Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial
Svendsen KB, Jensen TS and Bach FW;
Commented by , 22 Sep 2004
Background
It has recently been shown, that there is no significant effect of synthetic delta-9-tetrahydrocannabinol (sTHC) or cannabis extract, on objective measurements of spasticity in MS (ref. 1). Furthermore, the study showed a reduction of self reported pain, although this was a secondary outcome measure and not performed using state of the art methods.
Aim
To evaluate the effect of sTHC on central neuropatic pain in MS patients.
Methods
The authors selected 24 patients with central pain (intensity score³3 on a numerical 0-10 scale) who were examined at a pain clinic. The study was designed as a randomised double blind placebo controlled crossover trial, with three weeks (18-21 days) treatment, three weeks placebo, and a wash out period of at least 21 days between treatments. The dose of sTHC was increased from 2.5 mg daily to an end dose of 5 mg twice daily.
The primary outcome measure was median spontaneous pain intensity in the last week of treatment. Secondary outcome measures were median radiating pain intensity, pain relief, use of escape medication, patient preference, health related quality of life (SF-36), expanded disability status scale score (EDSS), and quantitative sensory testing.
An extensive statistical evaluation was carried out to evaluate treatment effect, see original paper for details. A significance level of 0.05 was used for the primary outcome measure.
Results
1. Median spontaneous pain intensity was significantly lower during the last week of sTHC treatment compared with placebo (p = 0.02).
2. Relative difference in pain reduction from baseline was 20.5%.
3. Median radiating pain intensity was lower during sTHC treatment compared with placebo.
4. Higher pain relief was obtained during sTHC treatment.
5. The numbers needed to treat for one additional case of 50% pain relief was 3.45 (95% CI 1.9-24.8).
6. Pressure pain threshold was higher after sTHC treatment.
7. Patients scored better in bodily pain and mental health on the SF-36.
Discussion
The study shows a modest effect of sTHC on neuropatic pain using a fairly low daily dose. The effect is still clinically relevant and comparable to the effect of other drugs used in the treatment of neuropatic pain. It is the first study to show a significant effect of sTHC on a primary outcome measure compared with placebo in an MS trial.
The study is well designed and the data analysis very thorough, although it should be mentioned that the authors did not correct data for multiple comparisons. It is important to comment on the possible inconsistency in the distinction between painful musclespasms and central pain, which may be difficult, and have implications for the interpretation of the results. Another important point is the masking of symptoms using cannabinoid drugs, which is not commented in the discussion.
Still the study has implications for treatment of central pain, and will hopefully modify the ongoing discussion regarding the use of medical cannabis in MS. Recently, three other studies have shown effect of cannabinoids on symptoms ranging from muscle spasm frequency (ref. 2), lower urinary tract symptoms (ref. 3) to a variety of other problematic symptoms (ref. 4). These studies are however more inconsistent regarding standards for trial design and outcome measures, but could inspire new trials using cannabinoid drugs.
References
1. Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, Thompson A. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003;362:1517-26.
2. Vaney C, Heinzel-Gutenbrunner M, Jobin P, Tschopp F, Gattlen B, Hagen U, Schnelle M, Reif M.Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study. Mult Scler 2004;10:417-24.
3. Brady CM, DasGupta R, Dalton C, Wiseman OJ, Berkley KJ, Fowler CJ.An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Mult Scler 2004;10:425-33.
4. Wade DT, Makela P, Robson P, House H, Bateman C.Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler 2004;10:434-41.