Safety and tolerability of nabiximols oromucosal spray: a review of more than 15 years” accumulated evidence from clinical trials

ABSTRACT

Introduction: Nabiximols, a cannabinoid-based oromucosal spray, is indicated as add-on therapy for symptomatic relief of spasticity in persons with multiple sclerosis (MS). This review compiles tolerability and safety data from clinical trials that investigated nabiximols for spasticity and/or chronic pain.

Areas covered: Systematic searches identified 38 placebo-controlled randomized controlled trials (RCTs) or post-RCT open-label studies reporting safety data: 15 in spasticity; 16 in neuropathic pain; six in chronic cancer pain; and one in rheumatoid arthritis pain. In RCTs, discontinuation rates due to adverse events (AEs) for nabiximols and placebo were lower in spasticity studies (5.4% and 2.8%) than in neuropathic pain (12.9% and 5.3%) or cancer pain (19.5% and 16.6%) studies. The most consistently identified AEs were dizziness, nausea and fatigue in spasticity or neuropathic pain studies; and dizziness, nausea, vomiting and somnolence in cancer pain studies. Serious AE (SAE) rates for nabiximols and placebo were higher in cancer pain (21.8% and 16.9%) than in MS spasticity (4.7% vs. 0.8%) and neuropathic pain (4.1% vs. 3.1%) studies despite similar dose ranges. Treatment-related SAEs showed no particular pattern.

Expert opinion: More than 15 years of investigation of nabiximols oromucosal spray in spasticity and chronic pain conditions indicates an acceptable overall safety profile.

KEYWORDS:

• Nabiximols
• Sativex
• safety
• tolerability
• spasticity
• multiple sclerosis
• neuropathic pain
• chronic cancer pain

Article highlights

• This review compiles safety and tolerability data from 38 randomised controlled trials (RCTs) and related open-label studies of nabiximols (Sativex®) oromucosal spray accumulated throughout more than 15 years of investigation.

• In addition to the clinical trials programme evaluating nabiximols in multiple sclerosis (MS) spasticity, the medicine has been investigated for spasticity of other origin and chronic pain.

• Among reviewed RCTs, discontinuation rates due to adverse events (AEs) for nabiximols and placebo were lower in patients with MS spasticity (5.4% and 2.8%, respectively) than in patients with neuropathic pain (12.9% and 5.3%) or cancer pain (19.5% and 16.6%).

• AEs reported most consistently with nabiximols were dizziness, nausea and fatigue in studies of spasticity or neuropathic pain; and dizziness, nausea, vomiting and somnolence in studies of cancer pain.

• Among studies which described serious AEs (SAEs), 32 treatment-related SAEs were reported in 23 (3.5%) of 666 patients treated with nabiximols for MS spasticity, and 21 treatment-related SAEs were reported in 19 (1.3%) of 1508 patients treated with nabiximols for pain. Treatment-related SAEs showed no particular pattern.

• Despite the limitations of this analysis, relating mainly to differing AE reporting methodologies across studies, it can be concluded that nabiximols oromucosal spray is generally well tolerated and has an acceptable safety profile in patients with spasticity and chronic pain conditions.

Declaration of interest

JM Prieto González has received honoraria as consultant in advisory boards, and as chairmen or lecturer in meetings, and has also participated in clinical trials and other research projects promoted by Actelion, Almirall, Bayer-Schering, Biogen-Idec, Merck-Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. C Vila Silván is a fulltime employee of Almirall S.A. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has received a speaker’s fee from Almirall. GW offered Sativex and Placebo for free for an ITT in Tourette Syndrome where the reviewer serves as principal investigator. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

Writing assistance for this article was provided by Rob Furlong and Kerry Dechant on behalf of Content Ed Net (Madrid, Spain) with funding from Almirall S.A. (Barcelona, Spain).