUPATIONAL THERAPIES
RETURN TO WORK
HANDICAPPED PARKING

NON-PHARMACOLOGIC TREATMENTS – TENS UNITS
NON-PHARMACOLOGIC TREATMENTS – RELIGION
NON-PHARMACOLOGIC TREATMENTS – PET THERAPY
NON-PHARMACOLOGIC TREATMENTS – SUPPORT GROUPS, DIARIES
NON-PHARMACOLOGIC TREATMENTS – KYPHOPLASTY
NON-PHARMACOLOGIC TREATMENTS – MAGNETS
NON-PHARMACOLOGIC TREATMENTS – ACUPUNCTURE AND MASSAGE

MORPHINE INTRATHECAL PUMP IMPLANTATION
SURGICAL MANAGEMENT
SURGICAL MANAGEMENT – OPTIMAL PATIENTS FOR SURGICAL REFERRAL
NON-PHARMACOLOGIC TREATMENTS – CHIROPRACTIC MANIPULATION
SUMMARY – INITIAL TREATMENT STRATEGIES
SUMMARY – SPECIAL POPULATIONS
FUTURE DIRECTIONS
 

DEFINITION / INTRODUCTION
 Pain is defined as a subjective unpleasant sensory and emotional experience associated with actual or potential tissue damage.  Persistent pain is a treatable condition, not unlike other medical conditions of hypertension, diabetes, emphysema, and cancer.  Pain is real.  Just as high blood sugar is real and mandates constant attention in the diabetic, so too is pain a valid medical condition that mandates constant attention.  Without constant attention to any medical condition, morbidity and mortality ensue. As with diabetes, hypertension, and other medical conditions, the generators of pain are dynamic and evolve with time, necessitating changes in management.
As with these other medical conditions, pain is dynamic in that it evolves with time.  Degenerative osteoarthritis and postsurgical scarring progress over sequential years with escalation in pain intensity.  Conversely, myofascial pain and fibromyalgia may decrease over time with treatment with progressively decreasing medication needs.  
Patients must be seen regularly to address pain as well as obesity, depression, anxiety, erectile dysfunction, restless legs syndrome, fatigue, insomnia, and other sequelae of pain in addition to obesity, depression, anxiety, and other conditions which contribute to intensification of pain.  
 

EPIDEMIOLOGY OF PAIN – SCOPE OF THE CONDITION
Approximately 65 million people in the U.S.A. suffer from chronic pain, and the annual prevalence of back pain ranges from 15%-45%.(34)  Of all patients suffereing from acute back pain, 5% will develop chronic, constant, and disabling pain.(254)  Malignant and nonmalignant pain is the single most common reason why patients present to a physician.(   )  Untreated pain results in unnecessary suffering, compromised quality of life, impaired work ability, and enormous avoidable stresses on the Medicare and Medicaid disability services.  
Inadequate treament of pain is not simply an issue of numbers.  Untreated pain has been described as a suicidogen.(248)  Pain may result in some patients committing suicide(13) or request physicians to assist them in early death to alleviate the burden, suffering, and despair of chronic pain.(10)  
There is great satisfaction for the clinician who decreases a patient’s pain, enhances their function, and allows them to lead a higher quality,(  ) more fulfilled life.  He who saves one life it is as if he saved the world entire.(258,259,260)  
Patients whose pain is not treated may pursue self-treatment, often with dangerous consequences given their limitations in medical knowledge.  Acetaminophen has been reported as the second leading cause of toxic drug ingestion in the U.S.A., and a portion of these deaths were related to accidental poisoning in an attempt to relieve pain.(17)  Other patients pursue illegal drugs such as alcohol, heroine, or cocaine for symptomatic relief when deprived of access to pain management.  It is not true that nobody dies because of pain.  In contra-distinction to practitioners who lack fundamental knowledge of pain management, the clear answer to chronic pain is not premature death but treatment with a higher, more productive quality of life.
 

CLASSIFICATION OF PAIN
Pain can be classified in several different ways.  In terms of duration since time of onset, pain can be acute or chronic.  Acute pain serves a critical biologic function to alert people to address pathology such as fracture or laceration.  Chronic pain may alert the patient to limit heavy lifting exertion to delay the progression of knee cartilage degradation, for example, but chronic pain often serves no valuable physiologic function.  The distinction is of value as acute pain is often curable with nonsteroid anti-inflammatories, sympathetic plexus blockade, and definitive surgery.  Subacute pain persists for 1-3 months and this is the vestige of the “therapeutic window” during which time it is important to be aggressive as once this window closes it is much more difficult to cure pain.  Chronic pain is present for approximately three months and though cure is occasionally possible, the primary goals change to decreasing pain intensity, increasing function with possible return to work, and improving quality of life.  Chronic pain often is accompanied by mood depression and other treatable comorbidities.  
Pain can be also classified in terms of the perpetuating mechanism, either mechanical, neuropathic, or visceral.  Mechanical pain is often referred to as nociceptive pain and includes arthritis, disc herniation, myofascial, fractures, and other pathologic entities.  Neuropathic pain diagnoses include thalamic pain, reflex sympathetic dystrophy, post-herpetic neuralgia, and other conditions.  Visceral pain may include the pain experienced from hollow organ distension as with constipation or urinary retention.  The distinction between classifications is important in terms of selecting medications most likely to be efficacious.  For example, nonsteroidal anti-inflammatories are not overwhelmingly helpful in the management of neuropathic pain whereas systemic anti-arrhythmic agents are rarely warranted in the treatment of mechanical pain.  Similarly, high dose opioids are rarely the foundation of care in the successful and most reasonable management of neuropathic pain.  Visceral bladder pain is often responsive to cimetidine.(   )  Visceral pain may also respond to smooth muscle relaxants, including the opioids as well as peripheral alpha antagonists.
 

PAIN MANAGEMENT TREATMENT GOALS
The goal of treatment of chronic pain is not the elimination of pain, as this is not often possible.  The goals of pain management include reduction in pain with consequent enhancement of quality of life as well as improved function, often with return to work.  Patients suffering in pain experience pain “taking over” their lives.  Pain is virtually integrated into “who they are” in terms of how they view themselves.  It is impossible for those of us without pain to fully relate, but we must have compassion.  They have to weigh every potential act to decide if it may exacerbate their pain and limit function for days.  Decreasing their pain allows them to live a more normal life.  Physicians must live the Golden Rule of “Do unto others as you wish done onto you” to mandate helping those in pain as the physician would wish if he had pain.  Conversely, the Golden Rule “Do not do onto others as you would not have done onto you” mandates not withholding pain management to those who are suffering.
In type II diabetics increased walking frequency as well as increased pace of walking decreased cardiovascular mortality.(2)  Reduction in pain frequently increases patient walking and exertional levels.  Suprascapular nerve block may allow patients with severe gleno-humeral arthritis to feed themselves, comb their hair, and perform other simple tasks (112) that most of the world takes for granted.  
 

MECHANISMS OF PAIN – PHYSIOLOGY
Normally, the action potential is generated at the peripheral nociceptor at the site of inflammation in acute pain. The action potential consists of an initial rapid voltage ion channel gated depolarization as positively charged sodium ions enter the cell, making it less negative.  The subsequent slow continued influx of positively charged calcium ions keeps the cell depolarized, and the efflux of potassium positively charged ions returns the cell to its depolarized state.  The signal is perpetuated down the length of the axon to the pre-synaptic terminal of the dorsal horn “pain command center” of the segmental spinal cord where voltage sensitive ion channels open and close with summation determining if neurotransmitter is released from the pre-synaptic axon terminal into the synaptic cleft.  Calcium influx at the pre-synaptic terminal is a potent force determining if neurotransmitter is released into the synaptic cleft. 
Action potentials must also be generated at the peripheral nociceptor before the signal is sent to the spinal cord, explaining the efficacy of peripherally active medications such as nonsteroidal anti-inflammatories.  
In the dorsal horn, convergence of terminals summation of afferent nociceptive axons from the peripheral nociceptor, segmental spinal cord modulating interneurons, and axons descending from the brain determine if a signal of pain is passed on to the brain to consciously interpret the pain signal or if the signal of pain is extinguished at the spinal cord level.  Synaptic release of inhibitory and excitatory neurotransmitters opens and closes neurotransmitter dependent cell membrane sodium, calcium, and potassium ion channels to allow these positively charged ions to enter and exit from the dorsal horn cell.  Other ion channels are voltage dependent, opening and closing in response to voltage.  
Temporal and spatial summation of all positive and negative ion charges at the second order neuron at the dorsal horn determines if the net effect depolarizes the resting cell membrane –90mV charge inside the cell sufficiently more positive to reach the –60mV threshold.  If threshold is achieved then the all or none action potential is generated with synaptic release of neurotransmitters by the dorsal horn to activate the post-synaptic neuron with transmission of an afferent nociceptive signal to the brain.  
Conversely, depolarization with nociception transmitted to the brain can be prevented by medications which make the cytosol more negative than –90mV by blocking sodium, calcium, and potassium ion channels.  The cell can also be made refractory to action potential generation by medications which enhance GABA and other inhibitory neurotransmitters such as zonisamide (Zonegran), tiagabine (Gabitril), topiramide (Topamax), and gabapentin (Neurontin) or decrease release of excitatory neurotransmitters such as glutamate, substance P, kinins, and histamine such as H1 and H2 receptor antihistamines.  Noradrenergic reuptake inhibitors increase the duration of time that noradrenaline spends in proximity to the post-synaptic membrane of the dorsal horn cell to decrease pain.  The cell can also be made more refractory to depolarization through the use of medications which block the positive influx of charge such as calcium channel blockade with the zonisamide (Zonegran), aminoglycocide Neomycin, magnesium, Ziconotide, and nifedipine (Adalat, Procardia), verapamil (Calan, Covera, Isoptin, Tarka, Veralan), diltiazem (Cardizem, Dilacor, Tiazac).
The brain itself may reduce pain.  Thalamic and limbic brain modulation of the signal may intensify or attenuate pain as evidenced by the efficacy of anti-anxiety medications.  Descending noradrenergic and serotonergic signals from the brain to the dorsal horn of the spinal cord may decrease pain.
Mechanisms of pain reduction may be via decreasing inflammation, opioid mediated agonism at mu receptors, antidepressant increases in serotonin, dopamine, and norepinephrine neurotransmitters, anticonvulsant and anti-arrhythmic blockade of sodium and calcium channels and GABA agonism, and other means discussed in this review.  Anatomic sites of action may include the peripheral nocicepting pain sensor, the segmental spinal cord, the dorsal horn, descending pathways from the brain to the dorsal horn, and the cerebral cortex itself.  Dorsal horn processing is the unifying basic science theme with respect to the brain receiving the signal to perceive pain and then translate that into innocuous or consuming levels of pain, suffering, and disability.  Given the unifying basic theme of modulating sodium, calcium, and potassium ion fluxes to regulate the action potential nociceptive signal to the brain, it is extremely difficult to appreciate any honest patient’s contention that only narcotics effectively decrease pain.
 

PATHOPHYSIOLOGIC MECHANISMS OF ACUTE AND CHRONIC PAIN
Acute pain occurred co-incident with injury and lasts for less than a month.  Acute pain has the greatest likelihood of response to treatment.  It is discussed as always being physiologic, but this is not the case in various situations of neuropathic pain such as reflex sympathetic dystrophy, thalamic pain, and other conditions in which the presence of pain does not alert the individual to an ongoing correctable source of tissue damage.  Subacute pain occurs between one to three months post-injury and this is referred to as the “therapeutic window” period during which aggressive treatment may still effect full resolution of mechanical and neuropathic pain in most patients.  Chronic pain has been described as maladaptive with no ongoing tissue damage.  This is usually but not universally true.  Chronic pain is felt in some cases to be normal as physiologically mediated by protracted inflammation as with rheumatoid arthritis.  However, most cases of chronic pain are not mediated by ongoing inflammation, but rather by a maladaptive hyperexcitable peripheral and central nervous system.  
In the periphery, the extrafusal muscle may be in varying degrees of perpetual spasm as with myofascial pain and fibromyalgia.  The intrafusal fiber may be at constant high tone as mediated by efferent A-gamma fibers from a similarly hyperaroused segmental spinal cord.  
The peripheral nociceptor of the skin may be sensitized to otherwise innocuous subthreshoold stimuli such as light touch which now result in a volley of action potentials transmitted to the presynaptic terminal.  The constant exposure to inflammatory mediators such as with burns may mediate this condition.(   )
The damaged peripheral nerve from traction, compression, transsection, or demyelination with exposure of the unprotected axon may fire spontaneous ectopic discharge to the dorsal horn.  The damaged axon may result in spontaneous depolarization of adjacent axons by ephaptic transmission with signals sent to the brain in the absence of pain.  The constant volleys of spontaneous discharges may create and maintain a central state of sensitization / wind-up / hyperexcitability(243) in the dorsal horn with the cell less negative and closer to threshhold to send an action potential to the brain. 
In the central nervous system, the dorsal horn wide dynamic range neuron is also sensitized and hyperexcitable such that it is more likely to discharge an action potential to send a nociceptive signal to the brain. The wide dynamic range neuron of the dorsal horn becomes less discriminate in terms of responding to afferent pain and light touch impulses.  This results in normal non-painful stimuli resulting in allodynia profound pain and mildly painful stimuli resulting in hyperalgesia.(243)  The afferent C and A-delta fiber from the periphery is more likely to generate a reflex response by the hyperexcited anterior horn cell to tell the muscle to contract and spasm.  The effect of anxiety to increase descending sympathetic tone may also activate peripheral mechanoreceptors whose afferents converge on the sensitized wide dynamic range neurons to prompt an ascending discharge to the brain.(218)
 

MECHANISMS – PHYSIOLOGY – CALCIUM CHANNELS
 Calcium is important in the generation of the action potential at the dendrite to transmit the nociception to the pre-synaptic terminal axon as mediated by slow influx of calcium after the initial rapid sodium influx.  In addition, calcium influx at the axon of the pre-synaptic terminal in response to the voltage from the action potential results in exocytosis neurotransmitter vesicles to the synaptic cleft to activate or suppress the post-synaptic cell membrane.
Medications which impair calcium influx into neurons at the nerve terminal at the pre-synaptic membrane will decrease the likelihood that the cell will release nociceptive glutamate neurotransmitter vesicles into the synaptic cleft to reach the post-synaptic membrane(246) such that the peripheral nociceptive signal does not get transmitted beyond that level to reach the brain for conscious perception of pain and interpretation into varying degrees of suffering.
Scientists have identified three main pathways for calcium influx into the neuron, include voltage opening of channels in response to depolarization, ligand gated nonspecific calcium channels, and receptor activated calcium channels.(26)  The calcium channel consists is genetically coded by different genes.  Six classes of voltage activated calcium channels include low threshold T-subtype as well as high threshhold L-, N-, P/Q-, and R-subtypes.(253)  Different isoform subtypes of each channel also exist as proven with N-type channels with different ease of activation kinetics.(232) Calcium channels of the P/Q-, N-, and R- type control glutamate neurotransmitter release.(58)  L-, N-, and P/Q calcium channels are presented in the dorsal horn, N- subtype channels are concentrated in the presynaptic terminals of primary nociceptive afferents of the superficial laminae I and II of the dorsal horn, L- subtype channels are present in proximal dendrites and cellular bodies in the central nervous system and in some glutamate synapses.(26)
 

MECHANISMS – PHYSIOLOGY – CALCIUM CHANNEL BLOCKING ANALGESICS
 Opioids bind to mu, delta, and kappa opioid receptors which activates different inhibitory G proteins which inhibit adenyl cyclase which decreases transmembrane L-, N,- and P/Q- channel subtype mediated influx of calcium ions.(26)  Opioid kappa receptor analgesia may also be mediated by shortening of calcium action potentials without any change in resting membrane potential such that calcium channel antagonists may act differently with respect to mu and delta opioid receptors.(26)  
 Supraspinal morphine activates descending pathways via serotonin (via intraspinal enkephalin or dynorphin) and noradrenaline (directly or via intraspinal acetylcholine) neurotransmitters to act on the dorsal horn to prevent afferent nociception.(26)
G-protein is a membrane bound subunit which modulates N-subtype and P/Q-subtype channels and aminoglycosides block N-subtype and P/Q subtypes.(26)  N-type calcium channel blockers are useful in the management of severe(245) and chronic(244) pain.  Topical N-type calcium channel blockers have been demonstrated in basic science studies to reduce pain after nerve injury.(243)  The aminoglycoside neomycin has been demonstrated to decrease both phasic as well as incisional pain.(246)  The N-channel blocker delivered as topical neomycin decreases pain following nerve injury and may interfere with initiation of sensitization of dorsal horn neurons.(247)  The N-type calcium channel blocker Ziconotide confers one thousand times the analgesic potency of morphine.(   )  Topical neomycin should also be considered as an option to reduce pain in burn injury and topical ulcers if systemic absorption is not felt to compromise renal function.  In one study topical application of bacitracin did not confer analgesic benefit(247) and may be sufficiently structurally different from gentamicin, streptomycin, and neomycin related analgesia(246) or it may be an individual histochemical uniqueness just as some individuals appreciate relief from one antidepressant, opioid, anticonvulsant, or skeletal muscle relaxant and not another medication of the same class but different molecular structure.
Aminoglycoside antibiotics decrease presynaptic release of acetylcholine at the neuromuscular junction and higher doses block postjunctional acetylcholine receptors, and this must be considered in nociceptive interaction as well as aminoglcoside related inhition of phospholipase C.(246)
Synergistic potentiation between L-type and T-type blockers at spinal mu opioid receptors but not at delta and kappa receptors has been described.(73)  Zonisemide (Zonegran) is a T-type calcium channel blocker.  Ziconotide is undergoing success in FDA trials as an N/T calcium channel blocker which has been described as having 1000 times the analgesic potency of morphine.(   )
In contra-distinction to antinociception with N-subtype blockade, analgesia with the L-subtype channel antagonist verapamil (Calan, Covera, Isoptin, Tarka, Veralan) is felt to be via agonism at mu, delta, and kappa-3 opioid receptor subtypes.(26)  The L-subtype channel antagonist nifedipine (Adalat, Procardia) may potentiate morphine induced analgesia although it lacked analgesia itself when given in isolation in one report.(63)  Nifedipine also has efficacy to decrease the opioid induced hyperalgesia with may accompany high doses of morphine via NMDA activation by the biometabolite morphine-3-glucuronide.(11)  Oral nifedipine may also decrease pain related to reflex sympathetic dystrophy.(49)  Basic science studies also support the efficacy of L-type antagonists in opioid potentiation.(246)  Diltiazem (Cardizem, Dilacor, Tiazac) has also been discussed as an L-type calcium channel blocker.(   )
Magnesium blocks calcium pores(26,246) as well as NMDA receptors(246) both of which are mechanisms to decrease pain.  Patients with severe refractory pain, systemic malabsorption, and inadequate diets should be assessed for hypomagnesiumemia.  Consideration for emperic prescription of a multi-vitamin should be entertained.
 

MECHANISMS – PHYSIOLOGY – SODIUM CHANNELS
The action potential consists of an initial rapid voltage ion channel gated depolarization as positively charged sodium ions enter the cell, making it less negative.  The subsequent slow continued influx of positively charged calcium ions keeps the cell depolarized, and the efflux of potassium positively charged ions returns the cell to its depolarized state.  
Temporal and spatial summation of all positive and negative ion charges at the second order neuron at the dorsal horn determines if the net effect depolarizes the resting cell membrane –90mV charge inside the cell sufficiently more positive to reach the –60mV threshold.  If threshold is achieved then the all or none action potential is generated with synaptic release of neurotransmitters by the dorsal horn to activate the post-synaptic neuron with transmission of an afferent nociceptive signal to the brain.  
 

MECHANISMS – PHYSIOLOGY – SODIUM CHANNEL BLOCKING ANALGESICS
 Local anesthetics exert their activity by temporarily blocking sodium channels to impair action potential regeneration and accompanying transmission of pain sensations to the brain.
It is felt that the mechanism of analgesic action of opioids is by blocking neuron excitability by depression of sodium conductance and increase membrane potassium conductance(23) or by blocking the opening of voltage-sensitive calcium channels with a conseuqent decreased pre-synaptic release of excitatory neurotransmitters and decreased afferent transmission of nociceptive impulses.(23, 26)
Lidocaine patch and crushed propoxyphene (Darvocet) topically block sodium channels to block afferent transmission of pain by preventing action potential generation at the nociceptor as well as attenuating conduction of pain along the length of the axon.  Zonisamide (Zonegran) and other anticonvulsants which stabilize sodium flux may similarly decrease pain.
 

MECHANISMS – PHYSIOLOGY – POTASSIUM CHANNELS
The action potential consists of an initial rapid voltage ion channel gated depolarization as positively charged sodium ions enter the cell, making it less negative.  The subsequent slow continued influx of positively charged calcium ions keeps the cell depolarized, and the efflux of potassium positively charged ions returns the cell to its depolarized state.  
 Antihistamine mediated antinociception transduction has been demonstrated as requiring potassium-ATP and calcium gated potassium channels contrary to voltage gated potassium channel Kv1.1.(186)
 

MECHANISMS – PHYSIOLOGY – POTASSIUM CHANNEL BLOCKING ANALGESICS
Facilitating efflux of potassium will more promptly return the depolarized neuron to the resting membrane state of inactivity.  Efflux of potassium positive charge at rest will also make the cytosol more negative such that it is less likely to depolarize unless the stimulus intensity if overwhelming.   This may mediate attenuation of response in allodynia, decreased response in hyperalgesia, and a more normal response to a valid nociceptive stimulus.
GABA-B receptor agonism by lioresal (Baclofen) may result in potassium channel mediated hyperpolarization of the alpha motoneuron.
The mechanism of analgesic action of opioids is by blocking neuron excitability by depression of sodium conductance.(23)
 

MEASUREMENT OF PAIN
Pain intensity can be measured quite quickly and productively with a 0-10 point scale with zero fixed as “no pain” and 10 fixed as “the most severe amputation intensity level pain that you can imagine.”   Several people with identical objectively assessed pathology may have quite different complaints of pain severity as assessed on a 0-10 point scale.  Similarly, patients with identical levels of pain may have different levels of perceived ability to function and work.  The value of the scale, therefore, is to assess a single patient over time with respect to improvement with treatment.  In addition, the patient who always indicates that his pain is 10 out of 10 may have comorbid or primary mood depression and the pain will not remit without addressing the depression.  Emotional and physiological factors influence perception of pain.  
The character of pain should also be assessed as this often strongly supports a clinical diagnosis and more individualized treatment.  Complaints of burning character pain suggests a diagnosis of reflex sympathetic dystrophy.  Dull, throbbing, and aching pain supports a diagnosis of osteoarthritis, myofascial pain, and fibromyalgia.  Electric, tingling, and numb quality of pain may suggest radiculopathy, plexopathy, polyneuropathy, compressive mononeuropathies such as carpal tunnel syndrome, and intracranial pathology such as thalamic pain, multiple sclerosis, and other conditions.  Cramping suggests visceral pain such as the constipation that not uncommonly results from prescription of opioids or anticholinergic antidepressants without concomitant treatment of medication induced intestinal hypomotility.  Patients who deny mood depression but describe their pain as suffering, miserable, depressing, or tiring may have atypical depression with pain highly responsive to antidepressants or anxiolytics.
 

DIAGNOSIS
 The value of defining a precise diagnosis is to identify a strategic target to treat. 
As with all branches in the practice of medicine, the clinician should always reserve the diagnosis of “idiopathic” after a reasonable and appropriate diagnostic investigation has concluded.  “Low back pain” is a symptom, not a diagnosis.  Defining a precise diagnosis can direct specific treatment.  To this end, the clinician must always review the extent of the diagnostic workup.  Metastatic testicular pain may disseminate via the retroperitoneum to result in back pain.  Multiple myeloma must be considered in the workup of back pain.  Back pain with hematuria must alert the clinician to consider CT-scan to assess for renal cell carcinoma.  Back pain with testicular mass suggests testicular cancer with retroperitoneal extension.  EMG and nerve conduction studies may indicate active ongoing pathophysiologic axonal denervation related to anatomic disc herniations on MRI to warrant referral to an anestheseologist for epidural injections versus reassurance that the disc herniation is old and not actively damaging neural tissue.  A triple phase bone scan may confirm an equivocal case of reflex sympathetic dystrophy to spur prompt referral for sympathetic nerve blockade.  
 Renal, testicular, and other malignancies may present with back pain.  Metastatic tumors should always be considered in patients aged fifty years or greater as well as those with family histories of malignancy or personal history of smoking or other pro-malignant risk factors.  
 

EMERGENCIES
Emergencies in pain mangement include compartment syndrome in which direct trauma to tissue may raise pressure in tissues bounded by tight fascial constraints with risks for compromise of arterial perfusion and tissue ischemia.  Acute embolic arterial events from the aortic arch and cardiac chambers may result in acute ischemia and profound limb pain.  Infectious conditions may result in sepsis.  Gouty arthropathy may rapidly mutilate tissues.  Guillain-Barre syndrome may present with back pain with rapid progression to compromise muscles of ventilation.  Dissecting abdominal aortic aneurysm may result in back pain prior to vascular collapse.  Tumor mass, epidural hematoma, or intervertebral disc herniation which compresses the central canal spinal cord or lower motor neuron cauda equina may result in irreversible paraplegia and urinary and fecal incontinence if not promptly neurosurgically decompressed.  The classic triad of cauda equina syndrome symptoms include urinary and/or fecal incontinence, lower extremity weakness, and saddle anesthesia.  Cauda equina syndrome must be surgically reversed within 48 hours to preserve neurologic function.(110)  Epidural tumors must be emergently debulked and radiated to avoid paraplegia.  If reflex sympathetic dystrophy is not treated aggressively within the first few months of onset, then it is much more likely to become disabling for ensuing decades.  
 The natural history of disc herniations are to recede spontaneously with activity modification.  Pain may persist as the subsequently degenerated and dehydrated disc suboptimally cushions the vertebral bodies with pain generated from the ?highly innervated periosteum of the vertebrae.
 Abdominal aortic aneurysm, nephrolithiasis, disc space infection, Guillain-Barre Syndrome may also present with back pain.
 

TREATMENT OF PAIN
Maximal success in the treatment of pain characteristically requires multimodal management.  This limits dose related side effects and also takes advantage of addressing pain not only through different pharmacologic mechanisms of action but also at different anatomic sites.  Though oral, topical, insufflated, and injected medications are powerful adjuncts, behavioral modifications, psychologic coping strategies, adaptive equipment, physical modalities, learning an independent exercise program, and definitive surgical treatment are fundamental to comprehensive care.  Comprehensive treatment must also include treatment of comorbid conditions that are commonly present in the chronic pain population.  The clinician must also be prepared to address the common side effects of analgesics.
  

COMORBID CONDITIONS
Comprehensive pain management includes the treatment of comorbid conditions such as mood depression, chronic fatigue, secondary myofascial pain, anxiety disorder, insomnia, restless legs syndrome, xerostomia, orthostatic hypotension, and erectile dysfunction.  Treating these comorbid conditions may result in decreased pain intensity with decreased analgesic prescription requirements.  If patients are appreciating analgesia with a particular medication, then onset of side effects does not mandate discontinuation of the precipitant is the comorbid condition can be treated.  A finite number of analgesics exists, and if the side effect is safely treated then the analgesic should be continued.
 

COMORBID CONDITIONS – MOOD DEPRESSION
 It is unfortunate that many people do not recognize mood depression as simply another medical condition to be treated.  Depression is present in    % of patients with chronic pain.(  )  Pain causes mood depression,(  ) and worsening of depression will increase pain in a cascading cycle that may result in patient death by suicide.  After family and friends, the first professional contact of depressed patients is a nonpsychiatric physician, not a psychiatrist or minister.(175)  As such, given the higher comorbidity between mood depression and chronic pain, the pain management physician must make it office protocol to discuss issues of mood depression and anxiety with chronic pain patients on regular follow-ups.  The physician striving towards comprehensive pain management should be aware of the fact “If you don’t ask [the patient about mood depression] then you don’t know.”
 Classic treatment of mood depression involves serotonergic and / or tricyclic antidepressants.  Synergistic care may be afforded with provigil, methylphenidate, psychologic counselling, and interventions such as electroconvulsive therapies.
 Provigil (Modafinil) is a novel psychostimulant with efficacy to address chronic fatigue without the diversion related concerns of methylphenidate.  It has synergistic efficacy with SSRI antidepressants to address depression.(     )  
 Methylphenidate (Ritalin) is a narcotic psychostimulant with noradrenergic and dopaminergic properties.  It is well tolerated, even in the elderly.  However, important criminal diversion related issues are discussed below in the psychostimulant section of this review.
 Psychologists expert in pain management do more than simply teach pain coping strategies.  They also assist the patient in dealing with contributory mood depression and anxiety disorders.  A competent psychologist will not hesitate to refer patients for pharmacologic treatment, and an expert psychologist will be familiar with the considerable adverse consequences of prescribing benzodiazepines.
Psychiatrists will often investigate whether the patient has been noncompliant with antidepressants and ingested them for too short a period of time to truly warrant documentation of inefficacy.  The psychiatric expert may also escalate the dose to an extent greater than that which the pain management clinician is comfortable.  Psychiatrists may also feel comfortable utilizing medications such as monoamine oxidase inhibitors with accompanying restrictions in terms of potential toxicity.  Psychiatrists also may discuss electroconvulsive therapy and other treatment options.
Electroconvulsive therapy (ECT) is a safe and highly efficacious treatment to address mood depression that is refractory to oral pharmacologic intervention.(  )  Patients should be educated as to the safety of ECT, and that successful treatment of pain is commonly hindered by refractory pain induced depression.  Electroconvulsive therapy has been described as successfully decreasing chronic pain.(   )  
 

COMORBID CONDITIONS – ANXIETY
Pain is as a subjective unpleasant sensory and emotional experience associated with actual or potential tissue damage.  The very nature of the worldwide acceptance of this definition declares that anxiety is inherent to pain interpretation and processing.  As such, anxiety may be the emotional reactivity response to pain.  The manner in which pain may create anxiety disorder can be appreciated by the fact that the cerebral cortex responds to the dyshomeostasis of pain by increasing sympathetic outflow to limbic structures to result in anxiety.(   )  
Anxiety increased pain is particularly common in patients with painful conditions such as multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosis, comorbid mental illness, cancer, and other conditions with unpredictable waxes and wanes in disease progression.  Even in the absence of these conditions, anxiety is often present by the unpredictable nature of day to day barometric pressure fluctuation effects on pain(   ) as well as concerns regarding not knowing if mildly increased exertion will precipitate major flairs in pain.
In a cyclic pattern, pain precipitates anxiety and anxiety may increase pain intensity(  ) which can in turn increase anxiety which can increase pain. 
Given the higher comorbidity between anxiety and chronic pain, the pain management physician must make it office protocol to discuss issues of mood depression and anxiety with chronic pain patients on regular follow-ups.  Anxiety is of central importance for coping with chronic pain,(195) and this must constantly be addressed by the clinician to avoid escalations in pain with functional decompensation. A component of every patient’s follow-up should encompass identifying and addressing stress related events as opposed to a reflex increase in patient’s opioid and nonopioid analgesic dose.
Resolution of stress related to pending litigation may decrease pain.(254)  
The importance of treating anxiety and not allowing acute pain to persist untreated cannot be overemphasized.  Transformation of acute to chronic pain is related to the duration as well as the intensity of pain as well as factors such as anxiety which enormously increase pain intensity and distribution.  This clearly implies that withholding all forms of pain management will predispose to entrenchment of pain to the chronic state as well as broadening the scope of suffering and disability.  In no way is this to mean that the clinician is ever compelled to utilize opioids as many nonopioid analgesics effect antinociception via the same secondary molecular mediators.
Psychologists expert in pain management do more than simply teach pain coping strategies.  They also assist the patient in dealing with contributory mood depression and anxiety disorders.  A competent psychologist will not hesitate to refer patients for pharmacologic treatment, and an expert psychologist will be familiar with the considerable adverse consequences of prescribing benzodiazepines.
The clinician should not hesitate to refer patients to psychologists who specialize in pain management as these experts may be extremely helpful to teach patients coping strategies through biofeedback, self hypnosis, visual imagery, deep breathing, and other coping strategies. 
Some authors have reported that pain may decrease in some patients following settlement of trauma related litigation as the accompanying anxiety remits following mental closure of the adversarial process.(160)  This is not surprising given the known anatomic relationship between the emotional centers of the limbic system and pain processing.  Conversely, patients who master relaxation techniques may attenuate pain such that less potent analgesics are required.
Patients should be encouraged to participate in regular aerobic exercise as well as consider learning yoga and meditation skills to treat anxiety.
 Anxiety may be a side effect of certain noradrenergic analgesics, including bupropion (Wellbutrin, Zyban),(5) methylphenidate (Ritalin), atomoxetine (Strattera) and high doses of modafinil (Provigil).
Seratonin agonists are often used to decrease anxiety disorders.
 GABA-B receptor agonists decrease anxiety disorders(  ) without the considerable complications of benzodiazepines.  GABA agonists are also valuable to decrease pain via brain stem originating descending inhibitory pathways to the dorsal horn(70) such that less afferent pain signal to the cerebral cortex is transmitted.  Lioresal (Baclofen) is discussed under “muscle relaxants” in this article.  It is generically available and not cost prohibitive.  Zonisamide (Zonegran), Tiagabine (Gabitril), and gabapentin (Neurontin) are GABA anticonvulsants discussed below with potent anxiolytic properties.
 The analagesic piperazine antihistamine hydroxyzine (Atarax, Vistaril) may also decrease anxiety.
 Buspirone (Buspar) may also decrease anxiety, although the first few weeks of its use may initially increase anxiety, limiting patient compliance.
 Zyprexa (Olanzapine) is an anxiolytic and mood stabilizer which has been successfully utilized to treat even severe cancer related pain associated with anxiety.(39) 
 Benzodiazepines are discussed below under “muscle relaxants” and are contra-indicated in the management of chronic pain.
 

COMORBID CONDITIONS – OBESITY
Patients who are in pain are often less active and the decreased caloric expenditure commonly results in obesity as a sequelae of pain.  In a cyclic pattern patients who are obese often suffer greater back,(  ) hip,(  ), knee,(  ) and ankle and foot pain.(   ) In a cyclic pattern pain leads to obesity which leads to greater pain and so forth.  It has been known for some time that “…osteoarthritis occur[s] more in obese people.”(20)  The corollary to this, of course, is that loss of weight will delay the manifestation and progression of osteoarthritis with its accompanying pain and dysfunction.
 Medical intervention of osteoarthritis includes treatment of obesity via weight reduction as being overweight is a major risk factor for osteoarthritis.(1)  
Patients with back pain should be taught the application of the physics formula “torque = force times distance.”  This equation indicates that the torque required to be generated by the paraspinals is increased as the distance from the spine axis of rotation is increased.  If the patient is taught to carry objects closer to the chest wall and spine as opposed to carrying them with the shoulders flexed and elbows extended, then the torque generated by the paraspinal extensors is less with less fatigue, strain, and pain of these tissues.  Similarly, obese patients that lose weight will suffer less back pain as the abdominal girth recedes and the distance from the spine diminishes.  Also, force is mass times gravity.  As such, as the obese patient loses mass, the force is reduced as is the torque required to be exerted by the paraspinals to maintain the erect posture.  Another mechanism by which obesity increases back pain is by obesity in the thorax resulting in increased weight and axial pressure on the lumbar discs.
Obesity increases forces magnified through the hips, knees, ankles, and feet, and assisting patients to lose weight will decrease pain at these sites.  During walking the knees absorb 300-400% of body weight.(  )  As such, it is not surprising that obesity exponentially contributes to knee pain.(61)  During deep knee bend the patellofemoral joint is exposed to a load 900%-1000% of body weight.(   )  As the superficial erector spinae iliocostalis and longissimus as well as the transversospinalis first deep layer transvers large spinal segments, connecting cervicothoracic and thoracolumbar paraspinals, it is understandable that decreasing stress on lumbar paraspinals through weight loss will decrease thoracic and cervical paraspinal stress with consequent decreased mid-back as well as decreased neck pain with weight loss.(   )  
Treatment of obesity must include education regarding limitation of caloric intake, particularly of fats and carbohydrates as well as increased energy expenditure through exercise.  Patients with physical findings to suggest thyroid hypofunction may also require testing.  Pharmacologic management does not constitute a replacement of behavioral modification in terms of increased aerobic exercise and dietary adjustments.  Substitution for medications such as amitriptyline (Elavil), mirtazapine (Remeron), paroxetine (Paxil) and zyprexa (Olanzapine) which result in weight gain should be considered.
 

COMORBID OBESITY – TREATMENT – IMPAIRING FAT ABSORPTION
Orlistat (Xenical) may be prescribed to decrease pain via promoting weight loss with the added health benefit of decreasing fat absorption.  An additional benefit of orlistat includes decreasing risks for atherosclerotic events of stroke and myocardial infarction.  It may also be quite helpful to treat diabetes by improving blood sugars and insulin responsiveness by decreasing central adiposity.(  )
Orlistat should be considered synergistic treatment with medications which suppress appetite.  Though it is still not covered by many prescription plans, at $1/pill, thirty meals a month for $30 is similar to the copay of most medications that are covered by insurance plans.
 

