Although
pain is common in
osteoarthritis, most people fail to achieve adequate
analgesia. Increasing acknowledgement of the contribution of
pain sensitisation has resulted in the investigation of medications affecting
pain processing with central effects.
Antidepressants contribute to
pain management in other conditions where
pain sensitisation is present.
OBJECTIVES: We used standard, extensive Cochrane search methods. The latest search was January 2021.
SELECTION CRITERIA: We used standard Cochrane methods. Major outcomes were
pain; responder rate; physical function; quality of life; and proportion of participants who withdrew due to adverse events, experienced any adverse events or had serious adverse events. Minor outcomes were proportion meeting the OARSI (
Osteoarthritis Research Society International) Response Criteria, radiographic joint structure changes and proportion of participants who dropped out of the study for any reason. We used GRADE to assess certainty of evidence.
MAIN RESULTS: Nine trials (2122 participants) met the inclusion criteria. Seven trials examined only
knee osteoarthritis. Two also included participants with
hip osteoarthritis. All trials compared
antidepressants to placebo, with or without non-steroidal anti-inflammatory drugs. Trial sizes were 36 to 388 participants. Most participants were female, with mean ages of 54.5 to 65.9 years. Trial durations were 8 to 16 weeks. Six trials examined
duloxetine. We combined data from nine trials in meta-analyses for knee and
hip osteoarthritis. One trial was at low risk of bias in all domains. Five trials were at risk of attrition and reporting bias. High-certainty evidence found that
antidepressants resulted in a clinically unimportant improvement in
pain compared to placebo. Mean reduction in
pain (0 to 10 scale, 0 = no
pain) was 1.7 points with placebo and 2.3 points with antidepressants (mean difference (MD) -0.59, 95% confidence interval (CI) -0.88 to -0.31; 9 trials, 2122 participants). Clinical response was defined as achieving a 50% or greater reduction in 24-hour mean
pain. High-certainty evidence demonstrated that 45% of participants receiving
antidepressants had a clinical response compared to 28.6% receiving placebo (RR 1.55, 95% CI 1.32 to 1.82; 6 RCTs, 1904 participants). This corresponded to an absolute improvement in
pain of 16% more responders with
antidepressants (8.9% more to 26% more) and a number needed to treat for an additional beneficial effect (NNTB) of 6 (95%
CI 4 to 11). High-certainty evidence showed that the mean improvement in function (on 0 to 100 Western Ontario and McMaster Universities
Arthritis Index, 0 = best function) was 10.51 points with placebo and 16.16 points with
antidepressants (MD -5.65 points, 95% CI -7.08 to -4.23; 6 RCTs, 1909 participants). This demonstrates a small, clinically unimportant response. Moderate-certainty evidence (downgraded for imprecision) showed that quality of life measured using the EuroQol 5-Dimension scale (-0.11 to 1.0, 1.0 = perfect health) improved by 0.07 points with placebo and 0.11 points with
antidepressants (MD 0.04, 95% CI 0.01 to 0.07; 3 RCTs, 815 participants). This is clinically unimportant. High-certainty evidence showed that total adverse events increased in the
antidepressant group (64%) compared to the placebo group (49%) (RR 1.27, 95% CI 1.15 to 1.41; 9 RCTs, 2102 participants). The number needed to treat for an additional harmful outcome (NNTH) was 7 (95% CI 5 to 11). Low-certainty evidence (downgraded twice for imprecision for very low numbers of events) found no evidence of a difference in serious adverse events between groups (RR 0.94, 95% CI 0.46 to 1.94; 9 RCTs, 2101 participants). The NNTH was 1000. Moderate-certainty evidence (downgraded for imprecision) showed that 11% of participants receiving
antidepressants withdrew from trials due to an adverse event compared to 5% receiving placebo (RR 2.15, 95% CI 1.56 to 2.97; 6 RCTs, 1977 participants). The NNTH was 17 (95% CI 10 to 35).
AUTHORS' CONCLUSIONS: There is high-certainty evidence that use of
antidepressants for
knee osteoarthritis leads to a non-clinically important improvement in mean
pain and function. However, a small number of people will have a 50% or greater important improvement in
pain and function. This finding was consistent across all trials.
Pain in
osteoarthritis may be due to a variety of causes that differ between individuals. It may be that the cause of
pain that responds to this
therapy is only present in a small number of people. There is moderate-certainty evidence that
antidepressants have a small positive effect on quality of life with heterogeneity between trials. High-certainty evidence indicates
antidepressants result in more adverse events and moderate-certainty evidence indicates more withdrawal due to adverse events. There was little to no difference in serious adverse events (low-certainty evidence due to low numbers of events). This suggests that if
antidepressants were being considered, there needs to be careful patient selection to optimise clinical benefit given the known propensity for adverse events with antidepressant use. Future trials should include alternative
antidepressant agents or phenotyping of
pain in people with
osteoarthritis, or both.