Treatment of Neuropathic Pain

Kristen Jefferies, Pharm.D.


Semin Neurol. 2010;30(4):425-432. 

In This Article

Serotonin-norepinephrine Reuptake Inhibitors (SNRIS)

Duloxetine (Cymbalta®; Eli Lilly & Co., Indianapolis, IN) and venlafaxine (Effexor®; Pfizer Pharmaceuticals, New York, NY) are the two serotonin-norepinephrine inhibitors studied for the treatment of neuropathic pain. Milnaciprin (Savella®; Forest Pharmaceuticals, New York, NY) is another SNRI that is effective for fibromyalgia, but has not been studied for neuropathic pain. The EFNS and NeuPSIG recommend SNRIs as first-line options for the treatment of painful diabetic neuropathy,[2,5] and the Canadian Pain Society recommends this class of medications as second-line treatment options.[4] However, Canadian guidelines were published prior to the completion of the more recent studies of SNRIs.

Duloxetine (Cymbalta®)

Duloxetine is approved by the Food and Drug Administration (FDA) for painful diabetic neuropathy as well as major depressive disorder, generalized anxiety disorder, and fibromyalgia.[8] It has not been studied for other types of neuropathic pain.[6]

The typical starting dose of duloxetine is 20 to 30 mg daily, which can be increased in 20 mg or 30 mg increments every week up to 60 mg daily. Initial treatment at 60 mg daily is associated with more nausea. Doses higher than 60 mg daily have not consistently shown additional benefit in clinical trials. A trial of 4 weeks at the maximum dose is considered adequate.[6]

Long duration studies are available for duloxetine. One open-label extension study showed continued benefit with duloxetine lasting up to 1 year.[6] The same dose is effective for treating depression, anxiety, and neuropathic pain, which makes duloxetine useful in patients with these comorbidities.[6] Duloxetine can be titrated to an effective dose in only one week. Duloxetine is typically well tolerated and is not associated with the anticholinergic side effects that often limit the use of TCAs. However, nausea is a common side effect of duloxetine. This typically improves over time and is less likely when the drug is initiated at a lower dose (30 mg daily). Other side effects include hepatotoxicity and increased blood pressure and heart rate, which are not typically clinically significant.[6] Duloxetine is not yet available as a generic and is much more expensive than the TCAs.

A Cochrane review[9] assessed the efficacy of duloxetine for neuropathic pain. This review included three trials (1139 patients) comparing duloxetine to placebo for treatment of painful diabetic neuropathy. The NNT with duloxetine 60 mg daily for 3 months to achieve over 50% improvement in pain was 6 (95% CI 5–10). To achieve over 30% improvement in pain, the NNT was 5 (95% CI 3–8). Each of the three duloxetine trials had dropout rates of over 20% with ~16% of patients discontinuing due to side effects. The NNH for duloxetine was 17 (95% CI 12–50) for side effects leading to discontinuation of medication.


Venlafaxine is available in an immediate release formulation dosed three times daily and extended release formulation dosed once daily. It is approved by the FDA for the treatment of major depressive disorder, generalized anxiety disorder, panic disorder, and social anxiety disorder.[10]

The initial dose is 37.5 mg daily or twice daily and can be titrated by 37.5 to 75 mg each week as tolerated. The maximum dose is 225 mg per day. A trial of 4 to 6 weeks at a dose of at least 150 mg per day is necessary to assess the benefit of venlafaxine.[6] Like duloxetine, a relatively fast titration is possible with venlafaxine, with the ability to reach an effective dose for both pain and depression in 2 to 3 weeks.[6]

Electrocardiogram abnormalities were reported in 5% of patients treated with venlafaxine in one clinical trial.[5] Elevated blood pressure and heart rate have also been reported. Gastrointestinal side effects are the most common side effects.

Venlafaxine was superior to placebo for the treatment of painful diabetic neuropathy and painful polyneuropathies of other etiologies at doses of 150 to 225 mg per day.[6] It was no better than placebo for the treatment of PHN or postmastectomy pain; however, some of these studies used doses less than 150 mg daily.[6] The efficacy of venlafaxine for neuropathic pain was assessed in a Cochrane review.[7] This review included three studies of venlafaxine (extended release formulation) at doses of 75 to 225 mg daily. The NNT to achieve moderate pain relief was 3.1 (95% CI 2.2–5.1). The NNH for side effects leading to discontinuation of the medication was 16 (95% CI 8–436).


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