COMORBID OBESITY – TREATMENT – SUPPRESSING APPETITE
Zonisemide (Zonegran) is an analgesic anticonvulsant that has been demonstrated in a randomized, double-blind, placebo-controlled trail to result in significantly greater weight loss when combined with a hypocaloric diet compared to dietary intervention alone.(200)  Though the precise mechanism(s) by which appetite suppression with zonisemide occurs, severe have been forwarded, including increase in serotonin release, enhanced dopamine synthesis, and dopamine-2 subtype receptor stimulation.(200)  In addition, zonisemide is a carbonic anhydrase inhibitor and may make carbonated beverages taste bitter and less likely to be consumed.
 Topiramate (Topamax) is a carbonic anhydrase inhibitor and may make carbonated beverages taste bitter and less likely to be consumed.
Bupropion (Wellbutrin SR, Zyban) may decrease appetite to facilitate weight loss.(5,88,89)  This medication may treat comorbid pain, mood depression, and tobacco craving.
Venlafaxine (Effexor) is an analgesic antidepressant which not uncommonly precipitates anorexia.
As a controlled substance, methylphenidate should not be prescribed for the indication of weight loss, but combined with comorbid refractory mood depression and severe pain, anorexia may be an efficacious side effect.
 As with all over the counter products free of close FDA and FTC scrutiny, patients should be aware that ephedra weight loss supplement has serious cardiovascular and cognitive toxic effects including stroke and psychosis, and that adverse effects occur in 20%-60% of patients.(116)
 

COMORBID CONDITIONS – MYOFASCIAL PAIN / FIBROMYALGIA
Myalgias precipitated by manual palpation is termed myofascial pain.  Fibromyalgia is diffuse myofascial pain of the neck, shoulders, and lower back.  Although myofascial pain may be a primary disorder following direct trauma as with contusions or following motor vehicle forceful cervical flexion and extension whiplash injuries, it most often is secondary to comorbid pathology.  Intervertebral disc herniation, degenerative osteoarthritis, and other conditions that establish a cycle of decreased activity with impaired muscle flexibility and strength, predisposing to enhanced susceptibility to secondary muscle strain.  Although most strains heal with rest and nonsterioidal anti-inflammatories, some strains persist as chronic pain in the form of myofascial pain and fibromyalgia.  Lupus, rheumatoid arthritis, colitis, Crohn’s disease, and other auto-immune conditions in which the body attacks multiple organ system may also result in secondary fibromyalgia.  Although anti-Jo 1, CPK, ESR, and other serologic markers for myopathy and vasculitis are negative in the workup, the increased frequency of fibromyalgia in recognized discrete auto-immune disorders suggests that the etiologic antibody simply remains to be identified.  The foundation of treatment of fibromyalgia is treatment of mood depression if present, addressing insomnia and chronic fatigue, trigger point injections, a program of aerobic exercise, and oral analgesics to allow the patient a measure of self control.  The use of opioids in the management of fibromyalgia remains controversial.  
Patients with cervicothoracic post-traumatic syrinx may present with diffuse fibromyalgia symptoms.  If not neurosurgically confirmed to be safe, patients at risk for cephalid progression to compromise medullary centers of respiration or caudal extension to compromise anal sphincter tone and reflexive bladder function.  Cervical and upper back/posterior shoudler pain may result from motor vehicle accident related whiplash with traction of the spinal accessory and suprascapular nerves from the violent head and neck motion.  Fibromyalgia is a diagnosis of exclusion which cannot be embraced until investigation for other etiologies such as syrinx, fracture, nerve traction, auto-immune dysfunction,….
Fibromyalgia is a condition of diffuse pain as opposed to regional myofascial pain, and both conditions are associated with chronic fatigue, insomnia, mood depression, and other conditions.  Because there exist no objective radiologic findings to confirm a diagnosis of primary ideopathic fibromyalgia, many clinicians do not feel as comfortable prescribing opioids or higher doses of opioids to such patients. This is distinct from the patient with regional myofascial pain who has comorbid degenerative arthritis, post-surgical scarring, or other objectively confirmed condition.  Ideopathic fibromyalgia patients do best with aerobic exercise, daily flexibility exercises, trigger point / nerve block injections, continued working, and treating comorbid mood depression and insomnia.  As discussed below, the clinician should feel more comfortable with opioid prescription if the opioids allow the patient to function by return to work.  Indeed, if modifications in terms of work intensity and social acceptance are embraced, 100% of patients with fibromyalgia often return to full time work.(160)  “Fibromyalgia does not necessarily cause work disability,” and it has been suggested that this may be achieved by “…abolishing disability awards based on the diagnosis of fibromyalgia,” thereby “…encouraging patients to get better, rather than to see themselves as disabled.”(160)
Secondary fibromyalgia patients have underlying objectively defined disease.  For example, fibromyalgia is more common in inflammatory bowel disease (IBD), particularly Crohn’s Disease.(57)  It certainly is not unexpected that patients with auto-immune conditions directed against the bowel would also have an as yet unidentified auto-immune mediator against muscle tissue just as IBD patients often suffer from peripheral arthritis and spondylitis.(  )  Similarly, patients with systemic lupus erythematosis(  ) and patients with rheumatoid arthritis(  ) have higher incidences of fibromyalgia.  Patients with clear histories of trauma should be considered better candidates for opioids as the forces involved in trauma may result in sufficient pathology to induce localized myofascial pain and diffuse fibromyalgia,(160) and the pain may persist for years following the trauma.(160)  Regional pain is a recognized entity in the absence of trauma in patients who work in repetitive strain environments.(160)
 

COMORBID CONDITIONS – SMOKING TOBACCO
 Nicotine of tobacco smoke may directly effect vasoconstriction surrounding the intervertebral disc as well as toxic changes in the discs themselves, including fibrosis and necrosis of the nucleus pulposus of the discs, cracks and detachment of the fibrous ring, and decreased collagen and proteoglycan synthesis in the disc.(144)  An unhealthy disc is more likely to herniate as well as dessicate with decreased cushioning between vertebral bodies in the form of degenerative disc disease.
Smokers experience more frequent episodes of back pain as well as greater intensity of back pain.  Multiple mechanisms by which this occurs has been suggested.  
 Smoking predisposes to neck pain.
 Smoking predisposes to knee pain.(61) 
 Smoking cigarrettes is associated with myofascial pain and fibromyalgia.(199)
Physician counceling, support, and education can markedly facilitate successful quitting of smoking.  Patients should be presented with a reasonable goal of smoking one less cigarette per week or month.  Though confrontational approaches succeed much less frequently than supportive physician mediated intervention, sometimes educating a patient that their second hand smoke increases the likelihood of amputation, stroke, myocardial infarction, cancers, and death(111) in their children and spouse will sufficiently motivate patients to pursue less dangerous habits.
 Bupropion (Wellbutrin SR, Zyban) increases dopamine and norepinephrine in the mesolimbic dopaminergic system and locus ceruleus of the brain to simulate the reward rush of cigarrette smoking as well as to lessen withdrawal symptoms to successfully help people quit smoking.(5)  Patients may require bupropion for up to a year, but its use may be complicated by insomnia, xerostomia, and anxiety.(5)  As such, patients should consume this noradrenergic medication early in the morning to avoid interference with sleep hygiene.  Greater success with smoking abstention may be achieved with concomitant prescription of the nicotine patch relative to unimodal pharmacologic treatment.(94)  Because the nicotine patch will only be utilized for a short time to effect cure of smoking addiction, its negative effects on disc health is warranted.
 

COMORBID CONDITIONS – INSOMNIA
Pain may result in insomnia.(7) Pain from the dorsal horn of the segmental spinal cord in transmitted up the spinoreticulothalamic tract to the hypothalamus.  The hypothalamus regulates the autonomic function of sleep and this defines a basic science mechanism by which pain results in insomnia.  In a cyclic pattern, insomnia may increase pain(  ) which may in turn increase insomnia with escalation in pain.  Sleep disorders may include delayed onset of sleep, frequent awakenings, decreased sleep duration, daytime grogginess, and nonrestorative sleep.(7) Poor sleep hygiene may increase daytime pain.
Insomnia may be a side effect of noradrenergic analgesics, including bupropion (Wellbutrin, Zyban),(5) methylphenidate (Ritalin), atomoxetine (Strattera) and high doses of modafinil (Provigil).
Insomnia may be addressed with a multitude of agents, including muscle relaxants, mirtazapine (Remeron), dextromethorphan, zonisamide (Zonegran), topiramide (Topamax), and other agents.  Tiagabine (Gabitril) is particularly advantageous in the promotion of sleep as this medication enhances the delta component of sleep such that patients awaken refreshed.(   )  Melatonin is a particularly wise selection in the elderly as this population often produces less melatonin than younger people as a normal consequence of aging, and exogenous repletion may counter this effect and promote restful sleep.(  )  Antihistamines are often sedating and have potent analgesic properties.(149,179,180)  Desyrel (Trazodone) is an excellent sleep aid in women, even the elderly, as it has minimal anticholinergic properties.  However, this medication is relatively contra-indicated in men as it may result in painful priapism with the urological emergent need for decompression with resultant impotence.(   )  Gabapentin (Neurontin) increases REM sleep without increasing delta sleep.(     )
Benzodiazepines reduce slow wave and REM sleep.  This class of nonalgesic narcotic is discussed in this review under the “MUSCLE RELAXANT” section.  Tricyclic antidepressants can improve sleep, but they also may intensify nocturnal myoclonus and restless legs syndrome. If tricyclics are utilized nortriptyline (Pamelor) may also improve insomnia with far less xerostomia and risk for subsequent periodontitis and tooth decay relative to the highly anticholinergic agent amitriptyline (Elavil).  Use of a mild psychostimulant at 8AM may decrease daytime fatigue and eliminate naps such that better sleep hygiene is fostered.  
Zaleplon (Sonata) and Zolpidem (Ambien) have been FDA approved as “benzodiazepine like” agents, but they have not been available for sufficient decades such that data has not yet been accumulated to define if they have similar “benzodiazepine like” risks for mood depression, rebound insomnia, and rebound anxiety with chronic use.  It would seem that “If it walks like a duck, if it quacks like a duck, then it is a duck” may apply to this class of medications marked as “benzodiazepine-like” until sufficient postmarketing surveillance studies sufficiently prove otherwise.  As such, they should be prescribed judiciously with close monitoring such that only perhaps two tabs are available per week for patient consumption with close monitoring in the patient’s chart of number of tabs prescribed over time. 
Though sedating in many patients, opioids should be utilized to treat pain, not escalated progressively to enhance sleep.  It is foolish to suggest that the only class of medications which improves sleep are opioids.  If another class of medication induces sleep then the unconscious patient will not suffer pain.  In addition, opioids reduce restorative delta wave sleep such that patients may be more likely to awaken in an unrefreshed state.
 

COMORBID CONDITIONS – RESTLESS LEGS SYNDROME
Restless legs syndrome (RLS) is a very disquieting feeling of needing to move the legs and not feeling comfortable without doing so.  Some clinicians have likened it to the akathisia that may be seen in patients with mental illness who receive excessive dopamine blocking medications.  
Tricyclic antidepressants have anti-cholinergic properties and may increase RLS as may dopamine blocking medications.  Substitution of offensive medications may alleviate RLS.  
Treatment of RLS may also include the use of dopaminergic agonists.  Ropinirole (Requip) as well as pramipexole (Mirapex) are non-ergot dopamine receptor agonists and may decrease symptoms.  Amantadine (Symmetrel) is a stimulating analgesic dopamine agonist which may also decrease RLS.  Carbidopa-levodopa (Sinemet) may also help in the management of RLS.
Gabapentin (Neurontin) is soon to become generically available analgesic and may also decrease RLS.(205)
Treatment of RLS may also include the use of cholinergic agonists.
 

COMORBID CONDITIONS – ERECTILE DYSFUNCTION
Erectile dysfunction is a common accompaniment to chronic pain(   ) and side effect of some antidepressants.  After treatable causes are excluded, working with the primary care physician to consider sildenafil  (Viagra), should be entertained.
The physician striving towards comprehensive pain management should be aware of the fact “If you don’t ask [the patient about erectile dysfunction] then you don’t know.”
 

COMORBID CONDITIONS – CHRONIC FATIGUE
Patients with chronic fatigue suffer debilitating exhaustion for at least six months that is not relieved by rest nor is it related to mood depression.(24).  Fatigue is distinct from weakness as patients lack neurologic weakness in ideopathic fatigue.  In addition, patients suffering from fatigue can summon full strength if motivated by a crisis, unlike the patient with fatigue.  Chronic fatigue may be a primary idiopathic disorder or it may be a medical sequelae such as viral or other infection or auto-immune rheumatologic condition.(24)  Fatigue secondary to insomnia is best addressed by enhancing sleep hygiene.  Intolerable fatigue may preclude dose advancement with opioids to treat pain with consequent suboptimal quality of life and unmet functional capacity.
Chronic pain is etiologically related to fatigue,(7,14,28) as supported by the development of fatigue following onset of pain, improvement of fatigue following a decrease in pain, greater the risks for developing fatigue with the longer duration of pain, and the increased chances for onset of fatigue with the more intense pain.(7)  Fatigue may respond to behavioral modification by incorporating aerobic exercise into their lifestyles.  As discussed below, patients without quadriplegia, paraplegia, severe orthopedic or rheumatologic deforming conditions or geriatric patiens with impaired balance should not be given handicapped parking.  However, the nature of the disease often precludes the requisite participation of two months before the endogenous endorphin and enkephalin systems can begin to address the condition.  As such, pharmacologic intervention is often of great utility to facilitate aerobic exercise several times a week.  
Sedation related to opioids is somewhat more challenging to treat than some of the other opioid induced side effects.  The clinician should first attempt to eliminate medications which are contributing to the sedation.  If the patient states that they cannot work and earn a living because of opioid induced sedation, then they should be managed with nonsteroidal anti-inflammatories and other medications free of cognitive side effects.  However, patients characteristically drive and perform quite well even with high dose opioids.(   )   Tramodol (Ultram) is an opioid with noradrenergic properties, such that it is less likely to induce sedation.  Several different psychostimulants may eliminate the sedation related to opioids to allow patients to continue with these medications.  Modafinil (Provigil), atomoxetine (Strattera), Protriptylline, and methylphenidate (Ritalin) may address daytime sedation which precludes work.  Given its abuse potential and the host of other uncontrolled alternative options available, many pain management clinicians restrict prescription of Ritalin only to those individuals who work. Considerable evidence exists to support the cognitive safety of opioids in that they do not preclude safe driving.(54)  If opioids or other analgesics result in sedation refractory to psychostimulants then the medication should be tapered.  If no other analgesics are effective then consideration for referral for morphine/clinodome pump implantation should be entertained.  Substitution of pain for coma quality of life is not acceptable in the non-hospice setting.
Medication strategies include dopaminergics, noradrenergics, and serotoninergics.  
 

COMORBID CHRONIC FATIGUE – TREATMENT– MODAFINIL
Modafinil (Provigil) decreases fatigue related to fibromyalgia(33) as well as multiple sclerosis(   ) and other chronic pain conditions.  Modafinil has been described as ameliorating the opioid side effect of sedation.(90)  Modafinil is distinct from methylphenidate in that it stimulates hypothalamic tuberomammillary nucleus pathways to the cerebral cortex without sympathomimetic effects to increase blood pressure or heart rate such that it appears safe even in the presence of coronary artery disease.  However, dyspnea, palpitations, angina, and transient ischemic T-wave changes have been identified with modafinl.(35)  Modafinil is also distinct from methylphenidate in that the former medication does not stimulate projections to the nucleus accumbens reward center such that potential for abuse is unremarkable.(90)  This medication is insoluble in water and so it cannot be injected, and it degrades when heated so it cannot be smoked.(90)  Unlike the use of methylphenidate in patients who decieve their physicians and solicit this noradrenergic stimulant to treat nonexistent pain and absent fatigue, modafinil does not have euphoric properties.(90)  
Modafinil loses its effect in the presence the alpha-one receptor antagonists(35) given to treat neuropathic pain as well as urinary retention. It increases cerebral dopamine(35) such that  postmarketing surveillance will need to define the extent of its safety in patients with comorbid schizophrenia, bipolar disorder, and other mental illness conditions.  It has been hypothesized that modafinil may decrease the release of antinociceptive GABA neurotransmitter as well as increase nociceptive excitatory neurotransmitter glutamate(35) such that postmarketing surveillance will need to define if it has any detrimental effects on pain management.  Modafinil has efficacy to treat mood depression.(   )  
Modafinil dosing should be lowered in hepatic failure as it is metabolized in this organ.  Modafinil causes a dose dependent induction of CYP-3A4 450 isoenzymes at doses in excess of 400 mg such that reduced levels of carbamazepine, phenobarbital, ketoconazole, cyclosporine, and other CYP-3A4 metabolized medications which are substrates for biodegradation by the same enzyemes.(35)  A dose dependent induction may also occur with CYP1A2 and CYP2B6 isoenzymes(35) with consequent lowering of serum levels of these medications.  Modafinil inhibits CYP2C19 which metabolizes diazepam, phenytoin, and tricyclic antidepressants as well as CYP2C9 which degrades warfarin and phenytoin(35) such that modafinil may result in accumulation of these other medications to toxic levels.  The CYP-2C19 effects are reportedly only clinically relavant in the presence of 2YP-2D6 deficiency.(35)
 

COMORBID CHRONIC FATIGUE – TREATMENT– ADDITIONAL OPTIONS
Atomoxetine (Strattera) is a selective norepinephrine reuptake inhibitor.  Upward titration whould be more gradual in patients consuming other CYP450 2D6 inhibitors as with paroxetine, fluoxetine, and quinidine.
Venlafaxine (Effexor) is a serotonin and norepinephrine reuptake inhibitor.
Bupropion has noradrenergic properties(5) and demonstrates efficacy to address chronic fatigue.
Protriptyline
Amantadine (   ) may decrease fatigue, and has been described as being efficious in multiple sclerosis.(   )  
Methylphenidate (Ritalin) is discussed in detail in this review as a psychostimulant narcotic which has potent dopaminergic and noradrenergic properties to treat fatigue, mood depression, and pain.  Clinicians should prescribe this medication with caution as it has a high street value and induces euphoria in normal patients who lack pain.(90)  It has the most marked efficacy in the treatment of profound chemotherapy related fatigue in the treatment of pain in oncology patients.
Chronic fatigue related to malnutrition as in oncology pain management may require appetite stimulants such as oxandrolone, dronabinol (Marinol) which also decreases pain and nausea, or cyproheptadine which may also decrease pain and pruritus as an anti-histamine.
 

MEDICATION INDUCED SIDE EFFECTS
Before discussing the scope of analgesics, it is fundamental for any pain management practioner to understand that nonopioid analgesics often address pain just as well as opioids, even more so for certain diagnoses.   Before discussing individual analgesics, it is important to discuss concepts of synergism, antagonism, and common general medication induced side effects. Medications from multiple classes may result in side effects.  Side effects are best addressed pro-actively such that they can be extinguished pror to adding to morbidity.  Untreated side effects contributes to noncompliance and unnecessary inadequacy of treatment of the underlying pain.
 

MEDICATION INDUCED SIDE EFFECTS – ORTHOSTATIC HYPOTENSION
Changing positions rapidly from supine to standing requires compensatory cardiovasculatory responses to prevent pre-syncope and falls.  Many analgesics blunt these reflex responses through various mechanisms and unless the system is exogenously pharmacologically enhanced by the clinician, patients may not tolerate various analgesics.  Opioid induced orthostatic hypotension occurs secondary to arterial vasodilation as well as venodilation with decreased cardiac return.  Medications with potent anticholinergic properties such as amitriptyline (Elavil) and other tricyclic antidepressants as well as diphenhydramine (Benadryl) and other antihistamines predictably increase the risks for orthostasis.
Tricyclic antidepressants with alpha antagonist blocking properties as well as direct alpha antagonist antihypertensives such as terazosin (Hytrin), prazosin (Minipress), tamsulosin (Flomax), and doxazosin (Cardura).  Nifedipine (Adalat, Procardia) is an L-subtype calcium channel blocker analgesic and antihypertensive.  Clonidine and tizanidine (Zanaflex) are central alpha-2 agonists with analgesic properties which may reduce blood pressure.  Medications which impair cognition and slow reaction time may also predispose to falls, particularly in the elderly.
Nonpharmacologic options include maintenance of good hydration, thigh high compressive stockings, abdominal binders, elevating leg rests, slow postural changes, intermittent isometric
contractions, and biofeedback.  If no contra-indication such as brittle congestive heart failure exists, salt tablets or salt fortified foods may result in passive water flow to increase intra-vascular volume and avoid
orthostasis.  Fludrocortisone (Flurinef) may achieve a similar goal via sodium retention.  Another option is use of Midodrine (ProAmitine) as a short duration of action alpha agonist.  Methylphenidate (Ritalin) may also address orthostasis as a noradrenergic agonist.  Orthostasis may also occur secondary to opioid mediated bradycardia and this may respond to concomitant treatment with nonopioid analgesics with anticholinergic properties such as the tricyclic antidepressants.
 

MEDICATION INDUCED SIDE EFFECTS – XEROSTOMIA
Dry mouth is not simply an irritating side effect of opioids, muscle relaxants, antidepressants, bupropion,(5) and other analgesics.  Excessively dry mouth with poor bathing of the gums by sublingual, parotid, and submandibular gland secretions can result in peridontitis and rapid loss of all teeth of the jaw.  Highly anticholinergic medications which dry the mouth such as amitriptyline (Elavil) should be substituted for less potent anticholinergics such as nortriptyline (Pamelor) or serotonergic medications.
Treatment options may include over the counter Biotene (888-246-8363) in the form of toothpaste, antibacterial alcohol free mouthwash, gel, and denture grip.  Biotene contains replacement enzymes including lysozyme to split bacterial cell walls, lactoferrin to deprive iron needed for bacterial growth, and lactoperoxidase with glucose oxidase to inhibit bacterial growth by production of hypothicyanite ion.
Salivart (800-321-9348) is viscous synthetic over the counter saliva spray of saline with sorbitol and is approved as safe by the American Dental Association.
Sage Products (800-323-2220) produces Moist Plus Mouth Moisturizer and Toothette Oral Care to moisturize the mouth with vitamin E and coconut oil.  This company also produces Antiseptic nonalcoholic Oral Rinse with oral enzymes.
Evoxac is a prescription medication which stimulates salivary production.
 

MEDICATION INDUCED SIDE EFFECTS - CONSTIPATION
Constipation is an extremely common side effect of opioid treatment and with every dose escalation the clinician should ask the patient if this is a problem to avoid iatrogenic visceral pain of obstipation.  Failure to solicit symptoms of constipation from patients reluctant to discuss this private issue results in unnecessary suffering and may result in patients refusing to ingest opioids as well as anticholinergic tricylcic antidepressants.  First line treatment of constipation should include increasing hydration, physical activity, and dietary fiber content and with over the counter psyllium products such as Konsyl, Metamucil, and Citrucel.  Psyllium products may have secondary medical benefits of reducing cholesterol as well as risks for colon cancer, breast cancer, and atherosclerotic related myocardial ischemic and stroke events.  If this strategy proves ineffective, then osmotic agents such as Lactulose, MiraLax, and Kristallose as well as the fecal lubricant Colace should be prescribed.  Osmotic agents are best described as “sponge-like” as they absorb water to help the stool remain hydrated and slide through the intestines.  In younger patients, the clinician should strive to avoid regular use of stimulants as these impair the integrity of the intrinsic intestinal neural network if ingested for years.(   )  Intermittent use several times a month of stimulants such as Senokot is safe and efficacious.  Colonic irrigation may disrupt electrolyte homeostasis with risks for cardiac arrhythmias and seizures, and should be restricted for occasional use only with obstipation or fecal obstruction. 
 

MEDICATION INDUCED SIDE EFFECTS – URINARY RETENTION
Urinary retention secondary to opioids occurs as a result of both increased tone of the external sphincter as well as decreased tone of the urinary bladder.(23)  Bladder distension from urinary retention may result in profound visceral pain.  The condition may be addressed with Urecholine as a cholinergic agonist to enhance bladder contractility.  Patients may require co-prescription of a proton pump inhibitor to block cholinergic muscarinic mediated increased gastric acid secretion with accompanying risks of peptic ulceration.  Alpha antagonists terazosin (Hytrin), prazosin (Minipress), and doxazosin (Cardura)  (Flomax) may also be prescribed to relax internal smooth muscle sphincter tone, particularly in males in whom the muscle is considerably more developed.  These agents may have dual utility to also diminish neuropathic pain, but the clinician will need to educate the patient regarding increased risks for orthostatic events, particularly if opioids are also prescribed with their venodilating effects and subsequent diminished cardiac return.  The analgesic muscle relaxants lioresal (Baclofen) and tizanidine (Zanaflex) relax the striated skeletal muscle of the external urethral sphincter to facilitate voiding, and these agents may also diminish pain and address pain related insomnia.
 

NON-ANALGESIC MEDICATIONS
A number of medications have been marketed as analgesics and have been inappropriately prescribed as analgesics.  Better controlled studies reveal that these medications either lack analgesic properties or are vastly inferior to other medications prescribed for the same analgesic, anxiolytic, sedative, and spasmogenic properties.  Use of these two classes of medications have documented extensive potential for abuse in terms of euphoria and addiction.  This author agrees with the published literature in that the class of medications known as benzodiazepines and barbiturates are to be prescribed only on rare occasion, such as a prescription for one tab of a benzodiazepine to allow a patient to tolerate the confines of an enclosed body MRI.
 Carisoprodol (Soma) abuse increased by 22% from 2000 to 2001(9) and it was ranked number 14 of 20 on the list of abused drugs in 2000.(15)  In Massachusetts and many states it is Schedule IV controlled and it has considerable street criminal diversion value.  Carisoprodol is metabolized to meprobamate, a barbiturate and schedule IV drug.  Carisoprodol is abused with cocaine(9) to soften the crash coming down from a cocaine euphoria.  It is abused to enhance the euphoria of hydrocodone and it is also abused with tramodol(22) to enhance euphoric psychotropic effects.  Larege doses of carisoprodol may result in coma when co-prescribed with OxyContin.(6)  Carisoprodol can result in euphoria and addiction(9) with patients discarding familial and work relationships and responsibilities in an all encompassing pursuit of the drug.  Given the diversion and addiction issues, the fact that eight clinical trials demonstrated Soma to have efficacy comparable to placebo, it has been suggested that this product be removed from the market.(9)  
Headaches often result in myofascial spasm related pain of the cervical spine with efficacy of TPI’s.  Clinicians should be aware of the preventability of one cause of this condition in the avoidance of butalbital-acetaminophen-caffeine (Fioricet) and butalbital-aspirin-caffeine (Fiorinal) combinations given the presence of the barbiturate butalbital.  This barbiturate has been linked to psychological dependency with significant abuse potential with “… no evidence in the literature demonstrating benefit over other agents or placebo [in the treatment of migraine headaches].(   )  It has been suggested by other authors that “butalbital-containing analgesics be banned.”(   )  At the very least, given the enormous difficulty of detoxification from barbiturates relative to the ease of opioid detoxification, it is suggested that the best strategy is to not start butalbital containing drugs which can transform episodic uncomfortable headaches to disabling chronic daily headaches.(    )
Benzodiazepines include lorazepam (Ativan), alprazolam (Xanax), clonazepam (Klonopin), diazepam (Valium), temazepam (Restoril), triazolam (Halcion), midazolam, oxazepam (Serax), estazolam (Prosom), flurazepam (Dalmane), and chlordiazepoxide (Librium).  “Benzodiazepine-like” drugs include zolpidem (Ambien) and zaleplon (Sonata). Benzodiazepines have been well documented to have limited efficacy to decrease pain(  ) and are felt by many pain management experts to be contra-indicated in chronic pain management.(75,99)  Regular use increases the risks for the common physician induced problems of rebound insomnia,(  ) rebound increased anxiety,(   ) and worsening or creation of mood depression.(76)  This class of medication impaired attention, insight, judgement, memory, and other cognitive functions that are also compromised in dementia.(76,78,83,92)  The individual often cannot appreciate the cognitive decline in themselves, just as the demented patient lacks insight into their own deficits.  The impaired physician often self-prescribes or obtains benzodiazepines.  Given their same risks for cognitive decline from these drugs relative to patients, they often freely prescribe these agents until surveillance agencies help them into detoxification programs.  
Benzodiazepines may antagonize opioid induced analgesic effects.(32)  Benzodiazepines increase sensitivity to pain by the inhibition of serotonin neurotransmitter release.(75)  This may also be the mechanism by which benzodiazepines result in mood depression.  Benzodiazepines have significant criminal diversion value to sell to drug addicts, as benzodiazepines are abused to soften the crash of coming down from a cocaine high.
Clonazepam results in side effects of mood depression, disinhibition, and sexual dysfunction.(76)  Alprazolam and lorazepam result in drowsiness, mood depression, lethargy, impaired memory, and compromised intellectual function.(92)  Alprazolam has also been discussed as worsening post-traumatic stress disorder.(78)
 

ANALGESIC MEDICATIONS
It is often most valuable to visualize analgesics in terms of classes of anti-inflammatories, muscle relaxants, anticonvulsants, antidepressants, opioids, anti-arrhythmics, and novel atypical agents.  The anti-inflammatories are particularly helpful as they do not simply treat the potentially disabling symptom of pain, but they also may facilitate cure or delaying inexorable progression of pathology by modifying the disease course.  Different classes of medications are best utilized to treat pain reflecting the mechanical, neuropathic, or visceral pain of which the patient complains.  Medications are selected based on safety, comorbid conditions which may be addressed with the same analgesic, and overall clinical presentation.  It is the truly uncommon patient whose pain is maximally attenuated with just one analgesic, and standard of care is to utilize polypharmacy to take advantage of the different mechanisms of action of medications of different classes.(   )  Nonopioid analgesics may block pain such that lower opioid doses are required with accompanying lower opioid related side effects.  Nonopioid analgesics not uncommonly will decrease pain as much as or even more so than opioids.  Use of calcitonin may allow a decrease in the consumption of analgesic medications(136) as well as complete withdrawal of opioid requirements(155).
Clinicians who practice pain management must have the patience to not uncommonly prescribed dozens of trials of medications until the optimal strategy is defined.
 Financial issues must be considered, and less expensive medications such as Baclofen, nortriptyline, glucosamine, chondroitin, generic opioids, and other agents must be considered. Topical phenytoin(242) and opioids(66,67) may decrease pain and are inexpensive when crushed in water and applied to an area with neuropathic pain or mechanical pain related to burns or cutaneous ulcers.
The clinician has many options in terms of narcotic and nonnarcotic based analgesics which he should prescribe in accord with his training and experience.  Safety, efficacy, and diversion issues determine which agent is selected as well as comorbid conditions.  One medication, for example, may address several conditions.
Analgesic potency may occur because of the effectiveness of a single mechanism or it may reflect a single medication effecting antinociception via activity of several analgesic pathways.  In terms of a single mechanism, local anesthetics act via impairing sodium conduction in the periphery as a very potent isolated means by which pain is profoundly extinguised.  Opioids, however, result in pain reduction by acting on sodium, potassium, and calcium channels.  Similarly, zonisemide (Zonegran) acts via sodium, calcium, and GABA mechanisms to reduce pain.
Pain should be treated with vigor before the plasticity of the peripheral and central nervous systems magnify the pain to the point of true disability.  This requires an aggressive, polymodal approach to address pain via several different mechanisms at several different anatomic sites to prevent the signal from reaching the consciousness of the cerebral cortex.  The additive analgesic effect of adding several drugs with distinctly different mechanisms of action supports the use of “rational polypharmacy” to target different pain mechanisms with different classes of medications(37) and also limit dose related side effects.
 

MEDICATIONS – SYNERGISM OF COMBINATIONS OF ANALGESICS
A number of anti-nociceptive medications, when co-prescribed, result in much greater analgesia than that which is expected from simple addition of individual pain relieving properties. When two potent analgesics are consumed together, one plus one may equal three in terms of the summed pain relief due to interactions amongst the two populations of receptors with consequent amplification of pain relief.  The concept of supra-additivity / potentiation / synergism is best explained to the patient by analogy.  Just as chocolate and peanut butter are individually delicious, when added together to form a Reese’s peanut butter cup the combined flavor is greater than the individual sums of the two ingredients. This greater antinociception than predicted from simple additivity may reflect interaction between secondary mediators of receptors, and allows for lower dosing than expected of each individual analgesic with accompanying decreased side effects.  Conversely, adding a synergistic agent to a patient’s regimen should allow a decrease in the opioid dose without any decrement in analgesic efficacy.
With respect to specific combinations confering supra-additive analgesia, low doses of methylphenidate and dextroamphetamine potentiate the effects of morphine analgesia.(250)  Calcitonin potentiates the analgesia induced by the serotonergic antidepressants.(189)  Clonidine, when co-prescribed with morphine, may yield greater than additive potentiated pain relief of each individual analgesic.(40)  The L-subtype channel antagonist nifedipine potentiates morphine induced analgesia.(63) Morphine, when combined with L-methadone, delivers analgesic synergy with greater anti-nociception relative to the sum of additive analgesia from the two analgesics.(12)  One of the greatest benefits of dronabinol is its synergy with the opioids to decrease pain.(121,122,125,126)  Local anesthetics potentiate opioid related analgesia,(67) and this explains the vast synergistic improvement in pain and function with a combination of opioid and local anesthetic injections.  Antihistamines may markedly potentiate opioids, including pentazocine, morphine, fentanyl, and nalbuphine.(149,179,180)
 

MEDICATIONS – ANTAGONISM OF COMBINATIONS OF ANALGESICS
Because fast kinetic blockade by lidocaine may compete with propoxyphene slow kinetic blockade, less sodium channel blockade has been observed during exposure to the combination of propoxyphene and lidocaine relative to lidocaine alone,(202) suggesting that these medications or systemic local anesthetic mexiletine (Mexitil) should not be concomitantly delivered to decrease pain.  Prior induction of morphine tolerance has been identified as enhancing the toxicity of norpropoxyphene,(203) suggesting that combination of these two opioids may not be an optimal management strategy.  Odansetron blocks the analgesia of tramodol (Ultram).(   ) Modafinil loses its effect in the presence the alpha-one receptor antagonists(35)  Methylphenidate should not be given to patients with reflex sympathetic dystrophy as this condition is sympathetically maintained and the potent noradrenergic properties of methylphenidate often intensify the pain.
 Cumulative pro-convulsant side effects must be considered when co-prescribing tricyclic anti-depressants, serotonergic antidepressants, bupropion (Wellbutrin SR, Zyban) olanzepine (Zyprexa), and tramodol (Ultram), suggesting benefit to co-prescribe anticonvulsant analgesics if combinations of these pro-convulsant analgesics are prescribed.
Cardiac toxicity may not be a clinical issue when prescribed in isolation, but consideration for alternative agents may or may not be advisable with other cardio-excitatory medications such as 5-HT3 agonists, propoxyphene,(   ) methylphenidate, mexiletene, and tricyclic antidepressants.(   )
 

MEDICATIONS – GLUCOSAMINE AND CHONDROITIN
 Glucosamine sulfate is a normal constituent of cartilage glycosaminoglycan and slowly decreases knee pain within two weeks of ingestion, and slowly acts to address the radiologic joint space narrowing correlating with loss of joint cartilage such that after three years of use 0.27 mm more cartilage is present in treated as opposed to untreated patients.(1)  This is significant as the healthy aticular cartilage diameter is 1-2 mm thick(   ) and 0.27 divided by 1.5 mm is approximately 20%, quite a substantial increase in cartilage for a medication with such an innocuous side effect profile.  Glucosamine has also been shown to decrease hip pain,(  ) and build cartilage in the hip.(   )  
 Chondroitin sulfate is a normal component of cartilage that slowly decreases joint pain over two weeks and radiographic progression of joint space narrowing over months.(1)  Chondroitin is synergistic with glucosamine such that both medications should be delivered simultaneously.(  )  
 As the facet joints are lined with cartilage, patients with lower back pain secondary to arthropathy at these joints may also be expected to benefit from glucosamine.(   )  In addition, patients who are status post cervical or lumbar laminectomy are at risk for advanced progression of osteoarthritis after stabilizing elements of bone have been extracted such that these patients may also benefit from glucosamine and chondroitin.(  ) Glucosamine and chondroitin have side effect profiles similar to placebo.(1)  It is important to instruct patients to purchase these products from reputable stores and manufacturers as the FDA chose to not monitor these medications and unscrupulous individuals may sell pharmacologically inactive placebo flour or sugar products.  Patients with the spectrum of mild to moderate to severe osteoarthritis appreciate improvement with glucosamine and chondoitin.(1)  
 

MEDICATIONS - ANTI-INFLAMMATORIES – ORAL STEROIDS
 Corticosteroids inhibit antiphospholipase-A2.  Arichidonic acid, a membrane phospholipid, is metabolized in the presence of inflammation into cyclooxygenase (COX) products of prostaglandins (PG’s) and thromboxanes as well as metabolized into lipoxygenase products of leukotrienes (LT) and lipoxins.(16)  Corticosteroids may also directly reduce peripheral neuronal excitability via activity at cell membranes as well as decrease pain via neurotransmitter mediated central effects.(32)  Steroids also have been discussed as blocking afferent C-fiber nociception.(254)  When prescribed at high dose taper for one week in the form of a Medrol dose pack it may decrease inflammation and pain without disrupting the endocrine hypothalamic – anterior pituitary – adrenal medulla axis.(   )  It should be utilized with caution in brittle diabetics as it may precipitate hyperglycemic reactions.  Similarly, prednisone should be utilized with caution in the immunocompromised as steroids impair leukocyte function to combat infection.  Corticosteroids have particular efficacy to decrease pain related to metastatic bone tumors, spinal cord compression, plexopathies, and hepatomegaly.(32)  They also have considerable efficacy to address chronic inflammation as related to rheumatoid arthritis, but this should be weighed against risks for proximal myopathy, osteoporosis with accompanying fractures, avascular necrosis, testicular atrophy, cataracts, hypertension, gastric perforation, and a host of additional complications related to chronic use. 
 

MEDICATIONS - ANTI-INFLAMMATORIES – INTRA-ARTICULAR STEROIDS
Intra-articular steroid injections to painful shoulder, knee, hip, and other synovially lined joints may displace inflamed joints into remission.  Long acting local anesthetic trigger point injections, nerve blocks, and joint injections may significantly decrease pain intensity while simultaneously decreasing the requirements for opioids and other oral analgesics with cumulative cognitive and other toxicities.  Trigger points should be not be performed with steroids in light of considerably lessened efficacy relative to local anesthetic injections.  Steroid injections into soft tissue may also result in atrophy of subcutaneous tissues.(   ) A one time steroid injection may obviate the need for weeks of physical therapy to address the common conditions of rotator cuff tendinitis, hip bursitis, or ischial tuberitis.  Patients who benefit from the analgesia of intra-articular steroid injections who are concerned regarding potential cartilage damage may elect to have local anesthetic injections instead, although the risks for septic arthropathy remain as a result of breach of the protective overlying skin.  By the time that cartilage loss and bone erosion are present on x-ray, steroid injection is not considered to be efficacious,(112) and such patients may benefit more from local anesthetic nerve block with or without local anesthetic injected into the joint to decrease pain.  Facet joint block with steroids may treat zygapophyseal degenerative arthritis.
 

MEDICATIONS -– INTRA-ARTICULAR STEROIDS – SACRO-ILIAC JOINTS
Sacroiliac (SI) joint dysfunction is quite uncommon despite existing as a common mislabel for patients with chronic back pain.  Tenderness over the S-I joint is very common in lumbar disc disease.(44) Dissection of the SI joint reveals that this joint is stabilized by the strongest ligaments of the entire body, including the sacrotuberous and sacroiliac ligaments.  The sacroiliac joint is innervated by L4, L5, S1, S2, and S3 dorsal rami (80) such that pathology at any one of multiple levels of the lumbar spine may result in referred pain to the SI joint.  In addition, the lower lumbar facet joints share overlapping innervation with the SI joint(80) such that the common condition of facet arthropathy may result in pain referred to the SI joint.  
Substantial controversy over the very existence of painful sacroiliac joint dysfunction(80) in the absence of radiographically defined osteoarthritis or pelvic fracture, pregnancy, and auto-immune inflammatory conditions.  In severe trauma resulting in pelvic fracture, extension may anatomically disrupt the SI joint.  Chronic inflammatory arthropathies such as ankylosing spondylitis or rheumatoid arthritis which may involve the anterior-inferior one-third synovially lined aspect of the SI joint.  Ligamentous laxity related to pregnancy may compromise structural cohesiveness of this joint.  As forwarded by Mass General Hospital Pain Service, the sacroiliac joint is rarely the cause of back pain, except possibly in ankylosing spondylitis and pelvic disruption.(44)
 

MEDICATIONS -– INTRA-ARTICULAR STEROIDS – EPIDURAL STEROIDS
Epidural steroid injections are delivered in translaminar and transforaminal approaches to the spine to potentially cure inflammation related to nerve root contusion, traction, or spinal stenosis compression as well as disc protrusion or herniation.  Despite risks for epidural abscess, retinal hemorrhages, arachnoiditis, and epidural and subdural hematoma with consequent spinal cord compression and paraplegia, these complications rarely occur.(80,254)  Patients who are truly in extreme pain rarely refuse referral to an anestheseologist to trial several courses of this procedure, particularly if an electromyogram and nerve conduction test confirms the presence of ongoing nerve damage.
 

MEDICATIONS - ANTI-INFLAMMATORIES – LIPOXYGENASE ANTAGONISTS
 Monteleukast is a D4 cysteinyl LT receptor antagonist, and it has been identified that LT-B4 mediates arthritic inflammation and cysteinyl LT’s are in involved in nociceptive inflammatory conditions such as inflammatory bowel disease.(16)  Inhibition of cyclooxygenase metabolism of arichidonic acid may shunt more of this subtrate to the lipoxygenase enzyme with enhanced synthesis of LTB4,(3) limiting the maximal efficacy of classical nonsteroidal anti-inflammatories.  It has also been reported that analgesia was appreciated with Montelukast 10 mg daily in patients with nociception related to rheumatoid arthritis as well as systemic lupus erythematosus within two to three weeks.(16)  Though lipoxygenase antagonists are not referred to as nonsteroidal anti-inflammatories, this class of medications are, in fact, not steroids and they do act to decrease inflammation.
 

