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Efficacy and Safety of Opioid Agonists in the Treatment of Neuropathic Pain of Nonmalignant Origin:  Systematic Review and Meta-analysis of Randomized Controlled Trials

Elon Eisenberg, MD; Ewan D. McNicol, RPh; Daniel B. Carr, MD
JAMA. 2005;293(24):3043-3052. doi:10.1001/jama.293.24.3043.
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Context In the United States, an estimated 2 million persons have neuropathic pain that is often resistant to therapy. The use of opioids for neuropathic pain remains controversial, in part because studies have been small, have yielded equivocal results, and have not established the long-term risk-benefit ratio of this treatment.

Objective To assess the efficacy and safety of opioid agonists for the treatment of neuropathic pain based on published randomized controlled trials (RCTs).

Data Sources We searched MEDLINE (1966 to December 2004) and the Cochrane Central Register of Controlled Trials (fourth quarter, 2004) for articles in any language, along with reference lists of reviews and retrieved articles, using a combination of 9 search terms for RCTs with 32 terms for opioids and 15 terms for neuropathic pain.

Study Selection 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 Extraction Data were extracted by 2 independent investigators and included demographic variables, diagnoses, interventions, efficacy, and adverse effects.

Data Synthesis Twenty-two articles met inclusion criteria and were classified as short-term (less than 24 hours; n = 14) or intermediate-term (median = 28 days; range = 8-56 days; n = 8) trials. The short-term trials had contradictory results. In contrast, all 8 intermediate-term trials demonstrated opioid efficacy for spontaneous neuropathic pain. A fixed-effects model meta-analysis of 6 intermediate-term studies showed mean posttreatment visual analog scale scores of pain intensity after opioids to be 14 units lower on a scale from 0 to 100 than after placebo (95% confidence interval [CI], −18 to −10; P<.001). According to number needed to harm (NNH), the most common adverse event was nausea (NNH, 3.6; 95% CI, 2.9-4.8), followed by constipation (NNH, 4.6; 95% CI, 3.4-7.1), drowsiness (NNH, 5.3; 95% CI, 3.7-8.3), vomiting (NNH, 6.2; 95% CI, 4.6-11.1), and dizziness (NNH, 6.7; 95% CI, 4.8-10.0).

Conclusions Short-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain. Intermediate-term studies demonstrate significant efficacy of opioids over placebo for neuropathic pain, which is likely to be clinically important. Reported adverse events of opioids are common but not life-threatening. Further RCTs are needed to establish their long-term efficacy, safety (including addiction potential), and effects on quality of life.

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Figures

Figure 1. Funnel Plot of Intermediate-term Efficacy Studies
Graphic Jump Location

Plot shows standard error of effect estimate vs effect estimate for each study (fixed-effects model). Vertical dotted line indicates overall effect estimate; dashed lines, 95% confidence intervals; and dots, individual studies.

Figure 2. Flow Diagram of Included and Excluded Studies
Graphic Jump Location

RCT indicates randomized controlled trial.

Figure 3. Results of the Meta-analysis of Short-term Trial Efficacy
Graphic Jump Location

Data are presented as mean (95% confidence interval [CI]) differences in last measured posttreatment pain intensity (on a visual analog scale from 0-100) between active treatment and placebo (fixed-effects model). Size of the data markers corresponds to the weight of the study in the meta-analysis.

Figure 4. Results of the Meta-analysis of Intermediate-term Trial Efficacy
Graphic Jump Location

Data are presented as mean (95% confidence interval [CI]) differences in posttreatment pain intensity (on a visual analog scale from 0-100) between active treatment and placebo (fixed-effects model). Size of the data markers corresponds to the weight of the study in the meta-analysis.

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