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Featured Report: Neuropathic Pain (A-06) Full Text
Background and Methods
Neurobiology of Pain
Neuropathic Pain
Definition
Classification of Pain
Epidemiology, Diagnosis, and Management of Neuropathic Pain
Pharmacologic Treatments for Neuropathic Pain
Antidepressants
Antiepileptic Drugs
Opioid Analgesics
Local Anesthetics
Cannabinoids
Topical Treatments
Other Pharmacologic Approaches
Neuraxial Drug Delivery
Neuromodulation
Transcutaneous Electrical Stimulation (TENS) for Chronic Pain
Spinal Cord Stimulation
Summary and Conclusion
Recommendations (Adopted AMA Directive)
References
NOTE: This report, written in response to Resolution 528 (A-05) and presented as CSAPH Report 5 at the 2006 American Medical Association (AMA) meeting, represents the medical/scientific literature on this subject as of June 2006.
The Council previously examined the issue of chronic noncancer pain, in particular the role of opioids in the management of chronic pain.1 This report updates knowledge subsequently gained about the pathogenesis of pain, especially changes that occur in response to persistent pain stimuli or that are triggered by damage to the peripheral or central nervous system (CNS). The neurobiology of nociceptive pain and neuropathic pain states is reviewed, and the definition, classification, and typical causes of neuropathic pain are noted. (A glossary of terms used in this report appears in the Appendix [PDF, 19 KB, requires Adobe® Reader®].) In addition, the basic diagnostic approach to presumed neuropathic pain is briefly presented. Attention is devoted to the primary treatments and interventions that may decrease pain intensity and suffering in patients with neuropathic pain, and in improving their function or quality of life. Finally, some research needs are identified.
Methods
English-language reports on studies using human subjects were selected from a MEDLINE search of the literature from 1995 to 2006 using the search terms neuropath*, in combination with pain, treatment, or pathophysiology. In addition, the Cochrane Central Controlled Trials Register was searched using the term pain, in combination with neuropathic or neuropathy’ and antidepressant, anticonvulsant, or antiepileptic, as well as 26 individual drug names from these and other classes. A total of 706 articles were retrieved for analysis.
Articles were selected for their ability to supply information about the pathogenesis of neuropathic pain or if they represented randomized controlled trials. When high-quality systematic reviews and meta-analyses were identified, they formed the basis for summary statements about treatment effectiveness. These reviews were supplemented with an updated literature search. Additional articles were identified by manual review of the references cited in these publications. Further information was obtained from the World Wide Web sites of the American Pain Society (www.ampainsoc.org), American Academy of Pain Medicine (www.painmed.org), and the American Academy of Pain Management (www.aapainmanage.org).
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.2 Human perception of pain is influenced by physiological, psychological, and social factors. As such, the distinction between pain (as the primary sensory experience arising from a noxious stimulus) and suffering (the human reaction to the sensory experience) is important. The latter takes on an added dimension when dealing with patients who have chronic pain. Some of these patients not only have persistent pain, but also have overriding affective components and learned responses that can lead to severe psychosocial disability and a pattern of overutilization of health care.
Nociceptive Pain. Nociception is the perception of noxious stimuli. Acute pain caused by a noxious stimulus is mediated by a specialized, high-threshold neuronal array, the nociceptive system. Pain is normally evoked only by stimuli that are sufficiently intense to activate primary afferent A-delta and C fiber nociceptors. Cell bodies of the primary afferent neurons are located in dorsal root ganglia and the spinal sensory nucleus of cranial nerve V; bifurcated axonal processes are distributed to the periphery for detection, and to the spinal cord to transmit information centrally. A-delta fibers (thinly myelinated) carry a well-localized “first” pain of sharp, pricking quality. C fibers (unmyelinated) carry a poorly localized “second” pain of dull and persistent or burning quality. Muscle and deep tissue nociceptor stimulation produce aching or cramping type pain.
Free nerve endings and sensory receptors are located in skin, viscera, muscle, fascia, blood vessels, and joint capsules, and comprise numerous varieties, the most important of which are nociceptive afferents, which respond to one specific noxious stimulus, or more commonly exhibit polymodal responses to chemical stimuli, heat and pressure or to heat and mechanical stimuli. Receptive properties are determined by specific ion-channel receptors (cation or Na+ channels) that are gated by temperature, chemical, or shearing forces.3 The peripheral terminals of these primary afferents are capable of transducing these stimuli into electrical activity (ie, action potentials). Two types of sodium channels are unique to nociceptors (Nav1.8 and Nav 1.9).4
In the spinal cord, pain-carrying primary afferent terminals synapse on (second order) neurons within the superficial lamina of the dorsal horn, which ascends to form the spinothalamic tract and spinoreticular system. The former transmits information about acute pain (location, intensity, quality) through the thalamus to the somatosensory cortex and the latter is involved with autonomic and affective reactions to pain. The main pain signal from nociceptor activation is accomplished by rapid synaptic transmission in the spinal cord mediated by the excitatory amino acid glutamate, acting on N-methyl-D-asparate (NMDA) receptors. In addition to the spinothalamic and spinoreticular pathways, numerous other pathways and brain areas are involved in the processing of pain.5-7
Modulation of the primary pain stimulus occurs at the level of the spinal cord where noxious stimuli become part of the overall sensory input; in response to descending neuronal influences; and at numerous supraspinal levels affecting the discriminative, emotional, and cognitive aspects of pain.5,8,9 The primary afferent terminal that transmits information to the dorsal horn is subject to several local dampening influences, including voltage-gated Ca++ channels and endogenous gamma amino butyric acid (GABA), opioid, and cannabinoid receptors. The dorsal horn cells, which transmit information centrally to the thalamus, also are subject to post-synaptic inhibition by opioids and GABA interneurons. In addition, descending controls modify sensory processing in the dorsal horn, including norepinephrine (NE) and serotonin (5-HT) pathways from the midbrain that inhibit pain transmission. Facilitatory pathways exist as well.