MEDICATIONS - ANTI-INFLAMMATORIES – CYCLOOXYGENASE (COX) ANTAGONISTS
Nonsteroidal anti-inflammatories (NSAID’s) are classically defined as those medications which diminish the activity of cyclooxygenase to decrease tissue injury induced activation of COX-2 which mediates production of prostaglandins and bradykin.  Impeding production of these nociceptor activators reduces pain and inflammation which can damage tissue.  As discussed below, the “COX-2’s” have limited activity against COX-1 such that less gastrointestinal bleeding occurs with COX-2’s.
Inflammatory mediators sensitize the peripheral nociceptor such that painful stimuli are transmitted to the brain in the absence of a painful stimulus (allodynia) or at a greater intensity than anticipated relative to the extent of tissue damage (hyperalgesia).  As such, NSAID’s do not simply attenuate acute pain, but actually facilitate cure.  Conversely, ignoring acute and chronic pain may result in sensitization with evolution to chronic pain in predisposed individuals and greater entrenchment / refractoriness to treatment of chronic pain.  Sensitization can lead to persistence of afferent nociception long after the inflammatory event has passed.  The physiopathology is compounded by the fact that the constant increase in afferent signals to the dorsal horn in the spinal cord subsequently becomes sensitized as well, making the pain less responsive to treatment.
NSAID’s have long been recognized as diminishing acute mechanical pain.  NSAID’s are now being recognized as also acting in the central nervous system to decrease pain by facilitation of the endogenous inhibitory descending pain pathways.(32)  This suggests efficacy in the treatment of pain in the absence of peripheral inflammation.  It also supports the treatment of neuropathic pain with NSAID’s.  NSAID’s have previously been felt to only have minimal efficacy in the treatment of neuropathic pain.  However, NSAID’s may decrease inflammation related neuropathic pain from neural infection as with shingles as well as with the inflammation consequent from reflex sympathetic dystrophy induced edema with consequent increased compartmental pressure pain.  Activity in the central nervous system also explains the occasional complaint of the patient who asserts that NSAID’s result in sedation.
NSAID’s are particularly efficacious in the management of bone pain secondary to malignancy.(  )   NSAID’s have enormous utility in decreasing the pain of metastatic tumors as these tumors elaborate prstaglandin E2.(  )
In addition to toxicities discussed below, a major limitation in the use of NSAID’s is their inherent ceiling effect in that progressive dose escalation increases potentially fatal side effects but does not confer added analgesia.  As such, NSAID’s should be used in conjunction with other analgesics.  Patients should be educated that the ceiling toxicity is additive, and over the counter NSAID’s, including aspirin, must be discussed with the physician.  Patients must be educated regarding the potency of NSAID’s.  The COX-2’s are safer equi-potent 
 

MEDICATIONS – NSAID’S – STRUCTURAL CLASSES
There are different molecular structural classes of NSAID’s, explaining inter-individual analgesic response and side effect variations to different NSAID’s.  This reflects the uniqueness of biophysiology of individual patients.  An analogy may be many locks to doors in a large apartment building with a key opening only one apartment door.  Similarly, one NSAID may have a specific molecular shape as a “key” such that it “fits” the desired “lock” receptor site to effect benefits for the patient.  This suggest that failure to respond to an agent of one class may result in suboptimal efficacy of a structurally similar NSAID and the clinician should select from another class. 
The new marketing of “COX-2’s” must be recognized as a pharmacologic class, not a categorization based on molecular structure.  It also must be recalled that etodolac (Lodine) and nabumetone (Relafen) are generically priced COX-2 selective NSAID’s.  
The molecular structural classes of NSAID’s are as follows; Pyranocarboxylic acids (etodolac (Lodine)), Naphthylalkanone (nabumetone (Relafen)), Furanone (rofecoxib (Vioxx)), Benzenesulfonamides (celecoxib (Celebrex) and valdecoxib (Bextra)), Pyrrolo (ketorolac (Toradol)), Propionic acids (ibuprofen (Motrin, Advil), naproxyn (Aleve, Anaprox, Naprosyn), ketoprofen (Orudis), flurbiprofen (Ansaid), oxaprozin (Daypro), Fenamate (mefenamic acid (Ponstel)), Oxicams (piroxicam (Feldene) and miloxicam (Mobic)), Salicylates (aspirin, choline magnesium trisalicylate (Trilisate), salsalate (Disalcid), diflunisal (Dolobid), choline salicylate (Arthrosan)), Phenylacetic acid (diclofenac (Cataflam, Voltaren, Arthrotec), and Indoles (indomethacin (Indocin), sulindac (Clinoril), tolmetin (Tolectin)).
If inflammation is indicated on exam by the presence of objective findings of edema, warmth, or erythema, and if the patient has already failed to respond to therapeutic doses of NSAID’s of all classes, it is very much appropriate to revisit different NSAID classes.  Clinicians should re-explore the history of use of prior agents as many patients do not appreciate that intermittent prn use of NSAID’s will decrease pain but inflammation will only be terminated if the NSAID is consumed as prescribed for a full two week course.(   )  
 

MEDICATIONS – NSAID’S - ASPIRIN
Aspirin is unique amongst the NSAID’s in that it irreversably inhibits cyclic endoperoxides such that thromboxanes are not produced.  Platelets can no longer contribute to hemostasis through platelet aggregation, and bleeding time increases for the 10-14 day lifespan of that platelet. This has enormous efficacy in the management of comorbid coronary or cerebral atherosclerotic disease, particularly in the smoker and diabetic, to markedly decrease risks for myocardial infarction and stroke.  
However, in the absence of these indications, aspirin is not the optimal NSAID as aspirin significantly contributes to thousands of deaths by inducing fatal gastrointestinal bleeding.  Patients taking aspirin for coronary or cerebral artery thrombosis prophylaxis quite often have symptomatic and asymptomatic endoscopically confirmed peptic ulcers from aspirin.(  )
It should be appreciated that nonaspirin COX-1 blocking NSAID’s also impair thromboxane production and increase the risks for bleeding complications.  Consuming these NSAID’s on a scheduled regimen will effectively irreversibly increase the bleeding time and predispose to bleeding as well as reduce cardiovascular obstructive events.  
Choline magnesium trisalicylate (Trilisate) is similar to the COX-2’s in that this generically priced NSAID has low GI toxicity and it does not affect platelet function or bleeding time.(   )  
 

MEDICATIONS –NSAID’S – NEGATIVE GI CONSIDERATIONS 
Nonselective NSAID’s interrupt peripheral constitutive COX-1 and inducible COX-2 isoforms of COX.  NSAID’s diminish the activity of cyclooxygenase to decrease inflammation mediated tissue injury mediated by production of prostaglandins and bradykinin.  Impeding production of these nociceptor activators reduces pain and inflammation which can damage tissue.
Blocking COX-1 results in compromise of protective prostaglandin synthesis in the stomach with consequent decreased mucin protection and resultant increased gastric ulcers and gastrointestinal (GI) bleeding.  Thus sparing COX-1 and inhibiting COX-2 selectively increases GI safety without compromising equivalent efficacy. In addition, selective blockade of COX-2 is not associated with impairing platelet aggregation such that bleeding time remains unchanged as another mechanism by which bleeding complications are reduced with selective COX-2’s.
 In 1997, approximately 16,500 people die every year from NSAID induced fatal gastrointestinal (GI) bleeding.(  )  This does not include acute and renal failure deaths induced by NSAID’s nor does it encompass the suffering, expense, and lost time due to survival after inpatient admission for GI bleeding and morbidity.  The 16,500-plus deaths must be considered in the context of 20,200 deaths from leukemia, 16,700 deaths from HIV, 10,500 deaths from myeloma, 5300 deaths from asthma, 4400 deaths from cervical cancer, and 1400 deaths from Hodgkin’s lymphoma.  
Approximately half the patients with a bleeding peptic ulcer have no abdominal pain,(27) and the correlation between heartburn/dyspepsia and mucosal damage is poor.(65)  Though all patients are at risk for NSAID induced potentially fatal GI bleeds, the risks are greater for individuals who are smokers, elderly, steroid ingesters, and consume alcohol.  Patients who consume anticoagulants such as aspirin and coumadin are more likely to bleed more profusely for any given bleeding event.  The over the counter medication ginkgo biloba is a significant anticoagulant and may also increase NSAID related bleeding.  High doses of fish oil also thin the blood to increase the risks for bleeding.  Patients with burns, head injury, and other major stresses such as requiring intensive care unit monitoring are also at elevated risks for NSAID related GI bleeding.  Given their enhanced risks, consideration for co-prescription of proton pump inhibitors should be entertained for this population.  Nonselective NSAID’s block COX-1 such that prostaglandins in the stomach are not produced.  This results in impaired protective mucosal mucin coat synthesis, predisposing to ulceration, perforation, and fatal hemodynamic shock. 
Patients who have H. pylori infection suffer over a 6% increased risks of the premalignant condition of atrophic gastritis.(84)  For this reason, patients who complain of severe dyspepsia with NSAID’s should not simply be treated with other analgesics with avoidance of this class of medications.  Rather, they should be tested and treated.  This is particularly important as eradicating the infection before treating with NSAID’s will reduce the risk of ulcers by almost 400%.(98)
 

MEDICATIONS – COX-2 SELECTIVE NSAID’S 
In vitro laboratory studies have defined NSAID COX-2 selectivity as a 50% COX-2 : 50% COX-1 inhibitory concentrations of <1.(82) Thus, in the spectrum of greatest to lowest COX-2 selectivity, this defined rofexoxib (ratio of 0.05) > diclofenac (0.05) > mefenamic acid (0.08) > meloxicam (0.09) > celecoxib (0.11) > etodolac (0.11) > nabumetone (0.64) > piroxicam (0.79) > ketorolac (1.64, nonselective) > ibuprofen (1.69) > indomethacin (1.78) > naproxen (1.79) > oxaprosin (2.52) > aspirin (3.12) > tolmetin (3.93) > fenoprofen (5.14) > ketoprofen (8.16) > flurbiprofen (10.27).
In vivo studies have enormously clarified the value of COX-2 selectivity in that in vitro suggestions of low gastro-intestinal toxicities have not uniformly been expressed in clinical application at therapeutic dosing.  For example, diclofenac has never distinguished itself as having inordinately low GI toxicity over the years and the GI toxicity of piroxicam is appreciated as being significantly greater than that of ibuprofen.  Simlarly, even low dose meloxicam exhibited an “insignificant difference” adverse GI event frequency relative to naproxen,(48) and the COX-2 preference of meloxicam observed in vitro may not result in ex vivo clinical advantages when the higher dose of 15 mg is needed.(255)  However, rofecoxib, celecoxib, generic etodolac,(257) and generic nabumetone(256) have all distinguished themselves as having significantly decreased GI toxicity relative to nonselective NSAID’s.  Nabumetone has in vitro COX-2 selectivity and has 10- fold less GI toxicity in vivo compared to nonselective NSAID’s.(256)  Etodolac has been demonstrated in a multi-centre, double-blind, randomised parallel-group study to have a statistically better tolerance than diclofenac with fewer adverse events.(257)  
 

MEDICATIONS – NONSELECTIVE NSAID BLEEDING CONSIDERATIONS OTHER 
THAN COX-2 RELATED ISSUES
 NSAID related GI toxicity may also be mitigated through COX independent issues involving pharmacokinetic metabolism of the drug.  Indomethacin and other nonselective NSAID’s are at higher risks to induce GI bleeding relative to other nonselective NSAID’s, indicating that GI toxicity is not solely mediated by COX-2 selective blocking in terms of gastric mucin coat and the absence of anticoagulant effects.  Conversely, choline magnesium trisalicylate (Trilisate) is not a COX-2 selective NSAID but it has no effects on bleeding time and should be prescribed before other nonselective NSAID’s given its lower risk for GI bleeding.(  )  If aspirin of the same salicylate class has proven inefficious, however, the clinician should consider prescribing from a different nonselective NSAID class.
 

MEDICATIONS – NSAID’S – PRESCRIBING RECOMMENDATIONS
The in vivo literature, viewed in the context of cost-consciousness without compromise in patient care, suggests that clinicians should initiate NSAID prescribing with generic etodolac and then generic nabumetone.  Subsequent options should include rofecoxib (Vioxx), celecoxib (Celebrex), or valdecoxib (Bextra) versus nonselective generically priced NSAID’s of intermediate GI toxicity with a proton pump inhibitor (PPI) to decrease GI toxicity.  The risks for bleeding complications are similar with selective COX-2 inhibitors versus nonselective NSAID’s with co-prescription of PPI’s.(    )  In the absence of other considerations, the clinician is advised to prescribe the COX-2 selective inhibitor as the goal of successful treatment is enhanced with patient compliance and this is greater with prescription of a single pill as opposed to two pills.  If patients have failed to respond to the benzenesulfonamide Celecoxib (Celebrex) then they should be prescribed rofecoxib (Vioxx) of the furanone class before receiving a trial with the benzenesulfonamide valdecoxib (Bextra).  Before both benzenesulfonamides are prescribed, patients should trial nonselective NSAID’s with a PPI.
Patients suffering from severe dyspepsia and gastroesophageal reflux may be better candidates for treatment with nonselective NSAID’s with PPI’s for a similar cost as the newer COX-2’s as all NSAID’s increase the risk for dyspepsia and this symptom is treated with PPI’s.  Without treatment of the symptom, patients would be anticipated as being more noncompliant with COX-2’s as opposed to nonselective NSAID’s with coprescription of PPI’s.
In addition, though mucin production and gastric blood flow is most closely related to retained function of COX-1 to prevent ulcers, it is important to be aware of the fact that COX-2 is elaborated in the margins of healing gastric ulcers to promote healing.(41)  As such, it is inadvisable to prescribe COX-2’s as well as nonselective NSAID’s in patients with known peptic ulcers as these will impair healing(   ) with presumed increased risks for progression and bleeding.  Furthermore, patients taking concomitant aspirin for coronary or cerebral artery thrombosis prophylaxis quite often have asymptomatic endoscopically confirmed peptic ulcers from aspirin.(   )  Given that PPI’s heal gastric and duodenal peptic ulcers, patients taking aspirin may be best treated with PPI’s and nonselective NSAID’s if NSAID’s are mandated in management.  If patients are actively bleeding then no NSAID should be given as acetaminophen (Tylenol) and other analgesic options are available.
 When selecting a nonselective NSAID to be co-prescribed with a PPI, the patient’s history of prior true failure with NSAID’s should be solicited.  Medications from different structural classes should be prescribed to enhance the likelihood of successful management.  The generically priced COX-2 selective NSAID nabumetone (Relafen)(   ) should be an early option in management as this is the only NSAID of the naphthylalkanone class.  An additional feature which distinguishes nabumetone is that all non-COX-2 NSAID’s are acidic and nabumetone is the only basic NSAID.  An additional nonselective NSAID which should be utilized sooner than later is choline magnesium trisalicylate (Trilisate) as this medication does not affect the bleeding time and anticoagulants such as all of the other nonselective NSAID’s are associated with increased GI bleeding because of their anticoagulant properties.(   )  In addition, though not mediated via COX-2 selectivity, the GI toxicity of Trilisate is quite low.(   )
NSAID’s with greatest risks for GI complications have been identified.  The nonselective NSAID’s are not identical in GI risks.  GI complications with indomethacin (Indocin) are 300% greater than with diclofenac and naproxen.(77)  Tolmetin (Tolectin), piroxicam (Feldene), and oxaprosin (Daypro) have distinguished themselves as having markedly greater GI toxicity and should be considered only after most other NSAID of other classes have been trialed.  In addition, these agents of high GI toxicity should not be prescribed without a proton pump inhibitor, preferably the maximally effective PPI, rabeprazole (Aciphex), as discussed below.
 

MEDICATIONS – NSAID’S –GI CONSIDERATIONS – PPI’s
Proton pump inhibitors (PPI’s) can diminish the likelihood of peptic ulceration in patients taking NSAID’s as PPI’s inhibit gastric acid secretion and hypersecretion is felt to be associated with H. pylori negative ulcers.(118)  In the presence of an impaired gastric protective layer from COX-1 inhibition, acid can increase the risks of peptic ulceration.(47)  PPI’s are effective to prevent gastric as well as duodenal ulcers.(118)  PPI’s are also effective to heal existing H. pylori negative gastric and duodenal ulcers.(118)  With antibiotics, PPI’s heal H. pylori positive gastric and duodenal ulcers.(   )  Patients at elevated risks for GI bleeding may appreciate incomplete but distinct risk reduction with generically available  omeprazole (Prilosec) and other PPI’s to decrease the risks for gastric ulcers.  Patients should be educated that omeprazole more dramatically reduces the risks for NSAID induced peptic ulceration relative to ranitidine (Zantac),(72) an H2 blocker of the same class as cimetidine (Tagamet), nizatidine (Axid), and famotidine (Merck).  If a patient cannot tolerate NSAID’s and have previously trialed omeprazole then Helicobacter pylori infection should be excluded.  In the absence of infection, such patients may benefit from BID omeprazole dosing given the fact that the maximum half life of currently available proton pump inhibitors is 14 hours.  Dyspepsia is not simply a nuisance problem.  Patients who suffer heartburn refuse to take the prescribed NSAID and this may result in deviance of an acute painful condition from cure to a new path of chronic pain disabling condition.  PPI’s provide symptom relief to treat gastroesophageal reflux.
Another option would be to trial rabeprazole (Aciphex) as this is the only proton pump inhibitor which blocks all four of the identified proton pump channels.(   )  Rabeprazole has additional advantages over omeprazole, esomeprazole (Nexium), lansoprazole (Prevacid), and pantoprazole (Protonix) in that it is the only PPI which increases protective gastric mucin and mucus production.(21)   Rabeprazole also exhibits only limited drug-drug interactions as it is not metabolized significantly by hepatic micro-enzyme systems.(  )  Use of a PPI with a generically available NSAID with COX-2 preferential selectivity may be preferable to brand name COX-2’s as epigastric pain and heartburn are diminished with PPI’s such that compliance with the NSAID may be greater to cure inflammation and decrease the risks for peripheral nociceptor sensitization and progression of acute to chronic pain.
 

MEDICATIONS – NSAID’s – NEGATIVE RENAL CONSIDERATIONS
 Acute renal failure commonly occurs in patients consuming NSAID’s, particularly if they are dehydrated or have comorbid chronic renal hypoperfusion or dysfunction as in the elderly and diabetic populations.  The COX-2 selective NSAID’s carry the same burden of precipitating acute renal failure as the nonselective NSAID’s.  In addition, the renal effects of NSAID’s predispose to fluid retention with consequent hypertension.(4)  Small increases in blood pressure may be life threatening for patients with brittle congestive heart failure.(  ) Because renal perfusion is mediated primarily by COX-1, the COX-2 selective blocking NSAID’s have identical risks for acute renal failure as the nonselective blockers just as they similar efficacies to decrease pain.  Patients must be educated to remain well hydrated when they ingest NSAID’s to decrease the risks for acute renal failure.
 Chronic renal failure not uncommonly occurs with years of ingestion of NSAID’s.  If determined by a rheumatologist, chronic NSAID’s may be required to attempt to modify the disease course in chronic inflammatory diseases and such patients .  In chronic degenerative changes, however, the risk to benefit ratio suggests that alternative agents be considered.  After         years(    ) of ingestion, NSAID’s may precipitate ?interstitial nephritis and the enormous quality of life compromises related to chronic dialysis.  Postmarketing surveillance over the years will be required to confirm if the COX-2 selective NSAID’s have the same risks for chronic renal failure as the nonselective NSAID’s.
 

MEDICATIONS – NSAID’s - CHRONIC PAIN
In the vast majority of chronic pain patients, NSAID’s are not indicated for daily use.  Even though the new COX-2’s markedly diminish the risks for gastrointestinal bleeding, all NSAID’s share risks for acute renal failure, chronic renal failure, and exacerbation of hypertension with consequent compromise of brittle congestive heart failure.  This statement excludes patients with ongoing inflammation should their rheumatologist determine that NSAID’s are required for disease and inflammation management.  However, several indications exist to indicate the considerable value of NSAID’s in pain management.

18 y.o. full time working female w. Crohn’s
2 yrs. edema, warmth, tenderness R ankle
Antalgic gait, dec. right stance phase duration.
Failed 3 prior NSAID’s, one of which COX-2.

Trial structurally different NSAID, no other meds.
Pain gone in 2 hours.
Edema, warmth, tenderness gone 3 weeks.
Patient resumed running after 2 year abstinence.
NSAID D/C’ed at 3 months.
No SX recurrence, now 2-3 years.

Occasionally curing of chronic pain can be achieved with NSAID’s.  If a patient with chronic inflammation has not been treated with an NSAID of a different structural class then certainly this should be trialed in patients with edema, erythema, and warmth objective evidence of ongoing inflammation, even if the inflammation has been present for years.  Patients with histories of auto-immune disorders such as Crohn’s disease, colitis, Sjogren’s, lupus, rheumatoid arthritis,… should also be considered candidates for trials of NSAID’s of different structural classes to extinguish smoldering inflammation associated with auto-immune conditions.
 NSAID’s have utility in the management of acute intensification of chronic pain.  Patients with chronic pain may wish to work in their gardens, play with their children, go hiking with family, or pursue other activities which may be more rigorous relative to their often otherwise sedentary lifestyles and abilities.  As such, NSAID’s have considerable value as prophylactic agents prior to anticipated exertion as pre-emptive analgesia.  By blocking activation of the nociceptor by impairing prostaglandin synthesis before the inflammatory cascade can amplify nociception, pain can be terminated before it explodes.  The concept is similar to treating a migraine as soon as it starts to easily abort it versus waiting until the migraine is full blown and the patient needs to be admitted to the hospital.  Another analogy may be the ease by which a campfire or cigarrette is extinguished relative to the havoc wrought by a forest fire.  NSAID’s also have considerable utility as breakthrough pain reducers to address unanticipated exertion and minor trauma. NSAID’s may confer similar analgesia as opioids(      ) and may be employed several times a week to negate breakthrough pain seemingly unrelated to exertion.  
Chronic pain patients who experience pain from new minor surgery such as dental work(19) or suffer new trauma such as a fall or motor vehicle accident should be treated with NSAID’s which do not affect the bleeding time such as choline magnesium salicylate (Trilisate) or rofecoxib (Vioxx), celecoxib (Celebrex), or valdecoxib (Bextra) as opioids do not extinguish inflammation related to the new pathology.  The exception to this rule is that patients with new fractures may wish to avoid COX-2 inhibitors(50) as well as nonselective NSAID’s(  ) as they may impair optimal rate of healing of new fractures.
Many patients with chronic pain have comorbid smoking addictions with accompanying enhanced risks for thrombotic events in terms of strokes and myocardial infarction.  As chronic pain impairs exercise tolerance and accompanying caloric expenditure, many patients with chronic pain become obese and then develop type II diabetes mellitus.  Diabetics are also at high risk for strokes and myocardial infarction.  Such patients may benefit from chronic prescription of 81 mg low dose aspirin to address their pain as well as reduce risks for cardiovascular morbidity and mortality.  Consideration for risks for acute renal failure must be considered as well, however, as the atherosclerosis of the coronary and cerebral vasculature also affects the renal arterioles with accompanying escalated low but definate risks for acute renal failure.
Similarly, an additional issue to be factored into patient management is that of reduction of colon cancer with nonselective as well as selective NSAID’s.  This is particularly important in patients with family histories of colon cancer or colonoscopy visualized polyps.  
 

MEDICATIONS – ACETAMINOPHEN
Acetaminophen (Tylenol) is not a classic NSAID as it does not decrease peripheral prostaglandin synthesis to decrease inflammation at the peripheral nociceptor to facilitate cure.  However, it also does not affect thromboxane synthesis so it is free of effects on platelet hemostasis.  Acetaminophen is without the cognitive side effects of the opioids and it is vastly underutilized in the management of pain.  Unlike NSAID’s, it has no GI, acute renal, or chronic renal toxicity.  Its potency and toxicity are also vastly underappreciated.  A slow release eight hour duration of action acetaminophen has recently been released.  
Its proposed mechanism of analgesic action is by inhibiting cyclooxygenase mediated prostaglandin synthesis in the brain.  The analgesic potency of acetaminophen is often minimized, but this agent actually has similar efficacy as low dose opioids.(    )  It is synergistic with all analgesics, and so it is often compounded with the opioids to enhance analgesic efficacy.  
Eighty to ninety percent of acetaminophen is hepatically metabolized via conjugation with glucuronic acid or sulphates to renally excreted nontoxic metabolites, but the remainder of acetaminophen is cytochrome P-450 metabolized to a highly toxic intermediate.(17)  Normally this intermediate is conjugated with glutathione to be rendered nontoxic.  However, alcohol can deplete glutathione as well as enhance P-450 activity such that overwhelmingly increased production of the toxic metabolite occurs with consequent fulminat hepatocellular necrosis.(17)  
Acetaminophen has hepatotoxic potential, and maximum daily dose is 4000 mg in healthy, young individuals without ingestion of other medications which may affect hepatic metabolism.  Dosing at any given four hour increment should not exceed 1000 mg as doses in excess of this amount yield minimal additional analgesia.(32)  Patients who are inappropriately prescribed high doses of short acting opioids such as Percocet and Vicodin are at risk for exceeding this upper limit, particularly if they are inadvertently ingesting over the counter acetaminophen containing medications.  Many over the counter medications also contain acetominophen and clinicians must solicit this information.  Clinicians must solicit all medications that patients ingest, including over the counter cold remedies which may contain acetominophen and contribute to the four gram maximum.  In addition, hepatitis C is ubiquitous and affects 10%(   ) of the population.  Such patients as well as those with prior and ongoing alcohol use histories as well as those with other hepatic conditions are best advised to restrict use of Tylenol to a much lower dose.  Some patients may require monitoring of their transaminases or assessment of a hepatitis panel if they have previously been inebriated and made sexually indiscriminate decisions.
 

MEDICATIONS – TOPICAL MEDICATIONS
 Topical medications have the benefit that only a small portion of the medication is absorbed into the systemic circulation.  As such, local pain can be attenuated with a minimum of systemic side effects.  An additional benefit of this class of medication is that they are often available over the counter. Lidocaine patch (Lido-derm), lidocaine cream (ELA-MAX), and topical phenytoin and gabapentin are discussed elsewhere in this review as anti-arrhythmics. Ketamine cream is discussed in the section entitled NMDA antagonists.  Capsaicin (Zostrix, Capzasin-P) is one topical medication and is discussed as a substance P inhibitor elsewhere in this article.  Topical neomycin is an N-type calcium channel blocker, a class which has been reported to diminish pain hundreds of times more than opioids, and is discussed above under “MECHANISMS – PHYSIOLOGY – CALCIUM CHANNELS.”  Nifedipine is an L-type calcium channel blocker that may be compounded into a cream and is discussed in the same section of this review.  Clonidine and amitriptyline can also be compounded to creams.  Topical odansetron (Zofran) is a 5-HT3 antagonist that has been topical applied to decrease pain.(   )
Many oral medications can be compounded as topical creams to avoid otherwise intolerable systemic side effects for application to the peripheral site of mechanical or neuropathic pain.  Discussed elsewhere in this review is the NMDA blocker ketamine, the L-type calcium channel blocker nifedipine, the anticonvulsant sodium channel blocker Neurontin, and the muscle relaxant orphenadrine.  NSAID’s may also be compounded to topical creams.  Patients with allergies to oral NSAID’s must be educated that they can express the same allergic reactions with topical NSAID’s.
Counterirritants stimulate peripheral nerve terminals to redirect the brain away from the underlying pathology to focus on the far less uncomfortable irritant.  Patients must be educated that not all over the counter topical anaglesics are equivalent as active ingrediants vary and include camphor, menthol, oil of wintergreen, eucalyptus oil, and dihydrochloride and methylnicotinate.  Peppermint oil effects analgesia due to its menthol content and the analgesia of up to 20% camphor are due to distracting enhancement fo the perception of skin temperature changes.(117)
 Options include BenGay, Aspercreme, Flexall, Mobisyl, Sportscreme, Arthricare, Eucalyptamint, Icy Hot, and Therapeutic Mineral Ice.
 Though opioids were classically felt to effect analgesia primarily through the central nervous system, peripheral somatic mu receptors have been identified.(46)  Topical application of morphine, oxycodone 5 mg in 1-2 cc’s of water, dissolving meperidine 100 mg in water may decrease ulcer related pain such that oral opioids dosing can be diminished with longer lasting effect.(66)  Analgesia with topical levorphanol and buprenorphine has also been demonstrated.(67)  In particular, propoxyphene has local anesthetic properties and is a potent sodium channel blocker and it takes over 850% longer for sodium current recovery with propoxyphene relative to lidocaine,(202) suggesting a long duration of anesthetic analgesic effect.
 

MEDICATIONS – MUSCLE RELAXANTS
Given the structural distinctiveness and different mechanisms of action of the different muscle relaxants,(9) failure of one spasmolytic medication to match the patient’s physioanatomy and afford relief does not preclude efficacy with another agent.  As such, the entire spectrum can be trialed.  Though all of the muscle relaxants can be sedating, they have additional mechanisms by which they attenuate spasms and pain through central depression of polysynaptic and monosynaptic reflexes as well as via depression of gross motor activity.  Patients who do not find this class of medication sedating can be educated to take them during the day.  As discussed above under “comorbid anxiety,” benzodiazepines do not have a place in the treatment of pain, including as muscle relaxants.  Trigger point and nerve block local anesthetic injections are nicely synergistic with muscle relaxants in that the former intervention is free of cognitive side effects such that a lower dose of the sedating muscle relaxant may be required.
 Spasms related to peripheral musculoneuroskeletal pathology must be distinguished from centrally mediated spasms as well as nocturnal muscle cramps.  Following spinal cord or brain damage, their exists impairment of descending control over the lower motor neuron of the anterior horn cell in the ventral spinal cord.  The motoneuron reflexively responds to stimulation such that the clinical triad of spasticity of spasms, hypertonus, and hyperreflexia with or without clonus occurs in varying proportion.  This is treated with botulinum injection, phenol injection, dantrolene, lioresal, and tizanidine.  The physical exam findings of hypertonus and hyperreflexia are never present in the spasms of peripheral etiology nor does the patient present a history of central nervous system pathology.  Use of dantrolene in peripheral spasms is relatively contra-indicated given the considerable potential hepatotoxicity of this medication.  Similarly, it is difficult to appreciate any value to the use of botulinum in the treatment of peripheral spasms as it is counter intuitive to make a chronically strained muscle weaker as opposed to strengthening it.  Similarly, making a muscle weaker will compel adjacent muscle fibers to assume the workload of the botulinum treated fibers, predisposing the intact fibers to strain and a wider distribution of myofascial pain.
 Cramps most commonly occur in the gastrocnemius muscle and are distinct from the spasms of spasticity as no central nervous system discrete lesion is present and no peripheral cause of pain can be historically elicited.  The cramps are brief and intense in nature, similar to the spasms of spasticity.  Cramps are best treated by behavioral approaches including stretching the affected muscle prior to bed as well as maintaining good hydration and mineral content in foods, including repletion of magnesium, potassium, sodium, and calcium, particularly in hot weather with increased insensible losses as well as following surgical blood loss.  Quinine was previously widely prescribed to treat cramps, but its frequent association with throbotic thrombocytopenic purpura(  ) and hemolytic uremia(  ) preclude its ready prescription without full informed consent.
MEDICATIONS – MUSCLE RELAXANTS
MEDICATIONS – MUSCLE RELAXANTS – SPECIFIC AGENTS
 

MEDICATIONS – MUSCLE RELAXANTS – SPECIFIC AGENTS
 Lioresal (Baclofen) is a structural analogue and agonist of gamma-aminobutyric acid (GABA).  It is a presynaptic GABA-B receptor agonist, decreasing intracellular calcium influx to presynaptic terminals.  This facilitates presynaptic inhibition of release of excitatory neurotransmitters  in the spinal cord.  Evidence also suggests postsynaptic GABA-B receptor agonism by baclofen with resultant potassium channel mediated hyperpolarization of the alpha motoneuron such that it is less likely to depolarize and send an efferent signal to the muscle fiber to dictate contractile spasms.  The half-life of Baclofen is 3-4 hours such that patients awaken without grogginess from residual medication in their systems.  Though Baclofen is bereft of addiction issues, patients must be warned that abrupt termination of ingestion of Baclofen at high doses may result in withdrawal seizures or psychosis.  As such, it should only be prescribed to a reliable patient.  Finally, in contradistinction to the PDR, Baclofen dosing should be initiated at 5 mg qd as patients who start the medication at excessively high a dose with consequent sedation will be reluctant to retrial the analgesic again.  Baclofen is the first line treatment of trigeminal neuralgia, followed by carbamazepine.  It has efficacy to decrease the opioid induced hyperalgesia with may accompany high doses of morphine via NMDA activation by the biometabolite morphine-3-glucuronide.(11)
 Tizanidine (Zanaflex) is a central alpha 2 adrenergic receptor agonist.  Zanaflex is sedating and has a short half life and so it can be utilized to address pain induced insomnia.  Liver function tests must be periodically monitored with this medication.  Clonidine is another central alpha 2 agonist and has the advantage that it is available in the form of a once a week patch such that compliance may be enhanced.  Tizanidine may also relax the skeletal muscle portion of the urethral sphincter to alleviate opioid induced and anticholinergic induced urinary retention.
 Orphenadrine (Norflex) is unique amongst the muscle relaxants as this medication is also an NMDA receptor blocker.  As such, it is similar to the non-NMDA blocking lioresal and tizanidine in that it also has utility in the management of neuropathic pain.  Orphenadrine is also an analgesic antihistamine(193) such that it may resemble other antihistamines in the potentiation of opioid induced analgesia.(149,179,180)
 Cyclobenzaprine (Flexeril) is a tricyclic antidepressant derivative(37) and acts primarily at the brain stem to influence both gamma and alpha motor systems to decrease spasm.(15)  Flexeril was recently reviewed in a multicenter, double-blind, placebo controlled study and it was concluded that this medication exerts its anti-spasm effect via mechanism(s) independent of sedation.(8)
 Metaxalone (Skelaxin) – 
 Methocarbamol (Robaxin)
 Chlorozoxazone (Parafon forte)
 Dronabinol (Marinol) has been described as having spasmolytic properties, including in the treatment of multiple sclerosis spasticity of central nervous system origin.(   )
Carisoprodol (Soma), butalbital-acetaminophen-caffeine (Fioricet) and butalbital-aspirin-caffeine (Fiorinal) and the benzodiazepines include lorazepam (Ativan), alprazolam (Xanax), clonazepam (Klonopin), diazepam (Valium), temazepam (   ), triazolam (    ), midazolam (   ), oxazepam (    ), and   (Librium) are not analgesics and are described in the earlier portion of this review as non-analgesic medications.
 

MEDICATIONS – ANTIDEPRESSANTS
Antidepressants can decrease pain in patients who fully lack any evidence of depression, and this has been demonstrated in a randomized, double-blind, placebo-controlled study of back pain.(147)  This is not surprising as antidepressants increase serotonin, noradrenaline, histamine, and dopamine neurotransmitters, all of which are involved in pain modulation.  Norepinephrine as well as serotonin are involved in the endogenous endorphin mediated pain modulation pathways in the central nervous system via descending pathways to the spinal cord.
Antidepressants may fall into several classes, including the selective seratonin releasing agents, dopaminergic and noradrenergic, and the tricyclic antidepressants (TCA’s).  Each medication of each class should be considered for trial as efficacy may markedly improve or decrease depending on the optimal fit of the patient’s physio-anatomy to the different molecular structural of each separate medication.   Different TCA’s have diffent affinities for agonism and antagonism at cholinergic, noradrenergic, histaminergic, and other receptors.   A very precise numeric review of affinities has been
published by Mayo Clinic.(   )  The concept is analogous to the woman with menstrual cramps who fails to respond to the NSAID ibuprofen but does respond to the NSAID naprosyn.  Just as failure to respond to one NSAID does not in any way preclude successful treatment with another NSAID, patients who fail to respond to one antidepressant should trial other antidepressants. 
The selection of antidepressant should be defined by comorbidities as well as side effects.  Obese patients may be better treated with venlafaxine (Effexor) or methylphenidate (Ritalin) to decrease appetite and address chronic fatigue while anorexic elderly patients or those with insomnia may respond better to mirtazapine (Remeron) or paroxetine (Paxil), as these serotonergics are more likely to result in weight gain.  WellButrin is also a good analgesic antidepressant in the obese patient as it is less likely to promote weight gain.  Dose escalation should be monitored closely, particularly if patients are on other agents which lower the seizure threshhold.  Similarly, as this agent has more dopaminergic agonism than other agents, it should be used with more caution in patients with comorbid bipolar disorder and schizophrenia.  The TCA amitriptyline has considerable anticholinergic properties and many clinicians favor nortriptyline as the latter agent is less likely to result in anticholinergic mediated tachycardia, xerostomia, urinary retention, and constipation.  
 

MEDICATIONS – TRICYCLIC ANTIDEPRESSANTS
TCA’s may decrease pain by blocking nociceptive neurotransmitters.  Histamine is a nociceptive neurotransmitter released from afferent C and A-delta fibers as with substance P and kinins.(218)  Blocking the binding of histamine to receptors decreases pain with analgesia from antihistaminergics.(32,128,149,179,180,188,193, 198) Antihistamines may markedly potentiate opioids, including pentazocine, morphine, fentanyl, and nalbuphine.(149,179,180)  A number of TCA’s block histamine.  Alpha antagonists have demonstrated efficacy to attenuate neuropathic pain.  TCA’s also block alpha-1 receptors.  
 Choosing a seratonin reuptake inhibitor (SSRI) should be defined by conditions comorbid with the depression.   Mirtazepine (Remeron) is a non-SSRI serotonergic antidepressant and helps treat insomnia, but some clinicians have reported that in doses greater than 15 mg it may increase anxiety.  Venlafaxine (Effexor) may be stimulating to address chronic fatigue as well as suppress appetite to address obesity.  Escitalopram (Lexapro), Cetalopram (Celexa), sertraline (Zoloft), paroxetine (Paxil), fluoxetine (Prozac) are additional SSRI’s.  In terms of drug interactions, escitalopram is favored as it does not interact with cytochrome P450 3A4, 2D6, 1A2, 2C19, and 2C9 isozymes.  Citalopram also has only very weak interactions, unlike moderate to strong interactions with fluoxetine at 3A4, 2D6, 2C19, and 2C9, paroxetine at 2D6, and sertraline at 2C19.
Increasing serotonin and noradrenaline treats mood depression and these neurotransmitters are also involved via descending inhibitory pathways to the dorsal horn to decrease pain by decreasing second order neurons from depolarizing to send afferent signals of pain to the cerebral cortex.  Paroxetine, amitriptyline, and nortriptyline induced a dose-dependent analgesic effect.(189)
Tricyclic antidepressants such as nortriptyline (Pamelor) may address depression as well as promote sleep and decrease pain.  These medications, however, have anticholinergic side effects of xerostomia, urinary retention, and tachycardia as well as hypotensive side effects.  Tachycardia may preclude safe prescription to elderly patients with comorbid coronary artery disease at risk for ischemic events.  The analgesic effect of tricyclics is separate from the antidepressant effects.(32)  
In terms of the continuum of minimal to mild to moderate to strong anticholinergic properties, trazodone (Desyrel) = fluoxetine (Prozac) = bupropion (Wellbutrin)=amoxapine (Ascendin) to nortriptyline (Pamelor) = sertraline (Zoloft) to doxepin (Sinequan) = imipramine (Tofranil) = protriptyline (Vivactil) to amitriptyline (Elavil).(32)
In terms of the continuum of minimal to mild to moderate to strong hypotensive properties,
bupropion = fluoxetine = protriptyline = sertraline to amoxepine = desipramine to imipramine = trazodone to amitriptyline = doxepin.(32)
In terms of the continuum of minimal to mild to moderate to strong sedating properties, amoxapine = buproprion = desipramine = fluoxetine to doxepin = nortriptyline = protriptyline = sertraline to imipramine to amitriptyline.(32)  Trazodone also has potent sedating prperties.
In terms of neurotransmitter agonism, antidepressants with the greatest serotoninergic properties include amitriptyline, doxepin, fluoxetine, imipramine, nortriptyline, sertraline, and trazodone.  Those with the greatest noradrenergic properties include amoxapine, desipramine, imipramine, nortriptyline, and protriptyline.  Less potent noradrenergic agonism has been identified with amitriptyline.(32)  Bupropion and methylphenidate are antidepressants with considerable dopaminergic agonism.
TCA’s may decrease pain by enhancing analgesic neurotransmitters.  Methylphenidate (Ritalin) is a noradrenergic agent with efficacy to decrease mechanical and neuropathic pain as well as potentiate opioids.(250)  TCA’s also potentiate opioids,(  ) possibly via both antihistaminergic as well as noradrenergic effects.  One of the mechanisms by which calcitonin is postulated to exert its profound analgesic effect is by activation of the descending serotonergic pathways(   ) to terminate pain at the dorsal horn spinal cord level before it ascends to the brain.  
Side effects of TCA’s include their proconvulsant properties as well as anticholinergic induced xerostomia, constipation, urinary retention, confusion, and tachycardia with risks for myocardial infarction and arrhythmias.
 

