Evidence-Based Reviews

Managing chronic pain: Consider psychotropics and other non-opioids

Kartik Ananth, MD
Pain Fellow, Department of Anesthesiology, University of Southern California Pain Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA
Steven Richeimer, MD
Chief, Division of Pain Medicine, University of Southern California Pain Center, Associate Professor of Anesthesiology and Psychiatry, Department of Anesthesiology, Keck School of Medicine of the University of Southern California, Los Angeles, CA
Melissa J. Durham, PharmD
Assistant Professor of Clinical, Pharmacy and Family Medicine, University of Southern California School of Pharmacy, Titus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, Department of Family Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA

For some patients, certain medications may be an alternative to opioids


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Of the 56 million American adults who report living with chronic pain almost 60% also exhibit psychiatric disorders such as depression or anxiety.1,2 Because patients with chronic pain suffer from a mixture of physical and psychological components, managing such conditions is complicated, and using opioids is tempting. However, treatment needs to address the underlying pathology along with social and psychological factors.

Because substance abuse treatment admissions increased by 400% from 1998 to 2008,3 many physicians look to non-opioids and other treatment modalities to control chronic non-cancer pain. Common pharmacologic therapies used to treat chronic pain include tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), antiepileptic drugs (AEDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and, to a lesser extent, atypical antipsychotics. TCAs, SNRIs, AEDs, NSAIDs, and atypical antipsychotics influence a variety of presumed underlying pathophysiological processes, including inflammatory mediators, activity of N-methyl-d-aspartate (NMDA) receptors, and voltage-gated calcium channels. In addition, they increase activity of descending inhibitory pain pathways. Animal studies suggest dysfunction of these inhibitory mechanisms contributes to the central sensitization and hyperexcitability of pain transmitting pathways.4

In this article, we discuss psychotropics and other non-opioid agents for treating pain. However, no single solution is best for all patients with chronic pain and this article is not a “how to” guide to avoid administering opioid medication. Also incorporate a multimodal, non-pharmacologic approach whenever possible.

Tricyclic antidepressants

Although this class acts primarily by increasing serotonin levels, norepinephrine and dopamine also are affected depending on the particular medication. Studies have shown that amitriptyline, nortriptyline, and desipramine function well as analgesics independent of their antidepressant effects.5 TCAs may improve pain symptoms at lower therapeutic dosages than those used for treating depression.5

Although researchers have not elucidated TCAs’ mechanism of action with regards to analgesia, they are thought to act within the concept of the gating theory of pain control,6 which functions by activation and inhibition of pain signal transmission. It is believed TCAs act on nociceptive pathways by blocking serotonin and norepinephrine reuptake. Although researchers previously thought that TCAs’ analgesic mechanism was correlated to serotonin reuptake inhibition, this theory has changed. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine have not demonstrated substantial effectiveness in neuropathic pain when compared with TCAs and SNRIs. Recent studies have shown that TCAs may work by blocking sodium channels, similar to local anesthetics and antiarrhythmic agents.7

Psychiatrists prescribe TCAs infrequently because of these drugs’ unfavorable side effect profile compared with SSRIs and SNRIs. However, TCAs often are prescribed for pain management as an adjunct to other medications for neuropathic conditions and at lower dosages than those used for treating depression (Table 1).8

Table 1

Tricyclic antidepressants used to treat pain

DrugDosage range for pain (off-label)Comments
Amitriptyline10 to 100 mg/dHigh sedation, high anticholinergic side effects
Amoxapine50 to 100 mg/dLow sedation, moderate anticholinergic side effects
Clomipramine25 to 100 mg/dLow sedation, low anticholinergic side effects
Desipramine25 to 100 mg/dLow sedation, low anticholinergic side effects
Imipramine25 to 100 mg/dModerate sedation, moderate anticholinergic side effects
Nortriptyline10 to 75 mg/dModerate sedation, low anticholinergic side effects
Source: Reference 8


Evidence supports using duloxetine, a potent SNRI that mediates pain inhibition in the descending pathways, for 4 chronic pain conditions:

  • diabetic peripheral neuropathic pain
  • fibromyalgia
  • mechanical low back pain
  • pain associated with osteoarthritis.9

Titrate the dosage to 60 mg/d and maintain the patient at this dose for at least 4 weeks. Thereafter, according to patient response, the dosage may be titrated to 120 mg/d (off-label) with appropriate vital sign monitoring and routine lab analysis.

Venlafaxine also can mediate pain response in a similar manner to duloxetine, but is not FDA-approved for treating pain. Use caution when prescribing venlafaxine for patients with a history of hypertension. Milnacipran is a relatively new SNRI that has been shown to be effective in treating fibromyalgia in divided doses of 100 to 200 mg/d (Table 2).9-11

Table 2

Treating pain with serotonin-norepinephrine reuptake inhibitors

DrugDosage range for painComments
Duloxetine60 to 120 mg/d9FDA maximum recommended dose is 60 mg/d
Milnacipran25 to 200 mg/d10Approved for treating depression outside the United States
Venlafaxine75 to 225 mg/d11Monitor blood pressure, LFTs, and kidney function
LFTs: liver function tests

Antiepileptic drugs

Several AEDs are used for pain management (Table 3).12-16 Gabapentin and pregabalin work by binding to voltage-gated calcium channels and decreasing excitatory neurotransmitter release. Along with TCAs, they are considered a first-line treatment for managing neuropathic pain.17 Gabapentin is FDA-approved for seizures and postherpetic neuralgia, but evidence supports its use in most types of neuropathic pain. Pregabalin is FDA-approved for treating seizures, diabetic peripheral neuropathy, central neuropathic pain, postherpetic neuralgia, and fibromyalgia.