BMJ  2004;329:253 (31 July), doi:10.1136/bmj.38149.566979.AE (published 16 July 2004)

Paper

Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial

¹ Danish Pain Research Center and Department of Neurology, Aarhus University Hospital, Noerrebrogade 44, DK-8000 Aarhus C, Denmark

Abstract

Objective To evaluate the effect of the oral synthetic -9-tetrahydrocannabinol dronabinol on central neuropathic pain in patients with multiple sclerosis.

Design Randomised double blind placebo controlled crossover trial.

Setting Outpatient clinic, University Hospital of Aarhus, Denmark.

Participants 24 patients aged between 23 and 55 years with multiple sclerosis and central pain.

Intervention Orally administered dronabinol at a maximum dose of 10 mg daily or corresponding placebo for three weeks (15-21 days), separated by a three week washout period.

Main outcome measure Median spontaneous pain intensity (numerical rating scale) in the last week of treatment.

Results Median spontaneous pain intensity was significantly lower during dronabinol treatment than during placebo treatment (4.0 (25th to 75th centiles 2.3 to 6.0) v 5.0 (4.0 to 6.4), P = 0.02), and median pain relief score (numerical rating scale) was significantly higher (3.0 (0 to 6.7) v 0 (0 to 2.3), P = 0.035). The number needed to treat for 50% pain relief was 3.5 (95% confidence interval 1.9 to 24.8). On the SF-36 quality of life scale, the two items bodily pain and mental health indicated benefits from active treatment compared with placebo. The number of patients with adverse events was higher during active treatment, especially in the first week of treatment. The functional ability of the multiple sclerosis patients did not change.

Conclusions Dronabinol has a modest but clinically relevant analgesic effect on central pain in patients with multiple sclerosis. Adverse events, including dizziness, were more frequent with dronabinol than with placebo during the first week of treatment.

Introduction

Pain is an important symptom accompanying multiple sclerosis; acute or chronic pain syndromes occur in 30-80% of patients.^1-6 The reported prevalence of central pain from sclerotic plaque lesions affecting pain pathways is around 33%.⁷

Recent animal studies suggest that cannabinoids can reduce allodynia or hyperalgesia in neuropathic, inflammatory, and cancer pain,^8-15 but few clinical studies have evaluated the analgesic action of cannabinoids in humans.^16-21 Two recent randomised trials of cannabinoids included patients with multiple sclerosis, and both reported a beneficial effect on patients' pain.^{22 23} A third trial, in patients with other pain syndromes, also reported that a synthetic cannabinoid alleviated neuropathic pain.²⁴

None of the previous studies has specifically explored the effect of cannabinoids on pain caused by central lesions in multiple sclerosis. We aimed to evaluate the efficacy of the synthetic -9-tetrahydrocannabinol dronabinol on central pain in patients with multiple sclerosis in a randomised placebo controlled study. The objective was to provide better treatment options for central pain in multiple sclerosis, and we hypothesised that dronabinol would reduce central pain in multiple sclerosis.

Methods

Protocol
We recruited participants from the population of patients with definite multiple sclerosis in Aarhus County, Denmark.²⁵ We recruited patients partly from the outpatient multiple sclerosis clinic at the University of Aarhus and partly from responders (n = 627) to a postal survey undertaken among all patients with multiple sclerosis in Aarhus County in 2001.⁶ All patients with suspected central pain had a clinical examination in the pain clinic.

Inclusion criteria were a diagnosis of multiple sclerosis (clinical definite multiple sclerosis and laboratory supported definite multiple sclerosis²⁵), age between 18 and 55 years, and central pain at the maximal pain site with a pain intensity score 3 on a 0-10 numerical rating scale. The definition of central pain was pain in a body territory with abnormal sensation to pinprick, touch, warmth, or cold, evaluated by the bedside or with quantitative sensory testing, corresponding to at least one lesion in the central nervous system.^{7 26} We allowed concurrent spasm related pain or other pain if the patient was able to distinguish it from central pain. We excluded patients who had used marihuana within the last three months, and those who were unwilling to stop using marijuana during the study period.

We designed the study as a randomised double blind placebo controlled crossover trial. We allocated patients to treatment after a one week baseline period. We planned for the patients to receive three weeks' (18-21 days') treatment with dronabinol and three weeks' (18-21 days') treatment with placebo, with a washout period of at least 21 days between the treatment periods. Any analgesic drug (except paracetamol) was discontinued at least one week before the first visit.

During active treatment, the initial dose of dronabinol was 2.5 mg daily (one capsule), and the dose was increased by 2.5 mg every other day to a maximum dose of 5 mg (two capsules) twice daily. The placebo capsules were identical to the dronabinal capsules in appearance, taste, and smell.