MEDICATIONS – DOPAMINERGIC ANTIDEPRESSANTS
Bupropion (Wellbutrin, Zyban) is a dopaminergic antidepressant.  It can be used concomitantly with serotonin increasing antidepressants without fear of precipitating serotonin syndrome.  Bupropion (Wellbutrin, Zyban) may also decrease appetite to facilitate weight loss, decrease pain,(   ) and decrease smoking craving.(   )
 

MEDICATIONS – SEROTONERGIC ANTIDEPRESSANTS
Serotonin agonists are used to decrease mechanical as well as neuropathic pain.  Though some studies have identified greater analgesic efficacy with TCA’s,(  ) the safer side effect profile of the serotonergics makes them better choices in some patients, particularly the elderly who may suffer myocardial ischemia secondary to the tachycardic anticholinergic mediated effects of TCA’s.  Similarly, the elderly often suffer cognitive decline related to the anticholinergic properties of TCA’s.  Many serotonergic antidepressants also increase noradrenaline and these may confer greater 
 

MEDICATIONS – ANTIHISTAMINES 
 Histamine is a nociceptive neurotransmitter released from afferent C and A-delta fibers as with substance P and kinins.(218)  Blocking the binding of histamine to receptors decreases pain.  Many tricyclic antidepressants block histamine even more potently than diphenhydramine.
Diphenhydramine (Benadryl) are H1 histamine receptor antagonists and have efficacy to treat severe cancer related pain,(149,198) neuropathic pain as with neuralgia and thalamic infarcts, and mechanical pain as with post-thoracotomy chest wall myofascial pain.(149)  Diphenhydramine may afford analgesic efficacy in patients refractory to morphine, fentanyl, methadone, methylphenidate, clonidine, lidocaine patch, gabapentin, amitriptyline, nortriptyline, and paroxetine, and this antihistamine may allow the opioid dose to be markedly decreased.(149)  Hydroxyzine, diphenhydramine and orphenadrine have direct analgesic properties.(188)  Diphenhydramine and other antihistamines potentiate the opioid analgesia of pentazocine, morphine, fentanyl, and nalbuphine.(149,179,180)  Several mechanisms have been suggested by which antihistamines decrease pain, including facilitation of binding of opioids to opioid receptors, augmenting cyclic GMP release, and interactions with substance P and phospholipase A1.(149)  Interaction with serotonergic, dopaminergic, histaminergic, and dopaminergic pathways have also been proposed.(193)  More recently, the importance of antinociception mediated by Gi-protein pathways(185) and potassium ATP and calcium gated potassium channels have been identified.(186)
 Cimetidine (Tagamet) is an H2 receptor antagonist and markedly potentiates opioid induced analgesia.(180)  Cimetidine is very effective in particular in relieving painful bladder and suprapubic pain.(128)
Hydroxyzine (Atarax, Vistaril) has antiemetic as well as anxiolytic as well as analgesic properties.(188,193,198)
 Cyproheptadine (Periactin) has analgesic properties(32) but is also an appetite stimulant.
 Orphenadrine (Norflex) is an analgesic antihistamine(188,193) discussed above as a muscle relaxant.  
 Fexofenadine (Allegra), loratadine (Claritin), and cetirizine (Zyrtec) are selective H1 receptor antagonists and may also be proven to decrease pain or address opioid induced pruritus.  This cannot be inferred without clinical trials, however, as not all antihistamines confer analgesia as noted with the lack of antinociception with chlorpheniramine (Chlor-Trimeton).(188)
 

MEDICATIONS – 5-HT3 ANTAGONISTS
The 5-HT3 antagonists of dolasetron (Anzemet), granisetron (Kytril), and odansetron (Zofran) are primarily utilized as potent anti-emetics but they also have been described as having analgesic properties.(   )  These agents have been demonstrated as confering analgesia when delivered in a topically compounded cream.(   )  
 Potential cardiac effects of the 5-HT3 antagonists have been described.(   )
 

MEDICATIONS – ANTICONVULSANTS
Anticonvulsants stabilize neuronal cell membranes via several mechanisms, including by impeding positively charged sodium and calcium influx into the post-synaptic cell to contribute to action potential generation as well as in the pre-synaptic terminal to contribute to neurotransmitter release into the synaptic cleft.  Anticonvulsants also facilitate GABA, an inhibitory neurotransmitter to prevent the hyperexcited nerve from responding to innocuous stimuli.  Selection of the initial agent should be based on likelihood of efficacy, comorbid conditions, and side effect profile of the various agents.  Antiseizure medications may counter the pro-convulsant effects of tramodol (Ultram) and tricyclic, dopaminergic, and serotonergic antidepressants.
It is important to discuss mechanisms of analgesic activity of anticonvulsants and anti-arrhythmics with patients as they may other be concerned when they find that anticonvulsants are FDA approved for treatment of seizures.  Sharing with them the analogy of aspirin’s considerable efficacy to treat muscular pain and its simultaneous benefit to treat myocardial infarction, two vastly disparate conditions, helps them appreciate the merit of anticonvulsant’s dual efficacy to treat seizures as well as mediate antinociception.  In addition, patients often relate to statements relating the efficacy of anticonvulsants to electrically stabilize neurones in the brain as well as electrically stabilize nerves in the spine and periphery.
Zonisamide (Zonegran) blocks sodium as well as T-type calcium channels in addition to being a GABA agonist such that it decreases pain through several different mechanisms.  It is sedating and so it useful to treat comorbid insomnia.  It was also recently discussed in JAMA as being an anorexic agent to treat obesity.(200)  As with topiramate, it inhibits carbonic anhydrase and should be used with caution in patients with histories of nephrolithiasis.
Topiramate (Topamax) is felt to potentially decrease pain by blocking sodium channels.  It should be used with caution in patients with multiple sclerosis as this medication has thermogenic properties via its oligohidrosis side effect.  As with zonisamide, it inhibits carbonic anhydrase and should be used with caution in patients with histories of nephrolithiasis.  It has anorexic properties and may promote early satiety and anorexia. 
Gabapentin (Neurontin) is felt to work as a GABA agonist.  Its greatest benefit is its enormous safety profile.  It has sedating properties such that it may promote sleep and it also has mood stabilizing properties.  The maximum dose of  is 6000 mg and so it may take months to slowly escalate the dose before either achieving efficacy or declaring its ineffectiveness.  Topical gabapenin has been been compounded to further add to analgesic efficacy.
Carbamazepine (Tegretol) inhibits norepinephrine uptake.(32)  This medication is a tertiary option for pain management as it has potential for fatal agranuloytosis, pancytopenia, aplastic anemia, and thrombocytopenia.(32)  Oxacarbazine (Trileptal) is the new formulation of carbamazepine without the risks for blood dyscrasias.  However, it retains the risks for hyponatremia and serologic monitoring is required.
 Valproic acid (Depakote) interferes with GABA transaminase to increase GABA (gamma-aminobutyric acid).(32) This medication is a tertiary option for pain management as it has potential for fatal   Liver function tests must be monitored in patients prescribed this medication given risks for hepatic failure.  It may also result in severe osteoporosis.(  ) 
 Phenytoin (Dilantin) stabilizes neuronal membranes by altering sodium, calcium, and potassium ion flux.(32) This medication is a tertiary option for pain management as it has potential for fatal  
Phenytoin interferes with folic acid metabolism and may result in peripheral neuropathy and megaloblastic anemia if folate is not ordered at all instances of prescribing this anticonvulsant.  Phenytoin may stimulate fibrocytes resulting in the need for surgery to address gingival hyperplasia, although it has been reported that this condition may respond to several weeks of metronidazole.(18)  Phenytoin may also inhibit insulin secretion,(32) a concern in a brittle diabetic who may otherwise be prescribed this agent to address pain related to diabetic neuropathy.  Phenytoin has cerebellar toxicity with chronic use.  Topical phenytoin has been demonstrated to have efficacy to decrease pain related to burn skin grafts and has dual efficacy in delivering faster wound healing relative to OpSite and Soframycin dressing.(242)
 Lamotrigine (Lamictal) is an anticonvulsant that was recently approved as a mood stabilizer.
 

MEDICATIONS –ANTI-ARRHYTHMICS 
Anticonvulsants and anti-arrhythmics stabilize neuronal cell membranes by impeding positively charged sodium and calcium influx into the post-synaptic cell to contribute to action potential generation as well as in the pre-synaptic terminal to contribute to neurotransmitter release into the synaptic cleft.  Selection of the initial agent should be based on likelihood of efficacy, comorbid conditions, and side effect profile of the various agents.  Antiseizure medications may counter the pro-convulsant effects of tramodol (Ultram) and tricyclic, dopaminergic, and serotonergic antidepressants.
It is important to discuss mechanisms of analgesic activity of anticonvulsants and anti-arrhythmics with patients as they may other be concerned when they find that anticonvulsants are FDA approved for treatment of seizures.  Sharing with them the analogy of aspirin’s considerable efficacy to treat muscular pain and its simultaneous benefit to treat myocardial infarction, two vastly disparate conditions, helps them appreciate the merit of anticonvulsant’s dual efficacy to treat seizures as well as mediate antinociception.  In addition, patients often relate to statements relating the efficacy of anticonvulsants to electrically stabilize neurones in the brain as well as electrically stabilize nerves in the spine and periphery.
 Lidocaine patch stabilizes pathologically irritable nerve cell membranes by impeding sodium influx.  It may decrease neuropathic pain(37) as well as mechanical pain such as post-thorocotomy myofascial pain.(37)  It is particularly advantageous as it is similar to Miacalcin, local anesthetic nerve blockade and trigger point injections, and topical analgesic creams in that it is bereft of cognitive side effects which commonly accompany use of opioids, muscle relaxants, and medications of other classes.  Efficacy of lidocaine patch which only penetrates a few millimeters under the skin supports the mechanism by which modulating superficial signals may attenuate deep somatic, disc related, or osteoarthritic pain.  The superficial nerves send the signal to the segmental spinal cord as well as to the dorsal horn.  The constant topical application of the lidocaine patch twelve hours a day may have advantages in the desensitization of reflex sympathetic dystrophy, just as occupational therapists instruct such patients to utilize a reversed isotoner glove for hand pain related to this condition.
 Lidocaine cream (ELA-cream) has similar benefits as lidocaine patch and has an advantage with respect to application over the elbow, knee, and other areas in which patients may report poor adherence of the patch.  The cream, however, is messy to apply and may be absorbed by the patient’s clothing instead of the skin.  In addition, patient’s must be educated not to touch their eyes as they need to wash their hands following application of the cream.  The cream also needs to often be reapplied during the day, unlike the lidocaine patch.  This is usually a disadvantage, but it is an advantage in the management of reflex sympathetic dystrophy, a condition in which constantly rubbing and desensitizing the area enormously facilitates cure.
 Mexiletine (Mexitil) is the oral form of lidocaine.  It is a class IB antiarrhythmic.  This medication may precipitate arrhythmias and cardiology consultation should predate all prescriptions of this agent to confirm the absence of occult structural or physiologic conduction related pathology which may predispose to pro-arrhythmic effects.  For this reason as well as its potential hepatotoxicity, it should be reserved as a tertiary option in pain management.
 Tocainide (Tonocard) is a class IB antiarrhythmic.  It has pro-arrhythmic properties and should be utilized with written informed consent and reserved as a last option to decrease severe neuropathic pain.
 

MEDICATIONS – PERIPHERAL ALPHA BLOCKING ANTIHYPERTENSIVES
All antihypertensive agents should be utilized with caution as they may add to the orthostatic effects of opioid induced arterial and venous dilation as well as anticholinergic mediated orthostasis of the muscle relaxants and tricyclic antidepressants.   Alpha adrenergic blocking medications may decrease neuropathic pain.  They also have utility to address urinary retention related to opioids by relaxing the smooth muscle at the base of the bladder.  The patient must be educated to avoid use of over the counter alpha agonists such as pseudoehedrine (Sudafed) as such medications will counter the beneficial effects of the antagonists.
 Terazosin (Hytrin), prazosin (Minipress), and doxazosin (Cardura) are alpha-1 blockers and have been utilized to decrease pain related to reflex sympathetic dystrophy by blocking response to hyperaroused sympathetic adrenergic outflow.  It is considered an adjunct to the far more potent pain relief related to anestheseologist mediated sympathetic plexus neurolysis.
 

MEDICATIONS – SUBSTANCE P INHIBITORS
Substance P is a nociceptive neurotransmitter peptide that is released from afferent C and A-delta fibers as with histamine and kinins.(218)  Blocking the binding of substance P to neurokinin receptors decreases pain.  Substance P is released from preganglionic adrenergic receptors at the dorsal horn of the segmental spinal cord.(32)  Substance P is felt to be involved in initial sensitization of nociceptors in the periphery(70) such that otherwise innocuous stimuli may now result in afferent signals of pain.  This suggests that aggressive early treatment of pain with substance P inhibitors may prevent peripheral mechanisms of sensitization before pain becomes chronic or before chronic pain leads to full disability.  It also suggests that fully depriving a patient of all treatments may predispose to entrenchment of acute or subacute pain to become chronic and intractable.  This is not to suggest that patients must be treated with opioids, as other medications similarly affect the common mediator of calcium influx.  Prescribing or terminating prescribing of opioids is fully at the discretion of the clinician, not the patient.  Substance P is also involved in long-term changes in dorsal horn noxious signal processing.(70)
Clonidine blocks the release of substance P in the dorsal horn of the spinal cord.(32)  Clonidine is a central alpha2 adrenergic agonist that also blcoks the release of norepinephrine from pregagnlionic adrenergic receptors in the dorsal horn.(32)  Clonidine is a vasodilator and should be used with caution in the elderly as they have less responsive compensatory vascular reflexes to prevent orthostasis and consequent falls.  Clonidine may inhibit insulin release(32) and result in hyperglycemia.  Clonidine, when co-prescribed with morphine, may yield greater than additive potentiated pain relief of each individual analgesic.(40)
The anti-emetic aprepitant (Emend) is also a substance P / neurokinin 1 receptor inhibitor and has extremely potent analgesic properties.  However, it has also been released from the manufacturer with an enormously expensive retail price and should be reserved as a tertiary agent to attenuate severe, refractory pain as these patients are particularly focused and at risk for suicide.
Topical Capsaicin cream selectively stimulates primary afferent C fibers to release its stored substance P to result in a long term desensitization of C fibers, possibly by depleting substance P.  Unfortunately, the initial several weeks of increased pain during the depletion of the peptide is intolerable to some patients such that compliance is low to reach the analgesic portion of the biphasic treatment.
 

MEDICATIONS – BISPHOSPHONATES
Alendronate (Fosamax) and actonel (Risedronate) are bisphosphonates, and these medications have efficacy to address pain related to bone cancer, including myeloma,(  ) metastatic breast cancer,(   ) and metastatic prostate cancer.(   )  They also have efficacy in the management of patients with osteoporotic fractures to decrease the frequency of recurrent fractures.  Bisphosphonates can be consumed with calcitonin to synergistically enhance bone quality / resistance to fractures.
 Once a week alendronate markedly enhances compliance and also reduces side effects.  
 

MEDICATIONS – CALCITONIN
Calcitonin (nasal formulation as Miacalcin) is an endogenous polypeptide hormone produced by theparafollicular C cells of the thyroid.  As it is produced by the human body, it is truly rare for patients to suffer allergic reactions to this endogenous substance.  Salmon calcitonin has dual efficacy in that this nonopioid analgesic also addresses osteoporosis by enhancing bone quality and resistance to fractures.  This is of value to a significant population of patients with pain as they suffer comorbid osteoporosis related to inactivity, smoking addiction, or accelerated bone loss related to analgesic utility of the older anticonvulsants.  An additional enormous benefit of calcitonin is that it has no sedating properties, unlike the opioids and most nonopioid analgesics.  As such, its use does not preclude patients from enjoying the satisfaction of work and contributing to society.  
Calitonin has exhibited efficacy to decrease pain in multicenter and/or prospective and/or double blind and/or placebo controlled studies.(113,124,153,156,158,167,192,261) Pain relief may be as quick as the first or second day following initiation of treatment(124) or it may be delayed for several weeks.  In one study of patients with painful vertebral crush fractures, analgesia was appreciated in less than ten days in greater than 50% of patients.(192)  Use of calcitonin may allow a decrease in the consumption of analgesic medications(136) as well as complete withdrawal of opioid requirements(155).  Calcitonin has efficacy in the treatment of intractable pain.(140,153)  Calcitonin potentiates the analgesia induced by the serotonergic antidepressants.(189)
Pain may be dramatically diminished in neuropathic pain(114,157,158,169,170) including such entities as reflex sympathetic dystrophy,(169,170) post-herpetic neuralgia,(169) nerve root compression,(114) and phantom pain.(157,158) Calcitonin may also markedly decrease mechanical pain(113,119,124,132,140,146,148,153,154,155,156,167,182,183,189,191,192,261) diagnoses, including vertebral crush fractures,(113,119,124,146,156,167,182,192) juvenile idiopathic arthritis,(183) and Paget’s disease.(132,154)  Even severe malignant mechanical pain may improve with calcitonin treatment, including osteolytic as well as osteoblastic metastatic cancer(140,148,155,168,191,261) in addition to multiple myeloma.(153)  Calcitonin has been reported as decreasing cancer pain related to breast cancer,(155,261) lung cancer,(140) and prostate cancer.(155)
Calcitonin inhibits pain through a variety of mechanisms.  It is important to discuss these mechanisms with patients as they may other be concerned when they find that the medication is FDA approved for treatment of osteoporosis.  Sharing with them the analogy of aspirin’s considerable efficacy to treat muscular pain and its simultaneous benefit to treat myocardial infarction, two vastly disparate conditions, helps them appreciate the merit of calcitonin’s dual efficacy to treat osteoporosis as well as mediate antinociception.
The immediate analgesia that some patients appreciate after use of this agent may be attributed to the higher serum endorphin endogenous opioid levels present within one hour of nasal inhalation.(  )  Endorphins act on wide dynamic range neurons in the dorsal horn segmental spinal cord to decrease firing and potentially return the bias of the sensitized cell to normal.(218)  Reduction in pain correlates with calcitonin induced increase in beta-endorphin.(191)  Calcitonin inhibits osteoclastic bone resorption such that this mechanism may decrease pain related to bone metastasis, Paget’s disease, and healing fractures.(  )  It has been proposed that calcitonin also acts slowly through the descending serotonin systems in the dorsal horn of the spinal cord.(32)  This would explain why some patients do not appreciate analgesia until the medicine has been used for several weeks.
Many clinicians percieve the role of calcitonin as that of ameliorating pain related to osteoporotic fractures in conjunction with other bone quality enhancing strategies such as increased weight bearing exercises,(  ) increased calcium intake, increased vitamin D intake, thiazide diuretics to decrease calciurea,(  ) and limiting vitamin A consumption(   ) despite the current dose in many multivitamin preparations.  It is hoped that rather than compete for favor amongst individuals with osteoporosis that the manufacturers of Miacalcin and the bisphosphonates will pursue collegiate studies to define if co-prescription enhances not just bone density but also bone quality in terms of resistance to fractures.
Calcitonin may result in hot flashes.  Hot flashes of menopause are treated with tizanidine (Zanaflex), clonidine, Megace, gabapentin (Neurontin), Effexor and other SSRI’s, and the over the counter product black cohosh.(205)
 

MEDICATIONS – DOPAMINE RECEPTOR BLOCKING MOOD STABILIZERS 
Zyprexa (Olanzapine) is an anxiolytic and may decrease even severe cancer related pain associated with anxiety.(39)  This medication may also decrease myofascial pain related to fibromyalgia.(45)  Patients who receive olanzepine should be cautioned that the medication is sedating so it should be consumed at night.  In addition, it is associated with weight gain.  Though olanzapine has utility in the management of pain in the absence of psychotic conditions, it may assist with thought processing in medical conditions of schizophrenia, bipolar disorder, and post-traumatic stress disorder.  Olanzapine has an enormous advantage in that it may be used to treat tardive dyskinesia, a condition which may occur as an irreversable side effect of phenothiazine and other similar dopamine blocking medications, precluding candidacy to treat most patients with chronic pain.
Anticonvulsants such as topamax Topiramate (Topamax), gabapentin (Neurontin), and valproic acid (Depakote) also have dual efficacy to decrease pain as well as stabilize mood, though less predictably for the latter condition relative to the potency of olanzapine.
 

NARCOTIC
The term “narcotic” simply reflects categorization by the FDA as a drug with potential beneficial properties but also potential for abuse as these medications have potential to induce euphoria when given inappropriately, particulary to individuals who deceive the physician with statements of pain when pain is not present.  Narcotic analgesic classes include opioids, ketamine, cannabinoid receptor agonists, and psychostimulants.  Non-analgesic narcotic classes include benzodiazepines and barbiturates.
 

MEDICATIONS – NMDA BLOCKERS
Primary afferents release glutamate into the synapse of the dorsal horn in the spinal cord.  The excitatory glutamate neurotransmitter results in removal of magnesium from the N-methyl-D-aspartate (NMDA) receptor which results in a increased calcium and sodium positively charged ion influx from entering the dorsal horn with consequent depolarization and transmission of the pain signal to the thalamus, limbic system, and cortex.  Blocking the NMDA receptor prevents glutamate from inducing the calcium positive charge influx such that the signal terminates in the spinal cord.  The NMDA receptor is felt to be involved in initial sensitization of nociceptors in the central nervous system such that otherwise innocuous stimuli now results in afferent signals of pain. This suggests that aggressive early treatment of pain with NMDA receptor blockers may prevent peripheral mechanisms of sensitization before pain becomes chronic or before chronic pain leads to full disability.  The NMDA receptor is also involved in long-term changes(70) in dorsal horn noxious signal processing to perpetuate pain even if the noxious stimulus is no longer present.
 NMDA receptor blockers may potentiate the analgesia of opioids.(   )
In patients with bone and soft tissue malignancies, dextromethorphan pre-operatively and following surgery considerably decreased analgesic requirements.(29)  This suggests that chronic opioid dosing may not need to be increased for dental and other procedures as NMDA receptor antagonists, NSAID’s, and other agents may effectively attenuate pain.  The NMDA receptor antagonist also has efficacy in chronic pain as it may help patients with fibromyalgia in combination with a weak opioid.(30)  This is particularly important in this population as opioids may contribute to fatigue, and patients with fibromyalgia should be encouraged to participate in aerobic exercise to potentially displace their condition into remission.  This is contra-distinction to patients with radiographically severe osteoarthritis, for example, as these patients should still engage in aerobic exercise for cardiovascular and conditioning benefits, but should limit lifting and other isotonic forms of exertion to limit disease progression.  
 Methadone is an opioid discussed below with NMDA receptor blocking properties.  
 Orphenadrine is a muscle relaxant discussed above to treat myofascial pain.
Dextromethorphan is an over the counter non-competitive NMDA blocker.  It may potentiate analgesia from methadone and morphine such that less opioid is required to achieve analgesia.(31)  
Ketamine is a controlled substance and it can be compounded at specific pharmacies into a topical cream.
Memantine has moderate affinity uncompetitive
 

MEDICATIONS – CANNABINOID RECEPTOR AGONISTS
Oral dronabinol (Marinol) is a safe narcotic analgesic as are opioids, ketamine, and the psychostimulant methylphenidate (Ritalin).  Dronabinol is delta(9)-tetrahydrocannabinol (THC) and it is a purified derivative of marijuana.  One of the greatest benefits of dronabinol is its synergy with the opioids to decrease pain.(121,122,125,126)  This potentiation is an extremely compelling indication to prescribe this medication.  This greater antinociception than predicted from simple additivity has been identified as increasing the analgesic potency of oral morphine by 310%-760%.(125)  Methadone analgesia was increased 400% and synergism was also identified with oxymorphone, hydromorphone, and merperidine.(121)  The synergism may reflect CB receptor interactions with mu, delta, and  kappa(121,122) opioid receptors.  In terms of the phenomenon of tolerance, use of dronabinol with opioids may have particular utility in that it may allow opioids to retain high antinociceptive effects without causing opioid receptor down-regulation with chronic use.(122)  It has also been suggested that dronabinol triggers the release of the endogenous opioid dynorphin,(121) not unlike the manner in which calcitonin may enhance release of the endogenous opioid beta-endorphin.  Dynorphins, met-enkephalins, and beta-endorphins are endogenous opioids which are felt to mediate pain relief via the epsilon opioid receptor.(  )  Dynorphin is metabolized to leu-enkephalin.(121)  Anandamide and 2-arachidonyl glycerol are thought to be the naturally occurring ligands(138) for CB-1 and CB-2 known receptors.  THC binds nonselectively to both known receptors,(139) and has also been suggested as interacting with the noradrenergic system in the spinal cord to modulate the perception of painful stimuli.(190)
 Dronabinol binds to CB receptors which act via G-protein coupling(141) to decrease intra-cellular calcium.(121)  These molecular receptors may exist at the cellular level on C-fibers which transmit pain to the dorsal horn.(141)   CB receptors are present in the brain and in the dorsal horn of the spinal cord.(122)  
THC has been described as an analgesic in the treatment of chronic non-cancer pain, including post-traumatic, post-surgical, and myofascial mechanical pain.(184)  THC has been described as having considerably greater potency in the treatment of neuropathic pain relative to the efficacy of opioids.(139)  CB1 cannabinoid pain reducing receptors have been identified in the peripheral nervous system,(130,166) and this suggests the potential efficay for dissolving dronabinol in water with topical application to ulcers, post-herpetic zoster sites, and other areas of pain to limit cognitive side effects of oral consumption.  CB1 receptors have also been identified in the central nervous system.   THC has been described as “an important novel analgesic approach for the treatment of sustained [chronic] pain states.”(141)  Other clinicians have remarked on the potency of THC, particularly to address chronic pain states.(139)
Dronabinol has additional efficacy to stimulate appetite and decrease nausea, benefits in the treatment of cancer related pain.  Just as dronabinol (Marinol) acting at CB-1 and CB-2 receptors decreases pain via a different mechanism relative to opioids acting at mu, delta, kappa, and epsiolon receptors, so too does dronabinol decrease nausea through a different mechanism from other anti-emetics. Dronabinol may also decrease pruritus,(184) increase sleep,(181) improve mood,(166) and decrease spasticity of multiple sclerosis.(145,181)
 

MARIJUANA
 The prescription use of dronabinol is distinct from dispassionate and illegal smoking marijuana.  Smoking the cannabis plant is markedly similar to smoking the tobacco plant in that each produces approximately 4000 chemicals when combusted, but the deleterious effects of marijuana is associated with bullous lung disease in young people(152) as opposed to usually presenting at a much older age with tobacco smoking.  Patients must be educated that “bullous lung disease” is not simply a term that is applied to them, but is the reality of walking ten feet and needing to stop, sit, and rest to catch one’s breath not unlike the shortness of breath secondary to myocardial infarction from tobacco or cannibis smoking.  The lung disorders related to marijuana include chronic bronchitis and emphysema, as well as lung, tongue, and other cancers.(152)  Smoking cannibis is associated with “significant risks of lung cancer,”(145) expecially the mouth, throat, and lung.(139)  
Marijuana increases heart rate and blood pressure, and it may lead to decreased vascular resistance with consequent orthostatic hypotension.(137)  Marijuana has been reported as a trigger for myocardial infarction,(137) and this has been reported to be 420% more likely within an hour of smoking cannabis.(152)  The high dose of THC seen in smoking marijuana increases anxiety and panic, and may exacerbate pre-existing mental illness, particularly schizophrenia.(139)  In this way, marijuana is similar to the benzodiazepine class of medications in that anxiety may initially be percieved as being diminished but repeated use results in seemingly paradoxical yet predictable escalation in anxiety.
Smoking marijuana delivers a rush to the brain such that euphoria results.  This is the antithesis of pain management, and prescription of an oncogenic drug such as smoking marijuana is only permissable if it were to occur in a patient with a known drastically limited life expectancy as in a patient with untreatable malignancy.  Oncogenic medications such as azathiprine (Imuran) extinguish the growth of a tumor or drastically modify the progression of a deforming disease such as rheumatoid arthritis, thus explaining the utility of such medications despite a predicted lengthy lifespan.  Clinicians should be encouraged not to condone marijuana smoking as pain can be attenuated with oral dronabinol without the oncogenesis of the inhaled poisons.  
 Patients who are found to have marijuana in their systems must be assessed for continued candidacy to receive opioids as such patients may be pursuing euphoria from both drugs.  In addition, the presence of marijuana in their systems suggests a lack of respect for the law as marijuana can only be acquired through illegal means.  Such a lack of respect may translate into a lack of concern regarding incarceration consequences for selling prescribed opioid medications.
 

MEDICATIONS – PSYCHOSTIMULANTS
Methylphenidate (Ritalin) is a safe narcotic analgesic as are opioids, ketamine, and Marinol.  Methylphenidate has analgesic properties(102,109) as well as efficacy to ameliorate mood depression and is discussed above as a medication to address comorbid chronic fatigue.  The analgesic properties of methylphenidate are not surprising given this agent’s noradrenergic potency and the demonstrated potency of other noradrenergic antidepressants to decrease chronic back pain in well designed, randomized, double-blind, placebo-controlled testing.(147)  Low doses of methylphenidate potentiate the effect of morphine analgesia.(250)
Methylphenidate has potent dopaminergic and noradrenergic properties.  It stimulates dopaminergic neurons in the ventral tegmental area to activate the cerebral cortex to address fatigue.  It decreases fatigue related to opioids.(109,120)  However, sympathomimetic effects with respect to increases in blood pressure may preclude prescription to patients with brittle congestive heart failure, and patients with coronary artery disease may not tolerate the tachycardic effects of this medication, particularly if they are also prescribed medications with anti-cholinergic properties which interfere with vagus nerve mediated rate slowing effects. This agent has a half life of 3-6 hours so use in the early morning does not compromise sleep hygiene.  Methylphenidate has pro-arrhythmic properties and may convert  atrial fibrillation in the presence of third degree AV node block into malignant ventricular tachycardia. 
Though methylphenidate has analgesic properties,(102,109) it should not be given to patients with reflex sympathetic dystrophy as this condition is sympathetically maintained and the sympathomimetic methylphenidate may increase pain.
Methylphenidate, though often well tolerated even in the elderly, stimulates projections to the nucleus accumbens reward center such that it has potential to induce euphoria as well as criminal diversion as a medication with street value.  Ritalin may decrease pain as well as mood depression. Clinicians should prescribe this medication with caution as it has a high street value and induces euphoria in normal patients who lack pain.(90)  It has the most marked efficacy in the treatment of profound chemotherapy related fatigue in the treatment of pain in oncology patients.
 Dextroamphetamine (Dexedrine) has a half-life of 34 hours and so its use is far more likely to exacerbate insomnia. Low doses of dextroamphetamine potentiate the effect of morphine analgesia.(250)
 

MEDICATIONS – OPIOIDS
 Opioids often constitute a safe and effective foundation in the management of many forms of non-cancer related chronic pain.(          ,96)  As with injected local anesthetics, opioids are extra-ordinarily and predictably effective to decrease pain.  Patients with chronic neuropathic pain often respond better to nonopioid analgesics, although methadone has considerable utility in the management of chronic pain.(   )  Patients with chronic pain respond well to opioids, and the dose is often stable for months to years.  Nonmalignant pain is still pain and suffering is not necessary.
The safety of opioids is impressive.  Opioids are bereft of the risks for potentially fatal GI bleeding, acute renal failure, and chronic renal failure associated with NSAID’s.  Appropriately prescribed opioids are without the potentially lethal cardiotoxicity of mexilitene, lethal bone marrow suppression of carbamazepine, and proconvulsant properties of tricyclic antidepressants and serotonergic antidepressants.  Opioids, unlike the narcotic controlled substance class of the benzodiazepine and barbiturate families, do not have risks for mood depression, rebound anxiety, rebound insomnia, or cognitive compromising features indistinguishable from dementia with chronic use.(    )
 It is felt that the mechanism of analgesic action of opioids is by blocking neuron excitability by depression of sodium conductance and increase membrane potassium conductance(23) or by blocking the opening of voltage-sensitive calcium channels with a conseuqent decreased pre-synaptic release of excitatory neurotransmitters and decreased afferent transmission of nociceptive impulses.(23, 26)  
 Opioids are potent agents and patients should be educated to avoid masking pain excessively, as post-laminectomy hardware may destabilize.  Excessively heavy lifting will increase physical forces and demands on the spine, facilitating a more rapid progression of degenerative disc disease and osteoarthritis.  Conversely, opioids may sufficiently mask pain to allow patients to remain functional and active with return to full time productive work at a safe activity level.  Patients who do not work are not placing nearly the same physical demands on their bodies and often are not optimal candidates to receive opioids.
 

MEDICATIONS – OPIOIDS – CURING PAIN
Opioids are not often thought of in the same manner as nonsteroidal anti-inflammatories in terms of curing pain.  However, in the management of acute and chronic pain, preventing or diminishing sensitization of the peripheral nociceptor or wide dynamic range dorsal horn neuron in the spinal cord may effect cure of pain or prevent acute pain from becoming chronic.  This proven construct must be embraced to diminish long term unnecessary suffering by a more aggressive approach to pain with earlier prescription of opioids to the honestly suffering patient.  When a hyperexcited nervous system is returned to normal, pain remits.
If acute pain can be extinguished before it pathologically modifies the peripheral and central nervous systems through sensitization, then the prevalence of chronic pain can be diminished through the early use of opioids in the responsible patient.  Opioids are without profound effect to attenuate the inflammatory process and so, unless contra-indicated, NSAID’s must be utilized first.  Given the ceiling analgesia of NSAID’s as well as the importance of avoiding bedrest and other forms of inactivity precipitated by pain, the potent analgesic class of opioids can be used in patients who are not already taking this class of medication.
 

MEDICATIONS – OPIOIDS – SUPRA-ADDITIVITY
As discussed above, a number of anti-nociceptive medications, when co-prescribed, result in much greater analgesia than that which is expected from simple addition of individual pain relieving properties. 
Clonidine, when co-prescribed with morphine, may yield greater than additive potentiated pain relief of each individual analgesic.(40)  The L-subtype channel antagonist nifedipine potentiates morphine induced analgesia.(63) Morphine, when combined with L-methadone, delivers analgesic synergy with greater anti-nociception relative to the sum of additive analgesia from the two analgesics.(12)  One of the greatest benefits of dronabinol (Marinol) is its synergy with the opioids to decrease pain.(121,122,125,126)  Local anesthetics potentiate opioid related analgesia,(67) and this explains the vast synergistic improvement in pain and function with a combination of opioid and local anesthetic injections.  Antihistamines may markedly potentiate opioids, including pentazocine, morphine, fentanyl, and nalbuphine.(149,179,180)
 

MEDICATIONS – OPIOIDS – OPIOID RECEPTOR SUBTYPES
 Opioid receptors are present in the peripheral nervous system.(   )  Opioid receptors are present in the brain as well as in the dorsal horn of the spinal cord.(122)  Over fifteen mu opioid receptor subtypes have been identified.(12)  It is felt that the mu, delta, and kappa opioid receptors mediate analgesia, though less potently with the latter two subtypes.  Patients have different genetically pre-determined numbers of mu opioid receptors such that one opioid may confer analgesia in one patient and not in another just as a single individual may suffer profound side effects with one opioid and another individual may exerpience no ill repercussions of ingesting the identical medication. This explains why methadone may decrease pain with no analgesic response to morphine(42) or other opioids.  Kappa receptors exhibit a preference for benzomorphans(203) such as pentazocine.(23)  Dextropropoxyphene has a low affinity for the mu and delta receptor sites and does not bind to kappa receptors.(203)  
With lower numbers indicating greater binding and potency, affinity for analgesia mediated via the mu receptor has been identified in one study as; buprenorphine=1, butorphanol =2, morphine=6, pentazocine=7, nalbuphine=10, L-methadone =10, met-enkephalin=39, dextropropoxyphene=492, codeine=600.  Again with lower numbers indicating greater affinity, analgesia mediated by the delta receptor binding is; butorphanol=5, met-enkephalin=6, buprenorphine=10, pentazocine=50, nalbuphine=59, L-methadone=63, morphine=74, dextropropoxyphene=367, codeine=5600.  Lastly, with lower numbers consistent with greater binding, dysphoria mediated by the kappa receptor binding is; butorphanol=2, buprenorphine=17, nalbuphine=28, pentazocine=75, morphine=167, and L-methadone = met-enkephalin = dextropropoxyphene = codeine >1000.(203)  
These receptor affinity designations are of value, but the clinician must also keep in mind that binding affinities do not encompass the entire picture in the complexity of the in vivo milieu.  In addition, some metabolites have considerable analgesic mu receptor agonist potency such as the morphine metabolite of morphine-6-glucuronide and the codeine metabolite of morphine.  Also, some medications confer additive analgesia via non-opioid receptors as suggested with codeine(  ) as well as with methadone’s NMDA blocking properties, and propoxyphene’s well described potent local anesthetic properties.(202,203)  Finally, because pain is a multi-dimensional phenomenon, the dysphoric effects of the morphine metabolite morphine-3-glucuronide or the kappa mediated dysphoria of butorphanol (Stadol), and excitatory effects of other bioactive metabolites from other opioids may counter the appreciation of analgesic potency by some patients.
The varied genetically defined mu receptors as well as the structural distinctiveness of the opioid molecules suggests that just as failure to respond to one SSRI or one NSAID mandates treatment with another drug of the same class in light of interindividual uniqueness at the biochemical receptor level, failure to tolerate or appreciate efficacy from one opioid does not preclude efficacy or tolerance of another. 
 

MEDICATIONS – OPIOIDS – OPIOID TYPES
 Opioids are classified in several different ways, including agonist vs. agonist-antagonist, short or long duration of action, structural class, natural or semisynthetic or synthetic origin, and stereoisomers.
Opioids are most commonly categorized in terms of pure agonist and agonist-antagonist.  Pure agonist opioids are bereft of the ceiling analgesic effect of NSAID’s and most other analgesics.  That is to say, as the dose is progressively escalated, opioids deliver progressively greater analgesia whereas as the dose of NSAID’s are progressively increased a point will be reached after which further analgesia will not be appreciated.  However, as with NSAID’s and other analgesics, as the dose of opioids are progressively increased, the risks increase for cumulative side effects increases including, constipation, nausea, urinary retention, xerostomia, orthostatic hypotension, and cognitive compromise as discussed below.  Most of these side effects can be treated such that the patient can realize the pain relief afforded by these safe medications for patients who are truly suffering in pain.
 Opioids with antagonist properties have a ceiling effect such that the dose cannot be escalated ad infinitum without precipitating withdrawal symptoms of profound nausea.  Antagonists have utility in the management of patients who may be at risk for discarding the physician’s prescribed frequency of ingestion.  As such, these may be good for a patient who is not a current addict, but rather for a patient in pain who had difficulties with self-control in the past.(   )  However, opioids with antagonist properties still have potential for abuse.(   )
 Opioids combined with pure antagonist drugs only include buprenorphine-naloxone (Suboxone).  Postmarketing surveillance will define if this meets the expectation as the way of the future in terms of safest delivery of opioids such that if the medication is physically altered for abuse it loses its euphoric potential.
Opioids may also be classified in terms of short or long duration of action.  Long lasting opioids provide a constant level of analgesia such that craving is minimized and patients can focus on work and life as opposed to their next dose of pain relieving medications.  Additionally, patients are at higher risk for addiction with short lasting opioids with abrupt peaks of highest blood levels and rapid decline.  As such, use should usually be limited to zero to two tabs a day.  
Opioids have structural distinctiveness.  Morphine has five alkaloid rings, morphinans such as levorphanol and butorphanol have four rings, benzomorphans such as pentazocine have three rings, and phenylpiperidines such as meperidine, fentanyl, sufentanil, and alfentanil have two rings.(23)  
Additional appreciation of the molecular uniqueness of each opioid is that the naturally occuring opioids include morphine, codeine, and the thebaines including oxycodone and oxymorphone.  Semisynthetic opioids include dihydromorphone/ morphinone and thebaine derivatives such as buprenorphine.  Synthetic opioids include those of the morphinans, benzomorphinans, phenylpiperidine, and methadone of the diphenylpropylamine series.(23)  
Just as stereoisomers define efficacy and side effects of antidepressants with escitalopram (Lexapro) being the active isomer of racemic citalopram (Celexa), the dextrorotatory stereoisomer of propoxyphene is felt to mediate analgesia relative to the laevo isomer which has been reported as being bereft of analgesic activity.(203)  Similarly, D-methadone has poor affinity for opioid receptors but does interact with NMDA receptors, whereas L-methadone has high affinity for opioid receptors.(12)  Purification of stereoisomers may confer greater efficacy and decreased side effects.
 

REALITY, OPIOID RECEPTORS, AND OPIOID TYPE
Even in basic science studies, methadone may effect analgesia with no analgesia with morphine.(42)  The reality of individual response to pain relief with minimization of side effects can be best appreciated by a clinical example.  
Nashua Pain Management treated a young male who suffered a work induced disc herniation.  He was treated with one to two dozen opioid and nonopioid analgesics.  His pain was finally controlled with a combination of OxyContin, Zanaflex, trigger point injections, and local anesthetic nerve blockade injections.  He was able to resume work at a lower intensity.  His worker’s compensation provider arbitrarily terminated his medical benefits despite the Labor Board’s decision and New Hampshire state law.  He continues to be seen for close to a year for injections only.  He refused coupons for complimentary fentanyl patch, Kadian, and Avinza despite the high street value of fentanyl patch.  He could afford methadone and was offered prescriptions for this opioid, but he refused as it did not help him.  He refused OxyContin prescriptions as he could not afford this safe and effective medication.  He could no longer work given his pain and required welfare assistance.
 The case demonstrates the true nature of optimal response given individual biophysiology with respect to opioid receptor subtypes and structural uniqueness of different opioid molecules.  If this patient were a drug addict or criminal selling opioids then he would have accepted other opioids or miraculously “found the money” to afford OxyContin over the past year.  He certainly would not solicit monthly injections, again indicating that his individual physiology best matched OxyContin.
 

