Low-quality evidence mars clinical guidance for treating chronic pain

Despite widespread use, antidepressant drugs have little impact on pain and disability scores among patients with back pain and osteoarthritis, according to results from a systematic review and meta-analysis — and the drugs might lead to an increased risk for adverse events, researchers found.

Back pain and osteoarthritis are the leading causes of disability across the globe, with the two conditions accounting for $214.5 billion in healthcare spending in the U.S. in 2016 alone, Giovanni E. Ferreira, PhD, of the University of Sydney and the Institute for Musculoskeletal Health in Sydney, Australia, and colleagues explained in The BMJ. Most clinical practice guidelines recommend antidepressants — particularly serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) — to treat this type of pain, despite uncertain evidence. Ferreira and colleagues conducted their analysis to assess the efficacy and safety of antidepressants in patients with back pain (including sciatica) and hip or knee osteoarthritis.

“We found moderate certainty evidence that SNRIs reduce pain and disability in people with back pain up to three months, but these effects are unlikely to be clinically important,” they found. ” For osteoarthritis, we found moderate certainty evidence that SNRIs reduce pain and disability up to three months, and a clinically important effect on pain cannot be excluded. Low certainty evidence showed that TCAs were ineffective for back pain and related disability. Tricyclic antidepressants and SNRIs might reduce pain in people with sciatica. In our review, only SNRIs statistically significantly increased the risk of adverse events. However, the number of studies evaluating the safety of other antidepressant classes was small, trials were underpowered to detect harm, and the certainty of evidence ranged from low to very low.”

In an editorial accompanying the study, Martin Underwood and Colin Tysall, professors from the Warwick Clinical Trials Unit at the University of Warwick in Coventry, U.K., noted that the review by Ferreira and colleagues is “timely,” calling attention to the flimsy guidance behind antidepressant prescribing for these conditions.

“Making sense of the various sources of evidence and inconsistent recommendations in this area is challenging,” they wrote. “For example, draft NICE guidance is to consider antidepressants for chronic pain but not for chronic sciatica. This problem is common across guidance on other drug groups for chronic painful disorders. A robust overview is needed to clarify guidance and to inform a consistent approach to use of antidepressants for people with painful disorders.

“Many people with chronic pain also have symptoms of depression,” they added. “Any such overview should consider the potential for reducing depressive symptoms.”

For their analysis, Ferreira and colleagues searched Medline, Embase, the Cochrane Register of Controlled Trials, CINAHL, International Pharmaceutical Abstracts, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform from inception to Nov. 15, 2020, for randomized controlled trials comparing the efficacy or safety — or both — of any antidepressant drug with placebo in participants with low back or neck pain, sciatica, or hip or knee osteoarthritis.

The primary outcomes for the review and meta-analysis were pain and disability, which were scored on a scale of 0 (no pain or disability) to 100 (worst pain or disability). A random effects model was used to calculate weighted mean differences and 95% confidence intervals (CIs), the authors explained, and a pooled between group mean difference of 10 points in pain and disability scores was considered to be “the smallest worthwile effect for pain and disability.”

The secondary outcome was safety, including any adverse events (AEs), serious AEs, and proportion of participants who withdrew from trials due to AEs. The review authors used the Cochrane Collaboration risk of bias tool to evaluate the risk of bias in each study, and the certainty of evidence was evaluated using the grading of recommendations assessment, development, and evaluation (GRADE) framework.

Ferreira and colleagues included 33 trials (5,318 participants) in their final analysis — for 26 of these, at least one domain was classified as high risk of bias. The trials evaluated six antidepressant drug classes: SNRIs (n=15), TCAs (n=14), serotonin reuptake inhibitors (SSRIs, n=3), noradrenaline-dopamine reuptake inhibitors (NDRIs, n=1), serotonin antagonist and reuptake inhibitors (SARIs, n=1), and tetracyclic antidepressants (n=1).

“Moderate certainty evidence showed that serotonin-noradrenaline reuptake inhibitors (SNRIs) reduced back pain (mean difference −5.30, 95% confidence interval −7.31 to −3.30) at 3-13 weeks and low certainty evidence that SNRIs reduced osteoarthritis pain (−9.72, −12.75 to −6.69) at 3-13 weeks,” they found. “Very low certainty evidence showed that SNRIs reduced sciatica at two weeks or less (−18.60, −31.87 to −5.33) but not at 3-13 weeks (−17.50, −42.90 to 7.89). Low to very low certainty evidence showed that tricyclic antidepressants (TCAs) did not reduce sciatica at two weeks or less (−7.55, −18.25 to 3.15) but did at 3-13 weeks (−15.95, −31.52 to −0.39) and 3-12 months (−27.0, −36.11 to −17.89). Moderate certainty evidence showed that SNRIs reduced disability from back pain at 3-13 weeks (−3.55, −5.22 to −1.88) and disability due to osteoarthritis at two weeks or less (−5.10, −7.31 to −2.89), with low certainty evidence at 3-13 weeks (−6.07, −8.13 to −4.02). TCAs and other antidepressants did not reduce pain or disability from back pain.”

Ferreira and colleagues also reported that low certainty evidence showed that SNRIs increase the risk for any AEs (62.5% versus 49.7%; relative risk 1.23, 95% CI 1.16-1.30), but not serious AEs (1.6% versus 1.3%; relative risk 1.12, 95% CI 0.61-2.07). Participants receiving SNRIs were also more likely to drop out of a study due to AEs (12.4% versus 5.3%; relative risk 2.16, 95% CI 1.71-2.73).

While other antidepressants (i.e., TCAs, SSRIs, NDRIs, SARIs, and tetracyclic antidepressants) did not seem to increase AE risk or drop out due to AEs, “the limited number of trials and large uncertainty around the risk estimates limit the ability of this systematic review and meta-analysis to determine the safety of these classes of antidepressants for back pain, sciatica, and osteoarthritis.” the authors noted.

Ferreira and colleagues acknowledged that their study had limitations, including an inability to explore a dose-response relationship for most antidepressants due to the low number of studies and varied drug doses, uncertainty in the effects for sciatica and safety outcomes, and the possibility that their analysis missed trials that were conducted before registries became active.

In their editorial, Underwood and Tysall noted that some patients with chronic pain might choose to use antidepressants such as SNRIs “for a one in 10 chance of a worthwhile reduction in pain after three months. They can easily stop if treatment is ineffective or does not suit them. As others put it: ’Expect analgesic failure; pursue analgesic success.’

“Overall, however, drug treatments are largely ineffective for back pain and osteoarthritis and have the potential for serious harm,” they added. “We need to work harder to help people with these disorders to live better with their pain without recourse to the prescription pad.”

  1. Results from a systematic review and meta-analysis suggest that antidepressants have a small, clinically unimportant effect on pain and disability scores for patients with chronic back and osteoarthritis pain and have the potential to increase adverse event risk.

  2. These results suggest the need for a robust overview to clarify guidance for use of antidepressants in patients with chronic pain disorders, editorialists argued.

John McKenna, Associate Editor, BreakingMED™

Ferreira and colleagues reported support from GlaxoSmithKline, Pfizer, and Flexeze, unrelated to this review and meta-analysis.

Underwood reported being director and shareholder of Clinvivo; an academic partnership with Serco, funded by the European Social Fund; and being coinvestigator on three National Institute for Health Research funded studies receiving additional support from Stryker, outside the scope of this editorial.

Cat ID: 393

Topic ID: 392,393,393,435,730,15,192,46,158,66,68,921,925