Cochrane for Clinicians
Putting Evidence into Practice
Are Opioids Effective in the Treatment of Neuropathic Pain?
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Am Fam Physician. 2007 Apr 1;75(7):999-1001.
A 70-year-old woman with poorly controlled type 2 diabetes presents with burning, bilateral pain in her legs that is worsening; she requests medication to relieve her symptoms.
Are opioids safe and effective for the treatment of neuropathic pain?
Eight to 60 days of opioid therapy for the treatment of neuropathic pain effectively reduces pain scores as measured by a visual analog scale. A lack of response to opioids in the first 24 hours should not be used to predict whether longer-term opioid therapy might be beneficial. There are no controlled clinical trials that include patients receiving opioids for more than 70 days. Adverse effects (e.g., nausea, vomiting, constipation, drowsiness, dizziness) are common. Tolerance and addiction were not addressed in this Cochrane review.1
This Cochrane review studied four opioids for neuropathic pain: morphine, oxycodone (Roxicodone), methadone, and levorphanol (Levo-Dromoran). Pooled results from seven of the nine studies in this review (405 total patients) showed that patients treated with low to moderate doses of opioids had a 13-point mean decrease in pain intensity on a 100-point scale compared with placebo. This clinical benefit is comparable to that achieved by the maximal daily dose of gabapentin (Neurontin; 3,600 mg per day). A 13-point reduction on a visual analog scale is on the threshold of clinical significance. It was not possible to determine the percentage of patients who experienced a clinically significant reduction in pain.
Five additional Cochrane reviews evaluated different treatment options for neuropathic pain including gabapentin, antidepressants, tramadol (Ultram), intravenous lidocaine (Xylocaine), and sympathectomy.2–6 Pooled data from 15 studies (1,468 total patients) showed that, compared with placebo, 1,200 to 3,600 mg of gabapentin per day reduced pain by at least 50 percent (number needed to treat [NNT] for improvement in all trials = 4; number needed to harm [NNH] for minor harm = 4). There was no significant difference in the incidence of major adverse events leading to withdrawal from a trial.2
Fifty placebo-controlled trials (2,515 total patients) investigated various antidepressants for the treatment of neuropathic pain. The strongest evidence exists for tricyclic antidepressants, which are effective, at least for moderate pain relief, in dosages up to 150 mg per day (amitriptyline: NNT = 2; NNH for major adverse effects leading to withdrawal from a trial = 16; NNH for minor adverse effects = 5).3
A meta-analysis of three randomized controlled trials (RCTs; 269 total patients) comparing tramadol (100 to 400 mg per day) with placebo showed significant pain reduction in the treatment group (NNT for 50 percent pain reduction = 4).4 Adverse effects included constipation, nausea, sedation, and dry mouth (NNH for adverse effects leading to withdrawal from a trial = 8).4
Twenty RCTs (750 total patients) showed that intravenous lidocaine (1 to 5 mg per kg per day) and mexiletine (Mexitil; 300 to 1,200 mg per day) were superior to placebo in the reduction of neuropathic pain scores.5 The systematic review of sympathectomy concluded that there is poor-quality evidence addressing its effectiveness, and the procedure may cause significant harms (e.g., worsening pain, new pain syndrome, hyperhidrosis).6
Background: The use of opioids for neuropathic pain remains controversial. Studies have been small, have yielded equivocal results, and have not established the long-term risk/benefit ratio of this treatment.
Objectives: To assess the efficacy and safety of opioid agonists for the treatment of neuropathic pain.
Search Strategy: We searched the Cochrane Central Register of Controlled Trials (2nd Quarter 2005), Medline (1966 to June 2005), and Embase (1980 to 2005 Week 27) for articles in any language, and reference lists of reviews and retrieved articles.
Selection Criteria: Trials were included in which opioid agonists were given to treat central or peripheral neuropathic pain of any etiology, pain was assessed using validated instruments, and adverse events were reported. Studies in which drugs other than opioid agonists were combined with opioids or opioids were administered epidurally or intrathecally were excluded.
Data Collection and Analysis: Data were extracted by two independent investigators and included demographic variables, diagnoses, interventions, efficacy, and adverse effects.
