Clinical aspects

Description

The peripheral neuropathy pain syndrome is a chronic condition. Therefore, the primary goal is effective pain management without the use of narcotics. Commonly used medications include antidepressants, anticonvulsants, antiarrhythmics, topical agents, and analgesics. Nonaddictive drugs are generally employed before narcotics or narcotic-like agents are tried.

Antidepressants. Amitriptyline is the gold standard in the tricyclic antidepressants group and has been investigated in several double-blind, randomized trials (56; 98; 12). Amitriptyline, desipramine, and fluoxetine were compared at a mean daily dose of 105, 111, and 40 mg, respectively, in two randomized, double-blind, crossover studies of painful diabetic neuropathy. Amitriptyline and desipramine relieved pain in 74% and 61% of 38 patients, respectively, whereas fluoxetine showed no difference compared with placebo in 46 patients (57). Amitriptyline inhibits serotonin and noradrenaline uptake and blocks N-methyl-D-aspartate receptors and active CNS sodium channels, which may influence descending pathways that modulate nociceptive pain transmission. Amitriptyline is extensively metabolized in the liver to nortriptyline. The terminal elimination half-life ranges from 12.9 to 36.1 hours. There is no clear relationship between amitriptyline plasma concentrations and analgesic effect. Amitriptyline should be started at a dosage of 10 to 25 mg/day and increased by 10 to 25 mg/week to the maximum effect or tolerated dosage. Although amitriptyline doses up to 150 mg per day were used in clinical trials, most patients need a maximum dose of 75 mg per day. Bedtime administration may help to circumvent sedation. The adverse events most commonly reported are dry mouth, sedation, constipation, nausea, urinary retention, orthostatic hypotension, and tachycardia in elderly patients. Amitriptyline should be administrated with caution in patients with urinary retention, prostatic hypertrophy, glaucoma, constipation, impaired liver function, or cardiovascular disease. It should be avoided immediately after myocardial infarction as well as in those with heart block, arrhythmia, or severe liver disease. Some advocate obtaining EKGs for tricyclic doses above 75 mg to rule out an atrioventricular block. Amitriptyline should not be given in conjunction with, or within 2 weeks of, treatment with monoamine oxidase inhibitor.

Desipramine is an effective alternative for patients who cannot tolerate amitriptyline, as demonstrated in the clinical trial mentioned above (57). Desipramine is a more specific noradrenergic reuptake blocker. After metabolization in the liver, 70% is excreted in the urine. Desipramine should be started at a dosage of 10 to 25 mg/day and increased by 10 to 25 mg/week to the maximum effect or tolerated dosage. Desipramine has fewer adverse events compared with amitriptyline. Desipramine should be cautiously administered in patients with unitary retention, prostatic hypertrophy, glaucoma, constipation, impaired liver function, or cardiovascular disease. It should not be given in conjunction with, or within 2 weeks of, treatment with MAO inhibitor, immediately after myocardial infarction, arrhythmia, seizures, and in patients with severe liver disease.

Nortriptyline is a noradrenergic metabolite of amitriptyline. Nortriptyline has similar pharmacological effect as amitriptyline but fewer adverse effects (99). Nortriptyline should be started at a dosage of 10 to 25 mg at bedtime and increased by 10 to 25 mg/week to the maximum effect or tolerated dosage. Most patients need a maximum dose of 75 mg a day. Nortriptyline is better tolerated by elderly patients due to less sedation and dry mouth. Cautions and contraindications are the same as amitriptyline.

Although the authors have never needed to employ other tricyclics for pain control, for completeness' sake these should be mentioned: protriptyline, imipramine, and doxepin. The latter has the most anticholinergic side effects, which sometimes can be helpful to reduce saliva production in patients with difficulty swallowing. Scientific experience with these agents for pain control is limited. On a cautionary note, a cohort study of over 3400 elderly patients found that higher cumulative anticholinergic use is associated with an increased risk for dementia (39).

Bupropion sustained-release is a second-generation nontricyclic antidepressant that inhibits norepinephrine reuptake. Bupropion sustained-release (150 to 300 mg daily) decreased average pain scores from 5.7 to 4.0 in 41 nondepressed patients with neuropathic pain in a single-center, randomized, double-blind, placebo-controlled crossover study (82). The pain relief was significant at week 2 and continued throughout the 6-week treatment. Side effects included dry mouth, insomnia, headache, gastrointestinal upset, tremor, constipation, and dizziness. Side effects occurred early in therapy and generally receded with continuation of therapy.