MEDICATIONS – OPIOIDS - PSEUDOADDICTION
Pseudoaddiction is the condition in which the patient behaves as an addict.  The patient behaves inappropriately not because his goal is the euphoria that the addict seeks, but rather with the goal of a higher dose of analgesics to appropriately address his pain.  That is to say, when the clinician does not adequately address the patient’s pain, the patient may, for example, consume the opioids earlier than prescribed and call the physician’s office requesting more analgesics to address the undertreated pain.  Similarly, individuals who are hungry and given a two pound bag of M&M’s are unlikely to take just a single candy as the hunger remains after they have consumed a single M&M candy and they immediately crave another.  The clinician may elect to utilize longer lasting, more potent opioids to treat pain in pseudo-addicted patients, but the clinician is not mandated by any means to address the pain with opioid analgesics.
 

MEDICATIONS – OPIOIDS – DEPENDENCE – PATIENT CONCERNS
Dependence on opioids simply means that the opioids need to be tapered slowly to avoid nausea and other uncomfortable side effects.  Dependence is a physical phenomenon akin to the need to slowly taper antihypertensive beta blockers to avoid untoward effects.  As expected, however, pain will usually return with termination of opioid related analgesia just as pain returns with termination of use of NSAID’s or blood pressure rises with termination of anti-hypertensive medications.
 

MEDICATIONS – OPIOIDS - ADDICTION
 Addiction is the pre-occupation and behavioral pursuit of a drug for illegal use to achieve euphoria above all other concerns such that patients make unwise decisions with disregard for the law as well as personal and professional relationships and responsibilities.  Addicts are pre-occupied with pursuit of euphoria, not treatment of pain.  As such, they may constantly request escalating doses of controlled substances, sell medications for money to buy cocaine and heroine, forge prescriptions, ignore their families, and sell themselves as prostititutes with eventual hepatitis and HIV infection to get money for drugs.  Addicts rob banks and murder people for money to buy drugs.  By prescribing medications to drug addicts, clinicians are simply fostering the patient’s illegal habit, but they are facilitating the destruction of the individual and many related and unrelated individuals with whom the addict encounters.  Clinicians who elect to prescribe opioids must appreciate that addiction is not a victimless crime.  Addicts should be referred to detoxification centers and should not be prescribed any narcotics.
 

MEDICATIONS – OPIOIDS – ADDICTION – PATIENT CONCERNS
Patients commonly fear becoming addicted to opioids.  This stems from a lack of education, as patients who consume opioids to address pain are enormously less likely to become addicted relative to patients who seek these narcotics to achieve euphoric states or out of foolish curiosity.(   )  Addiction is very rare when patients who truly have pain are prescribed opioids as the medication is “consumed” by the pain with none left to result in euphoria.  However, it is possible for even the patient in pain to become addicted to opioids if the clinician inappropriately prescribes too many short lasting opioids as discussed below.  Patients consuming long acting opioids are at very low risk to become addicts.(68)  One report of nearly 12,000 patients treated with narcotics in a hospital identified only four cases of addiction amongst patients who had no prior history of addiction with only one patient having a significant problem, and all four patients had been described as receiving only short lasting opioids, including meperidine (Demerol), oxycodone (Percocet), and hydromorphone (Dilaudid).(201)  
Patients with prior personal or family histories of alcohol and other substance abuse should be cautioned that their fears of addiction are reasonable,(   ) and such individuals should be particularly redirected from short to long lasting agents, though use of short lasting agents is not absolutely contra-indicated as long as the patient is honest with the clinician.  Such patients may need to be monitored more closely by the clinician if opioids are selected to address their pain.  
Just as patients indefinitely ingest antihypertensives to continuously control elevated blood pressure, so too do patients ingest opioids to safely control chronic pain.  The chronic use of a medication does not constitute addiction.  As discussed below, drug addicts constantly request higher and higher doses of opioids and fail in work and social relations.  They refuse injections which may potentially cure their pain.
 

MEDICATIONS – OPIOIDS – ADDICTION – PHYSICIAN CONCERNS
Clinicians commonly fear conversion of a responsible, working patient into an addict.  The fear is vastly unwarranted as long as nonopioid analgesics are used, substance abuse histories are solicited and integrated into the management plan, and short lasting opioids are used sparingly with greater reliance on long lasting opioids.  The relationship between alcoholism and other substance abuse predisposing to opioid abuse should not be minimized as the incidence of alcoholism in the U.S.A. is 10%-18%(   ) Patients with disregard for the law in terms of prior heroine or cocaine use must be viewed with even closer scrutiny.
The greater fear that the clinician should embrace is that of being deceived by the criminal opioid diverting patient as discussed below.  Numerous governmental agencies monitor for inappropriate prescribing, including the Drug Enforcement Agency, Federal Bureau of Investigation, State Police, Board of Medicine, and Board of Pharmacy.  Ethics, not fear of sanctions from the Drug Enforcement Administration and the state medical boards should prompt responsible prescribing to patients in pain and not to addicts or criminals.
When a patient is identified as being a drug addict, he must be referred for drug counseling.  Though clinicians must provide thirty days of treatment to a patient on discharge, no clinician is under any obligation to prescribe any particular medication.  Opioids should not be prescribed for thirty days to such patients as the addict will consume them without responsibility, not unlikley without consideration of driving restrictions if the entirety of the prescription is consumed at once.  Similarly, the criminal will have one additional thirty day supply of opioids to destroy the lives of opioid naïve individuals who lack pain and will experience euphoria from the medication.  
If the patient is an addict who also has a defined nociceptive generator such as post-surgical fibrosis, nonopioid analgesics only may be prescribed with the caveat that pentazocine (Talwin) may be considered.  This opioid decreases pain but it cannot be added indiscriminately to other illegally acquired opioids as the antagonist properties of this medication may precipitate withdrawal.  Pentazocine still has abuse potential, and even this opioid should not be prescribed indiscriminately.  The combination of the pure antagonist naloxone in the delivery mechanism of Buprenorphine-Naloxone (Suboxone) should herald a new era as a standard of opioid delivery to profoundly limit abuse potential.  The clinician is appropriately advised to beware of the patient who only wishes to utilize opioids to manage their pain as epidural injections, regional nerve blocks,(214) and trigger point injections may markedly decrease opioid requirements.  Serial injections may even terminate the cycle of pain.  The physician should insist that patients bring bottles of nonopioid analgesics to prove that the patient is at least trying nonnarcotics to attenuate pain.  If the goal is truly pain relief then nonopioids will be ingested as readily as opioids.
If opioids are to be terminated at a high dose then the dose should be decreased 25% every two to three days.(   )  The PDR discusses the abrupt termination of OxyContin even at relatively high doses.  Clonidine 0.1-0.2 mg TID can decrease withdrawal symptoms, and clinicians should not be distressed by the hypotensive properties of this agent as withdrawal will result in pain and anxiety with sympathetic outflow to result in increased blood pressure.  Anti-emetics and NSAID’s are also often helpful to address withdrawal nausea and myalgias, respectively.  Pepto-bismol may address nausea as well as diarrhea related to withdrawal.
 

OPIOID DIVERSION - CRIMINALS
 A discussion on the prescribing of opioids would be grossly incomplete without discussion regarding criminal opioid diversion.  Diversion is not simply an FBI, police, DEA, Board of Medicine, and Board of Pharmacy issue.  These protection agencies do not have the authority to write prescriptions.  Physicians write prescriptions and are ethically mandated to strive to discriminate presenting patients for true pursuit of pain management vs. drug addiction vs. criminals.  The addict is also often a criminal as they trade and purchase narcotics, supporting the illegal industry.  Physicians must be caring and empathetic to help patients suffering in pain.  The patient must always be given the benefit of the doubt based on the physician’s training and experience, but the physician must always strive to do no harm.  Physicians must always be alert for evidence of diversion.  The first rule of medicine is try to do no harm.  That includes doing harm by indiscriminately and silently prescribing opioids to every person who walks in the office door.  Silence is compliance.
Just as the tobacco companies constantly seek new naïve and foolish youngsters to smoke to replace the thousands who die every year from smoking cigarrettes, so too does the criminal opioid diverter seek to entice new naïve and foolish youngsters to try illegally sold opioid medications.  Once a patient who lacks pain trials an opioid, he may enjoy the euphoria that he would not experience if he had pain.  Once euphoria is tasted, it not uncommonly begins the downward spiral towards more potent drugs, culminating in cocaine, heroine, and death instead of growing up to be parents and teachers.
Patients with prior histories of criminal incarceration may report “prison is not so bad,” conveying a similar disrespect for society and law, suggesting a potential dismissal of ethical and legal issues related to redirection of opioid prescriptions.
Criminals are selfish.  They choose to help themselves and carelessly violate the rights of innocents.  Criminals belong in prison so they cannot hurt innocents.  The selfishness of the criminal who deceives the physician to solicit opioids for street sale can be demonstrated by illustration.  A patient that Nashua Pain Management discharged for selling his opioids declared his selfishness not simply by his criminal act, but by his behavior on September 11th, 2001.  Two hours into the murders when Al-Qaida was terrorizing the United States by bombing the 110 story high World Trade Center and hundreds of Americans were burning alive and jumping to their deaths because of Jihad murders, one patient stated “Yeah, it’s pretty bad, but my foot is really hurting me.”  The horror of terrorism on U.S. soil was obscured by his selfishness, just as he did not care about the children to whom he allegedly sold his opioids.
 

OPIOIDS – INSIGHTS INTO WORKER’S COMPENSATION
Physicians who elect to prescribe opioids must be vigilant even when giving patients the benefit of the doubt.  It is well recognized in the medical literature that some patients whose disc herniations are managed with surgical decompression will suffer fibrosis and accelerated osteoarthritis with consequent pain greater than that which was present pre-operatively.  However, many patients are managed surgically without any pain.  Worker’s compensation laws reflect inappropriate AMA disability criterion which declare that patients whose disc herniations are managed with surgery achieve greater financial settlements than those patients who are managed conservatively.  This contrasts with published literature indicating that the conservatively managed herniated disc often recedes spontaneously.(   )  This establishes support to explain that many surgeries are pursued by patients strictly for financial gain, not pain relief.  Such patients often suffer pain from fibrosis and osteoarthritis following surgery, but may solicit opioids out of proportion to their pain.  The additional opioids are often sold for further financial gain.  Until the AMA, Labor Board, and worker’s compensation recognize the deception and grant settlements independent of surgical management, the pain management physician will see greater numbers of inappropriately surgically managed patients.  Clinicians who elect to prescribe opioids must be able to recognize this diversion related behavior and set limits, indicating “I don’t feel comfortable prescribing higher doses.  Maybe we should revisit physical therapy, psychology pain coping strategies, or implantation of an intrathecal morphine/Ziconotide pump.”
 The goal of the worker’s compensation provider as a business is simply to save money.  For this reason such companies are able to arbitrarily terminate medical services to patients despite legal declarations mandating care for work related injuries by the Labor Board.  At this time, no repercussions are levied against the worker’s compensation companies, but patients often suffer profusely.  The sudden termination of pain control results in the peripheral nociceptor becoming more sensitized as does the dorsal horn with entrenchment of chronic pain, imposing long term changes from short sighted illegal profit driven motives.  The sudden pain escalation increases anxiety with consequent increased sympathetic outflow, increased adrenal medulla circulating catecholamines, and further increase in nociceptor sensitization.
 A more appropriate strategy of worker’s compensation should be facilitated by the physician until laws are passed to allow for worker’s compensation companies to legally rescind medical benefits of criminals who never should have won their initial cases.  Random drug testing is now only at the discretion of the physician.  Such testing as well as random pill counting will identify some criminals who make it harder for truly injured worker’s compensation patients to receive proper medical care. 
 

OPIOIDS – PRACTICE POLICIES TO LIMIT DIVERSION
 Prescription pads should not be stored in the physician’s office at night or on weekends.  The physician should keep a record of the numbers on the pad as well as patient records at a site accessible to law enforcement.  The clinician should introduce himself to local law enforcement to work in a collaborative manner should law enforcement prove willing.  Opioids and other narcotics should never be stored in a physician’s office.  Emergency rooms and pharmacies alone should dispense narcotics.  In the absence of any enticing features, the clinician’s office will not be considered a source for diversion.
Patients who refuse to allow their prior physician and pharmacy records to be reviewed as directly FAX’ed/mailed from the physician’s office should not receive opioids as not uncommonly a distinct reason existed for dismissal from a prior practice.  The patient cannot be fully held responsible for pseudo-addictive behavior caused by another physician’s lack of training and expertice in pain management, and review of the previously treating clinician’s notes may reveal true addiction versus pseudaddiction.  Patients with past mistakes in terms of prior substance abuse histories or prior criminal non-narcotic related incarceration must not be condemned to suffer should they have pain.  However, they should be monitored more closely than other patients.  They also may or may not be considered candidates for opioid management just as the alcoholic may not be considered by all clinicians to be sufficiently responsible to receive opioids.
 Clinicians are urged to not prescribe “brand name only” medications.  Brand name medications have a particular size and shape that allows rapid recognition amongst criminals and addicts, thereby commanding a far greater diversion criminal street price.  There is no indication to prescribe “brand name only” medications as the generic drug has the same active ingredient and opioids do not have the same narrow therapeutic window of efficacy and toxicity as coumadin, theophylline, lithium, levothyroxine (Synthroid), anticonvulsants, antipsychotics, and other medications which truly mandate “brand name only.”
 Offices are encouraged to not call opioid prescriptions to pharmacies as enormous potential for fraudulent prescriptions to be phoned in can occur.  If physicians make themselves uniformly available to speak to pharmacists, and if a fraudulent phone prescription is called in, then state police should be alerted to wait in plain clothes such that the criminal is apprehended immediately when they come to pick up the prescription. 
 

OPIOID – PRACTICE POLICIES TO LIMIT DIVERSION – OPIOID CONTRACT
All patients should sign a written opioid contract in which they agree to suffer withdrawal should they consume, lose, destroy down the toilet, or have their medications stolen such that they call for refills prior to their next scheduled visit.  The patient must understand that the situation is analogous to losing one’s wallet in that once a prescription is written and lost, it is not replaceable.  Frequently writing opioids to patients whose prior prescription should last for an additional period of time declares to DEA, FBI, State Police, Board of Medicine, and Board of Pharmacy that a clinician is sloppy and may require termination of priveleges while he attends educational classes to safely prescribe narcotics with responsibility and accountability.
A physician is never compelled to prescribe opioids, including to patients that are currently receiving opioids.  The contract must stipulate that the opioids can be terminated by the clinician without cause in accord with the training and experience of the prescribing physician.  Such a contract obviates the need to give the patient an extra thirty days of opioid medication on discharge from a practice.  As such, these thirty days of medication will not further contribute to the criminal economy.  This does not permit the patient to be abandoned, and at least thirty days of nonopioids must be offered to the patient.  The clinician with such a contract need not fear ever being successfully sued as the contract is binding.  Threats of litigation do not hold up in court when such a contract is signed, even if the clinician lacks definitive proof of diversion.  A beligerant, abusive patient should not be awarded opioids for his creative, indignant, well-acted behavior.
Patients frequently assert that the pharmacist miscounts their prescription and they are “short” a certain number of pills.  This may be so as pharmacists are often forced to work excessively hard to meet administrative demands.  However, the physician is not responsible to reconcile the problem as doing so by writing additional prescriptions flags the physician as being sloppy.  The patient must assume responsibility by counting his pills in front of the pharmacy technician such that correction can be effected before it becomes his word against that of the pharmacist’s.  The opioid contract should stipulate this.
The contract must stipulate the physician’s right to terminate opioids should the patient refuse drug testing at the clinician’s discretion.  The patient must be accessible to be called at home to present emergently for testing and the patient must be agree to come to the office for pill counting at any time to confirm that the medications are being consumed as prescribed.  Testing and counting must mandate that the patient has 30-60 minutes to present to the lab or to the physician such that criminal behavior is not masked by re-purchasing previously sold narcotics for consumption or counting.
Mentally sound patients who truly have pain and have no alterior criminal agenda will never have a problem signing such a contract.  The use of the term “contract” must be embraced because it reassures the patient that they will be held accountable for their actions.  By treating the criminal appropriately, the clinician helps assure that the patient who is truly suffering in pain will receive treatment with safe and effective opioids.
 

MEDICATIONS – SHORT LASTING OPIOIDS – BENEFICIAL USES
Short lasting opioids afford several hours of relief for a patient.  By giving the patient access to one to two short lasting opioids they appreciate a sense of self control over their pain and lives as opposed to feeling dominated by their pain.  This autonomy decreases anxiety which decreases pain.  The concept of fine tuning defined by the patient is analogous to the diabetic patient who utilizes regular insulin to fine tune his blood sugars and compliment the effects of his long lasting insulin formulation.
Patients who consume a short lasting opioid early in the course of unanticipated breakthrough pain can extinguish the ramping up phenomenon before the pain escalates out of control.  This is similar to the pre-emptive analgesia manner in which a migraine is abolished readily with sumatriptan (Imitrex) or rizatriptan (Maxalt) early in the headache course but may require inpatient hospitalization and sedation if untreated until the migraine is fulminant.  Similarly, it has been known for decades that decreasing a diabetic’s neuropathic or vasculopathic pain prior to amputation will markedly decrease the risks for that patient to develop phantom pain.(  )  One final analogy is that of the ease by which a campfire is extinguished relative to the enormous challenge of terminating a forest fire.  
The clinician must always remember that he is never obligated to prescribe opioids as NSAID’s, acetaminophen (Tylenol), topical medications, and muscle relaxants also extinguish breakthrough pain.  Sedating medications may also be utilized as therapeutic rest and relative disuse for a brief time will facilitate healing of acutely injured tissues.
Short lasting opioids are of value prior to anticipated exertion.  For example, this may allow a patient to work in his garden to enjoy an activity which individuals without pain do not have to weigh as “worth the risk” of a pain flair.  Short lasting opioids may also be of value following a long day of manual labor or pain intensifying positioning after which osteoarthritic nociceptive generators may activate.  Use of a short lasting agent is preferred for several hours prior to bedtime as opposed to long lasting opioids which may impair sleep hygiene.(   )
If a patient has only occasional mild pain which is controlled with zero to two short lasting opioids a day, then such patients may be managed successfully without long lasting opioid medications.  
 

MEDICATIONS – SHORT LASTING OPIOIDS – DETRIMENTAL CONSIDERATIONS
 Withdrawal symptoms are a reflection of physical dependence, and dependence and tolerance, when they occur, are felt to be physiologic events unrelated to the fault of the patient.  Sudden discontinuation of shorter acting opioids are more likely to produce withdrawal symptoms than longer acting agents.(51)  Short lasting opioids deliver a rapid serum peak opioid level and then a rapid decline such that patients are at greater risks for addiction with short lasting agents relative to long lasting opioids.(36)  This strongly suggests that clinicians should limit the frequency of short lasting opioids with much greater reliance on longer lasting opioids. Waiting for the next dose of short lasting opioid compels the patient to focus on when he will get his next dose as the pain remains in between doses.  The greater risks for withdrawal with short lasting agents may result in pseudo-addiction or true addiction as the brain craves the rapid peak of short acting opioids from a baseline serum level bereft of long lasting opioids.  
Addiction to cigarettes may be considered a model as patients who smoke get a rush of nicotine within six to seven seconds(  ) and efforts to help patients stop smoking are often felt to be limited by the inability to manufacture medications which can deliver such a rapid rush to the brain.  This is also felt to explain why individuals who inject heroine or insufflate cocaine are so hard to detoxify.  
 Most patients should be restricted to access of up to two short lasting opioids a day.  Long lasting agents maintain a constant high level of opioid in the system such that patients do not crave their next dose of pain relief. Opioid receptor up or down regulation does not occur with regularly scheduled dosing,(36) suggesting a physiologic indication in addition to psychologic reasons to limit reliance on short lasting opioids in chronic pain relative to long lasting opioids.
 

MEDICATIONS – OPIOIDS – SPECIFIC SHORT LASTING PURE AGONISTS
 Oxycodone (Percocet, Tylox, Roxicodone) is available as 5 mg, 7.5 mg, 10 mg, 15 mg, and 30 mg size doses.
 Hydrocodone (Vicodin, LorTab,…) is available as 5 mg, 7.5 mg, and 10 mg size doses.  As such, patients who may require greater than 10 mg size dosing are at a disadvantage until a manufacturer elects to meet the demand and produce a size comparable to options available to address pain with oxycodone 15 mg and 30 mg tabs and 15 mg of oxycodone is equi-analgesic with 15 mg of hydrocodone.(150)  However, given that hydrocodone is metabolized to hydromorphone and hydromorphone is considerably more potent than hydrocodone, clinicians can effectively address the problem by prescribing 4 mg or 8 mg tabs of hydromorphone as equivalent respective doses of hydrocodone are 16 mg and 32 mg of oxycodone.(150)
 Hydromorphone (Dilaudid) is the degredative metabolite of hydrocodone.(   )  Greater than additive analgesic synergism has been identified with dronabinol (Marinol) co-prescribed with hydromorphone.(121)
 Morphine (MSIR) is metabolized into morphine-6-glucuronide, an agent that may accumulate in renal and hepatic dysfunction(  ) and result in toxicity.  This is particularly important given the prevalence of occult hepatitis C infection and impaired hepatic function in the U.S., and the clinician should not hesitate to test patients who volunteer histories of IV drug abuse, cocaine insufflation, dialysis, indiscriminate sexual practices, and other risk factors.  Given the risks for acumulation in hepatorenal compromise, patients with malignancies involving these organs requiring high doses of analgesia with morphine may be at greater risk.  
 Codeine (Tylenol #2, #3, #4) is not a potent opioid.  It may decrease pain via mechanisms different from opioid receptor related antinociception.(   )  Ten percent of codeine is demethylated to form morphine, but codeine may also have intrinsic antinociceptive properties as codeine does not differentiate between kappa and delta opioid receptors whereas morphine has a much higher affinity for the delta than the kappa receptor.(121)
 

MEDICATIONS – SHORT LASTING OPIOIDS – TRAMODOL
 Tramodol (Ultram) weakly binds to the mu opioid receptor.  It also inhibits the reuptake of serotonin and norepinephrine in the dorsal horn(34) to increase the duration of activity of these neurotransmitters at the synapse.  Tramodol has pro-convulsant properties at 400 mg a day.  However, it must be appreciated that patients consuming other pro-convulsant medications such as the seratonin and dopaminergic antidepressants as well as the dopamine blocking antipsychotics may have a further reduced seizure threshhold.  Given the short duration of action of this agent, patients should utilize it only twice a day.  Tramodol, like meperidine, has potency to decrease the extremly uncomfortable condition of shivering(  ) associated with infection as well as post-operative recovery.  Tramodol’s analgesic potency is decreased with concomitant prescription of 5-HT3 analgesics.(  )
 

MEDICATIONS – SHORT LASTING OPIOIDS – MEPERIDINE
 Meperidine (Demerol) has very weak potency via the oral route.(  )  However, given the limited number of opioid options and patient interindividual uniqueness and responsiveness, meperidine may be given to a select small number of patients.  Meperidine has been described as having greater cognitive side effects relative to oxycodone and hydrocodone.(205)  Its metabolite normeperidine has a normal half life of 15-20 hours, and may accumulate in occult or gross chronic renal failure to precipitate seizures as well as dysphoria.(23)  Meperidine increases central serotonin activity by blocking reuptake of this neurotransmitter.(23)  Meperidine has unfortunately become a victim in the rush towards hospital standards of care for pain management in that it has not been appreciated that this opioid has enormous utility as unique amongst the opioids in its ability to attenuate the profound discomfort and oxygen consumption of shivering.(23)  Greater than additive analgesic synergism has been identified with dronabinol (Marinol) co-prescribed with meperidine.(121) with oxymorphone, hydromorphone.(121)  Meperidine is the only opioid which has vagolytic properties and may result in tachycardia, a concern in patients with severe coronary artery disease.(23)  
As with propoxyphene, though meperidine affords less analgesia than oxycodone or hydrocodone to the average patient, the structural distinctiveness of meperidine relative to other opioids and the unique physiology of some patients enables them to appreciate far greater analgesia with meperidine.  As such, meperidine should remain on the market and stocked in formularies but be utilized as a tertiary option for those patients who have failed to respond to other short lasting opioids.
 

MEDICATIONS – SHORT LASTING OPIOIDS – PROPOXYPHENE
 Propoxyphene (Darvocet, Wygesic) is a very weak opioid.(203) Propoxyphene has local anesthetic properties and is a potent sodium channel blocker and it takes over 850% longer for sodium current recovery with propoxyphene relative to lidocaine,(202) suggesting a long duration of anesthetic analgesic effect.  Given this fact as well as identification of peripheral opioid receptors(46) and efficacy of topical opioids(66,67) as well as topical local anesthetics(37) to decrease pain, propoxyphene should be considered an early option in the management of peripheral pain states such as reflex symptathetic dystrophy, post-herpetic neuralgia, herpes zoster, and ulcers.  Because fast kinetic blockade by lidocaine may compete with propoxyphene slow kinetic blockade, less sodium channel blockade has been observed during exposure to the combination of propoxyphene and lidocaine relative to lidocaine alone,(202) suggesting that these medications or systemic local anaesthetic mexiletine (Mexitil) should not be concomitantly delivered.  Prior induction of morphine tolerance has been identified as enhancing the toxicity of norpropoxyphene,(203) suggesting that combination of these two opioids may not be an optimal management strategy.
Propoxyphene has been described as having greater cognitive side effects relative to oxycodone and hydrocodone.(205)  Its metabolite norpropoxyphene stays in the body for thirty hours.(23)  Propoxyphene may also result in seizure activity.(178,203)  As propoxyphene is metabolized to norpropoxyphene by the liver, patients with hepatic dysfunction may experience an accumulation of propoxyphene with consequent profound sedation.(196) As norpropoxyphene is excreted renally, toxicity from this metabolite is increased in the presence of chronic renal failure.(210)  
The specific cardiac arrhythmias induced by propoxyphene include marked QRS widening(43) and left bundle branch block.(52,178)  Additional manifestations of cardiac toxicity include third degree AV note block, right bundle branch block, ventricular bigeminy, fibrillation, and irregular sinus rhythm.(178)  Bradycardia, asystole, diminished myocardial inotropy, and vascular smooth muscle relaxation induced hypotension may also be induced after high dose of propoxyphene ingestion.(202)  Propoxyphene induced cardiac toxicity is felt to be naloxone insensitive and mediated via sodium channel blockage of Purkinje fibers.(202)  The mortality rate from propoxyphene toxicity in one intensive care unit was 7.7%, over 300% that of tricyclic antidepressants.(202)  Patients who are noted to consume their medications early and not respect BID dosing or those who have hepatorenal dysfunction should not be prescribed propoxyphene.  
As with meperidine, though propoxyphene affords less analgesia than oxycodone or hydrocodone to the average patient, the structural distinctiveness of propoxyphene relative to other opioids and the unique physiology of some patients enables them to appreciate far greater analgesia with propoxyphene.  As such, propoxyphene should remain on the market and stocked in formularies but be utilized as a tertiary option for those patients who have failed to respond to other short lasting opioids.
 

MEDICATIONS – OPIOIDS – SPECIFIC AGONISTS/ANTAGONISTS
 Pentazocine (Talwin) is a partial opioid agonist antagonist.  As such, it has utility in the treatment of the patient at risk for opioid abuse as this medication has a ceiling effect such that progressive dose escalation does not add to analgesia or euphoria.  Inappropriate dose increases may cause dysphoria and patients who concomitantly take opioids from other sources may precipitate withdrawal.  However, it must be noted that the partial mu agonist buprenorphine was synergistic with cocaine,(56) suggesting that even partial agonist opioids should not be prescribed to patients suspected of cocaine use.
 Butorphanol (Stadol) is an agonist-antagonist which is available as a nasal spray.  It also binds to the sigma as well as kappa opioid receptors and may result in dysphoria.(23)
 

MEDICATIONS – OPIOIDS –AGONIST/ANTAGONIST COMBINED WITH PURE ANTAGONISTS
 Buprenorphine-Naloxone (Suboxone) is a partial opioid agonist combined with a pure opioid antagonist. As with morphine and levorphanol, buprenorphine has been identified as conferring a greater than additive analgesic synergicstic effect with lidocaine,(67) and this may explain the vast improvement in pain and function with a combination of opioid and local anesthetic injections.  The combination of naloxone in the delivery mechanism of this opioid should herald a new standard of opioid delivery to profoundly limit abuse potential.
 

MEDICATIONS – LONG LASTING OPIOIDS
Long lasting opioids maintain constant opioid concentrations in the plasma such that patients do not experience the cycles of withdrawal in between doses of short lasting opioids or the rapid rush euphoria of short lasting opioids.(68)  The constant level eliminates craving and nearly abolishes risks for addiction in patients who truly have pain and lack substance abuse histories predisposing them to addiction.
Long lasting opioids are available as medications with long half lives such as methadone, levorphanol, and oxymorphone which can be crushed without change in abuse potential.  This also allows the throat cancer or other patient with dysphagia to crush the medication without change in efficacy or toxicity.  Long lasting opioids are also produced with slow release formulations such as MS Contin,  OxyContin, and fentanyl patch.  Grinding, melting, and draining the opioid of slow release formulations is a manner of abuse to deliver a rapid rush to achieve euphoria.  Kadian and Avinza are slow release formulations with the benefit that the capsule may be opened to allow the pellets inside to be sprinkled on foods and ingested without dysphagia.
 

MEDICATIONS – LONG LASTING OPIOIDS – WHEN TO USE TWO AGENTS
Although the goal in pain management with respect to opioids is use of one long lasting opioid, sometimes use of two long lasting agents is a more optimal strategy.  One indication for this might be that the next higher incremental dose of the long lasting agent is accompanied by intolerable side effects.  For example, a patient may benefit from addition of a five mg dose of methadone as opposed to the marked increase in dose from escalating a 25 mcg/hr. fentanyl patch to 50 mcg/hr. as the manufacturer does not produce 12.4 mcg/hr. size patches.  This is of particular importance given the potency of fentanyl being 60-80 times that of morphine and the desire of clinicians to use the lowest effective dose to limit side effects.  Similarly, the manufacturers of Avinza long lasting once a day morphine elected to make the smallest capsule 30 mg such that clinicians cannot slowly upwardly titrate dose increments by the absence of a 15 mg size Avinza capsule.  
Potential toxicity of monotherapy may also prompt use of two long lasting opioids.  For example, concerns regarding QT prolongation and torsade de pointes with high methadone dosing may guide physicians to avoid further methadone dose escalation by adding a second long lasting opioid to the management regimen.  Similarly, if escalating Avinza, Kadian, or MS Contin results in morphine-3-glucuronide (M3G) accumulation with consequent dysphoria and/or hyperalgesia, it is preferable to utilize two long lasting opioids.
The synergy between L-methadone and morphine suggests that co-prescribing these two long lasting opioids simultaneously confers supra-additive analgesia with only mathematically additive side effects.(12)
 

MEDICATIONS – LONG LASTING OPIOIDS – OXYCONTIN
Oxycodone is available in a long lasting formulation (OxyContin).  Though OxyContin is an extremely safe opioid when given to patients who are truly suffering in pain, it has considerable diversion value and patients who obtain this opioid are at risk to be accosted or burglarized.  Patients receiving all opioids, but OxyContin in particular, should be educated to utilize drive-through pharmacies and not tell any individual that they are consuming this safe medication.  
OxyContin does not have a known toxic metabolite, unlike morphine.  OxyContin does not exhibit supra-additive potentiation with methadone or with morphine.(12)  OxyContin is considerably more expensive than methadone or long lasting morphine formulations.
 

MEDICATIONS – LONG LASTING OPIOIDS – OXYMORPHONE
Oxymorphone (Numorphan) is currently available as a rectal suppository but may soon be released as an long half life oral opioid.  Greater than additive analgesic synergism has been identified with dronabinol (Marinol) co-prescribed with oxymorphone.(121) 
 

MEDICATIONS – LONG LASTING OPIOIDS - MORPHINE
Morphine (Avinza, Kadian) may control pain for 12-24 hours or 8 hours (MS Contin, Oramorph), depending on the delivery technology.  Considerable analgesia is also effected by the morphine metabolite, morphine-6-glucuronide (M6G).  If doses are escalated too high, the morphine metabolite morphine-3-glucuronide (M3G) may result in paradoxically increased pain.(11)  As M3G is renally excreted,(36) morphine prescription should be monitored closely in patients with impaired renal function. 
Morphine has often been criticized in terms of histamine release.  However, during routine inductions, large doses of morphine, fentanyl, and oxymorphone do not appear to stimulate release of clinically significant plasma levels of histamine.(97)  
Supra-additive potentiation has been reported with co-prescription of morphine with other medications.  Greater antinociception than predicted from simple additivity has been identified as increasing the analgesic potency of oral morphine by 310%-760% when combined with dronabinol (Marinol).(125)  The combination of morphine and methadone analgesia was clearly greater than the sum of their independent pain relieving properties (P<0.001).(12)  Morphine, when co-prescribed with clonidine, may yield greater than additive potentiated pain relief of each individual analgesic.(40)  As with levorphanol and buprenorphine, morphine has been identified as conferring a greater than additive synergistic analgesic potentiating effect with lidocaine,(67) and this may explain the vast improvement in pain and function with a combination of opioid and local anesthetic injections.
 

MEDICATIONS – LONG LASTING OPIOIDS – METHADONE
Methadone is the optimal opioid for treatment of neuropathic pain if opioids are to be utilized to treat this condition.  Methadone works at the mu receptor to attenuate mechanical pain.  It also blocks the NMDA receptor to decrease mechanical as well as neuropathic pain. D-methadone has poor affinity for opioid receptors but interacts with NMDA receptors, whereas L-methadone has high affinity for opioid receptors.(12)  Purification of stereoisomers may confer greater efficacy and decreased side effects.
Methadone has a stigma just as inappropriate as the stigma associated with morphine and OxyContin.  These are all safe medications when given to the honest patient.  Methadone was chosen by the government to assist in heroine detoxification because methadone has a long half life, is a safe medication, has no change in activity if it is simply crushed, and OxyContin and fentanyl patch were not available when methadone was selected.
Morphine, when combined with L-methadone, delivers analgesic synergy with greater anti-nociception relative to the sum of additive analgesia from the two analgesics.  The side effects of ingesting the two medications, however, was not supra-additive.  This very important finding illustrates the different activities of different opioid medications as codeine with L-methadone also revealed supra-additivity, but L-methadone did not confer greater than additive analgesia with oxycodone, fentanyl, or meperidine and morphine was synergistic only with L-methadone.  Another important result from this investigation is to suggest that patients who cannot tolerate morphine or methadone long lasting opioids may benefit from lower doses of both agents prescribed simultaneously as the analgesia may be sufficient and the constipation and presumably other systemic side effects lessened by the lower prescribed dosing.  Synergy with some opioids but not with others suggests the complexity of interactions of medications and interactions amongst mu opioid receptors.  The combination of morphine and methadone analgesia was clearly greater than the sum of their independent pain relief (P<0.001).(12)  Methadone analgesia was increased 400% when combined with dronabinol (Marinol).(121)
Opioid rotation to methadone from another opioid should be performed with transition to 25% of the equianalgesic dose as patients who are acclimated to one opioid are sensitized to methadone.(  )  As such, though true tolerance in humans is extremely rare, methadone may be an effective option if opioid rotation is selected in lieu of opioid holiday.
 

MEDICATIONS – LONG LASTING OPIOIDS – METHADONE – NEGATIVE ASPECTS
Methadone (Dolophine) treatment of pain is usually given every 6-8 hours, but the medication may accumulate such that once a day dosing may be achievable.(  )  
Methadone blocks the cardiac human ether-a-go-go-related gene (HERG) mediated potassium current.(   )  As such, a dose related effect on QT prolongation(143) with risks for rare but potentially fatal torsade de pointes may occur.(143)  The mean dose implicated in torsade has been reported as ranging from 114 mg – 680 mg.(194)  The entity of methadone mediated torsade is novel, and may be overstated.  Cocaine has been detected in post-mortem drug testing, and cocaine is known precipitant of QT prolongation and torsade.(   )
 

MEDICATIONS – LONG LASTING OPIOIDS – LEVORPHANOL
Levorphanol (Levo-Dromoran) typically has a 6-8 hour duration of action.  As with morphine and buprenorphine, levorphanol has  been identified as conferring a greater than additive synergistic analgesic effect with lidocaine,(67) and this may explain the vast improvement in pain and function with a combination of opioid and local anesthetic injections.
As with morphine and buprenorphine, levorphanol has been identified as conferring a greater than additive synergistic analgesic potentiating effect with lidocaine,(67) and this may explain the vast improvement in pain and function with a combination of opioid and local anesthetic injections.
 

MEDICATIONS – LONG LASTING OPIOIDS – FENTANYL
Fentanyl patch (Duragesic) delivers opioid which is 60-80 times stronger than morphine.(23)  As a patch, compliance is quite high as it only needs to be changed every two to three days.
Though opioids were classically felt to effect analgesia primarily through the central nervous system, peripheral somatic mu receptors have been identified.(46)  Topical application of morphine, oxycodone 5 mg in 1-2 cc’s of water, dissolving meperidine 100 mg in water may decrease ulcer related pain such that oral opioids dosing can be diminished with longer lasting effect.(66)  Analgesia with topical levorphanol and buprenorphine has also been demonstrated.(67)  This suggests a mechanism by which fentanyl patch may have some advantages over other opioids in that topical placement of the patch over the site of pain may have additive analgesia relative to simply delivering the opioid to the central nervous system.  It may also suggest that lower dosing may be required to achieve analgesia with accompanying lesser systemic side effects.  
Use of the patch may result in skin rash.  The frequency of this event may be diminished by rotation of the site of the patch or by concomitant use of low dose topical steroids.  One means by which this may be effected is by utilizing a steroid metered dose inhaler and squirting a puff onto the skin.
Fentanyl, alfentanil, and sufentanil may result in chest wall rigidity,(23) an important consideration when educating patients with severe COPD or kyphoscoliosis who may be naïve to the medication.  In contrast to the dose dependent increases in sphincter of Oddi and biliary duct pressure seen with most other opioids, fentanyl as well as meperidine do not elevate intrabiliary duct pressure(23) and should be considered favored opioids in the management of pain related to cholelithiasis.  Fentanyl seldom results in hemodynamic changes(23) such that it may be preferred in patients with congestive heart failure or those with brittle orthostasis who may not tolerate other opioids.
Fentanyl patch is considerably more expensive than methadone or long lasting morphine formulations.  Contrary to common belief, fentanyl has considerable criminal diversion value as the contents of the patch may be extricated for euphoric use.  In addition, the patch may be frozen and cut into pieces for illegal applications.
 

MEDICATIONS – OPIOIDS –TOLERANCE, A RARE HUMAN PHENOMENON
Tolerance is the physical need for greater doses of a medication to achieve the identical result.  Patients often fear that once they begin taking opioids they will need progressively greater doses to achieve analgesia and continued functioning.  Tolerance develops less frequently during chronic opioid administration in a clinical context than in animal experiments.(68)  In fact, true tolerance in humans is exceedingly rare despite the common myth of tolerance.  Just as there is no convincing data to support the evolution of tolerance to anti-hypertensive medications, no good studies support the occurrence of tolerance to opioid medications to warrant progressive escalation in the treatment of pain and stable pathology.  Patients must understand that once their pain is addressed with the proper dose of opioid and nonopioid analgesics, the dose characteristically remains stable for years.(    )
Requests for dose escalation occur in the patient who ingests opioids to obtain euphoria as the drug addict can never get enough pleasure sensation.  Similar requests occur in some criminals who sell their opioids as they can never achieve enough illegally obtained money.  However, some criminals strive to blend with honest patients by keeping their doses stable.  The clinician can discriminate the patient types based on history, examination, drug testing, and other aspects of care that cannot be discussed and disseminated via this publically accessible web site.
 

