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Home , Intractable pain, Neuralgia, Neuropathic pain, Peripheral edema

CONTEMPORARY MANAGEMENT OF NEUROPATHICREVIEW

Contemporary Management of for the Primary Care Physician

HSIUPEI CHEN, MD; TIM J. LAMER, MD; RICHARD H. RHO, MD; KENNETH A. MARSHALL, MD; B. TODD SITZMAN, MD; SALIM M. GHAZI, MD; AND RANDALL P. BREWER, MD

Neuropathic pain (NP), caused by a primary or dysfunction term commitment from the patient and physician to ensure in the nervous system, affects approximately 4 million people in the United States each year. It is associated with many diseases, adequate adherence to frequently complex management including diabetic , postherpetic , strategies. Ultimately, many patients require multidisci- human immunodeficiency virus–related disorders, and chronic plinary strategies to adequately relieve and re- . Major pathophysiological mechanisms include pe- ripheral sensitization, sympathetic activation, disinhibition, and store function. In recent years, randomized clinical trials central sensitization. Unlike most acute pain conditions, NP is evaluating treatments of NP have led to specific recom- extremely difficult to treat successfully with conventional analge- mendations for first-line therapies.3 This article describes sics. This article introduces a contemporary management ap- proach, that is, one that incorporates nonpharmacological, pharma- the pathophysiology of NP, reviews common NP condi- cological, and interventional strategies. Some nonpharmacological tions, and summarizes a contemporary management ap- management strategies include patient education, physical reha- proach incorporating pharmacological, nonpharmacologi- bilitation, psychological techniques, and complementary medicine. Pharmacological strategies include the use of first-line agents that cal, and interventional management strategies. have been supported by randomized controlled trials. Finally, refer- ral to a pain specialist may be indicated for additional assessment, interventional techniques, and rehabilitation. Integrating a compre- NERVOUS SYSTEM TRANSMISSION OF PAIN hensive approach to NP gives the primary care physician and patient the greatest chance for success. The transmission of pain from the site of tissue injury is an Mayo Clin Proc. 2004;79(12):1533-1545 important biological response that protects the organism from further injury. The transduction of pain involves the CRPS = complex regional pain syndrome; DPN = diabetic peripheral conversion of a noxious mechanical, inflammatory, or ther- neuropathy; GABA = γγγ-aminobutyric acid; HIV = human immunodefi- mal stimulus into an electrical impulse. These electrical ciency virus; NMDA = N-methyl-D-aspartate; NP = neuropathic pain; PHN = ; SCS = spinal cord stimulation; TCA = impulses arise within tissue , sensory that tricyclic ; TENS = transcutaneous electrical stimu- are responsible for conducting pain signals into the dorsal lation; TN = horn of the spinal cord. Nociceptors, whose cell bodies are found in the dorsal root ganglia, transmit pain signals along he International Association for the Study of Pain thinly myelinated axons (A delta fibers) and unmyelinated Tdefines pain as “an unpleasant sensory and emotional axons (C fibers). Peripheral nociceptors, by release of the experience associated with actual or potential tissue dam- glutamate, activate neurons that are re- age or described in terms of such damage.”1 Neuropathic sponsible for the transmission of pain impulses centrally. pain (NP) is initiated or caused by a primary lesion or These projection neurons (nociceptive neurons) cross the dysfunction in the nervous system, commonly persists be- midline to form the contralateral . yond the normal healing period, and exhibits symptoms of Axons of the projection neurons terminate in the somato- positive and negative sensory phenomena.2 Because of its sensory (ventral posterolateral and ventral pos- poor response to traditional , NP requires a long- teromedial nuclei) and medial thalamus and provide collat- eral inputs to key brainstem nuclei such as the parabrachial From the Division of Pain Medicine, Duke University Medical Center, Durham, pontine nucleus, the periaqueductal gray matter, and the NC (H.C., R.P.B.); Department of , Mayo Clinic College of Medicine, Jacksonville, Fla (T.J.L., K.A.M., B.T.S., S.M.G.); and Division of reticular formation of brainstem. Pain Medicine, Mayo Clinic College of Medicine, Rochester, Minn (R.H.R.). Dr Information regarding the location, quality, and inten- Marshall is now with the Oconee Memorial Hospital Center for Comprehensive Pain Management, Seneca, SC. Dr Sitzman is now with the Center for Pain sity of pain is conveyed to the primary sensory cortex from Medicine, Wesley Medical Center, Hatiesburg, Miss. the somatosensory thalamus. Projections from the medial Dr Brewer has received research support from Merck & Co, Inc and Endo thalamus and brainstem nuclei are responsible for limbic Pharmaceuticals and has received honoraria from Alpharma Inc and Inc. and autonomic activation through projections to the hy- Address reprint requests and correspondence to Hsiupei Chen, MD, Critical pothalamus, insula, amygdala, and cingulate cortex. The Health Systems, PO Box 18623, Raleigh, NC 27619 (e-mail: chen0025@mc .duke.edu). cortical inputs culminate in the perception of a painful © 2004 Mayo Foundation for Medical Education and Research stimulus. Descending inhibitory pathways, predominantly