Duloxetine is a reuptake inhibitor of serotonin and norepinephrine. Duloxetine at doses of 60 and 120 mg a day improved neuropathic pain in several randomized, double-blind studies of diabetics and was rather well tolerated (38). The proportion of patients achieving pain relief in the duloxetine treatment groups was significantly greater than that in the placebo group at week 1 and at all subsequent study visits. The first significant separation from placebo in pain severity reduction for duloxetine 60 mg daily occurred on the third day using pooled data (71). Duloxetine also demonstrated pain reduction in a randomized, double-blind, placebo-controlled clinical trial for patients with painful, chemotherapy-induced peripheral neuropathy (87). Duloxetine may be better tolerated versus gabapentin (54). A common initial side effect, nausea, can be curtailed if the drug is started at a low dose of 20 or 30 mg during the first week.

Venlafaxine is unrelated to other antidepressants. It is a serotonin, norepinephrine, and dopamine reuptake inhibitor. Venlafaxine is extensively metabolized in the liver. Renal elimination is the primary route of excretion. Venlafaxine showed a reduction in neuropathic pain (75). In a randomized, double-blind, placebo-controlled study, 55 patients received venlafaxine XR at a dose of 75 mg, 150 mg, or placebo. Pain intensity decreased significantly compared to the baseline in all groups, with no significant difference. The areas of allodynia and pinprick hyperalgesia decreased significantly in venlafaxine groups compared to the placebo (101). Venlafaxine relieved oxaliplatin-induced acute neuropathic pain in 31.3% of patients versus control, which relieved pain in only 5.3% of patients (25). Venlafaxine is well tolerated; the adverse events are nausea, headache, somnolence, dry mouth, and dizziness. Venlafaxine should not be given in conjunction with, or within 2 weeks of, treatment with MAO inhibitors.

Anticonvulsants. Carbamazepine was the first anticonvulsant investigated for trigeminal neuralgia in the 1960s. Several randomized, placebo-controlled trials demonstrated efficacy in pain reduction for trigeminal neuralgia and diabetic neuropathy (16; 46; 64). Carbamazepine blocks sodium channels and depresses thalamic potential and polysynaptic reflexes. Carbamazepine is metabolized in the liver to Carbamazepine-10,11-epoxide, which has anticonvulsant activity. The initial dosage starts at 100 mg two times a day. The daily dose may be increased by 100 mg every 12 to 24 hours but not to exceed 1200 mg a day. The extended-release formulation is used twice a day, with conventional tablets needed three or four times a day. Carbamazepine should not be used in patients with a history of bone marrow depression or in conjunction with, or within 2 weeks of, treatment with a MAO inhibitor. The most frequent adverse reactions are dizziness, drowsiness, nausea, vomiting, hyponatremia, aplastic anemia, agranulocytosis, and thrombocytopenia. Carbamazepine intoxication may cause ataxia, restlessness, tremor, seizures, impaired consciousness, and coma. Therapeutic adult serum levels range from 4 to 12 µg/ml. Monitoring serum levels can be used to prevent carbamazepine intoxication.

Gabapentin is a frequently used anticonvulsant for painful neuropathy. Gabapentin is structurally related to GABA but does not interact with GABA receptors. It reduces neurotransmitter release by binding to the alpha2delta subunit of a voltage-dependent Ca2+ channel (35). Gabapentin does not bind to plasma proteins or interact with other drugs. A double-blind, placebo-controlled trial demonstrated pain reduction with gabapentin at 900 to 3600 mg/day in 165 patients with diabetic neuropathy (07). Gabapentin (1200 to 2400 mg/day) and amitriptyline (30 to 90 mg/day) were compared in a 12-week, open-label, prospective, randomized trial with 25 patients with type-II diabetic neuropathy. Gabapentin produced greater pain reductions than amitriptyline and was better tolerated (21). Gabapentin can reduce chemotherapy-induced neuropathic pain at a low dose of 800 mg/day (95). It is usually well tolerated; however, adverse reactions commonly occur with quick titration. Adverse events may include fatigue, dizziness, somnolence, and weight gain. Gabapentin should be started at a dose of 100 to 300 mg/day and slowly increased to the maximum effect or tolerated dosage. The usual maximum dosage is 4000 mg/day divided into three or four daily doses, although some patients benefit from and tolerate higher amounts. Occasionally, a previously effective dose needs to be increased to maintain pain control in the absence of objective evidence of disease progression, possibly due to habituation. The dose needs to be adjusted based on renal creatinine clearance (creatinine clearance 30 to 60 ml/min, 300 mg two times a day; creatinine clearance 15 to 30 ml/min, 300 mg one time a day; creatinine clearance less than 15 ml/min, 300 mg every other day). Gabapentin is being increasingly prescribed for a wide range of clinical conditions. Although the risk of dependence on gabapentinoids appears to be lower than that of sedatives and stimulants, in a given patient, especially in cases of a history of overuse or misuse, it should be weighed against the expected benefits (13).

