Off-Label Use of Antidepressants for Chronic Pain

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Off-label antidepressant use for chronic pain has increased in recent years in part as a result of the opioid epidemic and the need to reduce prescribing and use of opioids 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 studies3,4 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.

Nonetheless, the successful use of these agents in clinical practice has been commonly reported.

“Clinicians should quantify the potential benefit to be gained against the substantial side effect profile and risk of overdose when trying to treat neuropathic pain with TCA,” the authors advised.

Clinical Pain Advisor interviewed Dr Urits to glean additional insights and clinical implications regarding this topic.

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Clinical Pain Advisor: What are the reasons why off-label antidepressant use for chronic pain has increased in recent years?

Dr Urits: The opioid epidemic has demonstrated to the medical field the need to collectively reduce opioid prescribing and our use of opioids for the management of chronic pain conditions. As such, exploration of nonopioid adjunctive medications is paramount. Many chronic pain conditions have a strong neuropathic component. Antidepressant medications such as TCAs and SNRIs are thought to modulate the serotonergic and noradrenergic neurotransmission in the nervous system, which is likely dysfunctional in patients who experience neuropathic pain.

Clinical Pain Advisor: What are some of the most notable recent findings pertaining to this topic?

Dr Urits: In addition to known benefits in the treatment of neuropathic pain, in recent years, duloxetine has been demonstrated in numerous studies to be effective in the treatment of osteoarthritic pain.

Clinical Pain Advisor: What are the relevant implications for our physician audience?

Dr Urits: Beneficial effects of antidepressants prescribed for the management of chronic pain may not be immediate, and, in fact, take several weeks to achieve maximum effect. Although TCAs are the most commonly prescribed class of antidepressants for the treatment of chronic pain, common AEs include sedation and difficulty with concentration, which may be particularly problematic for patients. Most patients can achieve benefits with low doses, thus avoiding AEs. In patients with comorbid depression, SNRIs may confer the advantage of relieving both symptoms of depression and pain at effective dosages.

Clinical Pain Advisor: What should be the next steps in this area in terms of research, education, or otherwise?

Dr Urits: Chronic pain is best treated from a multimodal approach, which can include physical rehabilitative therapy, medical management, and minimally invasive interventions. Advances in neurostimulation in recent years have significantly improved the arsenal with which physicians can combat chronic pain. The rate of advancement is ever-increasing, and I expect that our ability to treat chronic pain with minimally invasive interventions such as spinal cord stimulation will continue to improve.  


1. Urits I, Peck J, Orhurhu MS, et al. Off-label antidepressant use for treatment and management of chronic pain: evolving understanding and comprehensive review. Curr Pain Headache Rep. 2019;23(9):66.

2. Semenchuk MR, Sherman S, Davis B. Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurology. 2001;57(9):1583-1588.

3. Kast RE, Altschuler EL. Remission of Crohn’s disease on bupropion. Gastroenterology. 2001;121(5):1260-1261.

4. Brustolim D, Ribeiro-dos-Santos R, Kast RE, Altschuler EL, Soares MBP. A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice. Int Immunopharmacol. 2006;6(6):903-907.

5. Hajhashemi V, Khanjani P. Analgesic and anti-inflammatory activities of bupropion in animal models. Res Pharm Sci. 2014;9(4):251-257.

6. Ito S, Suto T, Saito S, Obata H. Repeated administration of duloxetine suppresses neuropathic pain by accumulating effects of noradrenaline in the spinal cord. Anesth Analg. 2018;126(1):298-307.

7. Alev L, Fujikoshi S, Yoshikawa A, et al. Duloxetine 60 mg for chronic low back pain: post hoc responder analysis of double-blind, placebo-controlled trials. J Pain Res. 2017;10:1723-1731.

8. Hiroki T, Suto T, Saito S, Obata H. Repeated administration of amitriptyline in neuropathic pain: Modulation of the noradrenergic descending inhibitory system. Anesth Analg. 2017;125(4):1281-1288.

9. Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. Amitriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;(7):CD008242.

This article originally appeared on Clinical Pain Advisor