Mayo Clin Proc. • December 2004;79(12):1533-1545 • www.mayo.edu/proceedings 1533 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. CONTEMPORARY MANAGEMENT OF NEUROPATHIC PAIN located in the periaqueductal gray matter and dorsolateral of the dorsal horn of the spinal cord, spinotha- fasciculus (Lissauer tract) of the spinal cord, are activated lamic tract, thalamus, and/or cerebral cortex (somatosen- to modulate the transmission of nociceptive stimuli. Inhibi- sory and limbic cortex) may result in NP in patients with tion is achieved by release of endogenous , norepi- central pain. Reduced activation of key brainstem descend- nephrine, and serotonin in the dorsal horn, by recruitment ing inhibitory systems normally modulated through endog- of inhibitory interneurons that release the inhibitory neu- enous , serotonin, and norepinephrine pathways may rotransmitter γ-aminobutyric acid (GABA), and by direct result in neuropathic central pain (disinhibition). Disinhibi- inhibition of pain projection neurons. Non-nociceptive, tion also may result from loss of inhibitory inputs into the large-fiber input into the dorsal horn conveys information dorsal horn6,11,12 (Figure 2, B). Treatments believed to act regarding pressure, light touch, and joint position sensa- by restoring endogenous inhibitory systems include drugs tion. These fibers, principally A beta fibers, branch into that mimic descending or local inhibitory pathways (cloni- adjacent deeper layers of the dorsal horn and ascend as the dine, tricyclic [TCAs], opioids, GABA ipsilateral dorsal column (fasciculus gracilis, fasciculus agonists) and nonpharmacological techniques such as cuneatus) and contralateral medial lemniscus. These inputs transcutaneous electrical nerve stimulation (TENS), spinal also terminate in the ventrolateral somatosensory thalamus. cord stimulation (SCS), , massage, and thera- Large-fiber inputs into the dorsal horn also may activate peutic exercise.13 Despite the widespread use of TENS descending and local inhibitory mechanisms by activating units, evidence from randomized controlled trials is insuffi- local inhibitory interneurons through the release of GABA4 cient to show the efficacy of TENS in treating chronic (Figure 1). pain.14 Cognitive-behavioral interventions may contribute to central inhibitory systems.15 In sympathetic activation, sympathetic nerve endings sprouting from a nearby blood MECHANISMS OF NP vessel toward the site of injury can enhance signal trans- Neuropathic pain stems from neural dysfunction that mission in the dorsal root . Catecholamine release persists beyond the period of normal tissue healing; there- and up-regulation of adrenergic receptors on free nerve fore, long-lasting changes in the processing of sensory endings and also contribute to sympathetically information by the nervous system are believed to under- mediated pain (Figure 2, C). lie the presence of persistent pain. Both peripheral and Injury to peripheral may lead to the phenomenon central NP mechanisms have been identified in experimen- known as peripheral sensitization. Peripheral sensitization tal models.5 involves the hyperexcitability of peripheral nerve termi- In some individuals, central sensitization results after a nals, or nociceptors, normally responsible for the transduc- peripheral nerve injury induces changes in pain processing tion of painful stimuli. Inflammatory mediators released as within the dorsal horn.6 It is characterized by hypersensitiv- a result of tissue or nerve injury may induce spontaneous ity of dorsal horn neurons to both noxious and non-noxious activity and hypersensitivity to mechanical stimuli in periph- input, a lowered threshold for activation, and expanded eral nociceptors. This may be a result of altered expression of receptive fields. Sustained activation of nociceptors, such sodium channels, calcium channels, and adrenergic recep- as that which occurs after peripheral nerve injury, leads to tors in peripheral nerves and dorsal root ganglia.16-18 These the activation of key excitatory amino acid receptors such changes form the rationale for many of the drugs currently as the N-methyl-D-aspartate (NMDA) receptor (Figure 2, used in the treatment of peripheral NP (Figure 2, D). A). Persistent activation signals protein kinases and phosphorylation of the NMDA receptor, which results CLINICAL MANIFESTATIONS OF NP in intracellular calcium accumulation. Long-lasting changes in neuronal membrane excitability through the transcrip- The hallmark of NP is the experience of both tion of key gene products may be further induced and lead (nonpainful abnormal sensations) and (un- to long-lasting changes in the excitability of dorsal horn pleasant abnormal sensations). Spontaneous pain qualities neurons.7 Other phenotypic changes in nociceptive neurons such as burning, tingling, itching, and aching often coexist have been shown in experimental models, such as the with evoked pain qualities such as shooting, stabbing, or recruitment of A beta fiber terminals into the superficial electric . is an exaggerated response to a dorsal horn resulting in the aberrant A beta fiber activation painful stimulus, whereas , pain after an innocu- of nociceptive neurons.8 Although a key target for new ous stimulus, is common and often disabling. therapies has been the NMDA receptor, clinical trials of the or (reduction or loss, respectively, of normal efficacy and tolerability of the currently available NMDA sensation) in an area of NP is known as anesthesia antagonists have been disappointing.9,10 dolorosa. Symptoms of NP from various etiologies are

1534 Mayo Clin Proc. • December 2004;79(12):1533-1545 • www.mayo.edu/proceedings For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. CONTEMPORARY MANAGEMENT OF NEUROPATHIC PAIN

FIGURE 1. Normal sensory tracts. The spinothalamic tract transmits input encoded for pain and temperature, and the dorsal column transmits input encoded for light touch. The free nerve ending of an A delta fiber or a C fiber senses pain and temperature and has its cell body in the dorsal root ganglion. This in the dorsal horn with a second-order neuron that immediately crosses the midline and ascends on the contralateral side in the spinothalamic tract. The axons of the second-order neuron terminate in the hypothalamus and thalamus. In the thalamus, some pro- jections are made directly to the primary sensory cortex, whereas others go to the limbic system, which includes the insula, amygdala, and cingulate cortex. The Pacinian corpuscle is a first-order neuron that senses pressure. This neuron’s cell body is also in the dorsal horn, and the ascends a few levels, crosses the midline, and ascends in the contralateral dorsal column/ medial lemniscus, through the medulla and midbrain, and terminates in the thalamus. There, the neuron synapses with a second-order neuron, which projects to the primary sensory cortex.