Several adaptive mechanisms involving primary afferent receptors, their cell bodies, and other central neurons play fundamental roles in the modulation of nociceptive pain, and in the development of neuropathic pain symptoms and syndromes. With peripheral nerve injury, axons serve as retrograde transport vectors for neurotrophic factors that affect the cell bodies of dorsal root ganglion cells and dorsal horn cells. Triggered and adaptive mechanisms include peripheral and central sensitization, ectopic excitability/impulse generation, phenotypic switching in pain-carrying fibers, disinhibition; altered gene expression, and central structural reorganization.10
Peripheral Sensitization and Primary Hyperalgesia. Noxious stimuli of sufficient intensity and duration cause tissue damage. When this occurs, promotion of healing becomes important. Inflammation increases pain sensitivity in the affected area, limiting its use and allowing repair mechanisms to operate. This type of pain typically decreases as tissue damage and the inflammatory response resolve.
During tissue injury and inflammation, nociceptors are exposed to substances that either directly activate them or make them more sensitive (eg, ATP, H+, prostaglandin E, bradykinin, pro-inflammatory cytokines, neurotrophic factors).4 Sensitizing agents augment Ca++ entry and/or activate intracellular pathways that modify the conformation/expression of receptors and ion channels in nociceptors. These responses cause a decreased threshold of nociceptor activation, an increased response to normally painful stimuli (primary hyperalgesia), and spontaneous depolarization (ectopic activity) in primary afferents. After nerve injury, an increased expression of voltage-gated sodium channels and oscillations from membrane K+ currents may cause ectopic discharges in primary afferents.11
Central Sensitization, Secondary Hyperalgesia, and Allodynia. As a consequence of peripheral nociceptor hyperactivity, secondary changes occur in their spinal cord dorsal horn neuron targets that result in central sensitization; that is, increased excitability of these neurons.12,13 This process begins with a cascade of events in the dorsal horn of the spinal cord triggered by release of transmitters (glutamate; substance P) from nociceptor terminals.
In contrast to A-delta fibers, whose post-synaptic potentials are measured in milliseconds, C-fiber potentials last up to 20 seconds.14 Repetitive C-fiber input changes the excitability of so-called multireceptive spinal cord neurons in the dorsal horn that receive synaptic inputs from pain as well as other sensory stimuli. Brief repetitive afferent nociceptive input causes temporal summation of these slow potentials, which induces the “wind-up” phenomenon in central dorsal horn neurons. In this state, subsequent nociceptive input causes a progressive increase in the output of the central pain projecting neuron.
Central sensitization is based, in part, on the enabling of NMDA receptors, and ultimately is maintained by increases in intracellular calcium.4 At the cellular level, central sensitization manifests as a reduction in stimulation thresholds, increased neuronal activity in response to noxious stimuli, an expansion in the peripheral receptive fields of spinal cord neurons, and spread of hyperexcitability to other spinal segments.15 Clinically, it manifests as pain sensitivity beyond sites of tissue damage or inflammation (secondary hyperalgesia) and the ability of stimuli from low-threshold A-beta receptors (that normally mediate light touch and hair movement) to generate sensations of pain or tenderness (mechanical allodynia).15 Thus, in the presence of central sensitization, pain can be signaled by large-diameter, as well as small-diameter afferents.16
Structural Reorganization. In contrast to pain-carrying fibers, low-threshold sensory fibers activated by touch, pressure, vibration, and normal movement of joints terminate in the deep laminae of the dorsal horn. Peripheral nerve injury may prompt these terminals to sprout or grow into the more superficial layers, whereby these touch fibers may now elicit pain responses (phenotypic switching).17,18
Other Responses to Peripheral Nerve Injury. Peripheral nerve injury also activates microglia in the spinal cord, which is another significant source of cytokines and chemokines that act on spinal cord neurons to alter their membrane properties and gene transcription.19 Peripheral nerve injury also provokes a pathologic loss of spinal cord inhibitory neurons, particularly those that release GABA.20 This process (disinhibition) augments pain transmission. In animal models of nerve injury, sodium channels that appear to be necessary for the expression of neuropathic pain are also redistributed to the axons of uninjured neighboring C-fibers.21,22
Definition. Neuropathic pain is defined by the International Association for the Study of Pain as “pain initiated or caused by a primary lesion or dysfunction in the nervous system.” Some have argued that use of the term dysfunction makes this definition vague and unacceptably broad and that it may be more appropriate to define neuropathic pain as pain caused by a lesion of the peripheral or central nervous system (or both), manifesting with sensory symptoms and signs (positive and negative sensory phenomena).23 In any event, neuropathic pain is an intractable, chronic syndrome that may arise from injury to peripheral nerves, spinal cord, or other CNS structures, and is associated with hyperalgesia, spontaneous pain, allodynia, repetitive discharge of nociceptors, and the expansion of receptive fields of nociceptive input.