Pregabalin shares its pharmacological profile and its misuse and abuse potential with gabapentin. Pregabalin also reduces excitatory neurotransmitter release by binding to alpha2delta subunits of voltage-gated calcium channels (30). Pregabalin has a greater effect on paroxysmal pain than on surface or deep pain in patients with peripheral neuropathy (43). Pregabalin is given two to three times daily. From an initial dose of 150 mg/day, one may increase to 300 mg/day in 3 to 7 days, and, later, to 600 mg/day as needed. At 300 and 600 mg/day doses, pregabalin demonstrated efficacy in four randomized, double-blind, multicenter studies of painful diabetic neuropathy (Frampton and Scott 2004; 79). Pregabalin significantly reduced pain and improved pain-related sleep disturbance compared to placebo in a randomized, double-blind, multicenter, placebo-controlled study in patients with postherpetic neuralgia and painful diabetic peripheral neuropathy (32; 37). Based on 11 placebo-controlled trials to evaluate the efficacy of pregabalin, pain reduction was greatest in patients with severe baseline pain compared with moderate baseline pain (67). However, in two randomized, double-blind, placebo-controlled trials pregabalin showed no significant benefit versus placebo in painful HIV neuropathy (86) and neuropathic pain following surgical or nonsurgical nerve trauma (55). In a randomized, double-blind, crossover trial with variable dose titration, pregabalin showed better pain relief and fewer adverse effects than amitriptyline (10). Adverse effects of pregabalin include dizziness, somnolence, peripheral edema, headache, blurred vision, and constipation. Pregabalin significantly improves pain, affective symptoms, and sleep in patients with gabapentin-refractory peripheral neuropathic pain (77). The combination of pregabalin and tramadol for chronic neuropathic pain revealed no significant drug-drug interactions (51). The average dosage of pregabalin in patients undergoing hemodialysis has been reported as about 50 mg daily for peripheral neuropathic pain (66). In hemodialysis patients, gabapentin 300 mg and pregabalin 75 mg were administered after each dialysis session. Both drugs improved total pain scores and health-related quality of life to the same extent (04). Just like other medications for neuropathic pain, pregabalin increases the risk of erectile dysfunction (14). Cerebral edema after rapid withdrawal from pregabalin has been reported (65). Increased hazards of misuse and adverse outcomes related to coordination, mental health, and criminality have been reported (80; 68; 61); misuse risk seems to be higher when gabapentinoids are used in combination with opioids.

Lacosamide is another promising treatment for neuropathic pain. It decreases neuronal discharge frequency and synaptic excitability. At 100 to 400 mg/day it provided better pain relief than placebo in a study of diabetic neuropathy (73). Improvement was also seen in sleep and general activity. Adverse events included dizziness, nausea, headache, and diplopia.

Lamotrigine functions as a sodium channel blocker, suppressing the release of glutamate from presynaptic neurons. In a 59-patient randomized, placebo-controlled trial for painful diabetic neuropathy, it reduced pain intensity on one particular scale from 6.4+/-0.1 to 4.2+/-0.1 with a titrated dose of 25 to 400 mg/day (29). In a multicenter, randomized, double-blind, placebo-controlled trial for painful HIV-associated neuropathy, lamotrigine showed a reduction in average pain from baseline (85). However, there was a high dropout rate due to skin rash. In a similarly designed study lamotrigine was well-tolerated and effective for HIV-associated neuropathic pain in patients receiving neurotoxic antiretroviral therapy (84). The dose was titrated from 25 to 400 mg/day or 600 mg/day in 7 weeks. A long titration phase is required for lamotrigine, which limits its usefulness for pain management.

Oxcarbazepine is a dihydromonohydroxy analogue of carbamazepine with a superior side effect profile and effectiveness and good tolerability between 600 and 1800 mg/day for trigeminal neuralgia (102) and painful diabetic neuropathy (24; 11). Hyponatremia is a dose-dependent side effect. The most common adverse events are mild to moderate drowsiness and dizziness.