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Mechanisms Therapeutic options

Ca2+ channel antagonists NMDA receptor antagonists Glutamate antagonists

Central α-receptor agonists NE reuptake inhibition Serotonin reuptake inhibition GABA agonists TENS SCS Opioids

Central α-receptor agonists Peripheral α-receptor antagonists Sympathetic nerve blocks Systemic sympatholytics

Na+ channel antagonists Ca2+ channel antagonists

FIGURE 2. Mechanisms of neuropathic pain and therapeutic options. Mechanisms (left column): A, Central sensitization. Overactivity of a second-order neuron in the dorsal horn leads to enhanced pain transmis- sion. In some individuals, central sensitization results after a peripheral nerve injury induces changes in pain processing within the dorsal horn. It is characterized by a lowered threshold for activation and expanded receptive fields, leading to the activation of key excitatory amino acid receptors such as the N- methyl-D-aspartate (NMDA) receptor. B, Disinhibition. Reduced activation of key central inhibitory inputs from the dorsolateral fasciculus (purple) through endogenous opioid, serotonin, and norepinephrine pathways may result in neuropathic central pain (left). Disinhibition also may result from loss of local inhibitory pathways from an interneuron (right). C, Sympathetic activation. Sympathetic nerve endings sprout from a nearby blood vessel toward the site of injury and can enhance signal transmission in the dorsal root ganglion. Catecholamine release and up-regulation of adrenergic receptors on free nerve endings and neuromas also contribute to sympathetically mediated pain. D, Peripheral sensitization. Injury to peripheral nerves may lead to the hyperexcitability of peripheral nerve terminals, or nociceptors, normally responsible for the transduction of painful stimuli. This may be a result of altered expression of sodium channels, calcium channels, and adrenergic receptors in peripheral nerves and dorsal root ganglia. Therapeutic options (right column): Therapeutic options for modulating the transmission of neuropathic pain are shown adjacent to each of the 4 mechanisms. GABA = γ-aminobutyric acid; NE = norepinephrine; SCS = spinal cord stimulation; TENS = transcutaneous electrical nerve stimulation.

1536 Mayo Clin Proc. • December 2004;79(12):1533-1545 • www.mayo.edu/proceedings For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. CONTEMPORARY MANAGEMENT OF NEUROPATHIC PAIN remarkably similar (eg, 2 individuals with postherpetic Low back and are among the most common neuralgia [PHN] and diabetic peripheral neuropathy [DPN] reasons for physician visits.25 Although the percentage of may both experience burning pain). These observations patients with low back and neck pain of solely NP origin is have led to a shared-mechanism concept for the evaluation unknown, chronic radicular pain develops in more than of NP pathophysiology and prospective treatments.5 20% of those requiring spinal surgery, with an annual prevalence of more than 2 million cases in the United States.1,19 In addition to axial pain, patients with chronic EPIDEMIOLOGY AND ETIOLOGIES OF radiculopathy usually experience activity-dependent ach- COMMON NP DISORDERS ing, burning, and lancinating or stabbing pain in the sen- Neuropathic pain affects nearly 4 million people in the sory distribution of a . Occasionally, spontaneous United States.19 Disorders of the brain or spinal cord can burning or lancinating pain predominates, especially in pa- lead to “central pain,” such as that encountered in multiple tients with other evidence of neurologic dysfunction such as sclerosis, after a , and in spondylotic and posttrau- sensory loss, weakness, and/or loss of deep tendon reflexes. matic myelopathy. Peripheral nervous system disorders The degree of reported pain intensity or disability may not include diseases of the spinal nerve roots, dorsal root gan- correlate with the or radiographic find- , and peripheral nerves. Focal lesions of the peripheral ings. Superimposed myofascial, inflammatory, and skeletal nervous system that occur, for example, after amputation nociceptive pain generators often coexist. These factors, and with radiculopathy, , and other combined with physical deconditioning, psychological entrapment neuropathies are usually distinguishable from comorbidity, and third-party involvement (eg, disability diffuse disorders such as diabetic , human claims, litigation) contribute to the complexity of rehabili- immunodeficiency virus (HIV) sensory neuropathy, and tation. Unfortunately, in the setting of acute low back and idiopathic small-fiber sensory neuropathy. neck pain, few treatments have been evaluated adequately Diabetic peripheral neuropathy occurs in persons with for their ability to prevent the chronic condition or limit diabetes at a rate of 11.6% in those who are insulin depen- nerve injury. Opportunities for prevention of long-term dent and 32.1% in those who are not, with an estimated disability may include early mobilization and physical prevalence of up to 3 million persons in the United therapy facilitated by aggressive symptomatic manage- States.20,21 The most common form of painful DPN causes ment, patient education, and psychological interventions in spontaneous burning pain, numbness, and allodynia in the high-risk patients. Pharmacotherapy alone is rarely effec- lower extremities. There may be concomitant carpal tunnel tive, and interdisciplinary management strategies may be syndrome or meralgia paresthetica, pain in the distribution required. of the lateral femoral cutaneous nerve. Loss of small-fiber The complex regional pain syndrome (CRPS) has been sensation in the stocking-glove distribution usually is estimated to be present in 100,000 persons in the United present in patients with diabetes who have pain. Noctur- States.19 Formerly known as reflex sympathetic dystrophy, nally exacerbated symptoms are extremely common; they CRPS type I is characterized by the development of NP may prevent restorative sleep and lead to secondary fa- after tissue trauma such as surgery or bone fracture. In tigue, irritability, and myofascial dysfunction. Glycemic CRPS type II, formerly known as causalgia, NP results control currently is emphasized to delay onset and progres- from an injury to a peripheral nerve with pain that extends sion of DPN.22 beyond the distribution of the injured nerve.1 In both types, In the United States, 600,000 to 800,000 cases of hallmark features of CRPS such as asymmetric sweating, herpes zoster occur each year, and between 9% and 24% changes in skin texture, diminished skin temperature, and of these patients will develop PHN.21,23 After acute her- fluctuating degrees of swelling may accompany more uni- pes zoster infection, PHN develops in 50% of persons versal symptoms of NP such as burning, allodynia, and older than 70 years and may lead to disability, depression, motor dysfunction. By definition, these symptoms outlast and social isolation. Frequently, background burning or the period of normal tissue healing. Results of electro- aching pain is accompanied by paroxysmal stabbing diagnostic studies (eg, electromyography, nerve conduc- or itching and severe, evoked allodynia and hyperalge- tion studies), autonomic testing, and 3-phase radioisotope sia.17,18 Fields et al16 showed that both peripheral and bone scan may support the diagnosis and assist with the central mechanisms are responsible for the variable man- exclusion of other conditions. Neuropathic pain in CRPS ifestations of PHN. Promising strategies for prevention is considered sympathetically maintained when it is re- of PHN pain include early treatment with agents spe- duced by sympatholytics or sympathetic nerve blocks. cific for NP, antiviral , and varicella zoster Sympathetic-independent pain may emerge in the later alloimmunization.24 stages of the illness.26