MEDICATIONS – OPIOIDS – PSEUDOTOLERANCE
Pseudotolerance is the condition in which physiologic tolerance with opioid receptor changes has not occurred, but the patient’s pain has truly escalated.  To quote Mass General Hospital Pain Service, many chronic pain patients have been managed with stable, constant doses of opiates as long as the disease does not progress.(55)  Mass General is correct in the identification of one cause of pseudo-tolerance.  Opioid doses may need to be escalated to address disease progression such as the slow rate of progression of osteoarthritis and post-surgical fibrosis over the years.  Pain may increase if new pathology arises such as recurrence of a tumor or reactivation of rheumatoid arthritis related inflammation.  Pain may fluctuate transiently with changes in humidity, temperature, and barometric pressure, but seasonal changes with consistently colder and damper weather may effect biophysiologic changes in arthritic tissues with increased nociception and pain.  Day to day and week to week weather changes within a season are best addressed with breakthrough pain medications conserved for such days, and no opioid dosing change is warranted.
Patients who return to work with accompanying greater exertion can be anticipated as requiring greater opioid doses, just as patients who are sedentary and do not work should be expected to require considerably lower opioid doses or even be managed solely with nonopioid analgesics given the vastly lesser nociception anticipated in sedentary individuals.  If the patient requires progressively escalating opioid doses it may also mean that the patient’s pain and individual biophysiology is not responsive to either that opioid or the opioid class.  A presentation of tolerance may also suggest zinc or magnesium deficiencies as these minerals are essential for antinociceptive function.  Anorexic patients and those with known malabsorptive disorders, in particular, should be serologically evaluated for low levels of zinc and magnesium.  Opioid induced hyperalgesia is discussed below and remains in the differential diagnosis of patients suffering pseudo-tolerance.
Patients who exhibit tolerance in terms of requesting escalating doses of opioids may be suffering from refractory severe mood depression and appropriate treatment is to encourage the nonsuicidal patient to trial antidepressants or see a psychiatrist for additional options such as monoamine oxidase inhibitor trials, electroconvulsive therapy, or magnetic therapy.  Electroconvulsive therapy has been described as successfully decreasing chronic pain.(   )  Psychiatrists will often investigate whether the patient has been noncompliant with antidepressants and ingested them for too short a period of time to truly warrant documentation of inefficacy.  The psychiatric expert may also escalate the dose to an extent greater than that which the pain management clinician is comfortable.
Pain may also increase as a result of anxiety related to an unanticipated life stressor, reactivation of post-traumatic stress syndrome, or new stress from litigation.  These should be addressed with anxiolytics as well as psychologic counselling, not with escalation of opioid dosing.
 

MEDICATIONS – OPIOIDS – MANAGEMENT OF TRUE TOLERANCE
The rare patient who develops true tolerance to opioids may be treated with NMDA antagonists as these medications may be opioid sparing and decrease the incidence of tolerance.(   ) L-subtype calcium channel blockers such as nifedipine may prevent the development of opioid tolerance.(26) Prescription of dronabinol (Marinol) with opioids may have particular utility in that it may allow opioids to retain high antinociceptive effects without causing opioid receptor down-regulation with chronic use.(122)  Adding nonopioid potentiating analgesic medications may also decrease opioid needs as tolerance may be a response to high doses of opioids, and supra-additive analgesia effected by co-prescribing synergistic agents allows for lower opioid dosing.  Patients can be referred for retrials with epidural steroid injections to potentially cure the condition.
When patients are highly tolerant to one mu selective opioid are “opioid rotated” to another opioid, they often can be controlled by doses of the second opioid at a far lower than predicted equianalgesic dose that would be required in opioid naïve patients.(12)  Transition to another opioid may be successful as cross-tolerance is incomplete.  Patients who are tolerant to their opioid may be best transitioned to methadone as cross-tolerance is less to this opioid relative to other mu opioids.(12)  It may be that patients who have already developed tolerance will benefit from drug holiday or rotation to another opioid with subsequent addition of an NMDA blocker(   ) or L-subtype calcium channel blocker.(26)    
Another option to treat a patient tolerant to opioid related analgesia is with a drug holiday in which the opioids are rapidly tapered by 15-20% of the dose daily(51) with supplementation with anti-emetics, NSAID’s, and sympatholytics clonidine and/or beta blockers.  Opioid abstinence should strongly be entertained before tolerance and pseudo-addiction compromises any portion of the patient’s life.
Another option is to offer the patient an implantable morphine / Ziconotide / clonidine / lioresal pump with delivery of the opioid directly into the intrathecal space.  
 

OPIOID INDUCED SIDE EFFECTS
Failure to treat opioid induced side effects may limit opioid dosing with accompanying poorly controlled pain and functional regression.  Opioid induced side effects are not life threatening, unlike NSAID induced fatal gastrointestinal bleeding, anticonvulsant induced fatal blood dyscrasias, and systemic anti-arrhythmic induced fatal cardiac toxity.  Opioid related side effects are also treatable.  Common side effects that also occur with nonopioid analgesics are discussed above at the beginning of this review, and include constipation, nausea, urinary retention, xerostomia, orthostatic hypotension, and sedation / fatigue.  Less common are opioid specific side effects which include opioid induced nausea, opioid induced pruritus, opioid induced hyperalgesia, and opioid induced dysphoria.  The patient must be educated that though tolerance is extremely rare to the analgesic effects of opioids in the central nervous system, tolerance does occur in the periphery in terms of both groups of above side effects.(  )  
 

OPIOID INDUCED SIDE EFFECTS - NAUSEA
Nausea commonly accompanies treatment with opioids.  Clinicians should strive to treat with trimethobenzamide (Tigan) as this is distinct from promethazine (Phenergan), metoclopramide (Reglan) and prochlorperazine (Compazine) phenothiazine derivatives with accompanying risks for irreversible tardive dyskinesia, neuroleptic malignant syndrome, and other complications of the older antipsychotics.  
Though efforts to combat constipation, sedation, xerostomia, and urinary retention may need to be redoubled, the anticholinergic scopolamine (Transerm scop) as well as the anticholinergic tricyclic antidepressants are also helpful to diminish nausea.  The analgesic antihistamine meclizine (Antivert) and hydroxyzine (Atarax) decrease nausea.  The extremely expensive yet extremely potent analgesic aprepitant (Emend) is a substance P and neurokinin 1 receptor antagonist and an anti-emetic.  The analgesic cannabinoid dronabinol (Marinol) also has safe anti-emetic properties. Another option may be treatment with the analgesic class of  5-HT3 antagonists such as dolasetron (Anzemet), granisetron (Kytril), and odansetron (Zofran) as these agents are also not antipsychotic derivatives. 
 

OPIOID INDUCED SIDE EFFECTS – PRURITUS
Pruritus is may be controlled with the antihistamine hydroxyzine.  Odansetron (Zofran) has consistently demonstrated the ability to ameliorate opioid induced pruritus.(   )  Topical creams such as those containing menthol may decrease pruritus.  The analgesic dronabinol (Marinol) may also decrease pruritus.(184)  Pruritus may also be addressed by transitioning patients to another opioid.
 

OPIOID INDUCED SIDE EFFECTS - HYPERALGESIA
Hyperalgesia is an uncommon condition in which increased opioid dosing paradoxically results in increased pain.  Opioid induced hyperalgesia is recognized as a dose dependent event, though low doses may also precipitate the condition in the presence of impaired drug metabolism as with hepatorenal syndrome or with concomitant ingestion of medicatons which compete for metabolic pathways.  In addition, direct instillation of small amounts of opioid into the intrathecal space may also precipitate opioid induced hyperalgesia.
The phenomenon may be considered conceptually analogous to the patient with polymyositis who develops progressive weakness while receiving steroid treatment.  Steroids may result in myopathy and weakness, but polymyositis also produces weakness.  The clinician must distinguish between increasing or decreasing the medication to treat the cause of the weakness.  Patients who complain of progressively escalating pain at serial visits may be addicts seeking euphoria, patients with rapidly progressive pathology and pain as in malignant states, and patients who have transitioned from disabled states to working status.  In the latter two states, dose escalation is certainly appropriate.  
Morphine is metabolized to the analgesic morphine-6-beta-glucuronide, M6G, and the adversely neuro-excitatory agent morphine-3-glucuronide, M3G.  M3G indirectly activates the NMDA receptor to increase cytosolic calcium as a possible mechanism by which this morphine metabolite induces pain.(11)  Treatment may include lioresal or nifedipine(11) versus opioid rotation to another opioid versus opioid taper with treatment with nonopioid analgesics.  As discussed above, if the morphine dose is decreased then adding methadone may disproportionately increase the analgesia without supra-additive side effects.  Treatment may also include an NMDA antagonist.
Fentanyl as well as sufentanil may also result in opioid induced hyperalgesia.(   ) 
Hydromorphone has been discussed as a cause of opioid induced hyperalgesia.(   )  
This author has yet to review literature implicating oxycodone / OxyContin, methadone, or oxymorphone as a cause of opioid induced hyperalgesia.
 

OPIOID INDUCED SIDE EFFECTS - DYSPHORIA
Dysphoria is uncommon and must be distinguished from mood depression.  The  patient may become tearful and unhappy because of excessive opioid dosing.(    )  The dysphoria may not simply reflect the dose delivered, but also the particular agent selected, as the opioids buprenorphine (Stadol) is most frequently associated with dysphoria.  This is felt to be related to its binding to the kappa opioid receptor.(23)  Pentazocine also binds to the kappa receptor.(23)  The bioactive metabolite of meperidine, normeperidine, may result in dysphoria.(23) 
 

INTERVENTIONAL STRATEGIES
Interventional strategies are quite helpful in pain management.  Prompt referral to an anesthesiologist for sympathetic nerve blockade may cure true acute reflex sympathetic dystrophy. The value of injections is the lack of cognitive side effects that so often accompany use of most other analgesics.  However, risks for potentially fatal anaphylaxis, pneumothorax, infection, cardiac arrhythmia, and other complications mandate skill of the delivering clinician.
If a nerve is extracted from a rat and one end is electrically stimulated, it will transmit to the other end of the nerve.  However, if local anesthetic is applied to the middle of the length of the nerve, then stimulation will not travel beyond the pharmacologic region of blockade.  Local anesthetics ? prevent sodium ion?  Channel  ?opening? such that saltatory conduction cannot proceed. The ability to delivery local anesthetic injections is that which defines a major contribution of pain management experts.  If a practice does not have these skills then they must be able to refer to appropriate clinicians given the enormous safety of this intervention by trained clinicians.  Local anesthetics potentiate opioid related analgesia,(67) and this explains the vast synergistic improvement in pain and function with a combination of opioid and local anesthetic injections. 
The duration of therapeutic analgesic effect from local anesthetic injections often extends well byond the pharmacologic effect of the local anesthetic medication.(86,173,218,220)  Though not curative, local anesthetic injections predictably impair nerve transmission of pain impulses to the pain.  A nerve extracted from a rat will conduct from a stimulated end to the other end.  If Bupivicaine or another local anesthetic is applied to the center of the length of a nerve then stimulation from one end to the other will be impaired at the site of application of the local anesthetic as disruption of ion channels by the medication prevents nerve transmission.  Clinicians who elect to perform local anesthetic injections must be aware of the potential for weakness if excessively high doses are delivered.  Thin, finely myelinated A-delta and C fiber pain conducting sensory fibers will be blocked at lower doses but higher doses may affect thicker, heavily myelinated motor fibers controlling voluntary muscle contraction.
Many primary care physicians do not feel comfortable referring patients to pain management unless an interventional service beyond their specialty training can be offered.  However, additional indications for referral may be to trial the vast spectrum of nonopioid analgesics that the internist is less comfortable prescribing.  Once patients are stable on a regimen of medications, they may often be returned to their primary care physician with occasional follow-ups for trials with new medications as they are released.
 

INTERVENTIONAL STRATEGIES – TRIGGER POINT INJECTIONS
Trigger point injections (TPI’s) have been delivered for well over a century(218) across the entire world as far away as Japan(228) to focal muscular sites of spasm as present regionally in myofascial pain and diffusely in fibromyalgia, and thousands of articles(254) and actual books have been written discussing these injections.  Trigger point injections and nerve blockade are liberating as one treatment may provide pain relief for four to six weeks.  As such, these injections liberate the patient from constant visits to the clinician for treatment, allowing for only 9-12 visits out of a 365 day year relative to visits several times a week for acupuncture, massage, or chiropractic manipulation with over a hundred visits a year.  Trigger point injections with local anesthetics are considered to be the most effective treatment for myofascial pain.(217)  Trigger point injections constitute a foundation in the management of regional myofascial pain and generalized fibromylagia.(   )  Trigger point injections have also been described as being efficacious to treat neuropathic pain such as intercostal neuralgia.(215)
The exact genesis of trigger points is unknown.  It may be primary as in ideopathic fibromyalgia, or it may be a sequelae of defined pathology such as disc herniation, trauma, fracture, or other pathology.  Auto-immune attack of muscle may also generate trigger points.  Involvement of the sympathetic nervous system has been postulated as patients who are denied even nonopioid analgesics often suffer progression in the distribution of their pain from regional myofascial pain to diffuse fibromyalgia.
The duration of therapeutic analgesic effect from TPI’s often extends weeks, well beyond the pharmacologic effect of the local anesthetic medication.(218)  Numerous theories have been advanced forwarding proposed mechanisms to reconcile the clinically witnessed benefit relative to the half life of the medication.  By blocking afferent nociceptive impulses from the periphery it is felt that this can utilize plasticity of the central nervous system to reorganize the dorsal horn of the spinal cord.  Signals from the superficial layers can modulate the wide dynamic range cell of deeper layers such that the “gate is closed” and signals do not ascend further such that the brain does not perceive as extensive a pain signal.  Myofascial pain is a condition characterized by enhanced central spinal reflexes(79) which result in muscle spasms in response to stimuli which may otherwise not induce spasms and pain.  The pathology may be present peripherally in the muscle as well, and trigger point injections may decrease pain related to sensitized peripheral nerve endings by counterirritation and interruption of painful muscle spasms.(25)  A double-blind cross-over study has provided evidence to support that TPI’s may achieve efficacy via activation of the endogenous opioid system as naloxone was shown to preclude pain relief from TPI’s.(218)  Endorphins act on wide dynamic range neurons in the dorsal horn segmental spinal cord to decrease firing and potentially return the bias of the sensitized cell to normal.(218)
Clinicians with expertice in the technique of trigger point delivery will not simply inject a single layer at a given transcutaneous penetration site.  Maximum benefit is achieved by addressing multiple levels of tissue and several muscle groups with a single injection.  The paraspinals, for example, are truly an overlapping layer of numerous muscle groups.  Optimal injection management with limitation in patient discomfort is achieved by a single injection into the superficial iliocostalis, longissimus, and spinalis multiple muscle groups as well as the deep first level semispinalis group, second level multifidi group, and occasionally the rotatores third deep transversospinalis layer muscle group.  Some clinicians dilute the local anesthetic of TPI’s to decrease procedure related pain and have reported similar efficacies as with higher concentration injections.(227,228)
Patients with allergies to local anesthetic may be treated with sterile water trigger point injections with analgesic effect,(25) but the duration of antinociception is similar to acupuncture in that it is usually less than with local anesthetic delivery. This also an option in the management of the pregnant and breast feeding patient.  Antihistamines have local anesthetic activity and may be considered for trigger point injections should patients have allergies to local anesthetics.(149)
Series of TPI’s may effect cure of pain(218) such that opioid and nonopioid analgesics are no longer necessary.  Presumably this is achieved by terminating the cycle of pain by returning a hyperexcitable peripheral or central nervous system to the pre-pain state by consistently eliminating the noxious afferent impulses such that the acutely activated system gradually winds down.
Knee pain induces myofascial back pain as knee pain results in assumption of a knee flexion posture during standing to maximize the joint space. Degenerative changes of the knee also cause flexion/loss of extension.(85)  This knee flexion results in increased stretch and tension of the rectus femoris as this muscle crosses the anterior knee joint to insert on the tibia and also crosses the hip joint to originate on the anterior inferior iliac spine of the pelvis.  The tensed rectus femoris subsequently acts on the pelvis to decrease sacral inclination with reduction in the lumbar lordosis resulting in increased tension of the lower back muscles.(74)  Physiologic anterior pelvic tilt results in lumbar lordosis.  Reduction of the tilt results in reduction of the lordosis.  These degenerative changes in the knee with reduced lumbar lordosis and lumbar paraspinal spasm results in back pain(85)  The same loss of lumbar lordosis related to knee pain that results in back pain can occur in patients status post spinal instrumentation, particularly fusion, as patients lose the normal lumbar lordosis.  Back pain intensity often exceeds that of knee pain.  Further, back pain weakens knee extensors(237) with consequent greater knee flexion and further cyclic amplification of back pain.  
Yet another mechanism correlating anatomy and basic science has been forwarded to explain the common clincal event by which knee pain increases myofascial back pain.  Proximal tibiofibular knee joint dysfunction results in biceps femoris spasm and has been reported as causing years of chronic back pain.(151)  As the long head of the biceps femoris originates on the ischial tuberosity of the sacrum and inserts at the lateral aspect of the fibula and lateral condyle of the tibia, this muscle crosses the posterior knee and increases sacral inclination during gait to increase the lumbar lordosis.  Chronic overexaggeration of lumbar lordosis places the lumbar paraspinals in a chronic state of stretch which may result in structural compromise of the muscle fibers in unilateral asymmetric traction.
The etiologic role of the knee in producing back pain has been stated to be secondary to osteoarthritis in the knee resulting in abnormal [gait] biomechanics with resultant repetitive trauma of the lumbar spine resulting in back pain.(204)
Hip pain and pathology may also result in myofascial back pain.(87)  X-rays may be normal despite pain, and magnetic resonance arthrography or hip arthroscopy may be required to establish the diagnosis.(87)  The altered gait related to hip pathology results in myofascial back pain just as gait disorders in hip pathology results in back pain.  The etiologic role of the knee in producing back pain has been stated to be secondary to osteoarthritis in the hip resulting in abnormal [gait] biomechanics with resultant repetitive trauma of the lumbar spine resulting in back pain.(204)
 

INTERVENTIONAL STRATEGIES – PERIPHERAL / REGIONAL NERVE BLOCK
Nerve blocks are delivered to decrease chronic pain.(79,80,86,105,106,107,112,159,173,) (251,252) Given their safety, local anesthetic blocks to treat chronic pain are simply an extension of the use of these treatments for acute pain.  Patients may prefer the lack of cognitive and other side effects of local anesthetic injections to nonopioid as well as opioid analgesics.(106)  Injections are a safe option to further escalations in opioid ingestion.(226)  The “efficacy of nerve block [is] to avoid increasing the morphine dosage” in the care of chronic pain patients.(96)  Injections are of particular value in patients who are unfit or unwilling to consider surgical intervention.(86)  In some cases series of nerve blockade injections may cure myofascial pain as well as neuropathic pain(173) such that opioid and nonopioid medications can be discontinued.  Presumably this occurs as the brain acclimates to the lower pain state until the brain disavows the presence of pain in the absence of progressive pathology or nociceptive generation.  In most cases, however, nerve blocks contribute the enormous benefit of control of pain just as oral medications control pain and antihypertensives control blood pressure.  Profound relief is appreciated after local anesthetic injection as the anesthetic is sufficiently potent that a dentist can literally manually extract teeth from the jaw with nerve blockade.
Nerve blockade allows for a single injection to decrease pain in the entire distribution of the nerve.  An analogy that patients often find useful is blocking the base of a tree with a single injection as opposed to numerous injections to all of the branches of the tree.  A single nerve block may obviate numerous trigger point injections.(159) Thus pain is attenuated with less discomfort and less risks of infection relative to numerous trigger point injections. Nerve block with local anesthetics is delivered to decrease myofascial pain syndrome(79,160,173,217) as well as neuropathic pain such as reflex sympathetic dystrophy.(173)
The duration of therapeutic analgesic effect from local anesthetic blocks often extends weeks, well beyond the pharmacologic effect of the local anesthetic medication.(86,173,218,220)  A reflection of the safety, efficacy, and rapidity of treatment with nerve blocks is that even though chronic pain relief may persist for only one month, patients request repeat blocks.(105)  Patients with chronic pain vastly prefer to receive uncomfortable local anesthetic injections once every four weeks such that only 12 visits are required every 365 days to attenuate pain relative to the patient who sees a chiropractor, massage therapist, or acupuncturist several times a week for well over a hundred visits a year.
Numerous mechanisms have been forwarded to explain protracted analgesia following nerve blockade, well beyond the duration of the local anesthetic.(173)  Nerve blocks may favorably impact the chronic pain state by influencing the plasticity of the nervous system to reduce chronic peripheral and central sensitization.(80)  Decrease in dorsal horn sensitization may be related to decreased peripheral nociceptive input,(86,173) depletion of substance P and nerve growth factor of afferent C fibers, and infiltration of tiny penetrating nerve fibers in the bulk of the muscle may explain the weeks of relief as opposed to hours of relief following the injection and metabolism of the local anesthetic.(86)  Successful nerve block in the bulk of the muscle with greater volumes of local anesthetic without precise radiographic or skill based localization has also been reported by other authors,(107) but this raises concern that the larger volumes may place the patient at greater risk.  
Pain is transmitted to the central nervous system via A-delta and C nerve fibers.  Muscle spasms are mediated by A-alpha efferent motor fibers from the anterior horn cell to the extrafusal muscle fiber, and A-gamma fibers are efferent motor fibers to the intrafusal muscle spindle to define muscle tone and susceptilibility to spasm.  If the A-gamma tone is high and the spindle facilitates spasm, then muscle metabolic waste products from constant spasm may activate A-delta and C nociceptors such that pain signals can be transmitted afferently to the brain.  Thus, pain can be diminished by blocking A-gamma, A-delta, and C-fibers.
A-gamma fibers are 250% smaller than A-alpha fibers, A-delta fibers have a diameter 500% smaller than efferent A-alpha motoneuron fibers, and C fibers are unmyelinated and 1500% thinner than A-alpha fibers.(69)  As such, clinicians should deliver the smallest effective volumetric and percent concentration (106) dose of local anesthetic to reduce pain as escalating doses will affect thicker A-alpha motor fibers with consequent weakness.  A-alpha efferent motor fibers will only be blocked after A-delta and C fibers transmitting afferent pain are first blocked.(206,211)  For this reason, some clinicians dilute the local anesthetic to decrease procedure related pain and have reported similar efficacies as with higher concentration injections.(227,228)  C-fibers are more susceptible to local anesthetic induced conduction block than other fibers.(106)  After 1% lidocaine was injected around a nerve, no C-fiber activity could be recorded.(206)  C-fibers which mediate dull, slow, prolonged, burning pain and muscle pain(206) are blocked with lidocaine and bupivacaine before A-delta fibers(211) which mediate fast, sharp, pinprick pain.  In addition, progressively escalating doses of local anesthetic predispose to systemic absorption with systemic cardiac toxicity.(214)  The benefits of using a larger dose for novices, however, is that suboptimal needle placement may be countered by the larger volume infiltrating the adjacent tissues to reach the desired nerve.(86)  
One of the postulated mechanisms by which this occurs is that the entire scope of signals from a given dermatome are diminished after blocking the intercostal nerve.  The segmental spinal cord thereby receives lessened signal via the sensory dorsal root ganglions at that level and consequently sends less local excitation to reflexively stimulate the segmental motor anterior horn cells.(15)  This results in decreased efferent signal to the corresponding muscles of that myotome such that less spasm occurs.  Subsequently, the muscle sends less afferent nociceptive impulses ??? via the Golgi tendon apparatus??? and the injection can last weeks in the chronic pain patient.  Additionally, decreasing the spasms results in decreased nociceptor sensitization(15) such that spasms are further diminished.  With repetitive nerve blocks in the absence of persistent pain generating pathology, the injections may effect remission without the need to continue injections and with decreased opioid needs.  Injury may lead to sensitization of the dorsal horn neuron(70) and repeated blocks may sequentially decrease this hyperexcitable state.
As most forms of chronic pain are not accompanied by inflammation, the addition of steroid to local anesthetic blocks is often unwarranted.(107)
Clinical reports have stressed the safety of nerve blocks and their lack of complications.(173)  As long as the patient does not have an allergic reaction to the local anesthetic, nerve blocks are extremely safe, accompanied only by mild local irritation for a day or so at the cutaneous penetration site.  Several different nerve blocks with local anesthetic did not cause histopathologic changes in neural tissue or surrounding subcutaneous tissue nor did it cause neuritis.(106)  Unlike phenol injection, no scarring is induced and the nerve does not permanently lose function.  Unlike steroid injection, subcutaneous atrophy does not occur.  Examiner skill is necessary as intra-vascular injection may result in fatal cardiac arrhythmia and inadvertent penetration of the pleura may result in pneumothorax.  
Although some patients request trigger point injections every three weeks, local anesthetic nerve blockade can last far longer, often six weeks.
Traction and compression nerve injury may result from intraneural microvascular flow compromise during the stretch, leading to ischemia.(62)  The mechanical forces of traction may disrupt some of the fascicles of a nerve or the entire nerve itself, particularly if the stretch is rapid with no time for acclimation. As with all nerve injuries, involvement of the underlying axon will result in muscle atrophy but damage restricted to the myelin sheath will result only in pain, possibly with numbness and weakness.  Integrity of the axon indicated may be grossly inferred clinically by the absence of atrophy as the cell body in the central nervous system can still transport proteins and other constituents of the terminal axon to maintain innervation and bulk of the muscle.  If the forces involved are less profound, then only demyelination without axonal compromise and muscle atrophy will occur.  Demyelination exposes the underlying axon, making it hyperirritable and likely to spontaneously depolarize and send a pain signal to the brain in the absence of new tissue injury.
 

INTERVENTIONAL STRATEGIES – SPINAL ACCESSORY NERVE BLOCK
Spinal accessory nerve pathology is a cause of shoulder, periscapular, and neck cancer and non-cancer related pain.(62,142,162,164,165,174,187)  Several mechanisms of injury to this nerve may occur.  A drooping shoulder as seen with rotator cuff tendinopathy may result in traction of the spinal accessory nerve with consequent shoulder pain.(162)  The nerve may be injured by posterior triangle surgical exploration of the neck,(134,162,164) typically due to transection or simple pressure applied to the nerve.  Spinal accessory neuropathy may follow direct traumatic compressive trauma to the neck.(133)  Pain may become severe as normal scapulothoracic rhythm is disrupted by muscle imbalance from spasm.(174)
The spinal accessory nerve may be injured following motor vehicle accident related whiplash injury(62,71,81,165)  A proposed mechanism is that of rapid hyperextension-flexion combined with rotational torsion inducing a traction injury of the nerve,(81) as the nerve is fixated between the ventral roots of C2-C5 as well as the site at which it pierces the sternocleidomastoid and its penetration into the trapezius.(162)  Traction of the nerve due to head and neck positioning during coronary artery bypass surgery may also result in spinal accessory nerve palsy and recovery may take years.(163)  The spinal accessory nerve may also be damaged following surgery for rotator cuff disease.(230)  Simply lifting a heavy object may result in a traction injury.(142,165)  Traction palsy may also occur simply as a result of placing the arm in a sling(127) or self-cracking of the neck by manual lateral flexion,(187) indicating the susceptibility of this nerve to injury.  A drooping shoulder is also felt to damage the spinal accessory nerve via a traction neuritis, and may result in formation of a neuroma at some point in the length of the nerve.(219)
Even in the presence or absence of spinal accessory neuropathy, block may decrease diffuse myofascial pain related to muscle spasms of the trapezius.(108)  Muscles supplied by the spinal accessory nerve are known to be particularly prone to the development of trigger points characteristic of myofascial pain.(219)  In addition, as the spinal accessory nerve has been presented as having sensory transmitting afferents(164,165) which have been specifically characterized as non-propioceptive pain afferents.(219)  Selective blockade of pain transmitting afferent sensory fibers with smaller doses of local anesthetic will decrease pain and spare motor fibers of the nerve and avoid weakness.  Larger doses may decrease spasms, but progressive dose escalation will predictably result in weakness.  The clinician should take care to inject the nerve only after it has already innervated the sternocleidomastoid (81,162) to avoid potential weakening of this muscle.  Injections should also occur at the midpoint of the posterior border of the sternocleidomastoid where the nerve is superficial,(165) as this decreases the likelihood of potentially fatal pneumothorax or large vessel penetration relative to deeper injections.  Injections should not be too high in the neck as pain and spasms in the superior trapezius are felt to most commonly be mediated by the spinal accessory nerve and higher injections may compromise innervation from the upper cervical nerves to the middle and lower trapezius in the back.(135)  Myofascial pain may be difficult to distinguish from spinal accessory nerve palsy following whiplash injuries(62) as they may co-exist.  Spinal accessory nerve pathology may result in abnormal scapular motion with consequent strain of the rhomboids leading to secondary mid-thoracic back pain.(162)
 

INTERVENTIONAL STRATEGIES – SUPRASCAPULAR NERVE BLOCK
Suprascapular nerve block has been used successfully to decrease pain since 1941,(220) and it may attenuate diffuse superior and posterior shoulder pain over the scapulae.(86,213,214) Suprascapular nerve block may allow patients with severe gleno-humeral arthritis to feed themselves, comb their hair, and perform other simple tasks(112) that most of the world takes for granted.  The suprascapular nerve is the main sensory nerve to the shoulder(107) and supplies sensory fibers to approximately 70% of the glenohumeral joint and capsule as well as the acromioclavicular joint.(86,112,172,208,214)  The skin of the superior and posterior shoulder may also be supplied by the suprascapular nerve.(112,208,214)  As the suprascapular nerve includes a high proportion of sympathetic fibers, suprascapular nerve block has proven useful in the management of reflex sympathetic dystrophy associated with frozen shoulder.(197)  Addition of steroid methylprednisolone to the nerve block does not confer additional benefit in most(95) but not all patients.(213)
Suprascapular nerve blockade has been demonstrated to safely decrease chronic shoulder pain, impairment, and disability in many reports, including a randomised, double blind, placebo controlled trial with efficacy at least comparable with intra-articular injection.(86)  Shoulder pain with or without atrophy related to degenerative osteoarthritis, rheumatoid arthritis, supraspinatus rotator cuff tear, neuropathy, adhesive capsulitis, and other pathologies (86,93,95,104,107,112,197) improves from this safe and effective procedure.(107,112,197,213,214,220,223,226,229)  As related to management of rotator cuff pathology, resection of the distal clavicle may damage the suprascapular nerve and result in persistent pain.(224)  Demands for morphine and other opioids may be decreased as much as 51% following suprascapular nerve block,(214) and this block is so effective that it is utilized to decrease profound cancer related pain.(226,229)  Given its safety and efficacy, even though benefit with suprascapular nerve block is temporary, clinicians report it as being effective.(107)   The safety mandates experience as unskilled clinicians attempting to perform the block may result in potentially fatal pneumothorax or penetration of the large suprascapular artery and vein vessels as they course through the suprascapular notch.(209)  The ease by which these complications may occur in unskilled practitioners has limited the generalized implementation of this nerve block.(220)
 As discussed above, suprascapular nerve blocks may be utilized simply to attenuate chronic pain related to chronic pathology, but additional acute mechanisms of injury include traction neuropraxia with no clear site of impingement(207) as well as compressive pathologies.  The suprascapular nerve is enormously predisposed to traumatic injury as it is fixated at numerous sites in its course, predisposing to both traction and compression pathologies.  The fact that the area of nerve being stretched is concentrated within a short region accentuates the risks for traction injury to the suprascapular nerve.(207)  For this reason, simple muscular contraction lifting a heavy object or recreational weight lifting may result in traction suprascapular neuropathy.(172,213,221,222)  Lifting a heavy object may also precipitate cervical radiculopathy(239) and the clinician must evaluate for concomitant lesions causing neck and posterior shoulder pain.  The suprascapular nerve may also be damaged following surgery for rotator cuff disease.(230)
The anatomical course of the nerve is such that it originates at the ventral roots of C4-C6 and then courses obliquely through the suprascapular notch before is receives sensory branches from the shoulder.(112)  The nerve then passes under the rigid superior transverse ligament, a site which can calcify or hypertrophy and then encroach on the nerve and compress the nerve.(225)  The nerve sends a branch to the supraspinatus and then abruptly curves around the lateral scapular spine, another site at which a traction injury may occur as the nerve approximates the scapula.  Subsequently, the nerve passes under the spinoglenoid inferior transverse scapular ligament of the spinoglenoid notch to terminate in the infraspinatus.  When this ligament ossifies or hypertrophies,(212,238) the patient is at greater risk for compressive and traction injuries, particularly during sudden abduction and flexion as this movement is mediated by the supraspinatus and contraction of this muscle fixates the nerve such that it is less free to move and resist traction injury.  Sudden infraspinatus mediated external rotation, a motion which also may occur in a motor vehicle accident as the arm is thrust outwards to protect the body, also fixates the nerve and predisposes to traction neuropraxia.  This nerve is susceptible to traction during sudden arm movements.(207,209,221,225,238)  The suprascapular nerve is superficial throughout its entire course such that it is also susceptible to direct blunt trauma.(222,225)  In addition to the above anatomic discussion, the nerve is fixated by a fascial encasement of the anterior and middle scalene muscles in the neck as well as in the fascia of the sublavius and omohyoid muscles,(207) suggesting that blunt trauma to this region can damage this nerve.
Even in the presence or absence of suprascapular neuropathy, block may decrease diffuse myofascial pain related to muscle spasms as the nerve innervates the peri-scapular supraspinatus and infraspinatus.(225)  In addition, as the suprascapular nerve has been presented as having sensory transmitting afferents.(86,172,214)  Selective blockade of pain transmitting afferent sensory fibers with smaller doses of local anesthetic will decrease pain and spare motor fibers of the nerve and avoid weakness.  Larger doses may decrease spasms, but progressive dose escalation will may result in weakness.  Because the bulk of supraspinatus mediated shoulder abduction is effected by the deltoid with contribution from the long head of the biceps and infraspinatus mediated shoulder external rotation is effected by the teres minor and posterior head of the deltoid, full suprascapular nerve block blocking sensory as well as motor fibers may not result in any functional loss.(172)
Suprascapular nerve block may deliver greater benefit than intra-articular injection of steroid to address chronic shoulder pain.(104)  In the management of frozen shoulder/adhesive capsulitis, suprascapular nerve block produced a faster and more complete resolution of pain and restoration of range of motion than a series of intra-articular injections.(220)  Because of the disabling potential of severe or refractory adhesive capsulitis, this condition should be managed liberally with both injections as well as physical therapy, potent analgesics, and surgical manipulation under anesthesia.  This is of particular importance to the brittle diabetic who may suffer hyperglycemia with steroid injections or be at higher risk for septic arthropathy from shoulder joint injection.  The two procedures may afford additive pain relief from shoulder pain, however, as anterior shoulder pain diminishes with shoulder joint injection as the sheath of the bicipital tendon is contiguous with the rotator cuff and glenohumeral joint.  Addition of axillary nerve block, however, addresses anterior shoulder pain.(214)  The patient must be educated that only the superior and postero-superior areas of shoulder pain are diminished with suprascapular nerve block to avoid excessive expectations.(112)  
Conversely, intra-articular shoulder injection alone does not uniformly confer full shoulder pain relief, particularly because the suprascapular nerve may be damaged by traction from anterior dislocation of the shoulder(172) concomitantly creating pathology to the rotator cuff.  In situations of acute inflammation of the rotator cuff or joint, if only one procedure is to be performed, steroid injection is preferable as it may treat the pain as well as cure the disease process through the anti-inflammatory properties of steroid.  In diabetics, clinicians may prefer to perform glenohumeral injections with local anesthetic to restrict the risks for iatrogenic infection.  Similarly, otherwise healthy individuals may wish to pursue local anesthetic shoulder injections without steroid to reduce the risks for steroid arthropathy in terms of cartilage damage.  Indeed, by the time that cartilage loss and bone erosion are present on x-ray, steroid injection is not considered to be efficacious.(112)
 

INTERVENTIONAL STRATEGIES – AXILLARY NERVE BLOCK 
Axillay nerve blocks decrease pain in the glenohumeral joint as well as spasms of the deltoid muscle.  Axillary nerve block also addresses anterior shoulder pain.(214)
 The nerve is susceptile to compression as well as traction as it courses throught the quadrangular space bounded by the humerus, long head of the triceps, and teres minor and major.  Injection must be performed with caution as the posterior circumflex humeral artery courses through this space.
 

INTERVENTIONAL STRATEGIES – OCCIPITAL NERVE BLOCK
Occipital nerve blocks decrease pain in the posterior scalp to address head and neck pain, often related to tension headaches as well as following motor vehicle accidents whiplash injuries(44) during which the rapid flexion and extension of the head may place traction on the nerve at its penetration site through the fascia of the lower head.
 

INTERVENTIONAL STRATEGIES – INTERCOSTAL NERVE BLOCK
Intercostal nerve block can decrease back pain in an entire dermatome and myotome with a single injection.  Several adjacent blocks may be required given the multi-segmental redundant nondiscrete innervation of adjacent dermatomes.  Post-herpetic intercostal neuralgia results in myofascial pain in intercostal muscles,(215) and neuropathic pain in the form of intercostal neuralgia responds to intercostal nerve block.(159)  Chronic severe post-thoracotomy myofascial pain(217) and post-traumatic myofascial mechanical pain with damage to muscles of the upper abdomen and thorax, costovertebral ligaments, and posterior spinal muscles responds to nerve blocks.(105,159,176,177,216)  The clinician must have experience with this procedure as it may result in fatal pneumothorax if the needle passes beyond the inferior aspect of the rib and into the chest wall cavity.  Intercostal block is felt to be safer than interpleural block as plasma anesthetic concentrations are less with the former procedure.(216)  Four to five weeks(106) of relief from intractable chronic pain with intercostal nerve block is considered successful treatment.
 

INTERVENTIONAL STRATEGIES – SCIATIC NERVE BLOCK
Sciatic nerve block is used to address buttocks pain with radiation down the leg.
 Sciatic neuropathy may exist as a double crush syndrome in which compression of the nerve root in the spine produces back pain with increased susceptibility of the distal nerve to injury at common anatomical sites of compression as under the piriformis muscle in the buttocks.  This is supported in basic science studies in that compression impairs axonal transport distal to the compressive site closest to the protein synthesis site in the anterior horn cell.(249)  EMG and nerve conduction studies are of limited value to support the piriformis site of compression as this test is often negative,(  ) presumably reflecting either involvement primarily of small diameter sensory fibers which the test cannot identify or pure demyelinating pathology.  Differentiation between back pain related to radiculopathy resulting in radiation of pain down the leg and the identical clinical presentation as related to radiculopathy and comorbid sciatic neuropathy in a double crush syndrome presentation is by physical examination.  Identification of pain with compression of the sciatic nerve between the greater trochanter and ischial tuberosity as pain would not be anticipated with compression in isolated lesions of pure radiculopathy.  
 Patients with unilateral compressive radiculopathy often suffer pain related to bilateral sciatic involvement.  The mechanism for this is clear in that compression at one side of the root ipsilaterally displaces the nerve and causes the contra-lateral root to suffer dual injury.  Traction related to the displacement relative to fixed sites of cutaneous penetration of the nerve results in damage to the nerve as well as compression of the nerve against the boney spine as it is pulled medially by the contralateral compression.
Patients with double crush injury with sciatic neuropathy often markedly benefit from sciatic nerve block as long as insufficient doses of local anesthetic are utilized to decrease pain without compromise of motor function.
 

INTERVENTIONAL STRATEGIES – GENITOFEMORAL NERVE BLOCK
Genitofemoral nerve block can markedly decrease groin and testicular, pain.(44)  Because of possible convergence of visceral and somatic afferent input to the wide dynamic range neuron of lamina V of the dorsal horn of the segmental spinal cord,(70) it is important to assess the patient with groin pain for possible renal or ureteral pathology as the same L2 and L3 levels of the spinal cord receive signals from skin and muscle of the medial thigh as well as the internal organs.  The corrolary is that injection into the site of reference can reduce referred pain from the viscera(70) such that pain from cholecystectomy may be reduced by intercostal nerve block.(  )  Obturator nerve block may reduce groin pain.(  )  The frequency of chronic pain after inguinal hernia repair is as high as 54%, and the subsequent chronic pain is felt to be related to damage to the genitofemoral and ilioinguinal nerves in a distinct population of patients.(124) Hip pathology may result in groin pain.(87)
 

INTERVENTIONAL STRATEGIES – ILIOINGUINAL NERVE BLOCK
Ilioinguinal nerve block decreases pain in the testicles.(44)  This nerve block is so effective that it can be used immediately after the abdominal surgery of Cesarean delivery to relieve pain to such an extent that morphine requirements are vastly curtailed.(129)
 

INTERVENTIONAL STRATEGIES –  SAPHENOUS NERVE BLOCK
Saphenous nerve blockade may attenuate knee pain.(      )  
 

INTERVENTIONAL STRATEGIES – LATERAL FEMORAL CUTANEOUS NERVE BLOCK
Lateral (femoral) cutaneous nerve of the thigh block can decrease the tingling and burning paresthesias of the outer lateral thigh caused by compression or traction of the nerve as it borders the inguinal ligament.  The painful condition is known as meralgia paresthetica and must be differentiated from L2, L3 radiculopathy as well as lumbar plexopathy.      
 

INTERVENTIONAL STRATEGIES – SUPRAORBITAL NERVE BLOCK
Supraorbital nerve block can be utilized to attenuate facial pain.
 