Assignment and masking
We assigned patients to treatment using a computer generated randomisation code. Both investigators and patients were blinded to treatment allocation, and we maintained blinding until the data analysis was completed. At the end of the study we asked the patients to identify the treatment period in which they received the active treatment and which of the two treatments they preferred.

Assessments
The predefined primary outcome measure was median spontaneous pain intensity in the last week of treatment. Secondary outcome measures were median radiating pain intensity in the last week of treatment, pain relief, use of escape medication, patient preference, health related quality of life (SF-36), expanded disability status scale score, and quantitative sensory testing.

We asked the patients to assess pain intensity and pain relief at the maximal pain site throughout the study and record their assessments in a diary. They assessed pain intensity twice daily by using a numerical rating scale from 0 to 10 (0 = no pain, 10 = worst imaginable pain). They recorded pain relief on a numerical scale from 0 to 10 (0 = no pain relief, 10 = best pain relief) at the end of each treatment period. The patients also recorded the number of paracetamol taken daily.

At the end of the baseline period and at the end of each treatment period we administered a health related quality of life questionnaire (SF-36), the expanded disability status scale,²⁷ and quantitative sensory tests. We did the sensory tests at the maximal pain site and at the same site at all three visits. These tests measured patients' sensitivity to touch, pressure, heat, cold, and vibration (see bmj.com for details). We also tested temporal summation of pain to pinprick and mechanical and cold allodynia (pain evoked by stimuli not ordinarily painful). Patients used their own words to record adverse events in their dairies during each treatment period.

Data analyses and statistics
We analysed data according to the principle of intention to treat. For the daily pain scale ratings we determined a median value for the third week of treatment. We coded and summed the item scores in SF-36 and transformed them to a scale of 0 (poor health) to 100 (optimal health). We compared the effects of dronabinol and placebo on pain intensity, pain relief, escape medication, SF-36, expanded disability status scale, and quantitative sensory testing. We also compared the incidence of adverse events, analysed patients' preference of treatment period, tested for a carryover effect between treatment periods, and tested the efficiency of blinding by using patients' guesses of their active treatment period.

We considered a 25-30% pain reduction from baseline to be clinically relevant.²⁸ We calculated that we would need 23 patients for our study to have 90% power to detect this magnitude of effect.

Results

Participants
Patients were recruited between 27 February and 21 May 2002. The last telephone follow up took place on 26 July 2002. We screened 25 patients for the study and enrolled 24. All enrolled participants completed the study protocol. We excluded SF-36 and sensory testing data from one patient. Table 1 gives the characteristics of the participants and their pain.

View this table: [in this window] [in a new window]   Table 1 Characteristics of participants

 

Primary outcome measure
We observed no significant carryover effect for the primary outcome measure (P = 0.24). The median spontaneous pain intensity during the last week of treatment was significantly lower during dronabinol treatment than during placebo treatment (4.0 (25th to 75th centiles 2.3 to 6.0) v 5.0 (4.0 to 6.4), P = 0.02). The estimated difference in pain scores between dronabinol and placebo treatments was -0.6 (95% confidence interval -1.8 to 0).

In the group of patients randomised to active medication in the first period the change in spontaneous pain intensity from baseline was -1.0 (25th to 75th centiles -1.9 to -0.1) during dronabinol treatment and 0 (-2.0 to 0) during placebo treatment. In the group of patients randomised to placebo in first period the change in pain from baseline was -1.5 (-2.8 to -0.3) during dronabinol treatment and 0 (0 to 0.9) during placebo treatment. The estimated relative difference in pain reduction from baseline between dronabinol and placebo treatments was -20.5% (95% confidence interval -37.5 to -4.5).

Secondary outcome measures
Table 2 shows the secondary outcome measures. Median radiating pain intensity during the last week of treatment was lower during dronabinol treatment than during placebo treatment, and a higher pain relief score was obtained during dronabinol treatment than during placebo treatment. On the basis of pain relief scores, the number of patients that needed to be treated for one additional case of 50% pain relief was 3.45 (95% confidence interval 1.9 to 24.8). No differences between treatments occurred in period preference, escape medication, or expanded disability status scale score.

View this table: [in this window] [in a new window]   Table 2 Primary and secondary outcome measures. Values are medians (25th to 75th centiles) unless stated otherwise

 

The pressure pain threshold was higher after dronabinol treatment than after placebo treatment, but we found no other differences between the groups in results of quantitative sensory tests. On the SF-36, the patients scored slightly higher (better) in the bodily pain and mental health domains during dronabinol treatment than during placebo treatment.

