Are antidepressants safe to use for pain relief in older adults?

Use of antidepressants appears to have a small beneficial effect in older adults with knee osteoarthritis (OA), but potential risks far outweigh this benefit, reports a study.

“For most chronic painful conditions, the benefits and harms of antidepressant medicines are unclear,” the investigators said. “This evidence is predominantly from trials with sample sizes of <100, have disclosed industry ties, and classified as having unclear or high risk of bias.”

Thirteen databases were searched for trials published from inception to 1 February 2024. Two independent reviewers extracted data from the studies, including participant characteristics, primary efficacy (pain scores, converted to 0‒100 scale), and harms.

The investigators used a random effects model to pool estimates for efficacy and reported these as difference in means and 95 percent confidence interval (CI). They also assessed the quality of trials using the Cochrane risk of bias tool.

Fifteen studies, including a total of 1,369 participants, met the eligibility criteria. Duloxetine and amitriptyline were the most common antidepressant assessed, with six studies each. Knee OA-related pain, on the other hand, was analysed the most, with six out of 15 studies. [Br J Clin Pharmacol 2024;90:3097-3118]

Antidepressants provided no significant pain relief for knee OA (‒5.6, 95 percent CI, ‒11.5 to 0.3) in the immediate term (0‒2 weeks). Duloxetine, however, showed a statistically significant effect (‒9.1, 95 percent CI, ‒11.8 to ‒6.4), albeit a very small one in the intermediate term (≥6 weeks and <12 months).

Notably, nearly half of the included studies (7/15) reported greater withdrawal of participants who were taking antidepressants than those in comparator groups due to adverse events.

“The evidence to support [antidepressant] use is guided by high quality of evidence for knee OA pain only and is challenged by inconsistencies among the trials included in our review,” the investigators said. “The uncertainties in reporting of associated adverse events further challenge the use of antidepressants in older adults.”

Exclusion from trials

Clinical trials often exclude older adults due to their age and comorbidities. However, some practical difficulties explain why this population find it hard to participate in these studies. [JAMA Netw Open 2022;5:e2236149; Basic Clin Pharmacol Toxicol 2021;128:213-223; Am J Public Health 2010;100(Suppl 1):S105-S112; Int J Geriatr Psychiatry 2005;20:201-217]

“This is evident from the few trials that were eligible for inclusion in our review and the small sample sizes of those trials,” the investigators said.

Ironically, evidence from trials that did not include or had a small sample of older adults are often used to create guidelines in managing conditions such as chronic pain in this population. [Basic Clin Pharmacol Toxicol 2021;128:213-223]

In managing chronic noncancer pain among older adults, current guidelines advise a multidimensional approach and propose nonpharmacological strategies such as physical exercise and cognitive behaviour therapy based on trials conducted specifically in this population. [BMC Med 2023;21:372; Ann Intern Med 2017;166:514-530; Age Ageing 2018;47(suppl_1):i1-i22]

“Any future trials should focus on increasing the sample sizes to enhance the generalizability of their results, and adequate reporting of safety data is encouraged to produce clinically meaningful findings,” the investigators said.