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Opioids for Chronic Pain Only Nominally Better Than Placebo

For patients with chronic noncancer pain, the benefit of opioids may not outweigh the drugs‘ adverse effects, a new systematic review and meta-analysis suggest.

After analyzing data from 96 randomized controlled trials (RCTs) that included more than 26,000 patients, researchers found that opioid use was associated with statistically significant improvements in pain and physical functioning. However, these differences were not particularly clinically relevant and came at the cost of increased side effects, especially vomiting.

The meta-analysis also concluded that nonopioid alternatives offer comparable benefits with respect to pain and functioning, although the evidence for this finding derived from low- and moderate-quality studies.

“In general, we found high-quality evidence that opioids provide some benefit in chronic pain, physical function, and sleep quality vs placebo, but these benefits are quite modest,” lead author Jason W. Busse, PhD, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada, told Medscape Medical News.

“When we think of opioids, we tend to think of the most powerful analgesics available. And while they obviously show dramatic effects in terms of acute pain, the benefits appear quite modest for chronic noncancer pain,” Busse said.

“So for us, this just reinforces that opioids should not be first-line therapy for the management of chronic noncancer pain,” he said.

The study was published online December 18 in the Journal of the American Medical Association.

Significant Potential for Harm

An estimated 50 million American adults suffer from chronic noncancer pain, many of whom are prescribed opioids. Nevertheless, as the current opioid crisis has demonstrated, opioid use is associated with significant potential for harm, including diversion, addiction, overdose, and death.

Despite the ubiquity of these agents and their potential deleterious effects, the effect of opioids on chronic pain is unclear.

For example, the most recent systematic review of opioid efficacy in chronic noncancer pain included only trials with a follow-up of at least 1 year. The investigators did not find a single RCT eligible for analysis.

Prior to that, the most recent review included studies through mid-2009. Its results were reported as standardized mean differences, an approach the current investigators say has limitations. Although that review concluded that opioids offer superior analgesia for neuropathic and nociceptive pain than for fibromyalgia, no test for interaction was reported.

Given these shortcomings, Busse and his colleagues sought to include more recent data while addressing the limitations of previous efforts.

“We really thought that in order to get a handle on this, we’ve got to do a large, comprehensive review about all the relevant information that’s out there,” he explained.

The analysis began with a search from inception through April 1, 2018, of relevant databases, including CENTRAL, CINAHL, EMBASE, MEDLINE, AMED, and PsycINFO.

Trials were included only if patients with chronic noncancer pain were enrolled; participants were randomly assigned to receive an oral or transdermal opioid vs a nonopioid control; and the follow-up period was of at least 4 weeks. In total, 27 reviewers screened titles, abstracts, and full-text articles and reported potentially eligible studies; each was independently abstracted by a pair of reviewers.

The primary outcomes of the analysis included pain intensity on a visual analogue scale (score range, 0 – 10 cm; minimally important difference, 1 cm), physical functioning on the 36-item Short Form (score range, 0 – 100 points on the physical component score; minimally important difference, 5 points), and the incidence of vomiting.

Opioids Nominally Better Than Placebo

From an initial cohort of 44,345 citations, a total of 88 English and five non-English reports met eligibility criteria; three of these reported two RCTs each. The final analysis comprised 96 trials with 26,169 total patients (61% women; median age, 58 years).

Of the included studies, 25 were of neuropathic pain, 32 of nociceptive pain, 33 of central sensitization (pain present in the absence of tissue damage), and six of mixed pain types.

The analysis showed that, compared with placebo, opioid use was associated with the following:

  • reduced pain (weighted mean difference, -0.69 cm; 95% confidence interval [CI], 0.82 to −0.56 cm; modeled risk difference for achieving the minimally important difference, 11.9%);
  • improved physical functioning (weighted mean difference, 2.04 points; 95% CI, 1.41 – 2.68 points; modeled risk difference, 8.5%);
  • and increased vomiting (5.9% for opioids vs 2.3% for placebo).

In comparing opioids with other analgesic modalities, the analysis relied on low- and moderate-quality evidence. These findings suggested similar associations, with opioids providing moderate improvements in pain and physical functioning compared with the following:

  • nonsteroidal anti-inflammatory drugs (weighted mean differences, -0.60 cm for pain; -0.90 points for physical functioning);
  • tricyclic antidepressants (-0.13 cm for pain; -5.31 points for physical functioning); and
  • anticonvulsants (-0.90 cm for pain, and 0.45 points for physical functioning).

Interestingly, studies with longer follow-up periods reported less pain relief.

Busse noted that these findings help demonstrate the vast differences in treating acute and chronic pain.

“We know that after someone has a fracture, for example, if they are given a powerful opioid, it can be dramatic in reducing their pain,” he said. “Clearly, chronic pain is different. We can’t simply extrapolate that what works for acute pain is going to work in chronic pain.”

“Clear Risk” for Harm

In an accompanying editorial, Michael A. Ashburn, MD, and Lee A. Fleisher, MD, both from the Department of Anesthesiology and Critical Care at the University of Pennsylvania, Philadelphia, note that the findings illustrate that most patients who are prescribed opioids for chronic noncancer pain will not benefit from such therapy.

“However, when opioids fail to provide pain relief, a common response by clinicians may be dose escalation rather than reconsidering use of the drug,” Ashburn and Fleisher write.

“Given the clear risk of serious harm, opioids should not be continued without clear evidence of a clinically important benefit,” they add.

Busse agreed, adding that he hopes the findings “help temper patient and clinician enthusiasm by ensuring that the use of opioid therapy doesn’t exceed the evidence to support that therapy.

“It’s taken 30 years for the evidence to catch up with clinical practice with respect to opioid administration in chronic pain and demonstrate that the hopes for benefits were not realized for most patients and that the harms were greater than originally thought,” he said.

The study was supported by grants from the Canadian Institutes of Health Research and Health Canada. The authors and Dr Fleisher have disclosed no relevant financial relationships. Dr Ashburn has received personal fees from Teva, the Department of Justice, the Attorney General for the State of Maryland, the Department of State for the Commonwealth of Pennsylvania, the Montgomery County District Attorney, and the Carolinas Pain Society. He also holds patents for several drug-delivery systems and for adhesive peel-forming formulations for dermal delivery of drugs and methods.

JAMA. Published online December 18, 2018. Abstract, Editorial

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