As explained above, following peripheral nerve injury, primary afferents develop hyperexcitability. Ectopic discharges may originate in the region of nerve injury, causing pain directly and evoking central sensitization accompanied by allodynia and augmentation of spontaneous and movement-evoked pain.15 Ectopic discharges also may originate in the axotomized parent neuron in the dorsal root ganglion causing antidromic stimulation of afferent C fibers, release of mediators, and neurogenic inflammation. Regenerative sprouts (both primary afferents and low-threshold mechanoreceptors) also may discharge spontaneously, or in response to weak mechanical, thermal, ionic, or sympathetic stimuli.17 Completely denervated areas may receive collateral innervation from neighboring intact primary afferents. Alternatively, the axotomized primary afferent may sprout into new areas within the dorsal horn.17
Deafferentation (loss of normal input due to nervous system injury) can produce hyperresponsiveness and spontaneous discharges in spinal cord or thalamic neurons.23 The loss of tonic descending inhibitory inputs (disinhibition) may contribute to central pain.24 Additionally, patients with central pain may have suffered damage to the spinothalamic system.25 Primary afferent activity also may be heightened in response to sympathetic nervous system stimuli.26,27 This sympathetic-sensory coupling is thought, in some cases, to contribute to pain in inflamed tissue, and to pain associated with complex regional pain syndromes, diabetic neuropathy, post-herpetic neuralgia, phantom limb sensations, and other conditions.5 Complex regional pain syndromes (formerly called reflex sympathetic dystrophy and causalgia) appear to be especially linked with sympathetic-sensory coupling.28
Nerve injury and inflammation also modify gene expression in CNS neurons and may cause
phenotypic switches in subpopulations of A-beta fibers, as well as in certain dorsal root ganglion cells.4,6,10,29 Such phenomena, in addition to central lesions, may trigger changes in somatosensory circuitry, although the degree and ultimate significance of neuronal reorganization is not clearly established.10
Thus, the pain system is subject to ongoing and injury-provoked modulation. Maladaptive pain is uncoupled from a noxious stimulus or healing tissue, and is not merely an extension of acute nociceptive pain. The major mechanisms that underlie the development of neuropathic pain are: (1) autosensitization of nociceptive receptors; (2) calcium-induced molecular cascades from excess primary afferent glutamate release; (3) central sensitization; (4) ectopic firing of dorsal root ganglia (DRG) cells; (5) phenotypic change of afferent A-beta fibers and DRG cells to the characteristics of those associated with pain; (6) changes in gene expression of sodium channels and neuropeptides both at nociceptive terminals and at the DRG; and (7) anatomic changes of the superficial layers of the dorsal horn. 4,15 This is a progressive but plastic process that is reversible in its early stages and requires nociceptive input for its maintenance.
The classification of pain has been approached in many ways. Historically, attention was focused on whether the pain was acute or chronic, or developed into a syndrome complete with chronic pain, various co-morbidities, and biopsychosocial influences. Alternatively, pain has been classified based on a time continuum as acute, intermittent (subacute, episodic, recurrent), or persistent, or can be classified based on location (ie, focal, multi-focal, generalized, referred). Classification also has been based on severity, or on the site and etiology. The latter typically would include somatic (either malignant or nonmalignant), headache, visceral, and neurogenic (peripheral, central, autonomic) categories. While these classifications have some usefulness in the clinical arena, they lack a pathophysiologic basis.
The classification discussed above in the section on the Neurobiology of Pain classifies pain on a neurobiological basis, affording a better understanding of the etiology, pathogenesis, epidemiology, and management of neuropathic pain. Because of the taxonomic confusion, the American Academy of Pain Medicine has characterized pain by a new terminology, namely, eudynia for nociceptive pain, and maldynia for neuropathic pain.
Eudynia (nociceptive pain) is a normal physiologic response to noxious events and injury to somatic or visceral tissue. It can be beneficial and serves as an early warning mechanism. Eudynia often is acute, but can also be persistent (eg, cancer pain). In general, it consists of an afferent arm (transduction, transmission, modulation, perception of painful stimuli) and an efferent arm, reflecting pain behavior, both verbal and non-verbal.