Phenytoin was an effective treatment for painful neuropathy in randomized, placebo-controlled clinical trials when administered orally or by intravenous infusion (18; 59). However, it is no longer considered to be a first-line anticonvulsant for neurogenic pain. It is used for painful neuropathy when other anticonvulsants have no effect or intolerable side effects. Phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation. Phenytoin can be administrated at 15 mg/kg initially and maintained from 200 to 300 mg a day. Common adverse reactions, most dose-related, include nystagmus, ataxia, confusion, nausea, vomiting, and gingival hyperplasia. Toxic serum levels have marked variations among individuals. Nystagmus often appears at 20 µg/ml. When considering serum levels, it is important to obtain troughs, values, ie, just before the next daily dose. Phenytoin should be administrated with caution in patients with impaired liver function.

Topiramate has multiple inhibitory functions for excitation. It blocks sodium channels, increases GABA activity, antagonizes kainate excitatory amino acid receptor, modulates voltage-gated calcium ion channels, and inhibits carbonic anhydrase (19). In a double-blind study, 27 patients with diabetic neuropathy were randomized to topiramate or placebo in a 2:1 fashion. Topiramate was titrated to a target dose of 200 mg twice a day or maximum tolerated dose. Patients on topiramate had significantly less pain than the patients on placebo. The most common adverse events experienced by patients on topiramate were asthenia, weight loss greater than 10%, and confusion (28). Other randomized double-blind studies did not find topiramate to be significantly more effective than placebo in reducing pain scores in patients with painful diabetic polyneuropathy (94). Topiramate is eliminated unchanged in urine. The major adverse events are dose-related somnolence, psychomotor slowing, and dizziness, especially during quick titration. It should be started at 25 mg a day and increased by 25 to 50 mg every 1 to 2 weeks. The maximal dose is 200 mg twice a day. Topiramate should be used with caution in patients with renal or hepatic impairment.

Antiarrhythmics. Mexiletine is a local anesthetic, antiarrhythmic agent, and sodium channel inhibitor. Mexiletine has shown significant pain reduction in randomized, double-blind, placebo-controlled studies (22). In a 95-patient randomized trial, Stracke and colleagues found that stabbing and burning pain improved with mexiletine (88). Mexiletine was also found to reduce neuropathic pain and muscle cramps by reducing excitability in motor axons (50). Mexiletine reduces pain and suppresses abnormally increased Na(+) currents in large sensory fibers (42). The starting dosage is 150 mg one or two times a day. The maximal dose for pain control is about 200 mg three times daily. Mexiletine is contraindicated in some cardiac arrhythmias and hepatic impairment. Adverse events include nausea, vomiting, dizziness, and tremor.

NMDA receptor antagonists. Dextromethorphan is an NMDA receptor antagonist for neuropathic pain (78). In a crossover study of 19 patients with painful diabetic neuropathy, dextromethorphan 400 mg per day reduced pain intensity by a mean of 33% from baseline. Two other comparison drugs (memantine and lorazepam) reduced pain intensity by a mean of 17% and 16% respectively. Dextromethorphan was also investigated in a placebo-controlled, double-blind, randomized crossover study for posttraumatic neuropathic pain (17). In this 15-patient study, a single dose of 270 mg of dextromethorphan had up to a 30% reduction in pain for 1 to 3 hours when compared with placebo, but this effect varied among the patients. The patients who extensively metabolized dextromethorphan to dextrorphan had a better analgesic effect. Frequent adverse effects are mild to moderate lightheadedness and drowsiness. Currently, it is only used for cough and common cold symptoms.

Topical agents. Capsaicin, the active compound in hot chili pepper, selectively stimulates unmyelinated C fiber afferent neurons to release substance P. Prolonged application of capsaicin reversibly depletes substance P and, thus, abolishes the transmission of painful stimuli from peripheral nerve fibers to the CNS. Treatment should continue for at least 4 to 6 weeks. Capsaicin led to pain reduction in a double-blind, randomized, placebo-controlled study (91). Topical capsaicin is not associated with any severe systemic adverse effects. Coughing occurs in up to 5% of patients. Skin stinging and burning are present in 40% to 70% of patients during the first week of therapy. Topical capsaicin 0.025% or 0.075% is applied three to four times daily. A formulation of 8% capsaicin dermal patch (NGX-4010) was tested in postherpetic neuralgia. In a randomized, double-blind, 402-patient study, a 60-minute application of NGX-4010 (640 microg/cm2) had a significantly greater reduction in pain during weeks 2 to 12 than the low-dose control patch (3.2 microg/cm2). Short-lasting erythema and pain at the application site were common but were generally mild to moderate in the NGX-4010 group (08). Topical application of either 0.01% or 0.025% capsaicin gel on the dorsal part of the tongue three times daily provided relief of pain in burning mouth syndrome (44).

