Opioids are effective long-term therapy for cancer pain, but have not been accepted for the management of intractable pain due to postherpetic neuralgia (PHN) because of doubts about efficacy, safety, and addiction liability. PHN is quite prevalent and often refractory to available therapies. Twenty PHN patients in pain for >2 months were selected and enrolled in a prospective, 6-month follow-up open trial to assess the opioid effects on pain and cognition. Seventeen of the patients failed previous trials with tricyclic antidepressants, which represent the current standard therapy. Oral opioid preparations were titrated until satisfactory pain relief or unmanageable side effects occurred. The mean initial pain intensity score, on a scale of 0–10 (0 = no pain; 10 = the most intense pain) was 9.0 ± 0.3 (mean ± SEM, N = 20). The mean baseline Mini Mental Status was 30.0 ± 0.1 (N = 20). At 2 months of treatment, the average pain score was 4.0 ± 0.4 (p t-test) and the Mini Mental Status was 29.9 ± 0.1 (p = 0.6, NS). At the 6-month follow-up, two patients reported spontaneous resolution of their pain. Two patients withdrew from the trial because of unmanageable side effects. In the remaining 16 patients the average pain score was 3.8 ± 0.2 (p N = 16). None of the patients exhibited abnormal drug-seeking behavior suggestive of addiction. The opioids may represent an effective and safe treatment option for the management of PHN. Our preliminary observations warrant a controlled trial based on slow-release preparations, titration to satisfactory analgesia, and management of the initial side effects. The relative efficacy of opioids when compared to treatment with tricyclic antidepressants remains to be determined.