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Conclusions/Recommendations Conclusions: Based on 3 Class I and 5 Class II studies, the antidepressants amitriptyline, venlafaxine, and duloxetine are probably effective in lessening the pain of PDN . Venlafaxine and duloxetine also improve QOL. Venlafaxine is superior to placebo in relieving pain when added to gabapentin. Recommendations: Amitriptyline, venlafaxine, and duloxetine should be considered for the treatment of PDN (Level B). Data are insufficient to recommend one of these agents over the others. Venlafaxine may be added to gabapentin for a better response (Level C). Conclusion/Recommendation Conclusion: There is insufficient evidence to determine whether desipramine, imipramine, fluoxetine, or the combination of nortriptyline and fluphenazine are effective for the treatment of PDN. Recommendation: There is insufficient evidence to support or refute the use of desipramine, imipramine, fluoxetine, or the combination of nortriptyline and fluphenazine in the treatment of PDN (Level U). Conclusions/Recommendation Conclusions: Based on one Class I study, dextromethorphan is probably effective in lessening the pain of PDN and improving QOL. Based on Class II evidence, morphine sulphate, tramadol, and oxycodone controlled-release are probably effective in lessening the pain of PDN. Dextromethorphan, tramadol, and oxycodone controlled-release have moderate effect sizes, reducing pain by 27% compared with placebo. Recommendation: Dextromethorphan, morphine sulphate, tramadol, and oxycodone should be considered for the treatment of PDN (Level B). Data are insufficient to recommend one agent over the other. Clinical Context The use of opioids for chronic nonmalignant pain has gained credence over the last decade due to the studies reviewed in this article. Both tramadol and dextromethorphan were associated with substantial adverse events (e.g., sedation in 18% on tramadol and 58% on dextromethorphan, nausea in 23% on tramadol, and const