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An uncommon condition, idiopathic trigeminal neural- most cases, correlation of specific mechanisms with exami- gia (TN) is characterized by paroxysmal, lancinating, and nation findings is difficult. For example, allodynia may evoked pain in the distribution of 1 or more divisions of the result from either peripheral or central mechanisms. Also, . Patients who have sensory loss or other it may be challenging for the clinician to distinguish neuro- neurologic symptoms need to be evaluated for a primary pathic from nociceptive pain. Further elucidation of cogni- nervous system structural lesion or an inflammatory disor- tive and behavioral dimensions of a patient’s pain is an- der such as . The symptoms of TN can be other important step toward individualizing therapy. debilitating. For example, speaking or chewing may be- On the basis of current evidence from randomized clini- come incapacitating. Treatment of TN differs from that of cal trials, recommendations for first-line pharmacotherapy other neuropathic disorders because many patients with TN for NP have been established. First-line agents for treat- are sensitive to . Second-line alternatives ment of NP include TCAs, , topical , include , , baclofen, clonazepam, , and opioids. When choosing a first-line agent, and . In refractory TN, referral to a pain specialist the clinician should consider the weighted efficacy of each or a neurosurgeon is indicated for consideration of other agent, the adverse effects, the neuropathic disorder, and management strategies. These include gasserian ganglion any comorbidities.3 The most commonly used pharmaco- glycerol neurolysis, trigeminal balloon decompression, mi- logical options are summarized in Table 1. crovascular decompression, or gasserian ganglion lesioning with gamma knife or radiofrequency technology.27 ANTIDEPRESSANTS Neuropathic pain is a common and important source of Antidepressants commonly are prescribed for NP. Their morbidity in patients with . Neuropathic symptoms efficacy is not related simply to the treatment of coincident often coexist with nociceptive pain generators such as bone depression. Possible mechanisms include sodium channel metastases and visceral pain. The most common cancer- blockade and the facilitation of endogenous inhibition of related etiologies of NP include tumor-related neural com- pain.31 Evidence suggests that agents with adrenergic or pression, radiation-induced neural injuries, and neuropathies mixed serotonergic and adrenergic mechanisms, such as related to paraneoplastic disorders and chemotherapeutic TCAs, are generally more efficacious than selective seroto- agents.28 Although the mainstay of pharmacological treat- nin reuptake inhibitors.32,33 ment of cancer-related pain is opioids, referral to a pain The tertiary amine subclass of TCAs has been studied management center for neurolytic blocks or other medical most, particularly . Inhibition of H1-histamin- α management may be required to optimize quality of life. ergic, 1-adrenergic, and muscarinic cholinergic receptors In patients with HIV, NP may have multiple manifesta- accounts for most of the adverse effects, the most serious of tions. In moderately advanced disease (CD4 cell count, which are cardiac conduction disturbances, orthostatic hy- 0.200-0.500 × 109/L), concomitant infection with potension in the elderly population, agranulocytosis, C or human T-lymphotropic virus 1 can lead to painful thrombocytopenia, and precipitation of acute angle-closure peripheral neuropathy. In advanced HIV-1 disease (CD4 glaucoma.34 The TCAs are more lethal in overdose than cell count, <0.200 × 109/L), distal symmetrical sensory other antidepressants, an important consideration in pa- polyneuropathy can present with paresthesias, cramps, and tients with comorbid depression. Generally preferred over disabling burning and lancinating pain in the feet. Cyto- the tertiary amines, the secondary amines (eg, , megalovirus infection occurs in 2% of patients with ad- ) tend to have fewer adverse effects with simi- vanced HIV-1 disease and may cause debilitating low back lar efficacy.35 pain, radicular pain, and myelopathy. Several antiretroviral In general, the tricyclics are initiated at low doses (Table agents, including lamivudine and saquinavir, can cause 1) and are slowly increased every 3 to 7 days until the patients to develop acute toxic neuropathy, with 50% of patient experiences acceptable relief or develops unman- patients presenting with pain as their first symptom.29 Al- ageable adverse effects. Individual variability and the pres- though results of studies of the efficacy of amitriptyline ence of comorbid conditions dictate careful titration in each and in the treatment of HIV-related NP were patient. Serum drug levels are indicated when the dosage disappointing, lamotrigine showed decreased average pain exceeds approximately 100 mg daily and if pain relief or scores compared with .30 intolerable adverse effects have not occurred. Common adverse effects such as dry mouth, somnolence, constipa- tion, increased appetite, and urinary retention should be PHARMACOLOGICAL OPTIONS FOR TREATING NP reviewed carefully with the patient; close monitoring dur- Unfortunately, advanced understanding of NP mechanisms ing titration reinforces compliance and early feedback has not led to the ideal of mechanism-based treatment. In about adverse effects. Nightly dosing may be desirable in

1538 Mayo Clin Proc. • December 2004;79(12):1533-1545 • www.mayo.edu/proceedings For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. CONTEMPORARY MANAGEMENT OF NEUROPATHIC PAIN

