Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin: systematic review and meta-analysis of randomized controlled trials.
BACKGROUND
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).


METHODS
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.


METHODS
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.


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


RESULTS
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.
Eisenberg
Elon
E
Pain Relief Unit, Rambam Medical Center, and Haifa Pain Research Group, the Technion-Israel Institute of Technology, Haifa, Israel. e_eisenberg@rambam.health.gov.il
McNicol
Ewan D
ED
Carr
Daniel B
DB
D000701:Analgesics, Opioid / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D010148:Intractable Pain / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic
D000701:Analgesics, Opioid