As noted above, maldynia (neuropathic pain), derives from changes at the molecular and cellular level of the nervous system including the phenomenon of peripheral and central sensitization. It results in apparent structural alterations, as well as chemical, immunologic, and genetic changes that reflect the “plasticity” of the nervous system. These changes can result from injury, or diseases affecting the nervous system, or can be triggered by persistent, inadequately managed eudynia. Importantly, maldynia manifests in persistent pain attended by epiphenomena with physical, emotional, and sociologic characteristics, which may ultimately become secondary pain generators.
Epidemiology, Diagnosis, and Management of Neuropathic Pain
At least 4 million individuals suffer from peripheral neuropathic pain, most commonly peripheral diabetic neuropathy (PDN) and post-herpetic neuralgia (PHN). After spinal cord injury, pain develops in approximately 60% to 70% of patients.30,31 The number of individuals suffering from neuropathic pain is likely an underestimate, as more than 70 million individuals report suffering from some sort of chronic pain.
Diagnosis. Neuropathic pain syndromes typically comprise a combination of distinct sensory symptoms that can coexist in various combinations with motor and autonomic signs and symptoms.32 Diagnosis is based on medical history; review of systems; physical neurological examination; functional motor assessment, sensory examination (see below), and appropriate laboratory studies, including blood and serologic tests, magnetic resonance imaging, and electrophysiologic studies.33 See Table 1 (PDF, 19 KB) for the common causes and types of neuropathic pain states.
Positive sensory symptoms include pain, paresthesia (abnormal sensation, either evoked or spontaneous), dysesthesia (evoked or spontaneous unpleasant, abnormal sensation), hyperalgesia (increased response to a normally painful stimulus), and allodynia (painful response to a non-noxious stimulus). Negative sensory symptoms involve a loss of sensitivity to stimulation in general, and painful stimuli in particular (hypoesthesia and hypoalgesia). Neuropathic pain exhibits a heterogeneous presentation, including burning, tingling, paresthesias, shocklike pain, hypoesthesia, and phantom limb pain. Pain intensity can be rated with any of several verbal, numeric, or visual analog scales. Patients rate their pain using some type of continuum. The abnormal sensations in patients with neuropathic pain also can be assessed with measures of pain quality such as the Neuropathic Pain Scale34 and the Neuropathic Pain Questionnaire.35 A 30% reduction in pain scores using such scales is deemed clinically important.36
Sensory examination should include touch, pinprick, pressure, cold, heat, and vibration assessment.15 See Table 2 (PDF, 19 KB) for an alignment of typical tests. Responses are graded as normal, decreased, or increased to determine whether negative, or positive sensory phenomena are involved. The stimulus-evoked (positive) pain types are classified as dysesthetic, hyperalgesic, or allodynic, and according to the dynamic or static character of the stimulus.37 A more sophisticated neurophysiological technique (quantitative sensory testing [QST]) uses a battery of standardized mechanical and thermal stimuli. When present, allodynia or hyperalgesia can be quantified by measuring intensity, threshold for elicitation, duration, and area.
Management. Allodynia is a complex multidimensional syndrome, determined not only by actual tissue injury and responses provoked in the nervous system, but also by the patient’s personal beliefs, mood, previous experiences, psychosocial stressors, coping mechanisms, and motivation.38 Effective management often requires a biopsychosocial approach. Although this report devotes attention to the evaluation of pharmacologic interventions, comprehensive evaluation and multimodal treatment programs are needed to evaluate the complex issues confronted by patients with maldynia, including the use of nonpharmacologic, as well as pharmacologic treatments. Nonpharmacologic approaches include ice massage, heat or ultrasound therapy, relaxation techniques with biofeedback, exercise, massage, hypnosis, transcutaneous electrical nerve stimulation (TENS), physical therapy, acupuncture, or other ancillary techniques. Cognitive, rehabilitative, behavioral, and sometimes, invasive neuromodulatory or neurosurgical interventions may be needed as well.
Comprehensive treatments aim to eliminate maladaptive pain-related behaviors, achieve pain control, and improve coping through use of the above-noted techniques in combination with an interdisciplinary team approach to improve psychological functioning, reduce disability, and achieve rehabilitation. A number of cognitive and affective factors influence expressions of pain and participation in rehabilitation. Patients’ attitudes, beliefs, and expectations about their situation, their coping resources, and the health care system affect pain, activity, disability, and response to treatment.39
A multimodal approach requires the combined efforts of: (1) a physician(s) knowledgeable in pharmacologic and/or interventional procedures; (2) a psychiatrist or other mental health professional to diagnose and treat psychiatric conditions that may result from, cause, or exacerbate pain and suffering; referral for biofeedback, cognitive-behavioral techniques, group therapy, and counseling is warranted early in patients with psychosocial impairment; (3) a physical therapist or rehabilitation specialist to assess physical conditioning requirements; physical therapy referral is useful for neuromuscular rehabilitation, gait and prosthetic device assessment, therapeutic exercise instruction, desensitization (especially in patients with allodynia and hyperalgesia), and TENS trials (if warranted); and (4) nurses knowledgeable about these approaches who serve to improve team function, and provide valuable assistance in sustaining patient optimism and participation.
