Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies

Abstract

Background: Opioids are critical for managing cancer pain, but may provide inadequate relief and/or unacceptable side effects in some cases.

Objective: To assess the analgesic efficacy of adjunctive Sativex (Δ9-tetrahydrocannabinol (27 mg/mL): cannabidiol (25 mg/mL)) in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy.

Methods: This report describes two phase 3, double-blind, randomized, placebo-controlled trials. Eligible patients had advanced cancer and average pain numerical rating scale (NRS) scores ≥4 and ≤8 at baseline, despite optimized opioid therapy. In Study-1, patients were randomized to Sativex or placebo, and then self-titrated study medications over a 2-week period per effect and tolerability, followed by a 3-week treatment period. In Study-2, all patients self-titrated Sativex over a 2-week period. Patients with a ≥15% improvement from baseline in pain score were then randomized 1:1 to Sativex or placebo, followed by 5-week treatment period (randomized withdrawal design).

Results: The primary efficacy endpoint (percent improvement (Study-1) and mean change (Study-2) in average daily pain NRS scores) was not met in either study. Post hoc analyses of the primary endpoints identified statistically favourable treatment effect for Sativex in US patients <65 years (median treatment difference: 8.8; 95% confidence interval (CI): 0.00-17.95; p = 0.040) that was not observed in patients <65 years from the rest of the world (median treatment difference: 0.2; 95% CI: -5.00 to 7.74; p = 0.794). Treatment effect in favour of Sativex was observed on quality-of-life questionnaires, despite the fact that similar effects were not observed on NRS score. The safety profile of Sativex was consistent with earlier studies, and no evidence of abuse or misuse was identified.

Conclusions: Sativex did not demonstrate superiority to placebo in reducing self-reported pain NRS scores in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy, although further exploration of differences between United States and patients from the rest of the world is warranted.

Keywords: Pain; advanced cancer pain; cannabinoids; numerical rating scale; opioids; randomized control trial.

Conflict of interest statement

Conflict of interest: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Figures

Figure 1.

(a) Study designs for study 1 and (b) study designs for study 2.

Figure 2.

CONSORT flow diagram for study 1. ITT: intention-to-treat. *Two patients in the Sativex group did not administer any IMP, so although these patients were included in the patient demographic data, they were excluded from the efficacy and safety analysis sets.

Figure 3.

CONSORT Flow Diagram for study 2: (a) Patient disposition in the single-blind Sativex titration period. (b) Patient disposition in the double-blind, randomized, placebo-controlled treatment period. *Two patients who entered Phase A did not administer any IMP; they were excluded from the efficacy and safety analysis sets and were not counted as discontinued

Figure 4.

Median percent improvement from baseline in NRS average pain score by age.