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 ste