THC/CBD Spray for MS Nerve Pain Showed Mixed Results but Prevented Relapse When Stopped | Research

The takeaway

A phase III trial of THC/CBD spray for multiple sclerosis neuropathic pain did not meet its primary endpoint at 14 weeks, but a subsequent withdrawal phase showed that patients on the spray were significantly less likely to lose pain control when switched to placebo.

Read this if you have multiple sclerosis with neuropathic pain and are interested in cannabinoid spray treatments.

57% lost pain control when switched to placebo vs. 24% continuing THC/CBD spray

What the researchers found

This study had two phases. In Phase A, 339 MS patients with neuropathic pain were randomized to THC/CBD spray or placebo for 14 weeks. The primary endpoint (30% pain reduction responder rate) was not met: 50% responded on THC/CBD versus 45% on placebo (p=0.234). However, a pre-planned interim analysis at week 10 showed a significant difference favoring THC/CBD (p=0.046).

In Phase B, 58 responders were re-randomized to continue THC/CBD spray or switch to placebo for 4 weeks. The results were clear: 57% of placebo patients lost treatment benefit versus only 24% on THC/CBD spray (p=0.04). Pain scores and sleep quality also significantly favored continued treatment.

Why it matters

While the primary Phase A endpoint was not met, the Phase B withdrawal design clearly demonstrated that THC/CBD spray maintains pain control. The high placebo response rate in Phase A (45%) likely obscured a real treatment effect, a common problem in pain trials.

The numbers in context

Phase A: 339 patients (167 THC/CBD, 172 placebo). 50% vs 45% responders (p=0.234). Week 10 interim: significant (p=0.046). Phase B: 58 patients. Treatment failure: 57% placebo vs 24% THC/CBD (p=0.04). Pain difference: -0.79 points (p=0.028). Sleep quality: +0.99 points (p=0.015).

How the study worked

Phase III, double-blind, placebo-controlled, two-phase study. Phase A: parallel-group, 339 patients, 14-week THC/CBD spray vs. placebo. Phase B: randomized withdrawal in 58 responders, 4 weeks. Primary Phase A endpoint: 30% responder rate at week 14. Primary Phase B endpoint: time to treatment failure.

What this study cannot tell us

Phase A did not meet its primary endpoint, limiting regulatory conclusions. Phase B had a small sample (58 patients). The 4-week withdrawal phase was short. The high placebo response complicates interpretation. Not all Phase A participants entered Phase B, introducing selection bias.

How to read the evidence

Phase III RCT with mixed results; moderate evidence with clear withdrawal-phase demonstration of efficacy.

When this study was published

Published in 2013. THC/CBD spray (nabiximols) has continued regulatory development for MS pain.

The bigger picture

This study illustrates the challenge of pain clinical trials: high placebo response rates can mask real treatment effects. The enriched enrollment, randomized withdrawal design (Phase B) may be a better approach for demonstrating cannabinoid pain efficacy. This design has since become more common in pain research.

Questions still open

Would a larger Phase B trial confirm these findings? Is the enriched enrollment, randomized withdrawal design the right approach for cannabinoid pain trials? What characterizes the 50% of patients who respond to THC/CBD spray?

Common questions

Does THC/CBD spray work for MS nerve pain?

The results were mixed. In a straightforward 14-week comparison, THC/CBD spray was not significantly better than placebo (50% vs 45% response). However, when responders were re-randomized, those switched to placebo were much more likely to lose pain control (57% vs 24%), showing the spray was genuinely maintaining pain relief. The high placebo response rate may have obscured the drug's real effect.

Why did the placebo response rate make the study fail?

Pain trials often have high placebo response rates because pain is subjective and influenced by expectations, attention, and the act of receiving treatment. When 45% of placebo patients reported 30% pain improvement, the true drug effect was hard to detect statistically. The withdrawal phase addressed this by showing that removing the active drug clearly worsened outcomes.

Read the original research

A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis.

Journal of neurology, 260(4), 984-97

View on PubMed ↗Publisher’s paper ↗

Citation

Langford, R M; Mares, J; Novotna, A; Vachova, M; Novakova, I; Notcutt, W; Ratcliffe, S. (2013). A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis.. Journal of neurology, 260(4), 984-97. https://doi.org/10.1007/s00415-012-6739-4