Off-Label Use of Antidepressants for Chronic Pain

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.

More recent findings suggested that bupropion may also be effective in treating chronic pain associated with inflammatory bowel disease (IBD). This may be partially a result of anti-inflammatory properties of bupropion, as indicted by studies^3,4 in which bupropion reduced levels of “[tumor necrosis factor (TNF)]-α by increasing the intracellular cyclic adenosine monophosphate (cAMP) that inhibits [tumor necrosis factor]-α synthesis,” as well as interferon-γ levels, according to the review.¹ Emerging animal research⁵ has also “shown that bupropion possesses analgesic and anti-inflammatory properties that are likely mediated via inhibition of prostaglandin synthesis and a probable central inhibitory mechanism.”¹

Duloxetine, one of several serotonin-norepinephrine reuptake inhibitors (SNRIs) used in chronic pain treatment, is the SNRI that has been most widely studied for this indication. These drugs “suppress neuropathic pain by altering the recovery of noradrenergic descending inhibitory system in the spinal cord.”^1,6 Numerous studies have demonstrated the efficacy of duloxetine in the treatment of pain associated with knee and hand osteoarthritis, as well as neuropathic pain associated with diabetes, cancer, and chemotherapy. Various other results support its effectiveness in chronic low back pain.⁷ In a randomized double-blind study published in 2017, the perioperative use of duloxetine and etoricoxib led to reductions in postoperative pain and opioid use after a lumbar laminectomy; however, findings thus far have been mixed regarding this indication.

Tricyclic antidepressants (TCAs) are the most commonly prescribed antidepressants in chronic pain management, typically for the treatment of neuropathic pain.

“While the direct mechanism of action is largely unknown, TCAs may suppress the noradrenergic descending inhibitory system to produce an antihyperalgesic effect,” wrote Ivan Urits, MD, from Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, and colleagues.^1,8 Scant evidence to date support the efficacy of TCAs for chronic pain (eg, in a review of 17 studies involving the use of amitriptyline for neuropathic pain, no consistent benefit was observed).⁹ Numerous serious AEs are also associated with TCAs, ranging from tachycardia and urinary retention to confusion and hallucinations.