TABLE 1. Commonly Used Medications for Treating Neuropathic Pain*

Pharmacological Dosing mechanism(s) Drug (class) Starting† Maintenance† Frequency Common adverse effects Na channel blockade Topical lidocaine (5%) 1-4 patches 1-4 patches 12 h on, Erythema, local pruritus () 12 h off Serotonin, norepinephrine Amitriptyline 10-25 50-150 Once daily at Orthostasis, xerostomia, urinary reuptake inhibition, (antidepressant– nighttime retention, blurry vision, sedation, Na channel blockade tertiary amine constipation, weight gain tricyclic) Nortriptyline 10-25 50-100 Once daily at Orthostasis, xerostomia, urinary (antidepressant– nighttime retention, blurry vision, anxiety, secondary amine constipation, weight gain, tricyclic) sedation; less severe than with tertiary amines Selective serotonin reuptake 10-20 20-80 Once daily in , sweating, insomnia, inhibition (antidepressant) the morning nausea, sedation, sexual dysfunction 10-20 20-80 Once daily in Headache, sweating, insomnia, (antidepressant) the morning nausea, sedation, sexual dysfunction Serotonin, norepinephrine 20-30 60 Once or twice Nausea, somnolence, dizziness, reuptake inhibition (antidepressant) daily constipation, dry mouth, sweating, decreased appetite Selective serotonin, 37.5-50.0 150-300 Once daily in Insomnia, sweating, sexual norepinephrine reuptake (antidepressant) the morning dysfunction, headache, anorexia, inhibition Dopamine, norepinephrine 50-100 200-400 Once daily in Insomnia, anxiety, seizures reuptake inhibition (antidepressant) the morning α δ Calcium channel ( 2 subunit) Gabapentin 100-300 900-3600 3 times daily Ataxia, nausea, fatigue, dizziness, antagonism (antiepileptic) somnolence, peripheral Na channel blockade Carbamazepine 100-200 600-1200 Twice daily , sedation, ataxia, diplopia, (antiepileptic) nausea, vomiting, leukopenia, aplastic anemia (rare), hyponatremia (rare) Na channel blockade, Lamotrigine 25-50 300-500 Twice daily Rash, ataxia, blurred vision, glutamate release inhibition (antiepileptic) diplopia, headache, nausea, vomiting, Stevens-Johnson syndrome (rare) α δ Calcium channel ( 2 subunit) 50-100 150-600 3 times daily Dizziness, somnolence, peripheral antagonism (antiepileptic) edema, blurry vision, xerostomia Opioid µ-receptor agonist 5-10 20-160 Every 4 to 6 h; Sedation, nausea, vomiting, (semisynthetic opioid) twice daily pruritus, constipation, dysphoria if ER 15-30 30-300 Every 4 to 6 h; Sedation, nausea, vomiting, (opioid) 1-3 times pruritus, constipation, dysphoria daily if ER Transdermal 25 µg/h 25-150 µg/h Every 48-72 h Sedation, nausea, vomiting, pruritus, (synthetic opioid) patch patch constipation (less frequent), dysphoria Opioid µ-receptor agonist 5-10 20-80 1-4 times daily Dysphoria, sedation, nausea, (isomer l-methadone), (synthetic opioid) vomiting, constipation, drug NMDA receptor antagonism accumulation, respiratory (isomer d-methadone) depression Nonopioid µ-receptor agonist, Tramadol 37.5-50.0 200-400 Every 6-8 h Sedation, seizures, constipation, serotonin, norepinephrine (synthetic µ-receptor confusion (in the elderly reuptake inhibition agonist) population)

*ER = extended-release formulation; NMDA = N-methyl-D-aspartate. †Units are mg/d unless stated otherwise. patients with nocturnal pain and insomnia. Minor adverse The selective serotonin reuptake inhibitors citalopram effects can be treated symptomatically (eg, with use of and paroxetine have been shown to be superior to placebo sialagogues, stool softeners, changes in timing of adminis- in trials of DPN; however, clinical experience suggests tration). Inadequate trials are common because of poor their effects are weak.33,37 One randomized trial has sug- management of adverse effects, early discontinuation (tri- gested use of the antidepressant bupropion, a dopaminer- als should last 6-8 weeks), and insufficient dosing.35,36 gic, norepinephrine reuptake inhibitor, for treatment of

