Opioids for Chronic Noncancer Pain: A Systematic Review and Meta-analysis

Abstract

Importance: Harms and benefits of opioids for chronic noncancer pain remain unclear.

Objective: To systematically review randomized clinical trials (RCTs) of opioids for chronic noncancer pain.

Data sources and study selection: The databases of CENTRAL, CINAHL, EMBASE, MEDLINE, AMED, and PsycINFO were searched from inception to April 2018 for RCTs of opioids for chronic noncancer pain vs any nonopioid control.

Data extraction and synthesis: Paired reviewers independently extracted data. The analyses used random-effects models and the Grading of Recommendations Assessment, Development and Evaluation to rate the quality of the evidence.

Main outcomes and measures: The primary outcomes were pain intensity (score range, 0-10 cm on a visual analog scale for pain; lower is better and the minimally important difference [MID] is 1 cm), physical functioning (score range, 0-100 points on the 36-item Short Form physical component score [SF-36 PCS]; higher is better and the MID is 5 points), and incidence of vomiting.

Results: Ninety-six RCTs including 26 169 participants (61% female; median age, 58 years [interquartile range, 51-61 years]) were included. Of the included studies, there were 25 trials of neuropathic pain, 32 trials of nociceptive pain, 33 trials of central sensitization (pain present in the absence of tissue damage), and 6 trials of mixed types of pain. Compared with placebo, opioid use was associated with reduced pain (weighted mean difference [WMD], -0.69 cm [95% CI, -0.82 to -0.56 cm] on a 10-cm visual analog scale for pain; modeled risk difference for achieving the MID, 11.9% [95% CI, 9.7% to 14.1%]), improved physical functioning (WMD, 2.04 points [95% CI, 1.41 to 2.68 points] on the 100-point SF-36 PCS; modeled risk difference for achieving the MID, 8.5% [95% CI, 5.9% to 11.2%]), and increased vomiting (5.9% with opioids vs 2.3% with placebo for trials that excluded patients with adverse events during a run-in period). Low- to moderate-quality evidence suggested similar associations of opioids with improvements in pain and physical functioning compared with nonsteroidal anti-inflammatory drugs (pain: WMD, -0.60 cm [95% CI, -1.54 to 0.34 cm]; physical functioning: WMD, -0.90 points [95% CI, -2.69 to 0.89 points]), tricyclic antidepressants (pain: WMD, -0.13 cm [95% CI, -0.99 to 0.74 cm]; physical functioning: WMD, -5.31 points [95% CI, -13.77 to 3.14 points]), and anticonvulsants (pain: WMD, -0.90 cm [95% CI, -1.65 to -0.14 cm]; physical functioning: WMD, 0.45 points [95% CI, -5.77 to 6.66 points]).

Conclusions and relevance: In this meta-analysis of RCTs of patients with chronic noncancer pain, evidence from high-quality studies showed that opioid use was associated with statistically significant but small improvements in pain and physical functioning, and increased risk of vomiting compared with placebo. Comparisons of opioids with nonopioid alternatives suggested that the benefit for pain and functioning may be similar, although the evidence was from studies of only low to moderate quality.

Figure 1.. Diagram of the Study Selection Process for the Systematic Review and Meta-analysis

Figure 2.. Pain Relief on a 10-cm Visual Analog Scale Among Patients With Chronic Noncancer Pain Who Received Opioids vs Placebo in 42 High-Quality Randomized Clinical Trials

The blue line represents the minimally important difference of 1 cm on the 10-cm visual analog scale for pain. The dashed vertical line represents the overall pooled measure of association. ^aWithin-group change from baseline data. ^bBetween-group differences in change from baseline data. ^cWeights are from random-effects analyses. ^dArticle reported results from 2 randomized clinical trials. ^eArticle only reported between-group mean difference and 95% CI.

Figure 3.. Physical Functioning Assessed by the 100-Point 36-Item Short Form Physical Component Score Among Patients With Chronic Noncancer Pain Who Received Opioids vs Placebo in 51 High-Quality Randomized Clinical Trials

The blue line represents the minimally important difference of 5 points on the 100-point 36-item Short Form physical component score. The dashed vertical line represents the overall pooled measure of association. ^aWithin-group change from baseline data. ^bBetween-group differences in change from baseline data. ^cWeights are from random-effects analyses. ^dComparison was morphine plus gabapentin vs gabapentin alone. ^eComparison was morphine plus nortriptyline vs nortriptyline alone.