Patients who suffer from chronic pain experience higher rates of comorbid psychiatric disorders (eg, depression, anxiety), as well as sleep disturbances. Effective treatment of these conditions must be part of the management plan. Functional outcomes should be established to assist in evaluating treatment response.
Although primary care physicians play an important role in managing patients with neuropathic pain, when less invasive modalities have failed, referral to a pain specialist is imperative to optimize pharmacologic approaches and use of other modalities. Implantable drug delivery systems (eg, intraspinal infusion therapies), and nerve blocks are used in some patients with neuropathic pain. In selected patients with severe or unrelenting pain, spinal cord stimulation or stimulation of specific CNS structures, and various neuroablative procedures (eg, dorsal column stimulation; dorsal rhizotomy, neurolytic nerve block, intracranial lesioning) have been employed to reduce pain.
Pharmacologic Treatments for Neuropathic Pain
Commonly used medications that may at least partially relieve neuropathic pain include drugs that are traditionally classified as antidepressants, antiepileptic drugs, and local anesthetics/antiarrythmics, as well as opioids. Mechanistically, these drugs inhibit peripheral sensitization, modulate central sensitization, or potentiate descending inhibitory pathways. Drugs that are Food and Drug Administration (FDA)-approved include carbamazepine (trigeminal neuralgia); gabapentin (post-herpetic neuralgia [PHN]); pregabalin (diabetic painful neuropathy [DPN]; PHN), duloxetine (PHN), and the 5% lidocaine patch (PHN). Thus, a significant portion of drug therapy for neuropathic pain is off-label.
Antidepressants. Tricyclic antidepressants (TCAs) have a long history of use for neuropathic pain. These drugs have variable inhibitory effects on the neuronal uptake of NE and 5-HT. Neuronal uptake is the primary mechanism for terminating the synaptic signal of these neurotransmitters. Both are important components of descending control pathways originating in the mid-brain that serve to diminish pain transmission at the spinal level. TCAs also block serotonergic (5-HT1A, 5-HT2), noradrenergic (alpha1), histaminergic (H1), and cholinergic muscarinic receptors to varying degrees. These actions cause several side effects that may limit patient acceptance (eg, dry mouth, sedation, dizziness, tachycardia, urinary hesitancy, blurred vision).
Several systematic reviews are available, including a recent analysis of 50 randomized controlled trials of antidepressants in patients with neuropathic pain.40-43 There is substantial evidence for the effectiveness of TCAs, particularly amitryptiline and desipramine, in treating diabetic neuropathy and post-herpetic neuralgia, and some evidence for their effectiveness in central pain and atypical facial pain.43 These drugs, however, appear to be ineffective in HIV-related neuropathies.44 In addition to their effects on NE and 5-HT uptake, amitryptiline and desipramine also modulate Na+ channel activity.45
Antidepressant drugs that more selectively inhibit NE- and 5-HT-uptake, like venlafaxine and duloxetine (selective norepinephrine reuptake inhibitors), also may be effective in neuropathic pain; duloxetine is FDA-approved for the treatment of PDN.46-49 More limited evidence suggests that selective serotonin reuptake inhibitor (SSRI) antidepressants such as fluoxetine, sertraline, paroxetine, and citalopram are effective in neuropathic pain.43 Further research is needed into the role of SSRIs in the treatment of neuropathic pain because they are generally better tolerated than the TCAs. Other antidepressants that have been studied include bupropion, St. John’s wort, and phenelzine.
Antiepileptic Drugs. Antiepileptic drugs (AEDs) also have a long history of use for neuropathic pain management. AEDs currently used for neuropathic pain are gabapentin, carbamazepine, clonazepam, lamotrigine, oxcarbazepine, phenytoin, and valproate. Mechanisms vary among these agents, including sodium channel modulation, enhanced GABAergic function, and inhibition of Ca++ currents.
Carbamazepine/Oxcarbazepine. Seven controlled trials of carbamazepine have been reported in patients with trigeminal neuralgia, many conducted in the 1960s.50-52 Generally, carbamazepine diminishes pain intensity and provides meaningful benefit in more than half of patients with trigeminal neuralgia. Only limited evidence is available on the effectiveness of carbamazepine in patients with diabetic neuropathy, post-herpetic neuralgia, and post-stroke pain.53-56 Carbamazepine is believed to work primarily by virtue of its effect on sodium channels; it enhances the inactivation of voltage-gated sodium channels and reduces high-frequency repetitive firing.
In one randomized controlled trial of oxcarbazepine in trigeminal neuralgia, 35% of patients experienced more than a 50% reduction in pain scores.57 The active metabolite of oxcarbazepine acts in a similar manner to carbamazepine.
