New Research Shows Most Antidepressants Don't Work for Chronic Pain Conditions

Chronic pain affects about one in five adults in the United States. For decades, providers have prescribed antidepressants off-label to ease symptoms of conditions such as neuropathic pain, fibromyalgia, and migraine.

But a new review of data suggests that research on the antidepressants most often prescribed for pain isn’t very conclusive.

In 2021, U.K. health authorities recommended against using any medication for pain management except for antidepressants. In response, a team of researchers summarized evidence from 26 review papers spanning 156 trials and more than 25,000 adult participants.

The researchers analyzed studies on how each of the eight classes of antidepressants works to help patients manage 22 pain conditions. There was some evidence of efficacy for nearly a quarter of the antidepressant-condition match-ups. But in the other 31 cases, antidepressants appeared ineffective for pain management, or the evidence was inconclusive.

Tricyclic acids (TCAs) are the most commonly prescribed class of antidepressants for pain. But the review found there is “low certainty” that these drugs are effectively treating any pain condition. On the other hand, SNRIs appeared beneficial for people with seven pain conditions.

Offering these drugs without sufficient evidence that they are effective at relieving pain could cause patients to suffer uncomfortable side effects, according to Giovanni Ferreira, PhD, a fellow in the Institute for Musculoskeletal Health at the University of Sydney School of Public Health and lead author of the study.

“A person is not just a pain condition. The decision to use those drugs or not has to take into account not only the pain problem, but also the broader context of the individual,” Ferreira told Verywell. “Hopefully our review will be able to inform some of some of these situations where prescriptions might be appropriate or not.”

How Antidepressants Are Used for Pain Management

There is no one-size-fits-all drugs for pain management, and many come with deleterious side effects or unknown efficacy. Acetaminophen, for instance, is the most common non-opioid drug treatment for pain, but it’s unclear how effective it is in reducing acute lower back pain. Nonsteroidal anti-inflammatory drugs (NSAIDs), another common painkiller, may only be safely used for short periods.

Some clinicians may turn to antidepressants to avoid prescribing opioids, which can be powerfully addictive.  

Jamal Hasoon, MD, an assistant professor and director of the pain fellowship program at the UTHealth Houston, said he doesn’t consider antidepressants to be a first-line treatment for pain. He said he typically starts with Neurontin (gabapentin) or Lyrica (pregabalin) before turning to antidepressants or other options.

Hasoon, who is not affiliated with the study, said he finds that patients with neuropathic pain tend to see the most benefit from taking antidepressants, whereas those with more “mechanical” pain, like arthritis, may not see as many positive effects.

Scientists don’t yet know how antidepressants work to minimize pain. A leading theory is that they increase the levels of certain neurotransmitters, which then reduce pain signals.

“Chronic pain is such a complicated situation that even with our best scientific understanding of mechanism of action… there’s so much at play that I think we have a decent understanding but I don’t think we have it completely figured out,” Hasoon told Verywell.

Hasoon said there can be stigma around pain management doctors prescribing antidepressants. It’s important that patients understand that when providers use antidepressants for pain, they're not diagnosing a psychiatric condition. Still, while most antidepressant dosages for pain management are too low to fully treat depressive symptoms, there may be some overlapping effects.     

“If you have chronic pain and you’re in pain day after day 24/7, you’re going to be depressed. There’s so much comorbid depression and anxiety, that you’re co-managing at the same time,” Hasoon said.

SNRIs May Be the Most Effective at Pain Management

The review found that SNRIs appear to be more effective for managing more conditions than any other class of antidepressants. Four of the 11 drug-condition comparisons for which there is moderate certainty of evidence involve these drugs.

The SNRI duloxetine is the only FDA-approved antidepressant for neuropathic pain. It’s indicated for fibromyalgia, chronic musculoskeletal pain, and diabetic peripheral neuropathic pain.

According to the review, there is moderate certainty of evidence that SNRIs can alleviate back pain, postoperative pain, fibromyalgia, and neuropathic pain. Meanwhile, there is low certainty of evidence for knee osteoarthritis, depression with comorbid chronic pain, and pain induced by aromatase inhibitors (which are sometimes used to treat breast cancer).

But Ferreira gave the caveat that many of the studies of SNRI efficacy were sponsored by industry. “These trials tend to present more optimistic results in relation to, for example, trials done by independent investigators,” he said.

Many of the studies covered by the review had different ways of gauging how well drugs worked. The researchers indicated there was evidence of efficacy if, for example, the antidepressant was significantly better than a placebo at reducing pain.

“Whether that effect is large enough, we wanted to leave that up to the patient and clinician to decide that,” Ferreira said.

Rethinking the Benefits of TCAs for Pain

About three-quarters of antidepressant prescriptions for a pain condition concerned a TCA, according to a review from Quebec. Hasoon estimates this class makes up at least half of the antidepressants for pain prescriptions in the U.S.

But the studies supporting the use of TCAs for pain tend to be older and smaller than those for SNRIs.

“Most of the benefits have been shown from the SNRI pathway, but tricyclics are just more commonly prescribed,” Hasoon said. “My assumption on this is that tricyclics are older drugs, they’re cheaper, and it’s probably easier to get insurance to approve them.”

The review gave efficacy estimates for the use of TCAs to reduce pain for 14 conditions. They found the drugs to be effective for only three conditions—irritable bowel syndrome (IBS), neuropathic pain, and chronic tension-type headache—but all of the evidence for those conditions is of low certainty.

This class of antidepressants appears not to work for chronic indigestion, back pain, bladder pain syndrome, fibromyalgia, rheumatoid arthritis, and sciatica.

“As a patient, I would like to avoid receiving a treatment for which the evidence is inconclusive,” Ferreira said. “If there is uncertainty and there other options for pain management—which there are—I think it’s reasonable to wait until we know more about the efficacy of certain treatments.”

SSRIs Don't Appear Effective for Pain Management

SSRIs, including Prozac (fluoxetine) and Zoloft (sertraline), work by increasing the levels of serotonin in the brain.

“Most of the studies out there have shown that SSRIs only work on the serotonin pathway—people typically don’t get too much of a response from that. They may help with their depression symptoms, but it doesn’t truly help with their pain symptoms,” Hasoon said.

The review found that there is low certainty of evidence that SSRIs can help with depression and comorbid chronic pain, but no evidence that of efficacy for other pain conditions.

There is particularly little evidence to support their use for back pain, fibromyalgia, functional dyspepsia (chronic indigestion), non-cardiac chest pain, and IBS.