INTERVENTIONAL STRATEGIES – MEDIAN NERVE BLOCK
Median nerve block at the volar wrist is used to treat carpal tunnel syndrome.  As damage to the median nerve in the carpal tunnel is almost uniformly due to compression, it is unique from many other nerves such as the spinal accessory, suprascapular, and occipital nerves which are more often damaged by traction mechanisms of injury.  As such, it is important to keep in mind that compression of a nerve blocks large before small myelinated fibers(206) such that patients may suffer pain and weakness with normal sensory EMG/nerve conduction study testing.  This implies that even with a normal electrodiagnostic examination from a board certified examiner, patients with characteristic nocturnal symptoms, relief with shaking the wrist, reproducible symptoms with provacational testing, and symptoms confined to the median subserved hand should be referred to surgery instead of repeated nerve blockade. The nerve should be decompressed before muscle replacement by fibrotic tissue ensues, creating a contracted, dysfunctional hand.  In contra-distinction to the young patient with lateral disc herniation who should be managed conservatively first, patients with carpal tunnel syndrome should be treated first with surgery.  The natural history of spine lateral disc herniations if spontaneous healing in many patients, but the natural history of carpal tunnel syndrome is progressive nerve compression and nerve damage.  Those who do not respond to surgical management should be considered for chronic local anesthetic nerve blockade to decrease pain and enhance function.
 

INTERVENTIONAL STRATEGIES – SYMPATHETIC NERVE BLOCK
Stellate ganglion (cervicothoracic) block along with oral medications of several different mechanisms in addition to aggressive physical therapy may extinguish reflex sympathetic dystrophy of the upper extremity before it becomes disabling pain.  If the clinical presentation is not clear or if secondary financial gain issues are present as in the worker’s compensation or motor vehicle accident populations, then a triple phase bone scan should confirm the diagnosis before the block is performed.  The block itself should result in edema, erythema, and warmth which can interfere with subsequent clinical assessments if the diagnosis is in question.  If the objective findings alone are present without pain or evidence to suggest impairment or disability then the block was successful.  
 Celiac plexus nerve block may enormously decrease the intense back pain of pancreatic cancer.(38,79)
 Lumbar sympathetic block may extinguish lower extremity reflex sympathetic dystrophy.  It may be used in isolation to ameliorate pelvic cancers or delivered in combined with celiac plexus block to enhance the analgesic effect in patients with extensive intra-abdominal malignancy.(79)
 Hypogastric plexus block may attenuate pelvic pain.
 

RADIOPHARMACEUTICALS
Strontium 89 is preferentially reuptaken into bone to present radiation to metastases with reduction in pain 7-21 days after delivery and relief lasting up to six months.  Patients need to be monitored for secondary bone marrow suppression.  Exogenous radiation therapy may also markedly decrease pain related to skeletal metastasis.
 

HYALURONAN KNEE INJECTIONS
Viscosupplementation with hyaluronate(Hyalgan), sodium hyaluronate (NeoVisc) and hylan G-F 20 (Synvisc) injected into the knee may decrease pain more than intra-articular steroids with longer lasting effect, as suggested to be achieved by inhibition of inflammatory mediators such as cytokines and prostaglandins, stimulation of cartilage matrix synthesis and and inhibition of cartilage degradation, and a direct protective action on nociceptive nerve endings.(254)  Hyaluronan is a linerar polysaccharide naturally found in synovial fluid to maintain the structure of proteoglycans.(254)
 

NON-PHARMACOLOGIC TREATMENTS
Nonpharmacologic treatments are bereft of the cognitive side effects that so often limit prescription of the majority of nonopioid and opioid analgesics.  They are presented in this article following pharmacologic interventions as treatment with physical therapy, for example, without concomitant medication related attenuation of pain is far less likely to result in optimal patient participation relative to the patient treated in a team fashion by physicians as well as physical therapists. 
 

NON-PHARMACOLOGIC TREATMENTS - PHYSICAL AND OCCUPATIONAL THERAPIES
 Patients with prior histories of failure to tolerate physical therapy may benefit from retrials of therapy following control of their pain.  Therapy in these cases may consist of educating a patient safe body mechanics for lifting as well as teaching a patient an independent stretching, strengthening, and aerobic conditioning program.
Teaching the patient aggressive desensitization of areas of allodynia is a fundamental component of treatment of reflex sympathetic dystrophy.  It is most helpful to instruct the patient to rub the affected area before and after each meal as well as during commercials while watching television to increase the frequency of treatments.  Patients with osteoarthritis can be taught behavior modification such as avoiding heavy loads on joints by substitution of pool exercise and stationary bicycling for running on a treadmill.  Isometric exercises can be taught to patients to strengthen muscles with inflammatory arthropathies to lessen stress on joints during strengthening.  Patients with knee pain can be fitted with knee braces to redistribute the focal load from the joint to the diffuse proximal and distal soft tissues.  Strengthening the abdominal musculature will decrease back pain by ????
The use of passive modalities should be restricted in the treatment of most physical therapy patients.  Patients should be taught autonomy in the smallest number of visits by learning independent home flexibility, balance, and strengthening exercises. Patients do not need trained physical therapists to apply cold or heat, but the patient should be educated that both modalities are synergistic although cold should be utilized during the initial days after a new injury to slow enzymes active during inflammation.
L4, L5 radiculopathies, polyneuropathies, multiple sclerosis, stroke, and other diagnoses may result in footdrop.  This may be refractory to strengthening, electrical stimulation, and neuromuscular re-education techniques, and fitting for an ankle foot orthosis (AFO) may be necessary.  An AFO is a rigid plastic support on the foot and posterior lower leg to prevent passive ankle plantarflexion.  If the AFO is constructed with several degrees of fixed plantarflexion then this will transfer the ground reaction moment anterior to the knee joint to force it into extension to facilitate standing and walking in the patient with hip flexion contractures or weak knee extensors as seen in patients with femoral mononeuropathies, lumbosacral plexopathies, and L3, L4 radiculopathies.  
Teaching patients with hip pain the safe use of a cane in the contralateral hand may markedly decrease pain.  The cane substitutes for the gluteus medius such that the 300% less pressure is exerted on the femoral head.  
Teaching patients the use of a walker may enormously increase the safety of gait and decrease the risks for falls.  Patients must be educated that a simple fall from a standing height is the single most common cause of quadriplegia in patients age 45 and older as the anterior and posterior longitudinal ligaments calcify and become less flexible.  In addition, falls resulting in disc herniation are more likely to herniate centrally in the cervical spine as the posterior longitudinal ligament is stronger laterally.
Patients should be instructed on safe aerobic exercises as aerobic exercise increases endorphin and enkephalin endogenous opioid release. Enkephalins are felt to bind to delta opioid receptors and beta-endorphins bind to epsilon opioid receptors.(23)  Use of the stair climber should be avoided in the patient with knee pathology as ascension and descension of stairs markedly increases knee joint pressures.  The bicycle should be avoided in patients with disc herniation as sitting markedly increases disc pressures.  Fibromyalgia patients in particular should actively pursue aerobic exercise to decrease pain.
Patients with disc bulges and protrusions should be taught safe lifting biomechanics to reduce the likelihood of frank herniation of the nucleus pulposis.  The annular fibers of the intervertebral discs are subject to structural compromise during the stress of concomitant lumbar spine flexion and rotation.  Disc bulges and protrusions may be asymptomatic in many individuals, but herniation far more consistently induces neural compression and clinical symptomatology.  
Patients should always see a physician before seeing a physical therapist.  Therapists are expert at nonpharmacologic management as well as neuromusculoskeletal assessment, but physicians must first assess for occult malignancies, vascular pathology such as abdominal aortic aneurysms, inflammatory and autoimmune conditions, and a host of other systemic primary pathologies which may secondarily manifest with orthopedic presentations.  Given the expertice of the physical therapist in neuromusculoskeletal assessments, physicians should routinely solicit their input in objectively defining work capacity via physical and functional capacity assessments.  Patients advance much more quickly in physical therapy if their pain is attenuated pharmacologically co-incident with initiation of therapy.
 

RETURN TO WORK
Physicians address the medical generators of pain.  By decreasing pain, function necessarily is advanced.  Level II physical therapists are trained with an advanced degree to determine the safe level at which patients can return to work with gradual advancement to full time duties as monitored by the physician.  It is inappropriate for physicians to define work status in light the extensive training inherent to a level II advanced degree to perform a Functional Capacity Evaluation (FCE).  Patients should not be sent to a FCE until they are at maximal medical endpoint such that they have trialed a sufficient number of medications such that it is not anticipated that their pain will significantly improve.  However, physicians may intercede in terms of medically related issues such as limiting duties based on the extent of surgical manipulation and resection.  Patients with multiple sclerosis cannot safely be authorized to work in hot external environments or compelled to perform labots which increase body temperature as this may exacerbate the underlying disease.
If modifications in terms of work intensity and social acceptance are embraced, 100% of patients with fibromyalgia often return to full time work.(160)  As this occurs with the diffuse myofascial pain state of fibromylalgia, full time work certainly is expected of most patients with regional myofascial pain.  “Fibromyalgia does not necessarily cause work disability,” and it has been suggested that this may be achieved by “…abolishing disability awards based on the diagnosis of fibromyalgia,” thereby “…encouraging patients to get better, rather than to see themselves as disabled.”(160)  Humans are social animals.  The isolation passively imposed by failure to work results in increased mood depression.  In addition, the structure of awakening on a scheduled basis to get to work on time forces patients into a routine such that they focus on the intellectual demands of work as opposed to directing their attention inwardly towards their pain and impairments. 
 

HANDICAPPED PARKING
Patients often ask for handicapped parking placards.  It is in the patient’s best interests to educate fibromyalgia and other patients that these few spots are best reserved for those with spinal cord and traumatic brain injuries who may be wheelchair dependent.  Honoring all requests for handicapped parking is identical to rescinding handicapped parking for the neurologically impaired and the elderly.  Patients with chronic pain should be educated that the exercise is good for them to lubricate their joints and maintain muscle strength.  The first rule in medicine is “do no harm” and giving handicapped parking spots to all solicitors harms both groups of people.
The number of available handicapped parking spaces is very limited.  Patients with orthopedic deformities such as severe kyphoscoliosis, neurologically impaired patients such as those with spinal cord injury, multiple sclerosis patients in whom disease activation may be precipitated by inordinate exertion,  and cancer and elderly patients with profoundly compromised endurance should receive these limitied spots.  A preponderance of patients with chronic pain request handicapped placards, but they should be educated regarding allocation of the limited spots for those who are even more needy.  They should also be informed that the exertion to ambulate the greater distance in the parking lot is beneficial in terms of cardiovascular conditioning as well as maintaining flexibility and strength.
 

NON-PHARMACOLOGIC TREATMENTS – TENS UNITS
Transcutaneous electrical nerve stimulation (TENS) units look like wallet sized radios and deliver almost imperceptible electrical signals to the skin, usually in the area of pain.  The innocuous signal is transmitted by nonnociceptive large I-A fibers to the dorsal horn of the spinal cord to the level of lamina IV and then deeper to wide dynamic range neurons of level V.  It is felt that inhibitory interneurons at this level attenuates and may extinguish pain afferent signals from A-delta and C afferent nerve fibers which terminate at lamina I, II, and V.(70)  In the presence of I-A signals from the TENS unit, signals from A-delta and C fibers are attenuated or extinguished at lamina V and are unable to sufficiently depolarize the second order neuron to send the signal up the spinothalamic, spinoreticular, and other tracts to the cerebral cortex.  Though effective to varying degrees, the autonomy afforded by a TENS unit should not be minimized.  TENS units decrease both mechanical myofascial pain as well as neuropathic pain.(173)
 The efficacy of TENS units have resulted in the use of implantable dorsal column neurostimulators.
 

NON-PHARMACOLOGIC TREATMENTS - RELIGION
Rabbis, chaplains, priests, and other leaders of faith can be extremely helpful for patients to deal with living with chronic pain.(195)  The service can be invaluable, as many patients report that a life of chronic pain is quite lonely.  Religious leaders show that it’s not only the doctor who cares, as family members very frequently “just don’t understand.”  Rabbis, chaplains, and priests treat patients with respect and acknowledge the patient’s suffering.  Religious figures assist clinicians to reassure patients that pain does not reflect ongoing, dangerous tissue injury.
 

NON-PHARMACOLOGIC TREATMENTS – PET THERAPY
Dogs, cats, and other pets can enormously help the patient with pain, anxiety, and mood depression cope with their condition.(   )  The animal shows unconditional affection.  In addition, caring for another living being gives the patient a sense of purpose.  Walking a pet dog has benefits for the chronic pain patient in terms of maintaining strength and flexibility as well as activating the endogenous opioid endorphin and enkephalin pain pathways.
 

NON-PHARMACOLOGIC TREATMENTS – SUPPORT GROUPS, DIARIES
Support groups for chronic pain can be detrimental or helpful.  Patients are adversely affected when the focus of the support group is on commiserating and complaining.  Truly effective support groups focus on the better function appreciated with ongoing pain management.  Similarly, patient diaries can be negative or beneficial.  Keeping a log of pain every day forces the patient to focus on pain which is not desirable as it reinforces the foundation of depression, anxiety, and dome of isolation.  Rather, keeping a log of functional achievements is inspiring to continue to function at a higher level.
 

NON-PHARMACOLOGIC TREATMENTS – KYPHOPLASTY
In the acute management of new pathologic fractures, kyphoplasty and vertebroplasty may decrease pain.  Kyphoplasty expands a tiny balloon inside a collapsed vertebral body with subsequent instillation of cement to restore the vertebral body height and shape(115) in an attempt to prevent the kyphoscoliotic deformity which accompanies advanced age with sequential levels of collapsed vertebrae.  The deformity does not simply contribute to pain, but also may impair maximal ventilatory effort, predisposing to atalectasis with pneumonia, dypnea with mild exertion as well as increased risks for pulmonary hypertension and cor pulmonale.  Use of sedating analgesics may decline following the procedure with accompanying decreased risks of falls, head injury, and spinal cord injury in elderly patients.  Postmarketing surveillance will be required to define efficacy in younger patients in whom the cement will reside for numerous decades.  
An integral component of treating with kyphoplasty must include behavioral and pharmacotherapy to delay the underlying osteoporosis disease progression.  Patients should be educated to engage in a progressive resistance exercise program, weight bearing aerobic exercise, limit vitamin A ingestion, 1500 mg of daily calcium, 400-800 IU of vitamin D, substitution of anticalciuric thiazides for other antihypertensives or instead of calciuric low dose loop diuretics.  Calcitonin with or without bisphosphonates may also be given.
 

NON-PHARMACOLOGIC TREATMENTS – MAGNETS
Magnets may decrease chronic pain.(101)  They are particularly advantageous in the patient with limited cognitive reserve as they do not contribute to impaired intellectual function.
 

NON-PHARMACOLOGIC TREATMENTS – ACUPUNCTURE AND MASSAGE
Acupuncture and massage are safe treatments, but visits often need to occur two to three times a week such that patient autonomy is sacrificed as they focus on their pain and the next visit as opposed to focusing on function and return to work and other activities.  For this reason, most experts in pain management discourage the use of pain diaries as patients learn to focus on pain not on the positive aspect of resuming functional lives with pain in the background.  Acupuncture may work via a mechanism similar to TENS units(  ) or it may effect analgesia via tracts from the cerebral cortex descending to the dorsal horn.(   ) 
 

MORPHINE INTRATHECAL PUMP IMPLANTATION
 Despite the inconveniance of pump refills every 2-3 months and surgical removal every several years to replace the pump battary, many patients are very pleased with the results of morphine pump implantation.  Other medications such as clonidine and lioresal can be added to the pump in addition to morphine.  Patients often suffer far less systemic and cognitive effects with intrathecal delivery as opposed to oral opioid consumption.
 

SURGICAL MANAGEMENT
Given the risks for pain to intensify after removal of structural elements of the spine, pain itself is not an indication to pursue surgery.  The natural history of disc herniations is to spontaneously regress back into the spine.(   )  At least seventy percent of patients with far lateral disc herniations achieve a high nonoperative success rate.(241)  Patients with back pain and radiculopathy with pain radiating down the leg usually recover well without surgery(240) even with documented full nucleus pulposus disc herniation.(235)  Even large sized herniations characteristically decrease with time and dehydration.(234)  Serial MRI’s document progressive reduction in disc herniation which extends well beyond the year following injury.(236)
“Failed back syndrome” refers to the subset of patients who have persistent more severe pain following surgery.  It is often applied to the patient who was rushed to surgery before receiving conservative trials with analgesics, and such a patient often never returns to work.  The natural history of disc herniation is to recede with time,(   ) and treating pain during this period allows some patients to continue working in a restricted lifting capacity.  
In some patients who are surgically managed, they produce fibrotic tissue(254) in response to the physical manipulation during surgery, much akin to the adhesions that some patients suffer following intra-abdominal surgery.  With both types of surgery, this unidentifiable subset of patients will suffer greater pain following surgery as fibrotic tissue compresses neural tissue.  In an effort to help, the surgeon will revisit the area, but fibrotic tissue often regrows in exuberance with pain even greater than prior to surgery.  In addition, with resection of stabilizing bone of the spine, a subset of patients will respond by growing random osteophyte projections of bone, and the aberrant, unguided bone also compresses neural tissue and increases pain.  
In a further effort to help the patient, some surgeons will offer fusion to the patient to re-stabilize the spine, but fused spines lack the mobility of the healthy spine with increased stress generated in spinal segments above and below the fusion.  In addition, the fused spine lacks the normal lumbar lordosis such that patients are at high risk to develop strains in lumbar paraspinal tissues with consequent chronic myofascial back pain similar to the mechanism by which this occurs in patients with knee pain inducing severe back pain.(74,85,237)  Lumbar spine fusion surgery has a reoperation rate of 15% to 35% with very poor long-term success, a complication rate of 5%-18%, and does not improve sitting tolerance.(254)
Since it is impossible to identify which patient will respond to surgery by developing increased fibrotic and boney tissue overgrowth, and since patients who develop these complications are enormously more difficult to treat in terms of pain reduction and return to work, it is most appropriate to first trial conservative pain management before surgical treatment.
 

SURGICAL MANAGEMENT – OPTIMAL PATIENTS FOR SURGICAL REFERRAL
Intolerance or inefficacy to comprehensive conservative pain management as discussed above does require referral to the surgical colleague for evaluation.  For example, some patients have such limited cognitive reserve that they cannot tolerate opioid and nonopioid analgesics.  The elderly often constitute this class and they are characteristically less active than younger patients such that they are less likely to suffer secondary osteoarthritis from removal of stabilizing elements of the spine.  The elderly also are not working, and thus lack the incentive for greater worker’s compensation settlements which uniformly accompanies surgical treatment.  The surgeon may be more comfortable that the older patient is soliciting surgical treatment to attenuate pain as opposed to manipulating the surgeon for secondary gain.  Younger patients who require progressively escalating opioid doses beyond that which the clinician is comfortable prescribing should receive surgical referral.  If the surgeon deems the patient not to be a candidate for tissue resection or other procedures, then the patient should be evaluated for neurostimulator or intrathecal pump implantation.  No clinician is mandated to progressively escalate opioid dosing beyond that which he feels comfortable in his training and experience.
Patients with orthopedically or neurologically unstable spines are susceptible to further injury if not surgically managed.  Though patients with pas interarticularis fractures / spondylolysis do not require surgical stabilization,(233) individuals with spondylololisthesis may require surgically stabilization to prevent anterior translation of the spine onto the spinal cord.  Rheumatoid arthritis commonly affects the stabilizing ligaments of the cervical spine and failure to evaluate and treat this surgically may result in quadriplegia.  Patients status post motor vehicle accidents may suffer occult odontoid and other spine fractures with risks for spinal cord pathology without surgical stabilization.  Those patients with disc herniation to the central canal with weakness, saddle anesthesia over the buttocks, and/or urinary or fecal incontinence consistent with cauda equina syndrome must be emergently surgically decompressed within 48 hours to preserve neurologic function.(110).  Patients with severe cervical or lumbar spinal stenosis should consider pre-emptive surgical decompression to avoid insideously progressive loss of limb strength with accompanying risks for falls as well as acute quadriplegia and paraplegia should they fall or suffer a motor vehicle accident.
Patients with severe scoliosis develop restrictive lung disease with consequent cor pulmonale right sided congestive heart failure and premature death if the scoliosis is not addressed.  Untreated scoliosis does not simply result in back pain, but may also result in shortness of breath during simple everyday activities, particularly if the Cobb angle is greater than eighty degrees and a thoracic apex is present.(231)  Resection of malignant tumors clearly requires surgical resection, but so does resection of benign tumors such as osteoid osteoma which may result in profound pain.
Definitive surgical hip and knee replacement usually markedly reduces pain, but younger patients may need to defer this as the hardware has a limited longevity and repeated arthroplasties may be less durable.  Similarly, patients with carpal tunnel syndrome should be treated with surgery before volar wrist carpal tunnel injections are performed as the natural history of carpal tunnel compression is progression of nerve compression.  
 

NON-PHARMACOLOGIC TREATMENTS – CHIROPRACTIC MANIPULATION
 Chiropractic manipulation of the neck is often discouraged by pain management experts.  The anatomy of the neck is such that the vertebral arteries travel in the transverse processes(   ) and can be dissected during neck manipulation with consequent stroke.  Similarly, the spinal canal in the cervical spine is considerably more narrow relative to the lumbar spine.  As such, if manipulation results in compromise of the annulus fibrosis of the disc then the consequent herniation is far more likely to compress the spinal cord as opposed to the lumbar spine with its larger diameter canal with simple displacement of the spinal cord.  Furthermore, the posterior longitudinal ligament in the cervical cord is stonger laterally than it is centrally such that the extruded disc moving in the path of least resistance is more likely to herniate centrally onto the spinal cord with consequent quadriplegia.  Forceful lower back manipulation is also not without considerable risks, but the lumbar spine posterior longitudinal ligament is stronger centrally such that discs are more likely to herniate laterally onto the nerve roots. 
 

SUMMARY - INITIAL TREATMENT STRATEGIES
Obesity, mood depression, insomnia, and other comorbid conditions should be addressed as integral to comprehensive pain management.  Many analgesics impair cognition and so calcitonin, lidocain patch, NSAID’s, topical counterirritants, and glucosamine and chondroitin are amongst first line options as these don’t interfere with patient ability to work and these medications rarely contribute to chronic fatigue.  Glucosamine and chondroitin reverse osteoarthritis as new cartilage is built and also diminishes pain and disability.  Calcitonin may extinguish mechanical as well as neuropathic pain, and this medication has additional benefits to enhance bone quality.  This is an important virtue given the decreased activity that so often accompanies chronic pain as well as the advancing age of the general population with inherent female and male risks for pathologic osteoporosis related fractures.  In addition, calcitonin favorably affects disease progression in patients with pain related to pathologic fractures.  NSAID’s are extremely effective in states of clear inflammation, and clinicians should trial agents of multiple different classes to potentially cure even chronic pain.  Daily NSAID use should be prescribed with caution in chronic pain given the enormous frequency of deaths related to use of this class of medications.  Lidocaine patch predictably impairs afferent transmission of nociception and is synergistic with the other most predictably efficacious analgesic class, the opioids.  The patch has no cognitive toxicity and often signficantly decreases mechanical as well as neuropathic pain.  Over the counter topical counterirritants are vastly underutilized and patients should be educated that different products have different active ingrediants. The anesthetics also potentiate the opioids and co-prescription is a wise strategy.  Injected local anesthetics often better address pain relative to topical application given the better approximation to deeper neural tissue.  A single nerve block may obviate the need to perform dozens of trigger point injections.  Opioids should not be reserved for late in the disease course to avoid entrenchment of pain into a chronic state by well recognized mechanisms of peripheral and central sensitization.  The extreme rarity of tolerance and addiction in humans must be appreciated.  Kyphoplasty should be utilized in acute osteoporotic vertebral fractures to not just decrease pain but also deformity.  In true reflex sympathetic dystrophy the clinician should not hesitate to rapidly refer to anestheseologists for sympathetic nerve blockade, and the physician should intensively educate the patient regarding desensitization techniques.  There must be no delay in emergent neurosurgical or orthopedic referral to surgically decompress cauda equina syndrome within the first 48 hours of onset to avoid permanent paraplegia.(110)
 

SUMMARY – SPECIAL POPULATIONS
The patient with cancer often markedly benefits from NSAID’s, steroids, calcitonin, bisphosphonates, opioids, radiopharmaceuticals, radiation therapy, and coeliac plexus blockade. Methylphenidate addresses the profound pain, mood depression, and fatigue related to cancer, though its anorectic properties may mandate use of modafinil (Provigil) in its stead.  Remeron is also helpful to address pain and mood depression as well as stimulate appetite.  Several other analgesics may also contribute to weight gain, including amitriptyline (Elavil), paroxetine (Paxil), and zyprexa (Olanzapine).  Clinicians should entertain prophylactic treatment with antidepressants given the high incidence of this condition in the oncology population.  Marinol also has multiple indications for use in the oncology patient to decrease pain, stimulate appetite, and suppress nausea.  A celiac plexus nerve block may enormously decrease the intense back pain of pancreatic cancer.(38,79)  Though most non-pain management expert physicians feel most comfortable prescribing opioids to patients with malignancy related pain, even this group of patients is undertreated with opioids.  Clinicians must keep in mind the inordinate frequency of opioid theft from family and extra-familial caregivers.  A means to combat this is to utilize the fentanyl patch and have other family members work in unison to confirm that the patch is always changed and never dried up and empty.  
 Patients with peripheral neuropathic pain such as herpes zoster and reflex sympathetic dystrophy benefit from topical application of NMDA antagonists such as ketamine cream, opioids dissolved in water, topical local anesthetics, and topically compounded anticonvulsants as the constant rubbing of the cream and liquid desensitizes the area beyond the benefit of the medication itself.  
 Patients with multiple sclerosis induced pain, thalamic post-stroke pain, phantom spinal cord injury related pain, and other pain following central nervous system pathology benefit from lioresal and tizanidine as these medications decrease pain as well as the spasms of the spasticity triad.
 Patients with cognitive compromise respond best to creams, opioids dissolved in water, lidocaine patch, local anesthetic injections, calcitonin, glucosamine and chondroitin, magnet therapy, acupuncture, physical therapy, massage, alpha blocking and calcium blocking antihypertensives, and psychostimulants for both their analgesic as well as their cognition enhancing properties.
 

FUTURE DIRECTIONS
Nitric oxide delivering COX-2 selective NSAID’s may confer similar benefits as traditional NSAID’s without potentially less risks for acute renal failure(   ) and with low GI toxicity as nitric oxide replaces prostaglandins and mediators of mucosal protection.(3)  Medications such as licofelone to block both cyclooxygenase as well as 5-lipoxygenase are in clinical studies and may have low GI toxicity by virtue of blocking LTB4 synthesis.(3)  Phase I/II studies are ongoing with vascular endothelial growth factor gene transfer to address pain related to diabetic polyneuropathy.  Sufentanil may be available in a subcutaneous injectable form, and this opioid is 5-10 times stronger than fentanyl.(23)  Cannabis-1 receptor blockers have been considered as medications to suppress appetite to treat obesity.  N-subtype calcium channel antagonists such as intrathecal ziconotide have hundreds of times the analgesic potency of opioids and may profoundly decrease pain and the need for opioids in the treatment of chronic pain.(26) The combination of naloxone in the delivery mechanism of Buprenorphine-Naloxone (Suboxone) should herald a new era as a standard of opioid delivery to profoundly limit abuse potential.

No pharmaceutical company financial support was suggested, offered, or accepted in the production of this article.  It was conceived to educate physicians as well as patients.
 REFERENCES

