Using Antidepressants to Manage Chronic Pain 9/23/2021

This week’s article summarizes the potential benefits and the limitations of using antidepressant medications as co-analgesic agents along with other pain medication interventions from findings drawn from a recent article of Drs. Leo and Khalid from Current Psychiatry1.   They note the finding that pain syndromes are often associated with significant depressive symptomatology and they further note that some antidepressants have direct impacts on pain mediating neural pathways— both findings supporting the selective use of antidepressant medications in managing certain pain syndromes.

Going back to the 1960’s, antidepressant medications have been used to support pain management strategies. Between then and now, there has been lots of trial and error, a whole array of new antidepressant medications, and considerable research that can help guide clinical practice.

While hardly a panacea for our country’s current opioid crisis, any medication strategy that can be reduce patient’s reliance on opioid medications should be considered and utilized when supported by clinical and research findings.

In the 1960’s tricyclic antidepressant agents were the “go to” medications for treating depression and they were also prescribed for neuropathic pain, fibromyalgia and migraine prophylaxis.   Clinical studies at the time were few, but practitioners reported benefit for some patients, though tolerability of these medications was poor because of side effect impacts of the medications.   Since the 1990’s, we have had the benefit of the SSRIs and the SNRIs which have far less compromising side effect and some of these agents have proven to be particularly beneficial for selected pain syndromes.

Mechanism of Action:   The pathways by which antidepressants can contribute to pain management are both indirect and direct.   When effective in decreasing depression that exists in the face of chronic pain, the antidepressants improve mood and pain tolerance/amplification for the affected patient and this on its own is a worthy strategy to pursue – first obviously to treat the mood disorder and its negative impacts on the patients quality of life and then secondarily for whatever indirect impact occurs in the pain experience of the patient.

Beyond their impact on mood states, antidepressants have direct impact in modifying on ascending pain transmission through the nervous system related to neuromuscular pain sensation.   (Somatic and visceral pain transmission systems are not impacted by antidepressants in this manner.)   Biochemically, antidepressants that impact both norepinephrine (NE) and serotonin (5-HT) neurotransmitter systems seem to have greater analgesic impacts than antidepressants impacting only one of these systems as modification and modulation of these two chemical systems has impact on cellular mechanism associated with the pain experience.   Drilling down, the NE system is viewed as inhibitory of pain transmission and the 5-HT system is both inhibitory of transmission but also promotes pain sensation, but more prominently there is a general consensus that antidepressants work best when the patient’s core noradrenergic system is in balance and intact. Clinical findings that pain relief from antidepressants often precedes mood improvement in dually diagnosed patients.


  Serotonergic activity Noradrenergic activity
SSRIs: e.g., fluoxetine (Prozac); paroxetine (Paxil); sertraline (Zoloft) +
SNRIs:   duloxetine (Cymbalta), minalcipram (Savella) + +
Tertiary TCAs: amitriptyline (Elavil), desipramine (Norpramine) + +
Secondary TCCAs: nortriptyline (Pamelor), desipramine (Norpramine) +
Other:   trazodone (Desyrel) +
Other:   mirtazepine (Remeron) + +

Disorders with Evidence of Antidepressant Efficacy:

Neuropathic Pain

Duloxetine (Cymbalta) 60-120mg/day >50% improvement in pain severity rating for diabetic neuropathy.   FDA approved.

TCAs used off label and with limited research support


Duloxetine & Milnacipram (Savella) help pain but not measures of quality of life, sleep or fatigue sxs. FDA approved.   (low doses can be helpful)

Mirtazepine (Remeron) 15–45mg/d    >30% pain reduction and reduces sleep disturbance


Amitriptyline (Elavil): decreased frequency and intensity for tension headache

(SSRIs, SNRIs: not helpful)

Irritable Bowel Syndrome

TCAs for diarrheal prone IBS patients (anticholinergic effect?)

SSRIs helpful with constipated type

Other Pain Syndromes:         Little data

Oro-facial pain, interstitial cystitis, non-cardiac chest pain, others


  1. Antidepressants can alleviate both depression and pain.
  2. Antidepressants can reduce pain in non-depressed patients
  3. SNRIs help neuropathic pain
  4. SSRIs and TCAs help with Irritable Bowel Syndrome
  5. Pain mitigation precedes impact on mood
  6. Treatment Failure: Increase dose, try another agent.
  7. Co-analgesic strategies:   combine antidepressants with other analgesics


1 Antidepressants and Chronic Pain       Raphael J. Leo, MD, MA & Kiran Khalid, MBBS, Current Psychiatry Vol18. No.2 pp 9-22; Feb 2019



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