Background
Osteoarthritis is a disease of the joints characterised by reduced cartilage and narrowing of the space between the joints. It may result in pain, deformity and disability.
Antidepressant medicines are thought to affect pain by modulating nerve pathways in the central nervous system.
We aimed to evaluate the clinical benefits and harms of antidepressants for knee and hip osteoarthritis pain.
Study characteristics
This review is current to January 2021. We included nine clinical trials with 2122 participants comparing antidepressants to placebo (a dummy treatment) and non-steroidal anti-inflammatory medicines (which are widely used to relieve pain and reduce inflammation). More participants were female (70%) and the average age was 54.4 to 65.9 years. Seven trials examined only knee osteoarthritis. Two also included people with hip osteoarthritis. All trials compared antidepressants to placebo, with or without non-steroidal anti-inflammatory medicines.
Key results
Compared with a placebo, antidepressants resulted in a small benefit.
Pain
Pain reduced by 0.59 points more on a 0- to 10-point scale with antidepressants compared to placebo.
– The placebo group had a pain reduction of 1.73 points.
– The antidepressant group had a pain reduction of 2.32 points.
Response
A clinical response is considered a 50% or greater reduction in pain. About 16% more people taking an antidepressant had a reduction compared to placebo (that is, one in six people).
– 28.65% of people taking placebo had a clinical response.
– 45.2% of people taking antidepressants had a clinical response.
Function
Physical function is measured using walking, stair climbing and domestic duties. It improved 6% more with antidepressants compared to placebo. With antidepressants, the function score reduced by 5.65 on a 0- to 100-point scale (lower score = better function), compared to placebo. This is a small improvement.
– The placebo group had an improvement in function of 10.51 points.
– The antidepressant group had an improvement in function of 16.16 points.
Quality of life
Quality of life improved by 4% more with antidepressants compared to placebo. This was 0.04 points higher on a −0.11 to 1 scale in people taking antidepressants compared to placebo (higher score = better quality of life).
– In the placebo group, quality of life improved by 0.07 points.
– In the antidepressant group, quality of life improved by 0.11 points.
Withdrawals due to side effects
The risk of stopping treatment was 2.15 more in the antidepressant group compared to placebo. This means that 1 in 17 people stopped taking the antidepressant because of side effects.
– 5.1% of the placebo group withdrew because of side effects.
– 10.9% of the antidepressant group withdrew because of side effects.
Total side effects
The risk of having any side effects was 1.27 more in the antidepressant group compared to the placebo group. About 14.8% more people reported a side effect in the antidepressant group. This is equivalent to 1 in every 7 people having a side effect.
– 49.3% of the placebo group had a side effect.
– 64.1% of the antidepressant group had a side effect.
Serious side effects
There was no difference in serious side effects between groups.
– 1.7% of the placebo group had serious side effects.
– 1.6% of the antidepressant group had serious side effects.
Quality of the evidence
In people with osteoarthritis, high-quality evidence shows that antidepressants have a small positive effect on pain and function and that one in six people have a clinically important response of a 50% or greater reduction in their pain. High-quality evidence also demonstrates that people taking antidepressants have a higher frequency of side effects than those taking placebo.
Moderate-quality evidence shows very small, probably unimportant, improvements in quality of life for people taking antidepressants compared to placebo. People receiving antidepressants are more likely to stop them because of side effects than placebo.
Low-quality evidence shows little difference in serious side effects between antidepressants and placebo.
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.
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.
To assess the benefits and harms of antidepressants for the treatment of symptomatic knee and hip osteoarthritis in adults.
We used standard, extensive Cochrane search methods. The latest search was January 2021.
We included randomised controlled trials of adults with osteoarthritis that compared use of antidepressants to placebo or alternative comparator. We included trials that focused on efficacy (pain and function), treatment-related adverse effects and had documentation regarding discontinuation of participants. We excluded trials of less than six weeks of duration or had participants with concurrent mental health disorders.
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.
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).