Amitriptyline 2% cream was compared with capsaicin 0.75% cream in a randomized double-blind clinical trial of 102 patients with diabetic neuropathy (45). Both drugs significantly relieved pain. Adverse events were more common in the capsaicin group. In the amitriptyline group, skin dryness and itching were the most common dermatologic adverse effects. In the capsaicin group, adverse effects were itching, blister formation, and erythema. Treatment with topical amitriptyline was safe and without the significant side effects associated with systemic therapies.

Lidocaine patch 5% is a local anesthetic agent that can stabilize neuronal membranes. Only a fraction of the active compound is released and, thus, no significant blood levels are reached; however, oral ingestion of patches could be fatal. It has demonstrated effective pain control for postherpetic neuralgia (34) and other painful neuropathies (33). However, benefits are typically moderate, and combination therapy with other drugs is often necessary. Lidocaine patch elevates thresholds for touch and pin-prick pain, but not for heat- and cold-induced pain, or pressure pain, were not affected (100). A moderate decrease in epidermal nerve fiber density was also observed in this study. Lidocaine 5% patches are applied to intact skin to cover the most painful area. The maximal dose is three patches for 12 hours in a 24-hour period to avoid skin maceration. Caution must be exercised in severe hepatic disease at risk of intoxication.

For postherpetic neuralgia, topical diclofenac 1.5% showed a reduction of burning pain (01).

An interesting randomized, double-blind study used a nitroglycerin transdermal patch (0.2 mg/h) for diabetic patients with symmetric distal neuropathy based on the rationale that it could produce local vasodilation (90). Among the active drug group, 70% experienced a 50% reduction in pain. The major adverse effects were headaches, lightheadedness, and nausea/vomiting.

Analgesics. Tramadol is a centrally-acting synthetic analgesic compound. It inhibits the neuronal reuptake of central serotonin and norepinephrine and binds to mu opioid receptors. Tramadol 50 to 100 mg can be administrated as needed every 4 to 6 hours. It was effective in reducing pain in diabetic neuropathy (40). It may be habit-forming. Adverse events are dizziness, nausea, constipation, headaches, and somnolence. Seizures may occur at higher doses or when used with antidepressants, opioids, MAO inhibitors, and neuroleptics.

Opioids are used in some patients who have experienced an inadequate response to antidepressants, anticonvulsants, or other adjuvants to maximal tolerable dose. Patients treated with opioids may develop analgesic tolerance and physical dependence. Relative contraindication includes past or recent substance abuse, serious depression, and poor compliance with previous treatment regimens. The potent µ-opioid agonist levorphanol was compared to low strength and high strength in 81 patients with refractory neuropathic pain (76). High-strength levorphanol (0.75 mg) reduced pain by 36% compared to a 21% reduction by low-strength levorphanol (0.15 mg). However, higher doses produced more side effects such as itchy skin, sweating, confusion, and mood or personality change. Long-acting opioids are preferred because steady blood levels are associated with a lower incidence of opioid "high." Examples of regimens are: fentanyl 25 µg/h patch changed every 72 hours with maintenance dose of 25 to 75 µg/h, which may result in less constipation than other opioids; oxycodone at a starting dose of 10 mg twice per day, and maintenance dosage of 20 mg to 40 mg twice per day; sustained release morphine starting at 15 mg twice per day and maintenance dosage of 30 to 60 mg twice per day. Of note, in a retrospective population-based cohort study of 2892 patients with polyneuropathy, long-term opioid therapy did not improve functional status but was associated with depression, a higher risk of subsequent opioid dependency, and overdose (41).

Cannabinoids are emerging as potential options for neuropathic pain. Endocannabinoid signaling is altered in many neurologic disorders. Central and peripheral nervous system cannabinoid receptors modulate pain perception. Targeting the cannabinoid receptor 1 has unwanted central effects. The discovery of cannabinoid receptor 2 and of endogenous cannabinoid receptor ligands, endocannabinoids, opens new venues for targeting the endocannabinoid system (20). Although preclinical data support the role of the endocannabinoid system in many pain processes, evidence for the clinical use of cannabis-based drugs remains elusive. Small randomized trials showed no benefit for the active drug in chemotherapy and diabetes-induced neuropathic pain (81; 53). A review of 16 trials of medical cannabis involving 1750 adults with neuropathic pain found that cannabis-based medicines may increase the percentage of people achieving at least 50% pain relief versus placebo; however, active drug was associated with greater dropout numbers due to adverse events and with more sleepiness, dizziness, confusion, and psychiatric symptoms (63).

