Background for FF #187 Tricyclic antidepressants (TCAs) have long been recognized as effective agents for neuropathic pain (see Fast Fact #480). Due to their sedating and anticholinergic side effects there has been much interest in newer antidepressant agents with different side effect profiles. This Fast Fact 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 newer antidepressants such as serotonin norepinephrine reuptake inhibitors (SNRIs) which enhance NE action are more effective analgesics than older antidepressants which predominantly enhance 5HT action. 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.

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 some well controlled studies in the treatment and prevention of chemotherapy induced peripheral neuropathy (CIPN).

• 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):
  • Venlafaxine: Low doses of are predominantly serotonergic, but higher doses (150-225 mg/day) appear to have mild to moderate analgesic effects in neuropathic pain via substantial noradrenergic effects.
    • For example, doses of 150-225 mg/day appear to have mild to moderate analgesic effect in non-malignancy-related neuropathic pain (30-50% reduction in pain when compared with placebo) 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, TCAs have shown a NNT of 2-3.
    • For CIPN: a small randomized controlled trial, support the use of extended-release venlafaxine in preventing the onset of CIPN if given at doses of 25 mg to 75 mg a day one hour prior to chemotherapy infusion as well as 11 days after. Other small, controlled trials have shown effectiveness of treating CIPN with venlafaxine. One head-to-head study suggested its analgesic effectiveness for CIPN may be inferior to duloxetine, however. A different head-to-head trial showed venlafaxine 225 mg/day had the same tolerability as 150 mg/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 37.5 mg daily, increasing weekly in 37.5 mg increments. Use of venlafaxine for analgesia is not FDA approved; a 75 mg 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). In addition, a systematic review of 4 randomized controlled trials showed relatively small but significant analgesic effect compared with for the treatment of CIPN. Onset of analgesia is at about 1 week, with maximum effect at about 4 weeks. A dose of 60 mg a day has been best studied for both diabetic peripheral neuropathy and CIPN; 60 mg BID may lead to increased analgesia but at the expense of an increased risk of nausea, sedation, constipation, sweating, and insomnia. Duloxetine has an FDA indication for use in diabetic peripheral neuropathic pain in the USA. Many clinicians initiate at a dose of 30 mg per day for 1-2 weeks before going to 60 mg per day. A 60 mg tab costs approximately $3.50.
• Other Antidepressants Bupropion is a dopamine and norepinephrine reuptake inhibitor with mild analgesic effect according to one study involving 41 patients with a mix of neuropathic pain syndromes. Mirtazapine has a complicated pharmacology with unknown analgesic effects.

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, duloxetine in particular may be helpful.

References

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Version History: Originally published September 2007. Version re-copy-edited in May 2009; revised again July 2015; and then again in September 2024.
Conflicts of Interest: None to report.