Adverse events
Adverse events were more common during dronabinol treatment than during placebo treatment. During dronabinol treatment 23 (96%) patients had adverse events compared with 11 (46%) patients during placebo treatment (P = 0.001) (table 3). During active treatment four (17%) patients had their doses reduced (three patients to 7.5 mg daily and one patient to 5 mg daily) because of intolerable adverse events. All the others took 10mg daily. No withdrawals occurred. The most common adverse events during dronabinol treatment were related to the central nervous system (dizziness, headache, tiredness) and the muskuloskeletal system (myalgia, muscle weakness) (table 3).

View this table: [in this window] [in a new window]   Table 3 Adverse events during treatment with dronabinol and placebo. Values are numbers (percentages) of patients with adverse event, number of adverse events

 

Assessment of blinding
Sixteen (67%) of the patients correctly identified the period in which they received active medication. Six (25%) patients identified the wrong period, and two (8%) patients were unable to choose one of the treatments (P = 0.19).

Discussion

Oral dronabinol, at a maximum dose of 10 mg daily, reduced central pain in patients with multiple sclerosis. The primary outcome measure—median spontaneous pain intensity during the last week of treatment—was significantly reduced during dronabinol treatment compared with placebo. The difference between treatments in pain reduction from baseline was around 21%. The results of the secondary outcome measures supported the finding that dronabinol was superior to placebo in reducing pain, although we made no statistical correction for multiple comparisons.

What is already known on this topic Cannabinoids reduce hyperalgesia in animal models of neuropathic, inflammatory, and cancer pain Evidence from randomised controlled trials of the analgesic effect of cannabinoids in humans is sparse A recent large study with pain as a secondary outcome measure indicated that cannabinoids may alleviate unspecified pain in multiple sclerosis What this study adds Dronabinol has a modest but clear and clinically relevant analgesic effect in multiple sclerosis patients with central pain The effect size is comparable to that of other treatment options available Dronabinol should be available for patients whose central pain is not sufficiently treated with alternative drugs such as anticonvulsants, antidepressants, or opioids

It could be argued that dronabinol ameliorated pain by a non-specific effect on function other than that directly linked to pain. However, dronabinol did not alter the functional multiple sclerosis disability score during the trial, and on the SF-36 general health profile the only improvements seen were in bodily pain and mental health. These observations suggest that dronabinol had a specific effect on pain.

The definition of central neuropathic pain is vague.²⁶ We included only patients with sensory abnormalities at the maximal pain site, and we did not define spasm related pain as central pain as other authors have.⁷ We instructed all patients throughout the study to assess pain only at the site that was most painful at study start and only that diagnosed as central pain. However, we cannot exclude the possibility that some of the pain reduction was related to a decrease in spasm related pain. In addition, the higher mental health subscore on the SF-36 during dronabinol treatment may indicate that some of the benefit of dronabinol on pain may be due to a central effect.

Whether the small reduction in pain intensity we found is clinically important could be debated. However, the pain reduction seen during treatment with dronabinol in this study is comparable to the effect of other drugs used in the treatment of neuropathic pain.^{29 30}

The number of patients reporting adverse events was higher during dronabinol treatment than during placebo treatment. Previous studies have reported similar adverse events associated with dronabinol,^{23 31-33} although in at least one dronabinol caused no more adverse events than placebo.³⁴ In our study, no patients stopped their treatment because of adverse events, and only four patients had to reduce their dose.

Conclusion
In this study, oral dronabinol reduced central pain in patients with multiple sclerosis. It should be available as a treatment option to patients whose central pain does not respond adequately to other drugs.

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This is the abridged version of an article that was posted on bmj.com on 16 July 2004: http://bmj.com/cgi/doi/10.1136/bmj.38149.566979.AE

We thank chief consultants Hans Jacob Hansen and Thor Petersen at the multiple sclerosis clinic, Aarhus University Hospital, Denmark, for informing patients about the study and senior statistician Arne Andreasen for statistical support.

Contributors: See bmj.com

Funding: The study was supported by grants from the Danish Multiple Sclerosis Society (grant no 2002/71045), grant 900035 from manager Ejnar Jonasseon and his wife's memorial grant, and the Warwara Larsen Foundation (grant no 664.28), Denmark. Solvay Pharmaceuticals provided study medication (dronabinol (Marinol) and placebo capsules), labelling, and packaging. In addition, the company provided financial support for study monitoring and data analysis. IPC-Nordic, Denmark, packaged and labelled the study medication and monitored the study. These companies were not involved in the design or execution of the study or writing the manuscript.

Competing interests: None declared.

Ethical approval: The study was approved by the regional ethics committee (Aarhus, j.no.20010143), the Danish Medicines Agency (J.no.2612-170), and the Danish Data Protection Agency.

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(Accepted 12 May 2004)

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