Cannabinoids are known to have analgesic properties. We evaluated the effect of oro-mucosal sativex, (THC: CBD), an endocannabinoid system modulator, on pain and allodynia, in 125 patients with neuropathic pain of peripheral origin in a five-week, randomised, double-blind, placebo-controlled, parallel design trial. Patients remained on their existing stable analgesia. A self-titrating regimen was used to optimise drug administration. Sixty-three patients were randomised to receive sativex and 62 placebo. The mean reduction in pain intensity scores (primary outcome measure) was greater in patients receiving sativex than placebo (mean adjusted scores −1.48 points vs. −0.52 points on a 0–10 Numerical Rating Scale (p = 0.004; 95% CI: −1.59, −0.32). Improvements in Neuropathic Pain Scale composite score (p = 0.007), sleep NRS (p = 0.001), dynamic allodynia (p = 0.042), punctate allodynia (p = 0.021), Pain Disability Index (p = 0.003) and Patient’s Global Impression of Change (p < 0.001) were similarly greater on sativex vs. placebo. Sedative and gastrointestinal side effects were reported more commonly by patients on active medication. Of all participants, 18% on sativex and 3% on placebo withdrew during the study. An open-label extension study showed that the initial pain relief was maintained without dose escalation or toxicity for 52 weeks.