Dronabinol Is a Safe Long-Term Treatment Option for Neuropathic Pain Patients

Abstract

Treatment of neuropathic pain (NP) symptoms associated with multiple sclerosis (MS) is frequently insufficient. Yet, cannabis is still rarely offered for treatment of pain. This clinical trial aimed at showing the positive benefit-risk ratio of dronabinol. Two hundred forty MS patients with central NP entered a 16-weeks placebo-controlled phase-III study followed by a 32-weeks open-label period. One hundred patients continued therapy for overall up to 119 weeks. Primary endpoint was change of pain intensity on the 11-point Numerical Rating Scale over a 16-weeks treatment period. Safety was assessed on the basis of adverse reactions (ARs), signs of dependency and abuse. Pain intensity during 16-weeks dronabinol and placebo treatment was reduced by 1.92 and 1.81 points without significant difference in between (p = 0.676). Although the proportion of patients with ARs was higher under dronabinol compared to placebo (50.0 vs. 25.9%), it decreased during long-term use of dronabinol (26%). No signs of drug abuse and only one possible case of dependency occurred. The trial results demonstrate that dronabinol is a safe long-term treatment option.

Keywords: Clinical trial; Dronabinol; Long-term; Multiple sclerosis; Neuropathic pain; Safety; Tetrahydrocannabinol.

Fig. 1.

After the 2-week screening period (S) patients were randomized and included in a double-blind period, including a 4-week titration period (dashed line) in which patients established their individual tolerable dose (maximum 15 mg/day dronabinol or placebo), followed by a maintenance period of 12 weeks. Afterwards, patients entered an open-label period including a double-dummy 4-week titration period (dashed line) followed by a 32-week maintenance period. A subgroup continued dronabinol therapy within an open-label long-term safety follow-up planned to last up to 96 weeks. The start of each new period is indicated with an arrow. * Some patients did not directly enter the long-term follow-up but had a short break (planned duration ≤31 days) before continuing the treatment. ** Due to the nonsignificant efficacy result, long-term safety follow-up was prematurely terminated resulting in a maximum treatment duration of 119 weeks.

Fig. 2.

Patients’ allocation to treatment groups in different study periods is displayed. In the middle part, the patient numbers for each period per treatment group are given. On the left and right side the reasons for drop-outs are listed (multiple reasons for one patient possible). The arrows on the right indicate the different study periods and their duration. * Criteria appearing after randomization, which represent exclusion criteria for example, intake of disallowed concomitant medication.

Fig. 3.

The mean weekly pain intensities (NRS) are displayed for the double-blind (weeks 0–16) and open-label period (weeks 16–48). At the beginning of each period, a titration period of 4 weeks (T1, T2) was performed. The mean weekly pain intensities decreased substantially during the first 16 weeks and continued to decrease in the open-label period.

Fig. 4.

Dronabinol-induced (serious) adverse events (SAEs) and (serious) adverse reactions (SARs) are illustrated by the time of occurrence. Overall, the number of AEs and ARs decreased over time with no time dependency for SAEs and SARs occurrence. a shows the time course of SAEs and SARs for patients receiving dronabinol during the double-blind and open-label period for the first 32 weeks of treatment. Most AEs and ARs occurred during the first titration period (T1, weeks 1–4, dronabinol titration) and during second titration (T2, weeks 17–20, double-dummy placebo titration). b shows the time course of SAEs and SARs for patients switched from placebo to dronabinol starting from the first week of dronabinol intake (week 17). Most AEs and ARs occurred during the titration period (T2, weeks 17–20, dronabinol titration).