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NP.38 Bupropion has the added benefit of aiding in smoking ing.31,41,49 The need for serum monitoring, incidence of cessation and is generally nonsedating, both commonly adverse effects, and availability of newer agents have de- desired effects in many patients with . Newer creased use of phenytoin. antidepressants such as venlafaxine inhibit norepinephrine Carbamazepine, structurally related to TCAs, has a and serotonin reuptake without the adverse effects of mode of action similar to that of phenytoin. Trials in pa- TCAs. A recent study suggests the efficacy of venlafaxine tients with TN, DPN, and PHN have shown efficacy over is similar to that of the TCA imipramine in treatment of NP placebo.50,51 Serious adverse effects such as leukopenia, associated with painful polyneuropathy.39 Duloxetine, a aplastic anemia, and hyponatremia may develop during potent serotonin and norepinephrine reuptake inhibitor re- initiation of therapy. Routine serum monitoring of electro- cently approved by the Food and Drug Administration, has lytes and hematologic indexes should be conducted at been shown to be efficacious in treating pain caused by baseline and periodically throughout treatment. Patients DPN at doses of 60 mg and 120 mg daily.40 with an elevated risk of leukopenia (low or borderline pretreatment white blood cell counts) should be monitored ANTIEPILEPTICS regularly during the first 3 months of therapy.52 A carba- Antiepileptics modulate both peripheral and central mecha- mazepine analogue, oxcarbazepine, does not yield the ep- nisms via sodium channel antagonism, inhibition of excita- oxide metabolite that contributes to the drug interaction tory transmission (eg, NMDA receptor), or enhancement of and adverse-effect profile of carbamazepine.53 Oxcarbaz- GABA-mediated inhibition. Most antiepileptics have mul- epine has shown similar effects as carbamazepine against tiple potential modes of action that may be beneficial for mechanical hyperalgesia and allodynia in experimental NP. Individual variability occurs; even among drugs with models and may be effective in carbamazepine-responsive similar principal mechanisms, some patients may respond patients with poor tolerance.54 There is evidence for the preferentially to a certain drug. Current studies suggest efficacy of oxcarbazepine in treating PHN and DPN55; in 1 equal efficacy and tolerability with the use of antidepres- controlled trial, it was efficacious in treating DPN at a sants or antiepileptics in the treatment of NP.41 mean dose of 814 mg/d, and the most commonly experi- Gabapentin is recognized widely as an effective agent in enced adverse effects were drowsiness and dizziness.56 the treatment of NP. Although its exact mechanism of Lamotrigine works as a sodium channel inhibitor and action is unknown, it antagonizes voltage-gated calcium inhibits glutamate release. Recent trials have shown effi- channels in afferent neurons and modulates central nervous cacy in central pain, HIV-related NP, and DPN. Lamotri- system GABA activity.42 Trials in DPN and PHN have gine has a risk of serious rash and Stevens-Johnson syn- shown its efficacy, similar to that noted with amitripty- drome, especially with rapid titration.29,57 Although evidence line.43-45 Most patients tolerate a starting dosage of 300 mg from large-scale, randomized clinical trials is lacking, anec- nightly, with increases every 3 to 7 days to 300 mg twice dotal reports suggest that the antiepileptic drugs , daily and then 300 mg 3 times per day. Titration is contin- zonisamide, , , and may be ued in 300-mg increments until the patient experiences useful solely in selected patients or as additions to first-line acceptable relief, intolerable adverse effects, or lack of agents.40,58 effect despite a total dose of 3600 mg daily. Temporary suspension of dose escalation may allow tolerance of ad- OPIOIDS verse effects to develop. A recent study reinforced the fact Randomized controlled trials have shown the efficacy of that a total dose of 1800 to 3600 mg per day of gabapentin opioids in treating NP.43 Studies have shown oxycodone to is well tolerated by most patients.46 Elderly patients and be effective in treating PHN and DPN, with efficacy and patients sensitive to the drug should initially receive 100 tolerability comparable to TCAs and gabapentin.59,60 Low- mg at night with weekly increases of 100 mg. The most dose methadone has been shown effective in improving the common adverse effects are sedation, fatigue, nausea, and visual analog scale ratings of patients with NP of mixed incoordination. Currently awaiting Food and Drug Admin- etiologies.61 High-dose opioid therapy with the µ-receptor istration approval, pregabalin (isobutyl-GABA) inhibits agonist showed improved efficacy over low- ectopic discharges from injured nerves, inhibits voltage- dose therapy in reducing NP at the expense of increased α δ 62 gated calcium channels ( 2 subunit), and has shown effi- adverse effects and treatment-related study withdrawals. cacy in PHN.47 Opioids appear to block A delta fiber– and C fiber– Phenytoin suppresses ectopic discharges by inhibition mediated pain but may be less likely to reduce A beta fiber– of voltage-gated sodium channels and suppression of mediated mechanical allodynia. Additionally, methadone glutamate release.48 It is useful as a second-line agent in and propoxyphene antagonize the NMDA receptor. This patients with TN, but data in other disorders are conflict- property may be of benefit in opioid tolerance and central

1540 Mayo Clin Proc. • December 2004;79(12):1533-1545 • www.mayo.edu/proceedings For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. CONTEMPORARY MANAGEMENT OF NEUROPATHIC PAIN sensitization, but comparative efficacy trials with other chronic nonmalignant pain have been published.73,74 Persis- opioids are lacking.63 The unique pharmacokinetic and tent, intolerable adverse effects in opioid-responsive pa- pharmacodynamic profile of methadone requires careful tients may warrant consideration of intrathecal opioid consideration during dose titration and conversion from therapy. other opioids.64 Tramadol, a centrally acting, weak opioid µ-receptor OTHER AGENTS agonist, also weakly inhibits norepinephrine and serotonin Baclofen, a GABA-B receptor agonist used primarily as an reuptake and promotes serotonin release. Its effectiveness antispasticity agent, has been used effectively in patients in treating NP has been shown in patients with DPN and with TN and may be effective in other disorders.75 Seda- polyneuropathy.65,66 Tramadol may precipitate seizures at tion, hypotonia, and confusion in elderly persons may com- higher doses and interact with other drugs with serotonin plicate therapy. Effective in the treatment of dystonia asso- reuptake inhibition, such as TCAs. ciated with CRPS and refractory spasticity, intrathecal Benefits from long-term opioid therapy must be baclofen has produced anecdotal evidence as an adjuvant weighed against the possible occurrence of opioid-induced treatment of NP.76,77 α hyperalgesia, opioid tolerance (the need to increase the Clonidine, an 2-adrenergic receptor agonist, may be an dose to maintain an effect), and the potential for abuse.67,68 effective in some patients. Neuraxial clonidine Aberrant drug-seeking behavior may signal , has been shown effective in treatment of NP associated opioid diversion, or undertreatment. Empirical evidence with cancer and may be better tolerated than systemic suggests that the incidence of addiction in the population administration. It appears to work by mimicking the ef- with chronic pain is extremely low or at least similar to that fects of endogenous pain-inhibiting neuro- of the normal population (approximately 6%).69 Neverthe- transmitters (eg, norepinephrine).78 However, its long-term less, physiologic dependence may occur with prolonged efficacy in NP not associated with cancer will require use. Patients must be warned not to discontinue opioids validation.79 The reported analgesic benefit of tizanidine, α abruptly or without supervision. Patients with a recent another 2-adrenergic agonist and antispasticity agent, history of substance abuse usually require the assistance of awaits confirmation. pain specialists and addictionologists.70 Individual respon- Sodium channel blockers (intravenous lidocaine and siveness to opioids can vary substantially; therefore, care mexiletine) and NMDA antagonists ( and must be taken to ensure that the titration is done safely and ) may benefit selected, refractory syndromes.10,80-82 that treatment goals are set and maintained. Transfer of Because of the narrow therapeutic indexes of these agents, care back to the primary care physician after a suitable they are usually initiated by pain management specialists. regimen has been established allows for coordi- Topical agents have limited potential for systemic toxic- nation of care.71 ity and drug interactions. Effective in PHN, topical lido- The adverse effects of opioid use are well known but caine is considered a first-line therapy in NP.83 Topical often manageable. Common, troublesome adverse effects lidocaine also has been shown effective in DPN.84 Serum include constipation, cognitive dysfunction, and nausea. lidocaine levels are well below those observed during sys- Less frequent are pruritus, urinary hesitancy, and anorexia. temic infusions, with limited drug interactions. , Constipation prophylaxis should be initiated at outset of the active ingredient in chili peppers, opens a heat-acti- opioid therapy. Bulk agents, increased dietary fiber, and vated ion channel (vanilloid receptor subtype 1) modulat- generous fluid intake are often sufficient. Stool softeners ing in peripheral axon terminals.85 It is occa- and laxatives sometimes are needed. Tolerance to sedation sionally effective in patients who tolerate its initial burning occurs usually within several weeks. If sedation persists, effects. judicious use of methylphenidate or modafinil (psycho- ) can be effective. CONTEMPORARY PRINCIPLES OF The efficacy and risks associated with long-term opioid PAIN MANAGEMENT therapy have not been elucidated fully in NP. Notably, long-term opioid doses greater than 300-mg oral morphine Initial evaluation by the primary care physician entails equivalents per day have not undergone extensive longitu- detailed review of the diagnosis and previous treatments. dinal study. The important clinical issues of opioid-induced Patients need reassurance that disease-based treatments are hyperalgesia, immunosuppression, and effects on endo- optimized. Educating patients about pain mechanisms di- crine function have tempered enthusiasm for the “no ceil- minishes their fears of undiagnosed disease. Patients ing” paradigm for opioid dosing in chronic pain.72 Guide- should understand that complete relief may not occur and lines regarding use of opioids in the management of be reassured of the clinician’s commitment to helping them