Drugs for neuropathic pain. In patients with diabetic peripheral neuropathic pain, subcutaneous fulranumab 10 mg every 4 weeks, a monoclonal antibody against nerve growth factor, was more likely to provide greater than or equal to a 30% reduction in pain intensity versus placebo (97). And in postherpetic neuralgia, EMA401 100 mg twice daily, a selective angiotensin II type 2 receptor antagonist, resulted in significantly less pain versus placebo (74).

Botulinum toxin injections. Subcutaneous administrations of botulinum toxin A (at sites 1.5 to 2 cm apart, 5 units/site) were investigated in a randomized, double-blind, placebo-controlled clinical trial for peripheral neuropathic pain (05). The most common cause of neuropathic pain was posttraumatic or postsurgical neuropathic pain. Two administrations significantly reduced pain intensity over 24 weeks compared with placebo, especially in regard to mechanical allodynia and hyperalgesia. This was safe and generally well tolerated. In a trial of 27 patients with trigeminal neuralgia, botulinum toxin type-A injected at 100 units to the maxillary and mandibular nerves reduced pain attack intensity and frequency in over 75% of patients for 6 months after treatment, with 44% not experiencing any pain (96). In occipital neuralgia, Botulinum toxin type-A injection into regions traversed by the greater and lesser occipital nerve improved the sharp or shooting type of pain but not the dull or aching and pins and needles types of pain (92).

Spinal cord stimulation. Spinal cord stimulation was introduced over 40 years ago for the management of chronic and intractable pain, including pain of peripheral nerve origin. It uses electrical stimulation of the dorsal columns to reduce pain perception. The mechanism of pain control may involve the "gate control" theory: the activation of low-threshold, large myelinated fibers within the dorsal columns decreases pain transmission within the spinothalamic tracts (60). The surgical procedure is performed in two stages. First, electrodes are inserted percutaneously or through small laminotomies. Patients undergo a 3- to 7-day trial of self-stimulation. If pain relief is satisfactory, stimulation systems are surgically internalized. In a study of 30 patients with peripheral neuropathy, 19 had relief of pain on trial stimulation, and stimulators were permanently implanted; 14 of the 19 achieved long-term success in pain control, whereas five developed tolerance to stimulation (49). In a review of 138 patients, 103 patients achieved greater than 50% pain reduction and proceeded to permanent implantation (89); at 1-year follow-up, 84% maintained a pain reduction of over 50%, and opioid use dropped from 100% presurgery to 54.6% postoperation. Significant improvement in the activities of daily living occurred in 73.6% of patients. In the Prospective Randomized Controlled Multicenter Trial of the Effectiveness of Spinal Cord Stimulation study, 42 of 52 patients with spinal cord stimulation reported improved leg pain, quality of life, and functional capacity at 2-year follow-up. Greater than 50% pain reduction was achieved in 37% of patients with spinal cord stimulation, but in only 2% of patients with conventional medical management (48). Spinal cord stimulation also decreases pain and medication use for pediatric adolescent patients who improved functional status, including improved matriculation, gainful employment, and physical activity (09). Spinal cord stimulation is an alternative for chronic intractable painful neuropathy in selected patients.

Dorsal root ganglion stimulation. Dorsal root ganglion (DRG) stimulation is a novel treatment of chronic neuropathic pain. Small areas of pain can be stimulated precisely, focusing on the dorsal root ganglion directly. Krames proposed that pain control is achieved via normal afferent connective pathways and modulation of neurons within the dorsal root ganglion (47). In a prospective, longitudinal study, patients with discrete localized neuropathic pain in the knees, hands, or feet had a DRG stimulation generator implanted; patients were improved in several pain scales at the 3-year follow-up (62).

An evidence-based guideline for treating painful diabetic neuropathy was issued by the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation based on a systematic review of literature from 1960 to 2008 (15). This guideline recommends using pregabalin for painful diabetic neuropathy if clinically appropriate; venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids, capsaicin, and percutaneous electrical nerve stimulation are probably effective and should be considered. Pregabalin, amitriptyline, duloxetine, and two drugs in combination were compared in a multicenter, randomized, double-blind, crossover trial of diabetic peripheral neuropathic pain (93). All three drugs used alone had similar analgesic efficacy. Combination treatment was well tolerated and improved pain in patients with suboptimal pain control with monotherapy.

