Efficacy, long-term effectiveness and safety of opioids in chronic non-tumor associated pain syndromes (NTAS) are still under debate. The study (MONTAS) was performed by physicians and psychologists as a multicenter prospective, randomized, double-blind placebo-controlled crossover trial, followed by an open long-term study. Patients were enrolled only when pain relief from specific defined pretreatment was insufficient. Patients were randomly assigned to group I receiving sustained-release morphine (doses: 20mg/d titrated appropriately to a maximum of 180mg/d) in the first week, placebo in the second week or group II receiving study medication in reverse order. The primary endpoint was defined as: (i) adequate pain relief (pain intensity of less than 50% of pretreatment intensity or less than 5 on a 11 point Numerical Rating Scale) and (ii) pain rated as tolerable and (iii) adverse effects rated as tolerable. Full responders (all criteria fulfilled under morphine) and partial responders (less pain relief, but tolerable side effects) were offered continuation of treatment with oral morphine in an open long-term study (LAMONTAS), to be published later. Forty-nine patients of 997 patients screened fulfilled the inclusion criteria for MONTAS and were enrolled. Mean pain intensity in all patients was reduced by morphine from 7.8 to 5.2 (NNT: 2.2); in 17 (35.4%) responders from 7.4 to 2.9, in 17 (35.4%) partial responders from 7.8 to 5.6 and in 14 (29.2%) non-responders from 8.2 to 7.7. Pain reduction correlated with improvement of physical function. Pain disability, depression score, mood and exercise endurance improved, particularly in responders. Gastrointestinal complaints increased, central nervous system-related complaints were reduced. Efficacy and safety of morphine in NTAS were demonstrated in this randomized-controlled trial. Pretreatment failure was the indication for trying morphine treatment; predictive factors for responsiveness could not be identified.