Mayo Clin Proc. • December 2004;79(12):1533-1545 • www.mayo.edu/proceedings 1541 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. CONTEMPORARY MANAGEMENT OF NEUROPATHIC PAIN best tolerate their pain. Coexistent physical deconditioning, tertiary amines, such as amitriptyline, should be avoided in insomnia, and psychological comorbidity require directed elderly persons because of their increased risk of falling. approaches and periodic reassessment. To best evaluate efficacy and possible adverse effects, it is advisable to avoid simultaneous adjustments of an existing ASSESSMENT AND EVALUATION regimen and the addition of new agents. Incomplete or The primary care physician should first assess the nature of partial responses to drugs with minimal risk such as topical the patient’s pain. Individual pain assessment remains pri- lidocaine often can be augmented by the addition of a drug marily subjective. The visual analog scale and numeric with a different mechanism of action (such as gabapentin). rating scales allow pain to be rated from “no pain” to Although many patients respond favorably to 2 or 3 drugs “worst pain imaginable.” The pain diagram documents the with synergistic profiles, careful attention must be given to patient’s extent of pain and allows the pain to be monitored. the use of more than 3 drugs when incremental benefit does Pain diaries reviewed periodically by the physician encour- not occur.2 Physician and patient expectations often must age patient involvement and are useful for outcome assess- be tempered by the clinical experience of incomplete pain ments. A detailed history of the onset and nature of pain is relief in most patients. Improving the activities of daily important. Next, the physician should perform a detailed living is an important goal from the outset of therapy but is neurologic and musculoskeletal examination. Electromy- also important when a ceiling of analgesic efficacy has ography and nerve conduction studies are useful in assess- been reached with a pharmacological regimen. ing large-fiber involvement and the presence of axonal loss Tramadol can be considered a treatment option for pa- and reinnervation. Assessments of small-fiber tients in whom a TCA or gabapentin fails or is only par- with dermal biopsies or quantitative sensory testing remain tially effective, especially when nociceptive pain (eg, from principally research tools.86 Referrals to appropriate spe- osteoarthritis or cancer) coexists. Many of these individu- cialists for help in pinpointing a diagnosis allow for use of als will require more potent opioids, and individual toler- disease-based therapies, when available. Finally, for pa- ability varies widely. Rotation to a different opioid may be tients in whom concomitant psychological dysfunction is useful in patients with poor tolerability to an initial agent. suspected, psychological screening for depression and Although opioid abuse is uncommon in patients with anxiety should be performed. The Beck Depression Inven- chronic pain, many physicians use contracts defining the tory and other psychological assessment tools can be used terms of therapy, including the use of periodic serum and for mood assessment. urine drug testing. Patients who may benefit from opioid use can be identified with a trial of a short-acting agent APPROACH TO PHARMACOTHERAPY such as , oxycodone, or morphine, depending Despite improvements with pharmacotherapy, up to 30% on the severity of the problem. If the trial is effective, long- of patients may have intractable pain. Previous medical term therapy with a sustained-release or long-acting prepa- regimens, including dosing, escalation, and reasons for ration is advisable. A dosing schedule at regular intervals is failure, should be reviewed. preferable to use of “breakthrough” medications for pa- Many drugs are initiated at intolerable doses, escalated tients with chronic pain. Use of nonpharmacological op- too rapidly, and discontinued because of improperly ad- tions, such as psychological techniques, TENS, and local dressed manageable adverse effects.35 Patients should un- modalities (heat, ice, massage) should be encouraged in- derstand the goals of each step and need to know that stead of “as needed” or “breakthrough” medications when effects are not immediate. Serum levels are generally a stable dose of opioid has been achieved. unpredictive of response and should be monitored if maxi- mal doses are achieved without toxicity or benefit. Medica- NONPHARMACOLOGICAL MANAGEMENT tions are not necessarily lifelong therapy, and tapering Refractory pain leads to depression, anxiety, impaired pro- should be considered after a period of sustained relief and ductivity, declining social functioning, and diminished improved function.74 quality of life.87 Characterized by the escalating use of Many patients, especially those with localized symp- health care, affective disorders, and physical decondition- toms, may respond to initial therapy with topical lidocaine. ing, the chronic pain syndrome requires a comprehensive In diffuse syndromes, pharmacotherapy begins at the low- treatment strategy incorporating interdisciplinary manage- est available dose of a single drug, followed by gradual ment. Nonpharmacological management plays an impor- titration to efficacy and tolerability. Initial systemic ther- tant role in restoring function and reducing disability. Ev- apy may begin with gabapentin or nortriptyline. Tricyclic ery effort should be made to normalize the patient’s sleep antidepressants should be used with caution in patients schedule. Reviewing good sleep hygiene, limiting caffeine with a history of cardiac conduction disturbances. The intake, and encouraging exercise can prevent dependence