Gabapentin/Pregabalin. Gabapentin has been studied in several large trials and has a moderate effect on pain and quality of life measures in mixed neuropathic pain states, post-herpetic neuralgia, painful diabetic neuropathy, and spinal cord injury.50,52,58,59 Gabapentin is FDA-approved in the United States for the treatment of post-herpetic neuralgia, and is widely used for painful diabetic neuropathy; approximately one-third of patients derive significant benefit. In one short-term trial involving patients with painful HIV-associated sensory neuropathies, gabapentin, but not placebo, significantly decreased median pain ratings (44% vs 30%).60 The combination of gabapentin plus venlafaxine was more effective than gabapentin alone in the treatment of PDN.61 The combination of gabapentin plus morphine was superior to gabapentin or morphine alone in patients with PDN or PHN. Average pain scores decreased approximately 50%, and these results were achieved at lower doses of each drug than either as a single agent.62 A similar effect was observed in patients experiencing cancer-related neuropathic pain.63
Gabapentin and pregabalin modulate the activity of α2δ calcium channel subunits on synaptic terminals, which are activated/upregulated during central sensitization; through this action gabapentin decreases transmitter release at primary afferent terminals.64,65 Gabapentin also reduces central sensitization in humans evoked by intradermal application of capsacian.66 More recently, several trials have examined the ability of “preemptive” gabapentin to decrease post-surgical pain or analgesic requirements.67-69
Pregabalin, a structural analog of GABA similar to gabapentin, is FDA-approved for the treatment of both PHN and PDN. The efficacy of pregabalin appears to be comparable, or better than, gabapentin in the treatment of these conditions, although comparative studies have not been reported.70-75
Lamotrigine. Lamotrigine up to 400 mg daily diminishes pain in patients with diabetic neuropathy.76 Limited benefits have been observed in patients with HIV-associated painful sensory neuropathy, central post-stroke pain, and as an add-on to carbamazepine or phenytoin in patients with refractory trigeminal neuralgia.77-80 The drug was ineffective in one study on patients with spinal cord injury pain.81
Miscellaneous AEDs. In three trials generated by the same investigators, valproate (1 to 1.2 g daily) diminished pain scores approximately 50% in patients with non-insulin dependent diabetes suffering from PDN, and in patients with trigeminal neuralgia.82-84 These results have not been replicated in other settings. The drug was not effective in patients with central pain provoked by spinal cord injury.85
With one exception, randomized placebo-controlled trials of topiramate in PDN have been disappointing.86,87 In the one positive study, topiramate offered only a 15% benefit in reducing pain scores versus placebo.87
In a small pilot study of subjects with painful diabetic neuropathy, zonisamide was more effective than placebo, but was not well tolerated. Larger randomized trials are needed to establish the efficacy and tolerability of zonisamide for this condition.88
Opioid Analgesics. Opioid analgesics have been investigated intermittently over the last 20 years for efficacy in patients with neuropathic pain. Undoubtedly, earlier patterns of clinical use were based on the incorrect assumption that the pathogenesis of neuropathic pain was an extension of nociceptive mechanisms. A recent systematic review and meta-analysis of controlled trials involving opioid treatment of neuropathic pain is instructive; see this review for a compilation of key randomized controlled trials conducted over the last decade.89
The efficacy of single doses of pure opioid agonists, or their short-term use, is equivocal in significantly diminishing the intensity of pain in a variety of neuropathic pain states. Longer term use (in a variety of peripheral and central neuropathic pain states) is effective in reducing the intensity of neuropathic pain at a level (~30%) that is likely to be clinically significant. As noted above, the combination of morphine and gabapentin provided better pain relief (and at lower doses) than either agent alone.
Tramadol. Tramadol inhibits the neuronal uptake of both NE and 5-HT, and has a weak effect on the μ opioid receptor; its major metabolite has a somewhat stronger effect on this morphine-like receptor. Evidence from a limited number of randomized controlled trials indicates that tramadol provides some benefit in reducing the intensity of neuropathic pain in patients with post-herpetic neuralgia, PDN, and polyneuroapthy.90-93
Local Anesthetics. Lidocaine and its oral analogs, mexiletine, tocainide, and flecainide, provide an analgesic effect when administered orally or parenterally. Most randomized controlled trials in patients suffering from neuropathic pain have involved the parenteral administration of lidocaine or oral administration of mexiletine. A systematic review of the literature (through 2004) on the administration of local anesthetics to relieve neuropathic pain revealed 29 such studies.94,95 Sixteen trials examined the effects of intravenous lidocaine (1 to 5 mg/kg) on spontaneous pain relief. Twelve trials examined the effect of mexiletine at a dose range of 300 to 1200 mg/day (mean = 600 mg/day) for a period of 2 to 26 weeks (mean = 9 weeks). A number of different neuropathic pain states were included in this review. All studies used a visual analog scale (VAS) to measure pain. Intravenous lidocaine and oral mexiletine are more effective than placebo in decreasing neuropathic pain, with an average improvement of 11 points on the 100-point VAS, with nearly half of the patients reporting ≥30% reduction in pain intensity. Treatment effects were similar for both agents. Subgroup analysis indicated both drugs were more effective for patients with PDN, and for neuropathic pain developing after trauma or stroke. The treatment effects were somewhat less than those associated with the use of opioids, but the patient population, in general, had long-standing chronic pain that had not responded adequately to other measures.
