A more nuanced approach is needed when prescribing antidepressants for pain, researchers say

Some antidepressant drugs are effective for some pain conditions, but most are either ineffective or the evidence is inconclusive, despite being used for a range of pain conditions, finds an overview of the latest evidence published today by the BMJ.

Researchers call for a more nuanced approach when prescribing antidepressants for pain.

The use of antidepressants doubled in OECD countries from 2000 to 2015, and their off-label (unapproved) use to treat common pain conditions such as fibromyalgia, persistent headache, and osteoarthritis is thought to be part of this increase.

To explore this further, a team of researchers led by Giovanni Ferreira at the University of Sydney conducted an overview of the efficacy, safety and tolerability of antidepressants for pain depending on the condition.

They searched databases for systematic reviews comparing any antidepressant with placebo for any pain condition in adults and found 26 eligible evidence reviews published between 2012 and 2022 that included 156 separate trials and more than 25,000 participants.

These reviews reported on the effectiveness of eight classes of antidepressants covering 22 pain conditions (42 different antidepressant versus placebo comparisons). Almost half (45%) of the trials in these reviews were related to industry.

Using data from each review, the researchers estimated the relative risk or mean differences in pain between groups on a 0-100 point scale, taking into account dose, treatment duration, and the number of trials and participants.

They also assessed safety and tolerability (withdrawal due to adverse events), certainty of evidence, and risk of bias. Results were then categorized as effective, ineffective, or inconclusive from each comparison.

No review provided high definitive evidence on the effectiveness of antidepressants for pain for any condition.

Nine reviews provided evidence that some antidepressants were more effective than placebo for nine conditions in 11 different comparisons.

For example, moderate-certainty evidence suggests that serotonin-norepinephrine reuptake inhibitors (SNRIs) were effective for back pain (an average of 5.3 points lower on a pain scale than placebo), postoperative pain, fibromyalgia, and neuropathic pain.

Less definitive evidence suggested that SNRIs were effective for pain associated with breast cancer treatment, depression, knee osteoarthritis, and pain associated with other underlying conditions.

Less certain evidence also suggested that selective serotonin reuptake inhibitors (SSRIs) were effective for people with depression and pain associated with other conditions; And that tricyclic antidepressants (TCAs) were effective for irritable bowel syndrome, neuropathic pain, and chronic tension-type headaches.

For the other 31 comparisons, antidepressants were not effective (five comparisons) or the evidence was inconclusive (26 comparisons).

Most of the safety and tolerability data were imprecise, indicating that the safety of antidepressants for many conditions is still uncertain.

This was a well-designed review based on a thorough literature search and the researchers took steps to minimize the impact of issues such as variation in study design and quality, imprecision, and publication bias.

But they acknowledge that most comparisons had a limited number of trials, and the results may not apply to antidepressants prescribed for symptoms related to pain conditions, such as fatigue or sleep disturbances. Caution is also needed when interpreting these findings because 45% of the trials that made up the evidence for this review were industry-related, they add.

Finally, they say: “Some antidepressants were effective for some pain conditions; however, effectiveness appears to depend on the condition and class of antidepressant. The findings suggest that a more nuanced approach is needed when prescribing antidepressants for pain.”

These findings suggest that for most adults living with chronic pain, antidepressant treatment will be hopeless, the researchers said in a linked editorial.

They acknowledge that doctors continue to prescribe drugs for which the evidence is weak because they see that some people respond to them mildly, but other less potentially harmful options, such as exercise and support with mobility and social isolation, may help people. Live well with pain.

For people in pain, compassionate and ongoing relationships with therapists are the foundations of successful care, they write.

Studies should also include people living with pain because, among other things, pain research is meaningful to those living with pain and helps them and their physicians make better shared decisions about treatment, they conclude.


Journal Reference:

Ferreira, GE, et al. (2023) Efficacy, safety, and tolerability of antidepressants for pain in adults: an overview of systematic reviews. BMJ. doi.org/10.1136/bmj-2022-072415.

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