Treatment strategies for preservation of nerve function are directed at the underlying pathophysiologic process, such as correction of metabolic, nutritional, and endocrine abnormalities, decompression of nerve entrapment, and treatment for inflammation. In theory, the optimal drug would be one that modifies pain pathophysiology and simultaneously improves neuropathy. However, management of painful neuropathy is symptomatic, palliative, and supportive in nature. The goals of treatment are the reduction of symptoms and improvement of function. This article is focused on pharmacological management for painful neuropathy. Nonpharmacologic modalities, such as transcutaneous electrostimulation and peripheral nerve stimulation, will be discussed in the article on rehabilitation of peripheral nerve diseases. Spinal cord stimulation will be briefly mentioned in this article.

Indications

Painful neuropathies are associated with cranial neuralgias, nerve compression, neuromas, and poly- or mononeuropathies due to diverse etiologies. Adequate evaluation involves a determination of pain severity, aggravating and relieving factors, and the effects of the pain on activities of daily living, mood, affect, work, and sleep. Neurologic examination, nerve conduction studies, electromyography, and appropriate laboratory testing are essential to identify the neurologic deficits and etiologies. Obviously, successful etiologic treatment can be associated with better pain control.

Contraindications

Allergies are contraindicated for all pharmacological agents. Pregnancy is a relative contraindication because most medications for painful neuropathy are either unsafe or of uncertain safety (category D or C) in pregnancy. Other contraindications will be addressed under each individual medication.

Outcomes

The treatment of painful neuropathies is often more challenging than the treatment of other pain syndromes. It clearly must be individualized. It must be taken seriously because chronic pain almost invariably leads to depression. Common mistakes include rapid dose escalation or abandoning a drug before the maximal tolerable dose has been achieved. Other problems result from the combination of pain control agents with inappropriate sleep aids, leading to dangerous polypharmacy and the appearance of pseudodementia, especially in the elderly. Therapeutic response occurs at widely varying doses in different patients. Frequently, multiple medications are required. Combining gabapentin and morphine may achieve better analgesia at lower doses of each drug than either agent alone (36). Often, the differential side effect profile of the different tricyclics can be used to advantage. For instance, amitriptyline may be beneficial in patients with insomnia, whereas patients with preserved sleep are better off on a less sedating drug such as nortriptyline or desipramine; but if, as the dose is raised, daytime somnolence occurs, a switch to the other two drugs may be required. Occasionally, the authors have fine-tuned patients successfully on the insomnia-daytime somnolence gradient by combining two tricyclics. The majority of patients achieve tolerable pain control, and a few become pain-free. The extremes of intractable painful neuropathies may need other modalities and psychological support. In patients with peripheral neuropathic pain, lifetime and current prevalence of psychiatric comorbidity were 39% and 20.3%, respectively, for any anxiety disorder, and 47.2% and 29.7%, respectively, for any mood disorder (72). Depression and anxiety must be recognized and treated pharmacologically and psychologically in an approach that includes spouses and other family members. Comorbidities such as depression should be considered in the selection of antidepressants or anticonvulsants. An observational study was conducted in 2575 patients with painful diabetic neuropathy who were treated with either duloxetine or pregabalin/gabapentin. Better treatment responses with duloxetine were observed in patients with depression (103).

Adverse effects

All the medications mentioned above have adverse effects. The ratio of efficacy to adverse effect needs to be evaluated. Sedation is common for tricyclic antidepressants. As mentioned, pseudodementia or worsening cognition in patients with coexisting dementia may result from single-drug therapy but more commonly from polypharmacy. Bedtime administration will prevent daytime drowsiness and also improve nighttime sleep. Dizziness is the most common adverse event for anticonvulsants at initial administration, which can be prevented by slow titration. When severe adverse effects occur, the medication has to be discontinued and changed to another category of medication.

The prognosis of painful neuropathies is dependent on underlying etiology. Entrapment neuropathy may not need long-term pain management after decompressing the injured nerve. Chronic progressive neuropathy requires continuous pain management. Drug tolerance and resistance may develop during long-term therapy. The dose and class of medication need to be adjusted. Categories of therapy for painful neuropathies are under investigation such as nerve growth factors and cell transplants. Recombinant human nerve growth factor had two phase II and one phase III clinical trials with randomized, double-blind, placebo-controlled studies (02; 03; 58). Nerve growth factor trials had mixed results. In a phase II trial of HIV-associated sensory neuropathy, patients’ pain improved following 18 weeks of treatment with twice weekly subcutaneous nerve growth factor. Another phase II trial in diabetic polyneuropathy showed improved signs and symptoms after 6-months of treatment at the same dose thrice weekly. However, a large phase III trial failed to demonstrate significant benefits of nerve growth factor on diabetic polyneuropathy after 12 months of thrice weekly subcutaneous injections. Acetyl-L-carnitine was evaluated in two 52-week, randomized placebo-controlled, multicenter clinical trials for diabetic neuropathy. Acetyl-L-carnitine at a dose of 1000 mg three times a day showed significant improvement in sural nerve fiber density, regeneration, vibration perception, and pain reduction but did not improve nerve conduction velocities or amplitudes (83). Cell transplants for neuropathic pain have only been studied in animals (27).

