Background: Narcotic bowel syndrome (NBS) describes disabling chronic severe abdominal pain that worsens despite continuing or escalating doses of opiates. Therapy is very limited. Aim: To examine effects of blocking peripheral I?-opioid receptors on the symptomatology of patients with NBS and its safety. Methods: An open-label observational study was performed in four women with NBS. After a 2-week run-in period, patients were treated for 12weeks with 8-12mg methylnaltrexone bromide subcutaneously every other day, increasing to daily if there was poor response. Patient and physician assessment was documented, and patients completed an eight-symptom visual analogue scale weekly and the Functional Assessment of Chronic Illnesses Therapy-Fatigue questionnaire for fatigue. Patients were observed for 4weeks following withdrawal of the drug. Results: One patient was unable to tolerate the study medication because of worsening pain after injection, and withdrew. Two showed clear benefit with reduction of symptoms overall, pain, bloating, distension, nausea and tiredness, with improved satisfaction and consistency of bowel actions and fatigue scores. Both reduced analgesic usage. The third had improved ileostomy output and had no episodes of severe bloating, but pain scores remained high. All three worsened after drug withdrawal and requested retreatment. Three experienced abdominal pains of moderate severity for 30-60min consistently within 5min of each injection. No other adverse events were experienced. Conclusions: Methylnaltrexone has a positive impact on symptoms in women with NBS, although treatment does induce transient pain following its administration. Larger studies are required to examine its efficacy and longer term safety in this patient group.