1542 Mayo Clin Proc. • December 2004;79(12):1533-1545 • www.mayo.edu/proceedings For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. CONTEMPORARY MANAGEMENT OF NEUROPATHIC PAIN

TABLE 2. Steps for Contemporary Neuropathic Pain Evaluation and Management Step 1 Step 2 Step 3 Diagnostic evaluation Detailed medical history Neurological consultation Disease-specific tests by and physical examination Neurosurgical consultation subspecialist Neuroimaging and Pain clinic referral* electrodiagnostic studies when necessary Nonpharmacological Patient education Patient support groups Vocational rehabilitation management Functional assessment Physical therapy Pain rehabilitation program Psychological assessment Cognitive behavioral therapy Sleep assessment† Sleep hygiene optimization Exploration of complementary therapies (eg, acupuncture) Pharmacological First-line agents‡ Second-line agents or Determined by pain management adjuvant medications§ medicine specialist Interventional None; pursue nonpharma- Diagnostic somatic or Advanced pain management management cological and sympathetic nerve blocks techniques by pain pharmacological medicine specialist management first *Include early referral to a pain clinic if diagnostic somatic or sympathetic nerve blocks are warranted. †Patient’s sleep hygiene should be reviewed, and complementary medicine may be considered. ‡When instituting pharmacological agents, primary care physician should administer adequate trials (usually 6-8 weeks) of first-line agents (Table 1). Dose should be escalated until intolerable adverse effects occur or until efficacious. §Consider if first-line agents have been ineffective. Adjuvant medications include sleeping agents, muscle relaxants, antide- pressants, and anxiolytics. on a nightly sedative. Psychological referral for biofeed- jection.91-93 The primary care physician may consider inter- back, cognitive-behavioral techniques, group therapy, and ventional strategies such as epidural injec- counseling is warranted early in patients with psychosocial tions in acute radiculopathy if symptoms persist despite impairment.87 Physical therapy referral should be made for physical therapy and use of oral analgesics. neuromuscular rehabilitation, gait and prosthetic device In CRPS, early physical rehabilitation of the affected assessment, therapeutic exercise instruction, desensitiza- limb is crucial for recovery. If the patient is unable to tion (especially in patients with severe allodynia and hyper- undergo physical therapy despite adequate medication tri- algesia), and TENS trials. A structured program with als, referral to a pain clinic is appropriate. Nerve blocks stepwise advancement is imperative in many disorders, such as a lumbar sympathetic block (lower extremity), especially CRPS and chronic radiculopathy.88 Occupa- stellate ganglion block (upper extremity), or somatic nerve tional therapy and vocational rehabilitation may help the block may provide sufficient analgesia for participation in patient transition to functional independence. The network physical therapy and remobilization.88 The duration and of care completed by mental health providers and physical extent of analgesia should be considered when determining and occupational therapists often helps sustain patient opti- the need for subsequent nerve blocks and escalation of mism and participation. These interventions are summa- physical therapy. rized in Table 2. After multiple medication trials have been ineffective, referral to a pain clinic is warranted for additional medical INTERVENTIONAL THERAPY management and appropriate interventions by the pain spe- Interventional therapy (diagnostic or therapeutic nerve cialist. A trial of SCS may be indicated for certain NP blocks or implantable technologies) may be considered in diagnoses.94 The positive results of SCS for patients in patients with continuing pain and dysfunction who are whom other therapies have failed for low syn- unresponsive to conservative approaches. Techniques such drome and CRPS have led to the use of SCS in other as local anesthetic and corticosteroidal nerve blocks gener- neuropathic disorders.95 Also, in a cost-effectiveness analy- ally are used to hasten return of function while long-term sis of SCS vs conventional medical treatment, SCS was strategies are identified.89 Although evidence for the effi- cost-effective after 2.5 years of follow-up and resulted in cacy of epidural injections is limited, in some cases success more patients returning to work than patients in the medical rates are higher than with conservative therapy.90 Patients management group.96 In selected patients, intrathecal phar- with acute neck or back pain with a radicular pattern may macotherapy offers the potential for targeted therapy of the derive the greatest benefit from epidural corticosteroid in- spinal cord.94 Intrathecal opioids, clonidine, baclofen, and

Mayo Clin Proc. • December 2004;79(12):1533-1545 • www.mayo.edu/proceedings 1543 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. CONTEMPORARY MANAGEMENT OF NEUROPATHIC PAIN local anesthetics (alone or in various combinations) have 15. Ji RR, Woolf CJ. Neuronal plasticity and signal transduction in nocicep- tive neurons: implications for the initiation and maintenance of pathological been used long term in selected patients with refractory pain. Neurobiol Dis. 2001;8:1-10. pain.95 For example, intrathecal morphine has been used 16. Fields HL, Rowbotham M, Baron R. Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol Dis. 1998;5:209-227. successfully in patients who respond to oral opioids but 17. McLachlan EM, Janig W, Devor M, Michaelis M. Peripheral nerve have unmanageable adverse effects. Intrathecal drug deliv- injury triggers noradrenergic sprouting within dorsal root ganglia. 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