In recent years, the off-label prescription of antidepressants for the treatment of chronic pain has increased, along with evidence of their effectiveness and mechanistic underpinnings when used for this purpose. Depression is a common comorbidity among patients with chronic pain, and the use of these agents may alleviate symptoms of both disorders. Typically, however, significantly lower dosages are needed for analgesia than for depression treatment; thus the risk profile and potential adverse effects (AEs) differ between the two indications.1 

In addition, the “delay in onset of analgesic effects after administration appears after a shorter time than their given antidepressant effect,” as noted in a 2019 review by Ivan Urits, MD, a clinical fellow in anesthesia at Beth Israel Deaconess Medical Center, and colleagues at Harvard Medical School and multiple other US universities.1

“The proposed mechanism behind the analgesic properties of antidepressant drugs is typically described to result from the inhibition of monoamine reuptake in the [central nervous system], which leads to increased activity of the descending [serotonin or noradrenaline] pathways and their antinociceptive effects on pain homeostasis.’

The authors examined evidence pertaining to several antidepressants that are used in chronic pain management, including the selected findings summarized below.

Bupropion, a second-generation atypical antidepressant, is believed to act via norepinephrine-dopamine reuptake inhibition. Although this drug generally has a favorable safety profile, it may confer a dose-dependent increase in the risk for seizures, especially in patients with eating disorders, and is therefore contraindicated in patients with a history of seizures or eating disorders. A randomized double-blind crossover trial of 41 nondepressed patients with neuropathic pain demonstrated the use of bupropion in neuropathic pain management was demonstrated in 2001.2 Bupropion sustained release was associated with improvement in neuropathic pain in 73% of patients and a decrease in the mean average pain score compared with baseline (from 5.7 to 4; P <.001) vs no change in scores with placebo. Improvements in pain associated with bupropion were sustained at 6 weeks.

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