Neuropathic pain: treatment Yi Pan MD PhD ( Dr. Pan of St. Louis University has no relevant financial relationships to disclose. ) Florian P Thomas MD MA PhD MS ( Dr. Thomas of Seton Hall-Hackensack Meridian School of Medicine and Hackensack University Medical Center has no relevant financial relationships to disclose. ) Louis H Weimer MD, editor. ( Dr. Weimer of Columbia University has received consulting fees from Roche.) Originally released August 31, 2001; last updated June 7, 2018; expires June 7, 2021 Introduction Overview Treatment of neuropathic pain is an ongoing challenge for clinicians. In this article, the authors summarize pharmacological management based on published clinical trials. Not all medications mentioned in this article have been investigated in placebo-controlled, double-blind, randomized trials. The aim of this article is to provide a variety of updated information so clinicians can choose an optimal treatment for an individual patient. Key points • Neuropathic pain is frequently treated with antidepressants, anticonvulsants, antiarrhythmics, topical agents, and analgesics. • The treatment must be individualized. • Combination of different agents should be considered in some patients. • Slow dose escalation may improve drug tolerability. Historical note and terminology Neuropathic pain results from injury to the central or peripheral nerve systems and is characterized by a neuronal hyperexcitability. Treatment of painful neuropathies has been a challenge to clinicians. Definitive clinical trials to evaluate the efficacy of pharmacological agents or other therapies require careful randomization of subjects representative of the relevant population, appropriate sample sizes, and an adequate number of reliable measurement scales. One of the challenges stems from the fact that placebo treatments are effective in a significant number of patients (Petersen et al 2012). Treatment of central pain following stroke or spinal cord injury is similar to the treatment of painful neuropathy. This article will focus on painful neuropathy. 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. In general, nonaddictive drugs are 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 (Max et al 1987; Watson et al 1992; Biesbroeck et al 1995). Amitriptyline, desipramine, and fluoxetine were compared at a mean daily dose of 105, 111, and 40 mg respectively in 2 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 (Max et al 1992). Amitriptyline inhibits the reuptake of serotonin and noradrenaline 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, and urinary retention as well as 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 the presence of 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 the patients who cannot tolerate amitriptyline, as demonstrated in the clinical trial mentioned above (Max et al 1992). 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 administered with caution 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 less adverse effects (Watson et al 1998). 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 the 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 (Gray et al 2015). 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 (Semenchuk et al 2001). 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 (Goldstein et al 2005). 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 (Pritchett et al 2007). Duloxetine also demonstrated pain reduction in a randomized, double-blind, placebo- controlled clinical trial for patients with painful, chemotherapy-induced peripheral neuropathy (Smith et al 2013). 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 (Rowbotham et al 2004). 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 (Yucel et al 2005). Venlafaxine relieved oxaliplatin-induced acute neuropathic pain in 31.3% of patients versus control, which relieved pain in only 5.3% of patients (Durand et al 2012). 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 (Campbell et al 1966; Killian and Fromm 1968; Nicol 1969). Carbamazepine blocks sodium channels and