Background and objective: The aim of this prospective, randomized, double-blind investigation was to assess the dose–effect characteristics of postoperative nausea and vomiting after intrathecal administration of small doses of morphine (from 0.015 to 0.25 mg) in opioid-naïve, non-surgical patients. Methods: With Ethic Committee approval and written informed consent 144 opioid-naïve patients suffering from non-cancerous chronic back-pain, and receiving intrathecal morphine as diagnostic test for their chronic pain, were randomly allocated to receive intrathecal injection of 0.015 mg (Group I, n = 25), 0.03 mg (Group II, n = 30), 0.06 mg (Group III, n = 31) or 0.25 mg (Group IV, n = 33) morphine. The control group consisted in 25 further patients not included in the dose–effect study and receiving a placebo injection of normal saline in the interspinous ligament. A blinded observer recorded the occurrence of pruritus, nausea, vomiting, urinary retention and respiratory depression (respiratory rate < 6 bpm) at 2, 4 and 24 h after injection. Results: Clinically significant pain relief was observed in all patients receiving intrathecal morphine but only six patients (25%) of the control group (P = 0.0005). The incidence of pruritus was lower in patients of Groups III (6%) and IV (3%) than in Groups I (12%) and II (20%) (P = 0.002). The incidence of nausea and vomiting was higher at 2- and 4-h observation times, and decreased 24 h after intrathecal injection. Surprisingly, nausea was more frequent in Groups I (56%) and II (50%) than in Groups III (33%) and IV (24%) (P = 0.0005). Vomiting was higher in patients receiving morphine than in control group, but without differences among the four doses. No urinary retention was observed in the control group, while 2 h after intrathecal injection urinary retention was observed in 20–40% of cases, and decreased to less than 10% 24 h after spinal injection without differences among the four doses. Conclusions: The onset and incidence of minor opioid-related side-effects after intrathecal morphine administration do not depend on its dose, occurring with even very small doses of morphine. Accordingly, they can be considered as a patient-dependent effect of the drug, suggesting the presence of a primary dose-independent excitatory component that might be related to the theory of the bimodal activation of opioid receptors. The very low incidence major respiratory depression prevents us from drawing any conclusion about the dose–effect relationship for this side-effect, and further properly powered studies should be advocated to evaluate major respiratory depression after spinal morphine.