Since publication of this systematic review, two additional trials of lidocaine in patients with spinal cord injury pain have been published. Infusion of lidocaine at a dose of 5 mg/kg reduced neuropathic at and below the level of the injury; a dose of 2.5 mg/kg was ineffective.96,97 While interesting, the use of intravenous lidocaine is restricted to short-term use in the hospital environment.
Cannabinoids. Two main types of cannabinoid receptors (CB1 and CB2) have been identified.98 Central nervous system responses to cannabinoids are mediated largely by CB1 receptors on nerve terminals. These receptors inhibit voltage-gated calcium channels and increase potassium conductance, thereby dampening neurotransmitter release. CB1 receptors are located on the central and peripheral terminals of primary afferents and at other pain pathway sites. Endogenous cannabinoids are eicosanoid derivatives, which also may interact with the vanilloid receptor.
A systematic review published in 2001 found little benefit for the use of cannabinoids in acute pain, cancer pain, or chronic noncancer pain.99 Subsequently, randomized controlled trials of cannabinoids in patients with multiple sclerosis-related central pain found moderate, clinically relevant effects on pain intensity.100-101 One of these trials involved a commercial cannabis extract formulated as a mucosal spray containing equal portions of delta-9-tetrahydrocannabinol and cannabidiol.102 This product is approved for use in Canada and the United Kingdom for the treatment of pain in multiple sclerosis patients, and is undergoing Phase 3 trials in the United States as an adjunct in cancer pain. Another trial involving a synthetic cannabinoid that lacks psychoactive properties demonstrated analgesic benefits in patients with various types of neuropathic pain from nerve injury.102
Topical Treatments: Lidocaine Patch. Application of a 5% lidocaine patch relieves pain and allodynia in patients with PHN.103-105 Efficacy has also been demonstrated in other peripheral neuropathic pain syndromes characterized by localized areas of hyperalgesia and allodynia.106
Capsaicin. Topical creams with capsaicin are used to treat pain from PHN and PDN. This compound stimulates C-fiber nerve endings by binding to vanilloid-type receptors. With repeated administration, the central terminal becomes depleted of substance P, and peripheral receptive sites may degenerate, resulting in decreased pain sensations. A recent systematic review and pooled analysis confirmed that capsaicin is significantly better than placebo for the treatment of neuropathic pain.107 At 8 weeks, more than half of patients can expect at least a 50% decrease in pain intensity; the placebo response is also fairly robust with topical treatment, so that the number needed to treat in order to achieve a significant effect with capsaicin is fairly high (~5-6).
Other Pharmacologic Approaches
Many other drugs have been evaluated for their efficacy against neuropathic pain, including other antidepressants (eg, bupropion, clomipramine, imipramine), NMDA receptor antagonists (eg, dextromethorphan, ketamine, memantine, riluzone), baclofen, other antiepileptic drugs (eg, tiagabine, zonisamide, leviracetam), and magnesium sulfate.108 Investigational compounds target the putative pathophysiologic cascade involved in the development of neuropathic pain states, including compounds that target receptors for vanilloid receptors, and antagonists for bradykinin, glycine, tumor necrosis factor, and interleukin receptors. At least 38 different compounds and dosage forms are being investigated for use in patients with neuropathic pain.109
Neuraxial Drug Delivery. When systemic drug therapy and ancillary treatments do not offer adequate relief, epidural or intrathecal spinal delivery of opioids or other drugs may be beneficial. Epidural application has been used in clinical practice routinely for the last 30 years, primarily for post-surgical, obstetrical, and chronic noncancer pain. Intrathecal opioid therapy for neuropathic pain has become more common over the last decade.110-112 Intrathecal administration of clonidine, clonidine/opioid combinations, ketamine, and baclofen also have been employed.111-114
Nerve Blocks. The interruption, interference, or blockade of painful stimuli have been used in the management of pain for several decades. Acute, chronic, and post-operative pain can be diminished with various types of regional anesthesia or specific nerve blocks. In the setting of chronic pain management, various peripheral nerve blocks can be diagnostic, prognostic, or therapeutic in nature. Nerve blocks are generally most useful when a specific nerve or limb is affected. Neuropathies with bilateral or multiple areas of involvement may benefit from other forms of neuromodulation, including pharmacologic management, transcutaneous electrical stimulation (TENS), or spinal cord stimulation (see below).
Sympathetic blocks are widely employed for diagnostic and therapeutic purposes: eg, diagnosis of sympathetically maintained pain; neuropathic pain, including phantom limb pain; complex regional pain syndrome; and ischemic pain.
In the past 25 years, the field of pain management has increasingly incorporated technologies of neurostimulation as part of the treatment algorithm for patients with maldynia. There is a lack of high-quality evidence relating to spinal cord stimulation and motor cortex stimulation due to difficulties in conducting randomized controlled trials in this area. Methodologic problems are encountered in blinding, recruitment, and assessment in nearly all published trials of these interventions. Nevertheless, patients entered in these trials have generally suffered for extended periods, and many have reported substantial relief.