Special considerations

Antidepressants and anticonvulsants should be avoided especially during the first trimester of pregnancy. Alternative treatments during pregnancy are nonpharmacologic modalities such as transcutaneous electrostimulation or topical agents (capsaicin cream or lidocaine patch 5%).

Clinical vignette

A 56-year-old female teacher complained of burning and pin and needle sensation in her feet constantly for 5 months. She had a 7-year history of type II diabetes. She reported poor sleep as a result of the pain. Her foot pain was worse when teaching in a standing position. She had no limb weakness. She had been taking glimepiride 4 mg a day for diabetes, propoxyphene napsylate one to two tablets every 4 hours, and gabapentin 300 mg at bedtime for 2 months.

On neurologic examination, she had normal mental status, cranial nerves, motor bulk, and strength. She had decreased sensation to pinprick and vibration in a stocking distribution and absent ankle jerks.

Nerve conduction studies showed sensorimotor polyneuropathy. Laboratory tests did not reveal causes other than diabetes. During initial treatment, gabapentin was increased to 300 mg three times a day and 600 mg four times a day after 2 weeks. She no longer needed propoxyphene napsylate. She had no pain, but her sleep was still poor. Her feet felt cold and tight. Nortriptyline was added at 25 mg at bedtime and increased to 50 mg after 1 week. She did well for 1 year. Then her foot burning increased. Gabapentin was increased to 900 mg four times a day. This patient presents a typical painful diabetic neuropathy. Adequate pain control will hopefully maintain her normal function at work and at home.

In summary, superficial pain may be managed with the topical application of lidocaine patch 5% or capsaicin cream. Most patients dislike capsaicin cream because of the initial burning sensation. If the pain is mild to moderate and causes prominent sleep disturbance, a tricyclic antidepressant is the first choice. Nortriptyline is more tolerable than amitriptyline. In patients with moderate to severe pain, gabapentin can be an excellent choice because it can be titrated quicker than tricyclic antidepressants. Most patients need more than one class of medication. For example, gabapentin alleviates the sharp and shooting paroxysms of pain, tricyclic antidepressant manages sleep disturbance and depression, and tramadol is for breakthrough pain as needed. The Fourth International Conference on the Mechanism and Treatment of Neuropathic Pain recommended five first-line medications for neuropathic pain, ie, gabapentin, lidocaine patch 5%, opioid analgesics, tramadol, and tricyclic antidepressants (26).

Scientific basis

Pain is a perception subject to variability and interdependent on emotional states. Neuropathic pain often is described as burning, tingling, icy feeling, pins and needles sensation, shooting, lancinating, stabbing, tightness, cramping, and deep aching. Tissue damage also can result in nociception, the perception of pain. The interdependency of pain and depression is increasingly being recognized and must be addressed therapeutically.

Superficial burning, tingling, and allodynia may be caused by increased firing of damaged or abnormally excitable nociceptive fibers in a cutaneous or subcutaneous distribution, particularly spouting, and regenerating fibers. The sensation of stabbing, needle, or electric-like quality may be attributable to increased spontaneous activity in the dorsal root ganglia, loss of segmental inhibition of large myelinated and small unmyelinated fibers, ectopic impulses generated from damaged afferent fibers, or increased firing caused by physiologic stimulation at the endings of nociceptive afferents. Cramping, tightness, and aching muscles may result from injury to motor nerves or a reflex loop through the spinal cord (70). Not only are patients with painful neuropathy heterogeneous, but different types of hyperalgesia can also exist in one person.

Both the peripheral and the central nerve systems contribute to neuropathic pain. Nerve injury alters ion channel functions and allows electrical crosstalk between axons and cross-after discharge between neurons in the dorsal root ganglia (52; 23). Chemical substances such as substance P, serotonin, bradykinin, prostaglandin E enhance the response of nociceptors. Multiple neurotransmitters modulate pain centrally such as gamma-aminobutyric acid, excitatory amino acids, substance P, serotonin, norepinephrine, and endogenous opioids. Several descending pathways inhibit pain transmission in the CNS. Medications used for painful neuropathies act primarily on blocking pain transmission pathways, centrally or peripherally (06).