Peer-Reviewed Educational Materials

Results | Printer Friendly Version | New Search

Fast Fact and Concept #187: Non-Trycyclic Antidepressants for Neuropathic Pain

First Author: Pippa Hawley BMed, FRCPC

Background Tricyclic antidepressants (TCAs) have long been recognized as effective agents for neuropathic pain. Due to their sedating and anticholinergic side effects there has been much interest in newer antidepressant agents with different side effect profiles. This Fast Facts reviews the use of non-tricyclic antidepressants for neuropathic pain.

Pharmacology Serotonin (5HT) and norepinephrine (NE) mediate descending inhibition of ascending pain pathways in the brain and spinal cord. Experience has suggested that antidepressants which enhance NE action are more effective analgesics than those which predominantly enhance 5HT action, such as with many of the newer antidepressants. TCAs are thought to cause analgesia by NE and 5HT reuptake inhibition; they also have other pharmacologic properties that may contribute to analgesia such as reducing sympathetic activity, NMDA-receptor antagonism, anticholinergic activity, and sodium-channel blockade. Non-tricyclic antidepressants seem to be less efficacious for neuropathic pain (see below): this may in part be because of their ‘cleaner’ pharmacodynamic profiles.

Clinical Evidence Most randomized controlled trials of non-tricyclic antidepressants for pain have been for diabetic peripheral neuropathy or post-herpetic neuralgia. There have been few studies in other neuropathic conditions and none in cancer-related pain. There have been very few head-to-head comparisons of antidepressants, which limits understanding of their relative efficacy.

- Selective Serotonin Reuptake Inhibitors (SSRIs): Fluoxetine is not effective for neuropathic pain. Paroxetine and citalopram have shown only mild benefit for HIV-related and diabetic neuropathy in small studies. Other SSRIs have not been evaluated.

- Serotonin Norepinephrine Reuptake Inhibitors (SNRIs): 

• Low doses of venlafaxine are predominantly serotonergic, but higher doses add substantial noradrenergic effects. Doses of 150-225mg/day appear to have mild to moderate analgesic effect (30-50% reduction in pain) with a number needed-to-treat (NNT) of 4.6 in painful diabetic neuropathy (only one out of every 4-5 patients treated will benefit). In contrast, many trials of TCAs for neuropathic pain have shown NNT of 2-3.
  One head-to-head trial showed venlafaxine 225mg/day had the same tolerability as 150mg/day of imipramine (a TCA), but venlafaxine was less effective for pain. Side-effects of venlafaxine include nausea, sedation, headache and dizziness. The usual starting dose is 37.5mg daily, increasing weekly in 37.5mg increments. Use of venlafaxine for analgesia is not FDA approved; a 75mg tab costs approximately $3.70 (average US wholesale price).
• Duloxetine has been shown to have a mild to moderate analgesic effect in industry-sponsored trials in diabetic peripheral neuropathy (NNT 5.2) at a dose of 60mg daily. Onset of analgesia is at about 1 week, with maximum effect at about 4 weeks. A dose of 60mg BID may lead to increased analgesia but at the expense of an increased risk of side-effects, particularly nausea, sedation, constipation, sweating, and insomnia. Duloxetine is licensed for use in diabetic peripheral neuropathic pain in the USA. A 60mg tab costs approximately $3.50.

- Other Antidepressants Buproprion is a dopamine and norepinephrine reuptake inhibitor and was found to have a mild analgesic effect in one study involving 41 patients with a mix of neuropathic pain syndromes. Mirtazapine has a complicated pharmacology and has not yet been evaluated as an analgesic.

Summary There are relatively well defined and preferred therapies for neuropathic pain including newer generation anticonvulsants (such as gabapentin), TCAs, and opioids in select patients. In patients with ongoing pain despite treatment with these agents, or who are intolerant to them, venlafaxine or duloxetine may be helpful. There are no comparative studies between non-tricyclics for neuropathic pain, thus an agent should be selected based on its side-effect profile, cost, and familiarity with use.

References
1. Attal N et al. EFNS guidelines on pharmacological treatment of neuropathic pain. European Journal of Neurology. 2006;13:1153-1169.
2. Saarto T and Wiffen P. Antidepressants for neuropathic pain. Cochrane Database of Systemic Reviews. 2005;20:CD005454.
3. Moulin DE, et al. Pharmacological management of chronic neuropathic pain. Consensus statement and guidelines from the Canadian Pain Society. Pain Research and Management. 2007;12(1):13-21.
4. Rowbotham MC et al. Venlafaxine extended release in the treatment of painful diabetic neuropathy: A double-blind, placebo-controlled study. Pain. 2004;110:697-706. (Erratum in 2005;113:248).
5. Sindrup SH et al. Venlafaxine vs imipramine in painful polyneuropathy. A randomized, controlled trial. Neurology. 2003;60:1284-1289.
6. Goldstein DJ et al. Duloxetine vs placebo in patients with painful diabetic neuropathy. Pain. 2005;116:109-18.
7. Bomholt SF, Mikkelse JD, Blackburn-Munro G. Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain., Neuropharmacology. 2005;48(2):252-263.
8. Semenchuk MR, Sherman S, Davis B. A double blind randomized controlled trial of buproprion SR for the treatment of neuropathic pain. Neurology. 2001;57(9):1583-8.

Fast Facts are edited by Drew A. Rosielle MD, Palliative Care Center, Medical College of Wisconsin. For comments/questions write to: drosiell@mcw.edu. The complete set of Fast Facts is available at EPERC: www.eperc.mcw.edu.

Copyright/Referencing Information: Users are free to download and distribute Fast Facts for educational purposes only. Hawley P. Fast Fact and Concept #187. Non-tricyclic Antidepressants for Neuropathic Pain. September 2007. End-of-Life/Palliative Education Resource Center (www.eperc.mcw.edu).

Disclaimer: Fast Facts provide educational information. This information is not medical advice. Health care providers should exercise their own independent clinical judgment. Some Fast Fact information cites the use of a product in dosage, for an indication, or in a manner other than that recommended in the product labeling. Accordingly, the official prescribing information should be consulted before any such product is used.

Creation Date: September 2007

Format: Self-Study Guide Books

Purpose: Self-Study Guide, Teaching

Educational Objective: Fast Fact

ACGME Competencies: Medical Knowledge

Keyword(s): Addiction, Chronic non-malignant pain, Controlled substance regulations, Pain, Pain assessment, Pain treatment

Results | Printer Friendly Version | New Search