Transcutaneous Electrical Stimulation (TENS) for Chronic Pain. TENS is used in a variety of clinical settings to treat a range of acute and chronic pain conditions and has become popular with patients and health care professionals of different disciplines. By applying peripheral stimuli (rubbing, vibration, heat, cold), or in the case of TENS, electrical stimulation, directly over the area of pain, sensory information from larger diameter (non-pain carrying) afferents is activated, and affects the processing of pain impulses within the dorsal horn of the spinal cord. TENS is generally believed to be an effective, safe, and relatively noninvasive intervention that can be used to alleviate many different sorts of pain, including neuropathic pain.115 However, systematic reviews have concluded there is insufficient evidence to draw any conclusions about the effectiveness of TENS for the treatment of chronic pain in adults, or in the treatment of chronic lumbar back pain.116,117
Spinal Cord Stimulation. Spinal cord stimulation (SCS) is a form of therapy used to treat certain types of chronic pain. It involves an electrical generator that delivers pulses to a targeted spinal cord area. The leads can be implanted by laminectomy or percutaneously, and the source of power is supplied by an implanted battery or by an external radio-frequency transmitter. With regard to neuropathic pain, SCS is indicated for treatment of pain from isolated peripheral nerve injuries, spinal cord injury-related pain, deafferentation syndromes, and trigeminal neuralgia.118 It also is being used in the management of phantom limb pain, post-amputation stump pain, recalcitrant post-herpetic neuralgia, peripheral neuropathy, and pain associated with multiple sclerosis.119,120 Is also is used to treat other chronic pain conditions such as pain due to end-stage, ischemic, peripheral vascular disease, failed back surgery, and interstitial nephritis.118
Motor cortex stimulation is used for the treatment of complex central and neuropathic pain syndromes that have proven refractory to medical treatment, including post-stroke pain, deafferentation pain, and some neuropathic pain states of peripheral origin.121-126
Neuropathic pain is distinct from normal, nociceptive pain triggered by noxious stimuli. Nociceptive pain serves as an alerting/warning mechanism to decrease further harm. Neuropathic pain states are triggered by persistent nociceptive stimuli or frank nerve injury. These conditions activate a series of adaptive and eventually, maladaptive, changes in the function and properties of pain-carrying fibers and other sensory neurons, including phenotypic changes and alterations in gene expression, as well as the fundamental properties of specific neurons and sensory pathways.
Despite recent advances in understanding of the pathology related to nervous system injury, the pharmacologic management of neuropathic pain states remains a challenge. Patients who have substantial disability and psychosocial problems, and who have not benefited from conventional pain treatments, are often referred to multidisciplinary pain clinics. These multimodal programs aim to eliminate maladaptive pain-related behaviors, achieve pain control, and improve coping through biopsychosocial techniques in combination with an interdisciplinary team approach to improve psychological functioning, reduce disability, and achieve rehabilitation.
A large array of medications have been investigated for the treatment of various peripheral and central neuropathic pain states. At least half of the patients with diabetic neuropathy and post-herpetic neuralgia generally experience a significant response to one or more compounds from different pharmacologic classes. Patients with central pain syndrome are less likely to respond.
Drugs that modulate the activity of sodium channels (antiepileptics; local anesthetics), inhibit certain calcium channels (gabapentin; pregabalin), or potentiate spinal cord inhibition either locally (GABA-mimetics; opioids) or via descending controls (antidepressants; opioids) may be effective. There is a pressing need for comparative trials, as well as the development of compounds that may interrupt the cascade of pathophysiologic events responsible for the development of maladaptive pain syndromes. In addition, more attention should be paid to combination trials using drugs that have different mechanisms of action. A number of interventional approaches, including nerve blocks, spinal cord stimulation, and cortical stimulation may be required when patients do not respond adequately to medical, psychological, and pharmacologic management.
RECOMMENDATION (Adopted AMA Directive)
As recommended by the Council on Science and Public Health, the following statement was adopted as a directive by the AMA House of Delegates at the 2006 AMA Annual Meeting:
The AMA will disseminate [this report] to physicians, patients, payers, legislators, and regulators to increase their understanding of issues surrounding the diagnosis and management of maldynia (neuropathic pain). (Directive).
CSAPH home page
Reports by topic
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Resolution 528 (A-05)
Resolution 528 (A-05), introduced by the American Academy of Pain Medicine, American Academy of Hospice and Palliative Medicine, American Association of Neurological Surgeons, American Psychiatric Association, American Society of Clinical Oncology, American Society of Anesthesiologists, California Delegation, Congress of Neurological Surgeons, Florida Delegation, International Spinal Intervention Society, and the Medical Student Section at the 2005 Annual Meeting and referred to the Board of Trustees, asked:
That the AMA acknowledge the existence of neuropathic pain resulting from neurobiological pathology, as established in the scientific literature;
That the AMA educate physicians, patients, payers, legislators and regulators to increase their understanding of both nociceptive pain and particularly neuropathic pain; and
That the AMA work with appropriate specialty societies and report on the appropriate epidemiology, evaluation, treatment, and distinguishing characteristics of nociceptive pain and neuropathic pain. Back to top
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