1. Richy F, Bruyere O, Ethgen O, et al.  Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis.  Arch Intern Med 2003:163:1514-1522.
2. Tanasescu M, et al.  Physical activity in relation to cardiovascular disease and total mortality among men with type 2 diabetes.  Circulation.  2003;107:2435-2439.
3.  Skelly MM, Hawkey CJ.  Potential alternatives to COX 2 inhibitors.  BMJ 2002;324:1289-91.
4.  Fitzgerald GA, Patrono C.  The coxibs, selective inhibitors of cyclooxygenase-2.  N Engl J Med.  2001;345:433-442.
5.  Hays JT, Ebbert JO.  Bupropion sutained release for treatment of tobacco dependence.  Mayo Clin Proc. 2003;78:1020-24.
6.  Reeves RR, Mack JE.  Case report: Possible dangerous interaction of OxyContin and carisoprodol.  Am Fam Phys 2003 June 1;67(11):2273.
7.  Fishbain DA, Cole B, Cutler RB, et al.  Is pain fatiguing?  A structured evidence-based review.  Pain Medicine.  2003;4(1):51-62.
8.  Borenstein DG, Korn S. Efficacy of a low-dose regimen of cyclobenzaprine hydrochloride in acute skeletal muscle spasm: results of two placebo-controlled trials.  Clin Ther. 2003;25:1056-1073.
9.  Boothby, LA, Doering, PL, Hatton, RC.  Carisoprodol: A marginally effective skeletal muscle relaxant with serious abuse potential.  Hospital Pharmacy.  2003;38:337-345.
10. Meier DE, Emmons CA, Litke A, et al.  Characteristics of patients requesting and receiving physician-assisted death.  Arch Intern Med 2003;163:1537-1542.
11. Hemstapat K, Monteith GR, Smith D, et al.  Morphine-3-Glucuronide’s neuro-excitatory effects are mediated via indirect activation of N-methyl-D-aspartic acid receptors: Mechanistic studies in embryonic cultured hipocampal neurones.  Anesth Analg. 2003 Aug;97(2):494-505.
12. Bolan EA, Tallarida RJ, Pasternak GW.  Synergy between mu opioid ligands: Evidence for functional interactions among mu opioid receptor subtypes.  J of Pharmacology and Experimental Therapeutics 2002;303(2):557-62.
13. Fisher BJ, Haythornthwaite JA, Heinberg LJ, et al.  Suicidal intent in patients with chronic pain.  Pain  2001 Jan;89(2-3):199-206.
14.  Kurtze N, Svebak S.  Fatigue and patterns of pain in fibromyalgia:  Correlations with anxiety, depression and co-morbidity in a female county.  Br J Med Psychol 2001;74:523-37.
15. Cleary, JF (CME Reviewer): Developments in Treating the Lower Back Pain Patient: Muscle Relaxant Therapeutic Options. Jointly sponsored by the University of Wisconsin Medical School and ProCom International, June 2003.
16. Jenson, MG, Ward S, Hale GR.  Rofecoxib and Montelukast Sodium as Combination Therapy in Arthritis or Other Rheumatic Conditions: A Case Study.  The Pain Clinic. May/June 2003;22-24.
17. Gyamlani GG, Parikh CR.  Acetaminophen toxicity: suicidal vs accidental.  Crit Care 2002;6(2):155-59.
18.  Harkonen M.  Medically induced gingival hyperplasia (Letter to the Editor).  Mayo Clin Proc.  1999;74:742-45.
19.  Ehrich EW, Dallob A, De Lepeleire I, et al.  Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model.  Clin Pharmacol Ther.  1999;65:336-347.
20.  Crandall C.  Making strides in obesity management.  Internal Medicine. June 1997;62-84.
21.  Skoczylas T, Sarosiek I, Sostarich S, et al.  Significant enhancement of gastric mucin content after rabeprazole administration: its potential clinical significance in acid-related disorders.  Dig Dis Sci.  2003 Feb;48(2):322-28.
22. Reeves RR, Liberto V.  Abuse of combinations of carisoprodol and tramadol.  South Med J. 2001;94(5):512-4.
23. Hsieh JC, Carr DB. Choosing a therapeutic approach: Opioids. In: Borsook D, LeBel AA, McPeek B, eds. The Massachusetts General Hospital Handbook of Pain Management. New York, NY: Little, Brown 1995:47-75.
24. Reyes M, Nisenbaum R, Hoaglin DC, et al.  Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas.  Arch Intern Med. 2003:163:1530-1536.
25. Fischer AA.  Pain relief; Sterile water for whiplash syndrome.  Lancet 1993 Feb 20;341:470.
26. Prado WA.  Involvement of calcium in pain and antinociception.  Braz J Med Biol Res.  2001 Apr;34(4):449-61.
27.  Wilcox CM, Clark WS.  Features associated with painless peptic ulcer bleeding.  Am J Gastroenterol.  1997 Aug;92(8):1289-92.
28. Feuerstein M, Carter RL, Papciak AS.  A prospective analysis of stress and fatigue in recurrent low back pain.  Pain. 1987;31:333-44.
29.  Weinbroum AA, Gorodetzky A, Nirkin A, et al.  Dextromethorphan for the reduction of immediate and late postoperative pain and morphine consumption in orthopedic oncology patients: a randomized, placebo-controlled, double-blind study.  Cancer.  2002 Sep 1;95(5):1164-70.
30.  Henriksson KG, Sorensen J.  The promise of N-methyl-D-aspartate receptor antagonists in fibromyalgia.  Rheum Dis Clin North Am. 2002 May;28(2):343-51.
31.  Bulka A, Wiesenfeld-Hallin Z, Xu XJ.  Differential antinociception by morphine and methadone in two substrains of Sprague-Dawley rats and its potentiation by dextromethorphan.  Brain Res.  2002 Jun 28;942(1-2):95-100.
32.  Mohamed SA, Mohamed K, Borsook D. Choosing a phramacotherapeutic approach: Nonopioid and adjuvant analgesics.  In: Borsook D, LeBel AA, McPeek B, eds. The Massachusetts General Hospital Handbook of Pain Management. New York, NY: Little, Brown 1995;76-104.
33.  Schaller JL, Behar D.  Modafinil in fibromyalgia treatment.  J Neuropsychiatry Clin Neurosci 13:530-31.
34. Borenstein D, Bigos SJ, Krabak BJ, et al.  Acute Musculoskeletal Pain Management March 2003; 1(2): 1-7.
35.  Cox JM, Pappagallo M.  Modafinil: A gift to portmanteau.  Am J of Hospice & Palliative Care Nov/Dec 2001; 18(6):408-10.
36. Lipman AG, Jackson II, KC.  Use of opioids in chronic noncancer pain.  Power-Pak Communications, Inc., 1500 West Canal Court, Suite #500, Littleton, CO 80120-4569, 2000:1-10.
37. Devers A, Galer BS.  Topical lidocaine patch relieves a variety of neuropathic pain conditions: An open-label study.  Clinical J Pain 2000; 16(3):205-8.
38. Mercadante S.  Celiac plexus block versus analgesics in pancreatic cancer.  Pain 1993; 52:187-192.
39. Khojainova N, Santiago-Palma J, Kornick, C, et al.  Olanzapine in the management of cancer pain.  J Pain and Symptom Management 2002 23(4):346-50.
40. Tallarida RJ, Stone Jr. DJ, McCary JD, et al.  Response surface analysis of synergism between morphine and clonidine.  J Pharmacol Exp Ther.  1999 Apr;289(1):8-13.
41. Brzozowski T, Konturek PC, Konturek SJ, et al.  Classic NSAID and selective cyclooxygenase (COX)-1 and COX-2 inhibitors in healing of chronic gastric ulcers.  Microsc Res Tech.  2001 Jun 1;53(5):343-53.
42. Chang A, Emmel DW, Rossi BC, et al.  Methadone analgesia in morphine-insensitive CXBK mice.  Eur J Pharmacol.  1988 Jun 19:351(2):189-91.
43. Whitcomb DC, Gilliam FR III, Starmer CF, et al.  Marked QRS complex abnormalities and sodium channel blockade by propoxyphene reversed with lidocaine.  J Clin Invest. 1989 Nov;84(5):1629-36.
44. Todd DP, Mohamed SA.  Diagnostic and therapeutic procedures in pain management. In: Borsook D, LeBel AA, McPeek B, eds. The Massachusetts General Hospital Handbook of Pain Management. New York, NY: Little, Brown 1995:134-184.
45.  Kiser RS, Cohen HM, Freedenfeld RN, et al.  Olanzapine for the treatment of fibromyalgia symptoms.  J Pain and Symptom Management 2001 22(2):704-8.
46.  Kolesnikov YA, Jain S, Wilson R, et al.  Peripheral morphine analgesia : synergy with central sites and a target of morphine tolerance.  J Pharmacol Exp Ther 1996 279:502-6.
47.  Brown GJ, Yeomans ND.  Prevention of the gastrointestinal adverse effects of nonsteroidal anti-inflammatory drugs.  The role of proton pump inhibitors.  Drug Safety  1999 Dec;21(6):503-12.
48. Feldman M.  Cyclooxygenases and GI mucosal protection.  The Regulatory Peptide Letter – Cyclooxygenases 2001;8(4):56-60.
49.  Prough DS, McLeskey CH, Poehling GG, et al.  Efficacy of oral nifedipine in the treatment of reflex sympathetic dystrophy.  Anesthesiology.  1985:62:796-99.
50.  Endo K, Sairyo K, Komatsubara S, et al.  Cyclooxygenase-2 inhibitor inhibits the fracture healing.  J Physiol Anthropol Appl Human Sci.  2002 Sep;21(5):235-8.
51. Fishman SM, Greenberg DB.  AA.Special problems in the treatment of pain.  In: Borsook D, LeBel AA, McPeek B, eds. The Massachusetts General Hospital Handbook of Pain Management. New York, NY: Little, Brown 1995:370-378.
52.  Heaney RM.  Left bundle branch block associated with propoxyphene hydrochloride poisoning.  Ann Emerg Med.  1983 Dec;12(12):780-2.
53.  Morisset V, Nagy F.  Plateau potential-dependent windup of the response to primary afferent stimuli in rat dorsal horn neurons.  Eur J Neurosci.  2000 Sep;12(9):3087-95.
54.  Vainio A, Ollila J, Matikainen E, et al.  Driving ability in cancer patients receiving long-term morphine analgesia.  Lancet.  1995;346:668-69.
55. DiCapua JF, LeBel, AA.  Opioid management of chronic nonmalignant pain: Nonopioid and adjuvant analgesics.  In: Borsook D, LeBel AA, McPeek B, eds. The Massachusetts General Hospital Handbook of Pain Management. New York, NY: Little, Brown 1995:363-369.
56.  Kimmel HL, Tallarida RJ, Holtzman SG.  Synergism between buprenorphine and cocaine on the rotational behavior of the nigrally-lesioned rat.  Psychopharmacology (Berl).1997 Oct; 133(4):372-7.
57.  Buskila D, Odes LR, Neumann L, et al.  Fibromyalgia in inflammatory bowel disease.  J Rheumatol.  1999 May:26(5):1167-71.
58.  Wu LG, Westenbroek RE, Borst JGG, et al.  Calcium channel types with distinct presynaptic localization couple differentially to transmitter release in single calyx-type synapses.  Journal Neuroscience.  1999 Jan 15;19(2):726-36.
59.  Sluka KA.  Blockade of N-and P/Q-type calcium channels reduces the secondary heat hyperalgesia induced by acute inflammation.  Journal Pharmacology Exper Therap 1998 Oct;287(1)232-7.
60.  Bazzano LA, He J, Ogden LG, et al.  Dietary fiber intake and reduced risk of coronary heart disease in US men and women.  Arch Intern Med 2003;163:1897-1904.
61. Miranda H, Viikari-Juntura E, Martikainen R, et al.  A prospective study on knee pain and its risk factors.  Osteoarthritis Cartilage.  2002 Aug;10(8):623-30.
62.  Bodack MP, Tunkel RS, Marini SG, et al.  Spinal accessory nerve palsy as a cause of pain after whiplash injury: case report.  J Pain Symptom Manage.  1998 May;15(5):321-28.
63.  Carta F, Bianchi M, Argenton S, et al.  Effect of nifedipine on morphine-induced analgesia.  Anesthesia and Analgesia 1994;79:303-6.
64.  Katchman AN, McGroary KA, Kilborn MJ.  Influence of opioid agonists on cardiac human ether-a-go-go-related gene K(+) currents.  J Pharmacol Exp Ther.  2002 Nov;303(2):688-94.
65. Shallcross TM, Heatley RV.  Effect of non-steroidal anti-inflammatory drugs on dyspeptic symptoms.  BMJ 1990;300:368-9.
66.  Ballas SK.  To the editor: Treatment of painful sickle cell leg ulcers with topical opioids.  Blood 2002 Feb 1;99(3):1096-97.
67.  Kolesnikov YA, Chereshnev I, Pasternak GW.  Analgesic synergy between topical lidocaine and topical opioids.  J Pharmacol Exp Ther. 2000 Nov;295(2):546-51.
68.  Adriaensen H, Vissers K, Noorduin H, et al.  Opioid tolerance and dependence: an inevitable consequence of chronic treatment?  Acta Anesthesiol Belg.  2003;54(1):37-47.
69.  Kittelberger KP, Borsook D.  Neural basis of pain.  In: Borsook D, LeBel AA, McPeek B, eds. The Massachusetts General Hospital Handbook of Pain Management. New York, NY: Little, Brown 1995:8-25.
70.  Basbaum A.  Basic Mechanisms: Anatomy and physiology of nociception.  In: Kanner R.  Pain Management Secrets.  Philadelphia:Hanley & Belfus 1997:8-12.
71.  Bodner G, Harpf C, Gardetto A, et al.  Ultrasonography of the accessory nerve: normal and pathologic findings in cadavers and patients with iatrogenic accessory nerve palsy.  J Ultrasound Med.  2002 Oct;21(10):1159-63.
72.  Yeomans ND, Tulassay Z, Juhasz L, et al.  A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs.  N Engl J Med 1998;338:719-26.
73.  Dogrul A, Yesilyurt O, Isimer A, et al.  L-type and T-type calcium channel blockade potentiate the analgesic effects of morphine and selective mu opioid agonist, but not to selective delta and kappa agonist at the level of the spinal cord in mice. Pain. 2001 Jul;93(1):61-68.
74.  Tsuji Taichi, Matsuyama Y, Goto M, et al.  Knee-spine syndrome: correlation between sacral inclination and patellofemoral joint pain.  J Orthop Sci 2002;7:519-23.
75.  Boell R, Rubin J.  Benzodiazepines – contraindicated in the patient with chronic pain.  SAMJ 1991 Jul;80:59.
76.  Cohen LS, Rosenbaum JF.  Clonazepam: new uses and potential problems.  J Clin Psychiatry 1987 Oct;48 Suppl:50-56.
77.  Garcia Rodriguez LA, Jick H.  Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs.  Lancet 1994;343:769-72.
78.  Cole JO, Kando JC.  Adverse behavioral events reported in patients taking alprazolam and other benzodiazepines.  J Clin Psychiatry  1993 Oct;54 Suppl:49-63.
79.  Molloy AR, Cousins MJ.  Neural blockade in chronic pain.  Australian Fam Phys 1994 Dec;23(12):2295-2301.
80.  Aeschbach A, Mekhail NA.  Common nerve blocks in chronic pain management.  Anes Clin North Am.  2000 Jun;18(2):429-59.
81.  Zanette LTG.  Trapezius muscle atrophy after whiplash injury: accessory nerve or cervical plexus lesion?  J Neurology, Neurosurgery, Psych 1991;54:561-64.
82.  Feldman M, McMahon AT.  Do cyclooxygenase-2 inhibitors provide benefits similar to those of traditional nonsteroidal anti-inflammatory drugs, with less gastrointestinal toxicity?  Ann Intern Med. 2000;132:134-43.
83.  Nelson J, Chouinard G.  Guidelines for the clinical use of benzodiazepines: pharmacokinetics, dependency, rebound and withdrawal.  Can J Clin Pharmacol 1999 Summer;6(2):69-83.
84.  Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al.  Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication.  N Engl J Med 1996;334:1018-22.
85.  Murata Y, Takahashi K, Yamagata M, et al.  The knee-spine syndrome.  Association between lumbar lordosis and extension of the knee.  J Bone Joint Surg Br. 2003 Jan;85(1):95-99.
86.  Shanahan EM, Ahern M, Smith M, et al.  Suprascapular nerve block (using bupivacaine and methylprednisolone acetate) in chronic shoulder pain.  Ann Rheum Dis 2003;62:400-406.
87. McCrory MB, Brukner P, O’Donnnell J, et al.  Hip joint pathology: clinical presentation and correlation between magnetic resonance arthrography, ultrasound, and arthroscopic findings in 25 consecutive cases.  Clin J Sport Med.  2003 May;13(3):152-56.
88.  Hays JT, Hurt RD, Rigotti NA, et al.  Sustained-release bupropion for pharmacologic relapse prevention after smoking cessation: a randomized, controlled trial.  Ann Intern Med. 2001;135:423-33.
89.  Gadde KM, Parker CB, Maner LG, et al.  Bupropion for weight loss: an investigation of efficacy and tolerability in overweight and obese women.  Obes Res. 2001;9:544-51.
90.  Webster L, Andrews M, Stoddard G.  Modafinil treatment of opioid-induced sedation.  Pain Med. 2003;4(2)135-40.
91.  Viikari-Juntura E, Martikainen R, Luukkonen R, et al.  Longitudinal study on work related and individual risk factors affecting radiating neck pain.  Occup Environ Med. 2001;58:345-52.
92.  Rawson NS, Rawson MJ.  Acute adverse event signalling scheme using the Saskatchewan Administrative health care utilization datafiles: results for two benzodiazepines.  Can J Clin Pharmacol 1999 Autumn;6(3):159-66.
93. Dahan THM, Fortin L, Pelletier M, et al.  Double blind randomized clinical trial examining the efficacy of bupivacaine suprascapular nerve blocks in frozen shoulder.  J Rheumatol 2000;27(6):1464-69.
94.  Jorenby DE, Leischow SJ, Nides MA, et al.  A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation.  N Engl J Med. 1999;340:685-91.
95.  Gado K, Emery P.  Modified suprascapular nerve block with bupivacaine alone effectively controls chronic shoulder pain in patients with rheumatoid arthritis.  Ann Rheum Dis 1993:52:215-18.
96.  Saito K, Takanishi T, Okuda Y, et al.  [Long-term administration of large doses of oral morphine for chronic pain]  Masui.  1998 Jun;47(6):749-50 (abstract only – article in Japanese).
97.  Warner MA, Hosking MP, Gray JR, et al.  Narcotic-induced histamine release: a comparison of morphine, oxymorphone, and fentanyl infusions.  J Cardiothorac Vasc Anesth.  1991 Oct;5(5):481-84.
98.  Chan FK, Sung JJ, Chung SC, et al.  Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers.  Lancet 1997;350:975-79.
99.  King SA, Strain JJ.  Benzodiazepine use by chronic pain patients.  Clin J Pain 1990;6:143-47.
100.  Dellemijn PLI, Fields HL.  Do benzodiazepines have a role in chronic pain management? Pain 1994;57:137-52.
101.  Brown CS, Ling FW, Wan JY, et al.  Efficacy of static magnetic field therapy in chronic pelvic pain: a double-blind pilot study.  Am J Obstet Gynecol. 2002 Dec;187(6):1581-87.
102.  Bruera E, Fainsinger R, MacEachern T, et al.  The use of methylphenidate in patients with incident cancer pain receiving regular opiates.  A preliminary report.  Pain. 1992 Jul;50(1):75-77.
103.  Bruera E, Brenneis C, Paterson AH, et al.  Use of methylphenidate as an adjuvant to narcotic analgesics in patients with advanced cancer.  J Pain Symptom Manage 1989;4(1):3-6.
104.  Emery P, Wedderburn L, Grahame R.  Suprascapular nerve block for shoulder pain in rheumatoid arthritis.  BMJ 1989;299:1079-80.
105.  Kirvela O, Antila H.  Thoracic paravertebral block in chronic postoperative pain.  Reg Anes 1992;17:348-50.
106.  Choi YK, Liu J.  The use of 5% lidocaine for prolonged analgesia in chronic pain patients: a new technique.  Reg Anes Pain Med 1998;23(1):96-100.
107.  Vecchio PC, Adebajo AO, Hazleman BL.  Suprascapular nerve block for persistent rotator cuff lesions.  J Rheumatol 1993;20:453-55.
108.  Adriani, John.  Chapter 17: Non-surgical Uses of Regional Anesthesia: Diagnostic and Therapeutic Nerve Blocking.  In: Labat’s Regional Anesthesia, St. Louis;1985:634.
109.  Bruera E, Chadwick S, Brenneis C, et al.  Methylphenidate associated with narcotics for the treatment of cancer pain.  Cancer Treat Rep. 1987 Jan;71(1):67-70.
110.  Borenstein DG.  Epidemiology, etiology, diagnostic evaluation, and treatment of low back pain.  Curr Opin Rheumatol.  2001 Mar;13(2):128-34.
111. Woodward A, Laugesen M.  How many deaths are caused by second hand cigarette smoke?  Tob Control 2001 Winter;10:383-88.
112. Brown DE, James DC, Roy S.  Pain relief by suprascapular nerve block in glenohumeral arthritis.  Scand J Rheumatol 1988;17:411-15.
113.  Lyritis GP, Paspati I, Karachalios T, et al.  Pain relief from nasal salmon calcitonin in osteoporotic vertebral crush fractures.  Acta Orthop Scand (Suppl 275) 1997;68:112-14.
114.  Kovcin V, Jelic S, Babovic N, et al.  A pilot study to assess the efficacy of salmon calcitonin in the relief of neuropathic pain caused by extraskeletal metastases.  Support Care Cancer. 1994 Jan;2(1):71-73.
115.  Predey TA, Sewall LE, Smith SJ.  Percutaneous vertebroplasty: new treatment for vertebral compression fractures.  Am Fam Physician 2002:66:611-15.
116.  Ashar BH, Miller RG, Getz KJ, et al.  A critical evaluation of internet marketing of products that contain ephedra.  Mayo Clin Proc. 2003;78:944-46.
117. Cohen M, Wolfe R, Mai T, et al.  A randomized, double blind, placebo controlled trial of a topical cream containing glucosamine sulfate, chondroitin sulfate, and camphor for osteoarthritis of the knee.  J Rheumatol 2003;30:523-28.
118.  Freston JW.  Review article: role of proton pump inhibitors in non-H. pylori-related ulcers.  Aliment Pharmacol Ther. 2001 Sep;15 Suppl 2:2-5.
119. Rifat SF, Kiningham RB, Peggs JF.  Calcitonin in the treatment of osteoporotic bone pain.  J Fam Pract. 1992 Jul;35(1):93-96.
120. Wilwerding MB, Loprinzi CL, Mailliard JA, et al.  A randomized, crossover evaluation of methylphenidate in cancer patients receiving strong narcotics.  Support Care Cancer.  1995 Mar;3(2):135-38.
121. Cichewicz DL, Martin ZL, Smith FL.  Enhancement mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis and receptor identification.  J Pharmacol Exp Ther. 1999 May;289(2):859-67.
122. Cichewicz DL, Haller VL, Welch SP.  Changes in opioid and cannabinoid receptor protein following short-term combination treatment with delta-9-tetrahydrocannabinol and morphine.  J Pharmacol Exp Ther. 2001 April;297(1):121-27.
123. Lyritis GP, Tsakalakos N, Magiasis B, et al.  Analgesic effect of salmon calcitonin in osteoporotic vertebral fractures: a double-blind placebo controlled clinical study.  Calcific Tissue Int. 1991 Dec;49(6):369-72.
124. Poobalan AS, Bruce J, Smith WC.  A review of chronic pain after inguinal herniorrhaphy.  Clin J Pain. 2003 Jan-Feb;19(1):48-54.
125. Smith FL, Cichewicz D, Martin ZL, et al.  The enhancement of morphine antinociception in mice by delta9-tetrahydrocannabinol.  Pharmacol Biochem Behav. 1998 Jun;60(2):559-66.
126. Cichewicz DL, McCarthy EA.  Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration.  J Pharmacol Exp Ther. 2003 Mar;304(3):1010-15.
127. Woodruff AW.  Unilateral spinal accessory nerve palsy caused by an arm sling.  Br Med J 1950;1:821-22.
128. Thilagarajah R, Witherow RO, Walker MM.  Oral cimetidine gives effective symptom relief in painful bladder disease, a prospective, randomized, double-blind placebo-controlled trial.  BJU Int. 2001 Feb;87(3):207-12.
129. Bell EA, Jones BP, Olufolabi AJ, et al.  Iliohypogastric-ilioinguinal peripheral nerve block for post-Cesarean delivery analgesia decreases morphine use but not opioid-related side effects.  Can J Anaesth.  2002 Aug-Sep;49(7):694-700.
130. Rukwied R, Watkinson A, McGlone F, et al.  Cannabinoid agonists attenuate capsaicin-induced responses in human skin.  Pain. 2003 Apr;102(3):283-88.
131. Evans RA, Somers NM, Dunstan CR, et al.  Treatment of Paget’s disease of bone with a combination of intranasal salmon calcitonin and oral calcium and thiazide.  Calcif Tissue Int. 1991 Sep;49(3):164-67.
132. Wilwerding MB, Loprinzi CL, Mailliard JA, et al.  A randomized, crossover evaluation of methylphenidate in cancer patients receiving strong narcotics.  Support Care Cancer.  1995 Mar;3(2):135-38.
133.  Cohn BT, Brahms MA, Cohn M.  Injury to the eleventh cranial nerve in a high school wrestler.  Orthop Rev 1986;15:59-66.
134.  Swift TR.  Involvement of peripheral nerves in radical neck dissection.  Am J Surg.  1970 Jun;119:694-98.
135.  Woodhall B.  Trapezius paralysis following minor surgical procedures in the posterior cervical triangle.  Ann Surg. 1952 Sept;136(3):375-80.
136. Pun KK, Chan LW.  Analgesic effect of intranasal salmon calcitonin in the treatment of osteoporotic vertebral fractures.  Clin Ther. 1989 Mar-Apr;11(2):205-209.
137.  Sidney S. Cardiovascular consequences of marijuana use.  J Clin Pharmacol. 2002 Nov;42(Suppl):64S-70S.
138.  Iversen L.  High times for cannabis research.  Proc Natl Acad Sci USA. 1999 May 11;96(10):5538-39.
139.  Vaughan CW, Christie MJ.  An analgesic role for cannabinoids.  MJA 2000;173:270-72.
140. Schiraldi GF, Soresi E, Locicero S, et al.  Salmon calcitonin in cancer pain: comparison between two different treatment schedules.  Int J Clin Pharmacol Ther Toxicol. 1987 Apr;25(4):229-32.
141.  Drew LJ, Harris J, Millns PJ, et al.  Activation of spinal cannabinoid 1 receptors inhibits C-fibre driven hyperexcitable neuronal responses and increases [35S]GTPgammaS binding in the dorsal horn of the spinal cord of noninflamed and inflamed rats.  Eur J Neurosci. 2000 Jun;12(6):2079-86.
142.  Logigian EL, McInnes JM, Berger AR, et al.  Stretch-induced spinal accessory nerve palsy.  Muscle Nerve. 1988;11:146-50.
143.  Krantz MJ, Kutinsky IB, Robertson AD, et al.  Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes.  Pharmacotherapy.  2003 Jun;23(6):802-805.
144.  Uematsu Y, Matuzaki H, Iwahashi M.  Effects of nicotine on the intervertebral disc: an experimental study in rabbits.  J Orthop Sci. 2001;6(2):177-82.
145.  Smith PF.  Cannabinoids in the treatment of pain and spasticity in multiple sclerosis.  Curr Opin Investig Drugs. 2002 Jun;3(6):859-64.
146.  Ringe JD, Welzel D.  Salmon calcitonin in the therapy of corticoid-induced osteoporosis.  Eur J Clin Pharmacol. 1987;33(1):35-39.
147.  Atkinson JH, Slater MA, Wahlgren DR, et al.  Effects of noradrenergic and serotonergic antidepressants on chronic low back pain intensity.  Pain. 1999 Nov;83(2):137-45.
148.  Serdengecti S, Serdengecti K, Derman U, et al.  Salmon calcitonin in the treatment of bone metastases.  Int J Clin Pharmcol Res.  1986;6(2):151-55.
149.  Santiago-Palma J, Fischberg D, Kornick C, et al.  Diphenhydramine as an analgesic adjuvant in refractory cancer pain.  J Pain Symptom Management 2001 Aug;22(2):699-703.
150.  Carr DB, Jacox AK, Chapman CR, eds. et al.  Appendix C Dosage tables for adult and pediatric patients In: Acute Pain Management: Operative or Medical Procedures and Trauma.  Rockville, MD:AHCPR U.S. Department of Health and Human Services Publication Feb 1992;112-13.
151.  De Franca GG.  Proximal tibiofibular joint dysfunction and chronic knee and low back pain.  J Manip Physio Ther.  1992 Jul/Aug;15(6)382-87.
152.  Henry JA, Oldfield WLG, Kon OM.  Comparing cannabis with tobacco.  BMJ 2003 May;326:942-43.
153. Allan E.  Calcitonin in the treatment of intractable pain from advanced malignancy.  Pharmatherapeutica.  1983:3(7):482-86.
154. Luboshitzky R, Bar-Shalom R.  Calcitonin nasal spray for Paget’s disease of the bone.  (abstract only – article in Hebrew) Harefuah. 1995 Mar 15;128(6):358-62, 399.
155.  Jelic S, Borkovacki R, Babovic N, et al.  Anti-pain effect of salmon calcitonin in bone metastases of malignant tumors with the exception of breast and prostatic carcinoma. (abstract only – article in Serbo-Croatian Roman) Vojnosanit Pregl. 1995 Mar-Apr;52(2):151-54.
156.  Abellan Perez M, Bayina Garcia FJ, Calabozo M, et al.  Multicenter coparative study of synthetic salmon calcitonin administered nasally in the treatment of established postmenopausal osteoporosis. (abstract only – article in Spanish) An Med Interna. 1995 Jan;12(1):12-16.
157. Simanski C, Bathis H, Bouillon B, et al.  Therapeutic concept for preventing chronic phantom pain after traumatic brachial plexus lesion.  (abstract only – article in German)  Unfallchirurg. 2001 Jul;104(7):659-64.
158.  Simanski C, Lempa M, Koch G, et al.  Therapy of phantom pain with salmon calcitonin and effect on postoperative patient satisfaction. (abstract only – article in German)  Chirurg. 1999 Jun;70(6):674-81.
159.  Doi K, Nikai T, Sakura S, et al.  Intercostal nerve block with 5% tetracaine for chronic pain syndromes.  J Clin Anes. 2002;14:39-41.
160.  Buskila D, Neumann L.  Musculoskeletal injury as a trigger for fibromyalgia/posttraumatic fibromyalgia.  Curr Rheum Rep 2000;2:104-108.
161.  Richelson E.  Antidepressants and brain neurochemistry.  Mayo Clin Proc 1990;65:1227-36.
162.  Braatz JH, Gogia PP.  Paralysis of the trapezius: a case report.  Arch Phys Med Rehabil 1991;72:598-600.
163.  Marini SG, Rook JL, Green RF, et al.  Spinal accessory nerve palsy: an unusual complication of coronary artery bypass.  Arch Phys Med Rehabil 1991;72:247-49.
164.  Petrera JE, Trojaborg W.  Conduction studies along the accessory nerve and follow-up of patients with trapezius palsy.  J Neurology, Neurosurg, Psych.  1984;47:630-36.
165.  Eisen A, Bertrand G.  Isolated accessory nerve palsy of spontaneous origin.  Arch Neurol. 1972 Dec;27:496-502.
166.  Walsh D, Nelson KA, Mahmoud FA.  Established and potential therapeutic applications of cannabinoids in oncology.  Support Care Cancer. 2003 Mar;11(3):137-43.
167.  Lyritis GP, Ioannidis GV, Karachalios T, et al.  Analgesic effect of salmon calcitonin suppositories in patients with acute pain due to recent osteoporotic vertebral crush fractures: a prospective double-blind, randomized, placebo-controlled clinical study.  Clin J Pain. 1999 Dec;15(4):284-89.
168. Szanto J, Ady N, Jozsef S.  Pain killing with calcitonin nasal spray in patients with malignant tumors.  Oncology.  1992;49(3):180-82.
169. Querol I, Cisneros T.  Reflex sympathetic dystrophy syndrome following herpes zoster. (abstract only)  Cutis. 2001 Sep;68(3):179-82.
170.  Hamamci N, Dursun E, Ural C, et al.  Calcitonin treatment in reflex sympathetic dystrophy: a preliminary study.  Br J Clin Pract. 1996 Oct-Nov;50(7):373-75.
171.  Ware MA, Doyle CR, Woods R, et al.  Cannabis use for chronic non-cancer pain: results of a prospective survey.  Pain. 2003 Mar;102(1-2):211-16.
172.  Zoltan JD.  Injury to the suprascapular nerve associated with anterior dislocation of the shoulder: case report and review of the literature.  J Trauma.  1979;19(3):203-206.
173.  Urban BJ.  Treatment of chronic pain with nerve blocks and stimulation.  Gen Hosp Psych.  1984;6:43-47.
174.  Jensen KL, Rockwood Jr CA.  Delayed primary repair of a kyrogenic spinal accessory nerve injury.  Clin Ortho Rel Res.  1997 Mar;336:116-21.
175.  McAlpine DE.  Suicide: recognition and management.  Mayo Clin Proc 1987;62:778-81.
176.  Lu G, Frost AM, Goldiner PL.  Intercostal nerve block in obese patients.  Can J Aneaesth. 1990 Mar;37(2):268-269.
177.  Ganapathy S, Murkin JM, Boyd DW.  Continuous percutaneous paravertebral block for minimally invasive cardiac surgery.  J Cardiothor Vasc Anesth. 1999 Oct;13(5):594-96.
178.  Hantson P, Evenepoel M, Ziade D, et al.  Adverse cardiac manifestations following dextropropoxyphene overdose: can naloxone be helpful?  Ann Emerg Med.  1995 Feb;25(2):263-66.
179.  Bluhm RE, Evans MA, Zsigmond EK.  Analgesic potentiation and the distribution of morphine in the presence of triplennamine in mice.  Life Sci. 1983;33 Suppl 11:673-76.
180.  Bluhm R, Zsigmond EK, Winnie AP.  Potentiation of opioid analgesia by H1 and H2 antagonists.  Life Sci 1982;31:1229-32.
181.  Croxford JL.  Therapeutic potential of cannabinoids in CNS disease.  CNS Drugs.  2003;17(3):179-202.
182.  Silverman SL, Azria M.  The analgesic role of calcitonin following osteoporotic fracture.  Osteoporosis Int. 2002 Nov;13(11):858-67.
183.  Siamopoulou A, Challa A, Kapoglou P, et al.  Effects of intranasal salmon calcitonin in juvenile idiopathic arthritis: an observational study.  Calcif Tissue Int. 2001 Jul;69(1):25-30.
184.  Neff GW, O’Brien CB, Reddy KR, et al.  Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease.  Am J Gastroenterol. 2002 Aug;97(8):2117-19.
185.  Galeottis N, Ghelardini C, Bartolini A.  Antihistamine antinociception is mediated by Gi-protein activation.  Neuroscience. 2002;109(4):811-18.
186.  Galeotti N, Ghelardini C, Bartolini A.  The role of potassium channels in antihistamine analgesia.  Neuropharmacology. 1999 Dec;38(12):1893-1901.
187.  Nelson KR, Tibbs P.  Neck-cracker neuropathy.  N Engl J Med 1988 Apr 21;318(16):1072.
188.  Rumore MM, Schlichting DA.  Clinical efficacy of antihistamines as analgesics.  Pain. 1986 Apr;25(1):7-22.
189.  Ormazabal MJ, Goicoechea C, Sanchez E, et al.  Salmon calcitonin potentiates the analgesia induced by antidepressants.  Pharmacol Biochem Behav.  2001 Jan;68(1):125-33.
190.  Martin BR, Lichtman AH.  Cannabinoid transmission and pain perception.  Neurobiol Dis. 1998 Dec;5(6 Pt B):447-61.
191.  Mystakidou K, Befon S, Hondros K, et al.  Continuous subcutaneous administration of high-dose salmon calcitonin in bone metastasis: pain control and beta-endorphin plasma levels.  J Pain Symptom Manage. 1999 Nov;18(5):323-30.
192.  Combe B, Cohen C, Aubin F.  Equivalence of nasal spray and subcutaneous formulations of salmon calcitonin.  Calcific Tissue Int. 1997 Jul;61(1):10-15.
193.  Rumore MM, Schlichting DA.  Analgesic effects of antihistamines.  Life Sci. 1985 Feb 4;36(5):403-16.
194.  Krantz MJ, Lewkowiez L, Hays H, et al.  Torsade de pointes associated with very-high-dose methadone.  Ann Intern Med. 2002 Sep 17;137(6):501-504.
195.  Hallberg LR, Carlsson SG.  Anxiety and coping in patients with chronic work-related muscular pain and patients with fibromyalgia.  Eur J Pain. 1998;2(4):309-19.
196.  Giacomini KM, Giacomini JC, Gibson TP, et al.  Propoxyphene and norpropoxyphene plasma concentrations after oral propoxyphene in cirrhotic patients with and without surgically constructed portacaval shunt.  Clin Pharmacol Ther. 1980 Sep;28(3):417-24.
197. Wassef MR.  Suprascapular nerve block. A new approach for the management of frozen shoulder. Anaesthesia 1992 Feg;47(2):120-24.
198.  Stambaugh JE Jr, Lane C.  Analgesic efficacy and pharmacokinetic evaluation of meperidine and hydroxyzine, alone and in combination.  Cancer Invest. 1983;1(2):111-17.
199.  Brage S, Bjerkedal T.  Musculoskeletal pain and smoking in Norway.  J Epidemiol Community Health.  1996 Apr;50(2):166-69.
200.  Gadde KM, Franciscy DM, Wagner II HR, et al.  Zonisamide for weight loss in obese adults.  A randomized controlled trial.  JAMA. 2003 Apr 9;289(14):1820-25.
201. Porter J, Jick H.  Addiction rare in patients treated with narcotics.  N Engl J Med.  1980 Jan 10;302(2):123.
202.  Whitcomb DC, Gilliam III FR, Starmer CF, et al.  Marked QRS complex abnormalities and sodium channel blockade by propoxyphene reversed with lidocaine.  J Clin Invest. 1989 Nov;84:1629-36.
203.  Nickander RC, Emmerson JL, Hynes, et al.  Pharmacologic and toxic effects in animals of dextropropoxyphene and its major metabolite norpropoxyphene: a review.  Human Toxicol. 1984;3:13S-36S.
204.  Rosse C.  The Thigh and the Knee. In: Rosse C, Clawson DK, eds. The Musculoskeletal System in Health and Disease.  New York, NY: Harper & Row 1980:300.
205.  Jellin J, Gregory PJ, Davidson K, eds., et al.  Prescriber’s Letter.  2003 Aug;10(8):43-48.
206. Laursen RJ, Graven-Nielsen T, Jensen TS, et al.  The effect of differential and complete nerve block on experimental muscle pain in humans.  Muscle & Nerve. 1999 Nov;22:1564-70.
207. Ringel SP, Treihaft M, Carry M, et al.  Suprascapular neuropathy in pitchers.  Am J Sports Med. 1990;18(1);80-86.
208.  Horiguchi M.  The cutaneous branch of some human suprascapular nerves.  J Anat. 1980;130(1):191-95.
209. Bryan WJ, Wild Jr. JJ.  Isolated infraspinatus atrophy: a common cause of posterior shoulder pain and weakness in throwing athletes?  Am J Sports Med. 1989;17(1):130-31.
210.  Gibson TP, Giacomini KM, Briggs WA, et al.  Propoxyphene and norpropoxyphene plasma concentrations in the anephric patient.  Clin Pharmacol Ther. 1980 May;27(5):665-70.
211.  Ford DJ, Raj PP, Singh P, et al.  Differential peripheral nerve block by local anesthetics in the cat.  Anesthesiology 1984 Jan;60(1):28-33.
212.  Kiss G, Komar J.  Suprascapular nerve compression at the spinoglenoid notch.  Muscle & Nerve 1990 Jun;13:556-57.
213. Torres-Ramos FM, Biundo Jr. JJ.  Suprascapular neuropathy during progressive resistive exercises in a cardiac rehabilitation program.  Arch Phys Med Rehabi. 1992 Nov;73:1107-11.
214. Ritchie ED, Tong D, Chung F, et al.  Suprascapular nerve block for postoperative pain relief in arthroscopic shoulder surgery: a new modality?  Anesth Analg 1997;84:1306-12.
215. Chen S-M, Chen J-T, Kuan T-S, et al.  Myofascial trigger points in intercostal muscles secondary to herpes zoster infection of the intercostal nerves.  Arch Phys Med Rehabil 1988 Mar;79:336-38.
216.  Matsota P, Livanios S, Marinopoulou E.  Intercostal nerve block with bupivacaine for post-thoracotomy pain relief in children.  Eur J Pediatr Surg 2001;11:219-22.
217.  Hamada H, Moriwaki K, Shiroyama K, et al.  Myofascial pain in patients with postthoracotomy pain syndrome.  Reg Anesth Pain Med 2000 May-Jun;25(3):302-305.
218.  Fine PG, Milano R, Hare BD.  Effects of myofascial trigger point injections are naloxone reversible.  Pain 1988;32:15-20.
219. Bremner-Smith AT, Unwin AJ, Williams WW.  Sensory pathways in the spinal accessory nerve. J Bone Joint Surg [Br] 1991;81-B:226-28.
220.  Jones DS, Chattopadhyay C.  Suprascapular nerve block for the treatment of frozen shoulder in primary care: a randomized trial.  Br J Gen Pract 1999 Jan;49:39-41.
221.  Zeiss J, Woldenberg LS, Saddemi SR.  MRI of suprascapular neuropathy in a weight lifter.  J Computer Assisted Tomography 1993 Mar-Apr;17(2):303-308.
222.  Agre JC, Ash N, Cameron C, et al.  Suprascapular neuropathy after intensive progressive resistive exercise: case report.  Arch Phys Med Rehabil 1987 Apr;68:236-38.
223.  Steiman I. Painless infraspinatus atrophy due to suprascapular nerve entrapment.  Arch Phys Med Rehabil 1988 Aug;69:641-43.
224.  Mallon WJ, Bronec PR, Spinner RJ, et al.  Suprascapular neuropathy after distal clavicle excision.  Clin Orthop 1996 Aug;(329):207-11.
225.  Cohen SB, Dines DM, Moorman CT.  Familial calcification of the superior transverse scapular ligament causing neuropathy.  Clin Ortho Rel Res 1997 Jan;334:131-35.
226.  Mercadante S, Sapio M, Villari P.  Suprascapular nerve block by catheter for breakthrough shoulder cancer pain.  Reg Anesth 1995 Jul-aug;20(4):343-46.
227.  Iwama H, Akama Y.  The superiority of water-diluted 0.25% to neat 1% lidocaine for trigger-point injections in myofascial pain syndrome: a prospective, randomized double-blinded trial.  Anesth Analg 2000 Aug;91(2):408-409.
228.  Ewama H, Ohmori S, Kaneko T, et al.  Water-diluted local anesthetic for trigger-point injection in chronic myofascial pain syndrome: evaluation of types of local anesthetic and concentrations in water.  Reg Anesth Pain Med 2001 Jul-Aug;26(4):333-36.
229.  Meyer-Whitting M, Foster JM.  Suprascapular nerve block in the management of cancer pain.  Anesthesia 1992 Jul;47(7):626.
230.  Williams GR Jr.. Painful shoulder after surgery for rotator cuff disease.  J Am Acad Orthop Surg 1997 Mar;5(2):97-108.
231.  Weinstein SL, Dolan LA, Spratt KF, et al.  Health and function of patients with untreated idiopathic scoliosis: a 50-year natural history study.  JAMA 2003 Feb 5;289(5):559-67.
232.  Zhong H, Li B, Scheuer T, et al.  Control of gating mode by a single amino acid residue in transmembrane segment IS3 of the N-type Ca2+ channel.  Proc Natl Acad Sci USA 2001 Apr 10;98(8):4705-709.
233. Gibson JN, Waddell G, Grant IC.  Surgery for degenerative lumbar sponylosis.  Cochrane Database Syst Rev. 2000;(3):CD001352.
234.  Henmi T, Sairyo K, Nakano S, et al.  Natural history of extruded lumbar intervertebral disc herniation.  J Med Invest 2002 Feb;49(1-2):40-43.
235.  Benoist M.  The natural history of lumbar disc herniation and radiculopathy.  Joint Bone Spine 2002 Mar;69(2):155-60.
236. Yukawa Y, Kato F, Matsubara Y, et al.  Serial magnetic resonance imaging follow-up study of lumbar disc herniation conservatively treated for average 30 months: relation between reduction of herniation and degeneration of disc.  J Spinal Disord. 1996 Jun;9(3):251-56.
237. Suter E, Lindsay D.  Back muscle fatigability is associated with knee extensor inhibition in subjects with low back pain.  Spine 2001;26:E361-66.
238. Ferretti A, Cerullo G, Russo G.  Suprascapular neuropathy in volleyball players.  J Bone Joint Surg 1987 Feb;69A(2):260-63.
239. Jordan BD, Istrico R, Zimmerman RD, et al.  Acute cervical radiculopathy in weight lifters.  Phys Sports Med 1990 Jan;18(1):73-76.
240. Rainville J, Sobel JB, Banco RJ, et al.  Low back and cervical spine disorders.  Orthop Clin North Am 1996 Oct;27(4):729-46.
241. Rust MS, Olivero WC. Far-lateral disc herniations: the results of conservative management.  J Spinal Disord 1999 Apr;12(2):138-40.
242.  Yadav JK, Singhvi AM, Kumar N, et al.  Topical phenytoin in the treatment of split-thickness skin autograft donor sites: a comparative study with polyurethane membrane drape and conventional dressing.  Burns 1993 Aug;19(4):306-10.
243.  Xiao WH, Bennett GJ.  Syntehtic omega-conopeptides applied to the site of nerve injury suppress neuropathic pains in rats.  J Pharmacol Exp Ther. 1995 Aug;274(2):666-72.
244.  Bowersox S, Mandema J, Tarczy-Hornoch K, et al.  Pharmacokinetics of SNX-111, a selective N-Type calcium channel blocker, in rats and cynomolgus monkeys.  Drug Metab Disposition 1997;25(3):379-86.
245. Lewis R, Nielsen KJ, Craik DJ, et al.  Novel w-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes.  J Biol Chem 2000 Aug 10;275(45):35335-44.
246.  Prado WA, Filho M.  Antinociceptive potency of aminoglycoside antibiotics and magnesium chloride: a comparative study on models of phasic and incisional pain in rats. Braz J Med Biol Res 2002 Mar;35(3):395-403.
247.  Blenk KH, Habler HJ, Janig W.  Neomycin and gadolinium applied to an L5 spinal nerve lesion prevent mechanical and allodynia-like behavior in rats.  Pain 1997 Apr;70(2-3):155-65.
248.  Goldstein FJ. Adjuncts to opioid therapy.  J Am Osteopath Assoc 2002 Sep;102(9Suppl 3):S15-21.
249. Dahlin LB, Archer DR, McLean WG.  Axonal transport and morphological changes following nerve compression.  An experimental study in the rabbit vagus nerve.  J Hand Surg [Br] 1993 Feb;18(1):106-10.
250.  Dalal S, Melzack R.  Psychostimulant drugs potentiate morphine analgesia in the formalin test.  J Pain Symptom Manage 1998 Oct;16(4):230-39.
251.  Didei G, Oberoi GS.  Pain clinic in Goroka Base Hospital: a retrospective analalysis. (abstract only) P N G Med J 1994 Dec;37(4):214-18.
252. Johansson A, Sjolund B. Nerve blocks with local anesthetics and corticosteroids in chronic pain: a clinical follow-up study.  J Pain Symptom Manage 1996 Mar;11(3):181-87.
253. Herlitze S, Zhong H, Scheuer T, et al.  Allosteric modulation of Ca2+ channels by G proteins, voltage-dependent facilitation, protein kinase C, and Ca-v-beta subunits. Proc Natl Acad Sci USA 2001 Apr 10;98(8):4699-704.
254. Shah RV, Ericksen JJ, Lacerte M. Interventions in chronic pain management. 2. New frontiers: invasive nonsurgical interventions. Arch Phys Med Rehabil 2003;84 Suppl 1:S39-44.
255. Tegeder I, Lotsch J, Krebs S, et al.  Comparison of inhibitory effects of meloxicam and diclofenac on human thromboxane biosynthesis after single doses and at steady state.  Clin Pharmacol Ther.  1999 May;65(5):533-44.
256. Freston JW.  Rationalizing cyclooxygenase (COX) inhibition for maximal efficacy and minimal adverse events.  Am J Med 1999 Dec 13;107(67A):78S-88S.
257. Liang TH, Hsu PN.  Double-blind, randomised, comparative trial of etodolac SR versus diclofenac in the treatment of osteoarthritis of the knee.  Curr Med Res Opin  2003;19(4):336-41.
258. Talmud
259. Schindler’s List [the movie], Steven Spielberg, 1993.
260. Carr JJ.  Christian Heroes of the Holocaust – The Righteous Gentiles. South Plainfield, NJ: Bridge Publishing, Inc. 1984.
261. Roth A, Kolaric K.  Analgetic activity of calcitonin in patients with painful osteolytic metastases of breast cancer.  Results of a controlled randomized study.  Oncology. 1986;43(5):283-87.  
262. Substance Abuse and Mental Health Services Administration (SAMHSA), Department of Health and Human Services.  Opioid drugs in maintenance and detoxification treatment of opiate addiction; addition of buprenorphine and buprenorphine combination to list of approved opioid treatment medications.  Interim final rule.  Fed Regist. 2003 May 22;68(99):27937-39.
263. Rose D, Wykes T, Leese M, et al.  Patient’s perspectives on electroconvulsive therapy: systematic review.  BMJ USA.  2003 Aug;3:421-23.
264. Wagner J, Wagner ML, Hening WA.  Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia.  Ann Pharmacother. 1998 Jun;32(6):680-91.
265. Zwanzger P, Baghai TC, Schfile C, et al.  Tiagabine improves panic and agoraphobia in panic disorder patients.  J Clin Psychiatry 2001 Aug;62(8):656-57.
266. DeVane CL.  Substance P: a new era, a new role.  Pharmacotherapy. 2001 Sep;21(9):1061-69.
267. Koenig HG.  An 83-year-old woman with chronic illness and strong religious beliefs.  JAMA 2002 Jul 24/31;288(4):487-93.
268.  Noda M, Tatsumi Y, Tomizawa M, et al.  Effects of etodolac, a selective cyclooxygenase-2 inhibitor, on the expression of E-cadherin-catenin complexes in gastrointestinal cell lines.  J Gastroenterol 2002;37:896-904.
269. Bauman JL, DiDomenico RJ.  Cocaine-induced channelopathies:emerging evidence on the multiple mechanisms of sudden death.  J Cardiovasc Pharmacol Ther 2002 Jul;7(3):195-202.
270.  Malone DG, Baldwin NG, Tomecek FJ, et al.  Complications of cervical spine manipulation therapy: 5-year retrospective sudy in a single-group practice.  Neurosurg Focus 2002;13(6):1-11.
271.  Haldeman S, Kohlbeck FJ, McGregor M.  Unpredictability of cerebrovascular ischemia associated with cervical spine manipulation therapy: a review of sixty-four cases after cervical spine manipulation.  Spine 2002 Jan 1;27(1):49-55.
272. Gammaitoni AR, Alvarez NA, Galer BS.  Safety and tolerability of the lidocaine patch 5%, a targeted peripheral analgesic: a review of the literature.  J Clin Pharmacol 2003;43:1-7.
273.  Gammaitoni AR, Alvarez NA, Galer BS.  Pharmacokinetics and safety of continuously applied lidocaine patches 5%.  Am J Health-Syst Pharm 2002 Nov 15;59:2215-20.
274.  Hines R, Keaney D, Moskowitz MH, et al.  Use of lidocaine patch 5% for chronic low back pain: a report of four cases. Pain Medicine 2002;3(4):361-65.
 

This web site is constantly being updated and evolving as new pain related research is reviewed.  To avoid constantly re-reading the same material, the visitor is encouraged to make a note of the number of references cited at the end of the article.  New versions will have more references.

As this site was hastened to be posted in October 2003 at the request of numerous patients, the visitor is requested to appreciate that grammatical corrections, redundancy, and addition of pending references will be forthcoming.  The authors apologize and anticipate prompt refinement to this site.

The material herein is notarized, copyright Aaron S. Geller, M.D. DBA Nashua Pain Management.  All rights reserved.  

The material herein reflects the extensive research and experience of the author.  Any medication discussed herein must be prescribed and consumed in accord with the prescribing information released from the manufacturer.
 
 
 
 
 
 
 
 
 
 
 
 
 

Directions to Dr. Geller's offices

To get to Dr. Geller’s NASHUA office near the Nashua Mall, one block off the Everett Turnpike, 30 minutes south of Concord, take 93 South to 293 South, then veer left to the Everett Turnpike and take exit #6 to 130-West. At the first set of lights, make a U-turn back to the highway. After you pass the Shell gas station, take an immediate right at 150 Broad Street at the Carlson Real Estate Building. Continue through the parking lot past the Japanese Bistro to the adjacent building at 154 Broad Street, Nashua, NH 03063.