Primary Results: Twenty-three trials met the inclusion criteria and were classified as short-term (less than 24 hours; n = 14) or intermediate-term (median = 28 days; range = eight to 70 days; n = 9). The short-term trials had contradictory results. In contrast, all nine intermediate-term trials demonstrated opioid efficacy for spontaneous neuropathic pain. Meta-analysis of seven intermediate-term studies showed mean posttreatment visual analog scale scores of pain intensity after opioids to be 13 points lower on a scale from 0 to 100 than after placebo (95% confidence interval, −16 to −9; P < .00001). The most common adverse events were nausea (33 percent opioid versus 9 percent control; number needed to harm [NNH] = 4.2) and constipation (33 percent opioid versus 10 percent control; NNH = 4.2), followed by drowsiness (29 percent opioid versus 12 percent control; NNH = 6.2), dizziness (21 percent opioid versus 6 percent control; NNH = 7.1), and vomiting (15 percent opioid versus 3 percent control; NNH = 8.3). Where reported, 23 out of 212 participants (11 percent) withdrew because of adverse events during opioid therapy versus nine out of 202 (4 percent) receiving placebo.
Reviewers' Conclusions: Short-term studies provide only equivocal evidence about the efficacy of opioids in reducing the intensity of neuropathic pain, whereas intermediate-term studies demonstrate significant efficacy of opioids over placebo, which is likely to be clinically important. Reported adverse events of opioids are common but not life threatening. Further randomized controlled trials are needed to establish long-term efficacy, safety (including addiction potential), and effects on quality of life.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org)
Based on these reviews, it is reasonable to use gabapentin, opioids, or tricyclic antidepressants as first-tier agents for the treatment of neuropathic pain. Patient comorbidities, current medication use, goals of treatment, and potential adverse effects should be considered when deciding which of these agents to initiate.2–6
Consensus guidelines for the treatment of diabetic peripheral neuropathic pain recommend duloxetine (Cymbalta; a serotonergic noradrenergic reuptake inhibitor), pregabalin (Lyrica; an alpha2-delta calcium channel modulator), controlled-release oxycodone, and tricyclic antidepressants as first-tier agents based on evidence from two or more RCTs.7 Gabapentin, venlafaxine (Effexor), lamotrigine (Lamictal), carbamazepine (Tegretol), and tramadol are recommended as second-tier agents based on one RCT of diabetic peripheral neuropathy and at least one RCT of peripheral neuropathy.7 These guidelines acknowledge that some patients may require therapy with multiple agents and advise that polypharmacy decisions be based on the mechanism of action and adverse-effect profiles.7
Address correspondence to Janelle Guirguis-Blake, M.D., at email@example.com.Reprints are not available from the authors.
Author disclosure: Nothing to disclose.
1. Eisenberg E, McNicol E, Carr DB. Opioids for neuropathic pain. Cochrane Database Syst Rev. 2006;(3):CD006146.
2. Wiffen PJ, McQuay HJ, Edwards JE, Moore RA. Gaba-pentin for acute and chronic pain. Cochrane Database Syst Rev. 2005;(3):CD005452.
3. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2005;(3):CD005454.
4. Hollingshead J, Dühmke RM, Cornblath DR. Tramadol for neuropathic pain. Cochrane Database Syst Rev. 2006;(3):CD003726.
5. Challapalli V, Tremont-Lukats IW, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database Syst Rev. 2005;(4):CD003345.
6. Mailis A, Furlan A. Sympathectomy for neuropathic pain. Cochrane Database Syst Rev. 2002;(1):CD002918.
7. Argoff CE, Backonja MM, Belgrade MJ, Bennett GJ, Clark MR, Cole BE, et al. Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain [Published correction appears in Mayo Clin Proc 2006;81:854]. Mayo Clin Proc. 2006;81(4 suppl):S12–25.
The Cochrane Abstract is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Drs. Guirguis-Blake and Kelly present a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a critique of the review. The practice recommendations in this activity are available at http://www.cochrane.org/reviews/en/ab006146.html.
The series coordinator for AFP is Clarissa Kripke, M.D., Department of Family and Community Medicine, University of California, San Francisco.
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