By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: Antidepressant medications have been widely used for treating a variety of chronic pain disorders, but strong evidence to support their efficacy is lacking. Some patients may respond, but available data do not help us determine which agents may be helpful in a specific type of chronic pain condition.
SOURCE: Ferreira GE, Abdel-Shaheed C, Underwood M, et al. Efficacy, safety, and tolerability of antidepressants for pain in adults: Overview of systematic reviews. BMJ 2023;380:e072415.
Chronic pain results from physiologic, psychologic, and social factors and often requires a multifactorial approach to management, with many patients requiring pharmacologic therapy. The optimal choice of medication for pain is determined by the type of chronic pain syndrome. For neuropathic pain, clinicians initiate treatment with either antidepressants, including tricyclic antidepressants (TCA) or serotonin-norepinephrine reuptake inhibitors (SNRI), or antiepileptic medications. Are antidepressants efficacious and, if so, which ones, and for which disorders?
Following guidelines from the “preferred reporting items for overviews of reviews” (PRIOR) statement, researchers searched PubMed, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials from inception to June 20, 2022, for systematic reviews published in peer-reviewed journals. They were searching for investigations of the efficacy of any antidepressant drug, compared with placebo, used for any pain condition in adults. No restriction was placed on antidepressant class, dose, or regimen, nor on language of the review. However, reviews that included children or adolescents or omitted pain or safety outcomes were excluded.
Pain, as measured by any instrument and reported as between group differences, along with corresponding 95% confidence intervals, was the primary outcome measure. When multiple pain outcomes were available, the primary outcome selected was chosen, and when multiple time points existed for the same pain outcome within a review, data were extracted from the time point closest to the end of treatment in more than 50% of trials.
Safety outcomes, considered secondary outcomes, were defined as beneficial or harmful when risk ratio estimates included 0.75 or 1.25 values, respectively. Outcomes data, reported separately by pain condition and antidepressant class, were classified as efficacious when the difference between intervention and placebo groups was statistically significantly in favor of the antidepressant, not efficacious when the difference was not statistically significantly in favor of antidepressants, or inconclusive when the certainty of evidence was very low or the comparison included only one small trial (defined arbitrarily as a sample size of fewer than 100 participants per arm), or both.
Among 1,732 reviews identified, 948 were excluded as duplicates, leaving 784. Of those 784, 26 satisfied inclusion criteria, encompassing 156 unique trials with more than 25,000 patients covering 22 pain conditions representing 42 distinct antidepressant vs. placebo comparisons. Although none provided high-certainty evidence for any pain condition for any antidepressant, nine reviews provided evidence that some antidepressants were efficacious, compared with placebo for nine conditions in 11 distinct comparisons.
Moderate-certainty evidence suggested SNRIs, mostly duloxetine at 60 mg to 120 mg, were efficacious for chronic back pain, postoperative pain (most trials were in orthopedic surgery), fibromyalgia, and neuropathic pain, but only low-certainty evidence supported their efficacy for aromatase inhibitor-induced pain in breast cancer, depression and comorbid chronic pain, and knee osteoarthritis. Only low-certainty evidence similarly supported selective serotonin reuptake inhibitors (SSRIs), mostly paroxetine (median dose = 20 mg), for depression and comorbid chronic pain, and TCAs for irritable bowel syndrome, neuropathic pain, and chronic tension-type headache. When prescribing antidepressants for pain, a more nuanced approach seems warranted.
COMMENTARY
If patients with neuropathic pain do not respond to current therapeutic regimens, it could be because of multiple factors, including the lack of specificity of current treatment, a lack of adequate experimental models, and insufficient consideration of the heterogeneity of neuropathic pain, with different symptoms possibly reflecting diverse pathophysiologic mechanisms. Personalization of neuropathic pain management would be ideal, with objective, measurable biomarkers able to predict treatment response, offering the ultimate mode to match the patient with the medication.
Sadly, this quest has remained fruitless, despite efforts aimed at identifying genetic, genomic, functional (both electrophysiologic and neuroimaging), structural, or clinical (sensory phenotyping or patient-reported) markers. Powerful new techniques that map the brain “connectome” in patients with chronic pain may yet yield the answer.1
REFERENCE
1. Bouhassira D, Attal N. Personalized treatment of neuropathic pain: Where are we now? Eur J Pain 2023; Apr 28. doi: 10.1002/ejp.2120. [Online ahead of print].
Antidepressant medications have been widely used for treating a variety of chronic pain disorders, but strong evidence to support their efficacy is lacking. Some patients may respond, but available data do not help us determine which agents may be helpful in a specific type of chronic pain condition.
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