A recent network meta-analysis found that there was “no reliable evidence for the long‐term efficacy of any antidepressant and no reliable evidence for the safety of antidepressants for chronic pain at any time point.”
The research, part of The Cochrane Database of Systematic Reviews (CDSR)—the leading database for systematic reviews in health care—found “insufficient evidence to draw robust conclusions for the [short term] efficacy and safety of” antidepressants other than duloxetine and milnacipran. The study authors, led by Hollie Birkinshaw from the University of Southampton, write:
“Our review and NMAs [network meta-analyses] show that despite studies investigating 25 different antidepressants, the only antidepressant we are certain about for the treatment of chronic pain is duloxetine… Evidence for all other antidepressants was low certainty.”
Two of the paper’s authors systematically reviewed 176 studies, which included 28,664 participants. Most of the studies were double-blind, placebo-controlled studies, and the main chronic conditions included in the examinations were “fibromyalgia (59 studies), neuropathic pain (49 studies), and musculoskeletal pain (40 studies).
Seven studies were excluded because they did not include data that was useable for the statistical measures the researchers were using, meaning 169 studies were included in the final review. Additionally, most studies they reviewed only measured short-term outcomes, and many excluded people with low mood issues and other mental health concerns.
The primary outcomes being measured were substantial pain relief, pain intensity, mood, and medication adverse effects. The secondary measures included moderate pain relief, increased physical function, better quality sleep, a better quality of life, “Patient Global Impression of Change (PGIC),” serious adverse effects, and withdrawal issues from discontinuing the medications.
The two antidepressants to show efficacy in controlling substantial pain were duloxetine and milnacipran, both of which are from the class of drugs known as SNRIs (Selective Norepinephrine-Reuptake Inhibitors). Duloxetine showed a small to moderate effect on pain relief and lowered “continuous pain intensity.” On the other hand, Milnacipran showed only a small effect on pain intensity. This is important, as milnacipran, while being of the same class as antidepressants, is mainly prescribed for neuropathic pain control.
An additional medication, Mirtazapine, did not substantially affect pain relief. However, it did have a moderate effect on mood. Duloxetine, in addition to the evidence for pain relief, also showed a negligible effect on mood. However, as the researchers point out, “most studies excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the ‘normal’ or ‘subclinical’ ranges at baseline already.”
As for the secondary outcomes the reviewers were looking for, duloxetine and milnacipran were once again the highest rated across those measures (moderate pain relief, physical function, sleep, quality of life, and PGIC). Yet, the effect found in both was relatively small. The researchers also found that increases in doses did not yield an increased impact on these measures.
As for the safety measures (adverse events, serious adverse events, and withdrawal), the researchers could not draw conclusions about these outcomes. There was “very low-certainty evidence” for safety outcomes when these medications are used for chronic pain.
This report comes around the same time a review purporting evidence for using SNRIs for chronic pain was released. Yet, that review found evidence similar to these recent network meta-analyses, such as “the direct correlation between SNRIs and pain relief in chronic pain fibromyalgia patients is yet to be found” and “there was no statistically significant decrease in pain sensitivity in patients taking milnacipran compared to the placebo.”
Many of these drugs are being used for chronic pain as part of the push to identify alternatives to opioids for chronic pain relief. Lack of sufficient evidence for the use of these medications as alternatives should be widely discussed within the medical community before patients are started on these medications, as they do have long-term effects, including possible severe and long-lasting withdrawal syndromes.
There is also evidence that a growing fear of opioids , due to the ongoing overdose epidemic may be pushing people into tapering or discontinuing their medication. For example, a recent study found that end-stage cancer patients are having difficulty accessing prescriptions for opioids. These forced tapers have been connected to negative life outcomes, including increased risk of overdose, increased risk of serious mental health concerns, increased difficulties in managing chronic conditions, and decreased interaction with primary care providers.
While antidepressant medications, such as SNRIs, may have efficacy in assisting with pain relief, this recent research shows insufficient evidence of this efficacy, nor is there evidence of long-term safety when used for chronic pain. Therefore, there may not be enough evidence to support replacing opioids with antidepressants, especially if the patient does not agree with that treatment plan.
The decision on what works best for that patient needs to be made by the patient in communication with their physician, and both parties need to have the most complete and timely information when making those decisions.
Birkinshaw, H., Friedrich, C. M., Cole, P., Eccleston, C., Serfaty, M., Stewart, G., … & Pincus, T. (2023). Antidepressants for pain management in adults with chronic pain: a network meta‐analysis. Cochrane Database of Systematic Reviews, (5). (Link)