No Reliable Evidence Antidepressants Help Chronic Pain

The majority of antidepressants prescribed for chronic pain lack sufficient evidence of efficacy and safety, results of a large Cochrane review show.

“This is a global public health concern. Chronic pain is a problem for millions who are prescribed antidepressants without sufficient scientific proof they help,” lead author Tamar Pincus, PhD, from the University of Southampton, UK, said in a news release.

In what is reportedly the largest-ever investigation into antidepressants for chronic pain, the review showed moderate evidence for the short-term effectiveness of only one antidepressant for chronic pain ― the serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine.

Data suggest duloxetine can provide short-term pain relief, but there is concern about the possible long-term harm, owing to the gaps in current evidence, Pincus said.

The review showed no reliable evidence for the long-term efficacy of any antidepressant or their safety for chronic pain at any point.

According to the researchers, one third of people globally live with chronic pain, and many of these individuals are treated with antidepressants.

Patients with chronic pain don’t take antidepressants for weeks, they take it for months, and it’s “shocking that we don’t have any evidence for long-term use” of antidepressants in patients with chronic pain, Pincus said during a press briefing.

The review was published online May 10 in the Cochrane Database of Systematic Reviews.

Low Confidence

The systematic review and network meta-analysis included 176 randomized controlled trials with almost 30,000 people with chronic pain. The studies mainly investigated the effect of antidepressants on fibromyalgia, nerve pain, and musculoskeletal pain. The average length of the trials was just 10 weeks.

The most common antidepressant classes investigated were SNRIs, tricyclic antidepressants (TCAs), and selective serotonin reuptake inhibitors. The most common antidepressants investigated were the TCA amitriptyline and the SNRIs duloxetine and milnacipran.

Duloxetine was consistently the highest-ranked antidepressant and was equally effective for fibromyalgia, musculoskeletal, and neuropathic pain conditions, with moderate- to high-certainty evidence, the researchers found.

A standard 60-mg dose of duloxetine showed a small to moderate effect for substantial pain relief (odds ratio [OR], 1.91; 95% CI, 1.69 – 2.17) and continuous pain intensity (standardized mean difference [SMD], −0.31; 95% CI, −0.39 to −0.24).

There was no evidence that higher doses of duloxetine provided any added benefits.

“Duloxetine was the only antidepressant that we had moderate certainty in the results; all the rest were low or very low certainty,” first author Holly Birkinshaw, PhD, with University of Southampton, told reporters.

Milnacipran also appeared to be effective at reducing pain, but “we are not as confident in this result as duloxetine because there were fewer studies with fewer people,” Birkinshaw noted.

For pain intensity, a standard 100-mg dose of milnacipran showed a small effect (SMD, −0.22; 95% CI, −0.39 to 0.06).

“Aside from duloxetine and milnacipran, we do not have confidence in the results from any other antidepressant included in this review. This includes amitriptyline, even though it’s the most common antidepressant used clinically,” Birkinshaw added.

The researchers were unable to assess the effects on mood, as most studies excluded people with mental health conditions. They also couldn’t establish the safety of any antidepressant, owing to poor data.

In the news release, statistician and co-author Gavin Stewart, PhD, with Newcastle University, urged governing bodies, including UK’s National Institute for Health and Care Excellence and the US Food and Drug Administration, to update their guidelines to reflect this new scientific evidence and called on funders to “stop supporting small and flawed trials.”

“Evidence synthesis is often complex and nuanced, but the evidence underpinning the use of these treatments is not equivalent, so current treatment modalities are hard to justify,” Stewart said.

The study had no commercial funding. The authors report no relevant financial relationships.

Cochrane Database Syst Rev. Published online May 10, 2023. Full text

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