Dronabinol is a safe long-term treatment approch for the treatment of neuropathic pain. 

Analgesia is one of the pharmacological actions of cannabinoids, which are often used to treat chronic pain. Cannabinoids are the central nervous system (CNS) acting drugs which mainly works on CB1 and CB2 receptors located in the CNS and other tissues like lungs, liver and immune cells. Several studies have investigated the long-term effects of the cannabis-based medicine and these studies lasting from 38 weeks to 3.5 years showed no significant safety concerns and reported good tolerability. Nevertheless, the medical use of cannabis was controversially discussed. Dronabinol,  a synthetic form of tetrahydrocannabinol (THC) is approved by the Food and Drug Association (FDA). Svendsen et al showed that dronabinol has a clinically relevant analgesic effect with good tolerability. Another study by Rog et al showed significant results and provided evidence for the safe and efficient reduction of pain and sleep disturbance after four weeks treatment with cannabis-based medicine containing dronabinol and CBD. On the other hand, Langford et al failed to show the efficacy of an oromucosal dronabinol/CBD spray in patients treated for 33 weeks, whereas the occurrence of adverse events (AEs) was similar for verum and placebo. Therefore, to address these safety issues, Sebastian Schimrigk et al performed this clinical trial to demonstrate the efficacy and safety of dronabinol in the treatment of patients with multiple sclerosis (MS) and chronic neuropathic pain (CNP).

Rationale behind the research:

The number of clinical trials with cannabis-based therapeutics have been performed, but the medical use of cannabis was still controversially discussed. Therefore, the present study addresses these open safety issues, and aimed to show efficacy and long-term safety of dronabinol in the treatment of patients with MS and CNP.

Objective:

To demonstrate the positive benefit-risk ratio of dronabinol against the neuropathic pain.

Study outcome measures:

• 11-point NRS for pain intensity (0= no pain to 10= strongest pain imaginable) and the SF-36 quality of life (QoL) questionnaire. The main endpoint was the mean change from baseline pain intensity to mean weekly pain scores within a maximum of 16 weeks
• For safety analysis, vital signs, laboratory parameters, SAEs including (serious) adverse reactions (SARs) were regularly assessed during all three periods
• Furthermore, patients rated the global tolerability on a 4-point rating scale (1= very good to 4= poor)

Time period:  Baseline, 16 weeks, 32 weeks and 96 weeks. 

Study Outcomes

• Efficacy Results:

There was not statistically significant (p= 0.6760) difference between the mean change of pain intensity from baseline to mean of weeks 1–16 compared between dronabinol (1.92 ± 2.01; 30%) and placebo (1.81 ± 1.94; 27%). (Figure 1).

Figure 1. Coparison between dronabinol and placebo for difference between the mean change of pain intensity from baseline to mean of weeks 1–16.

The QoL assessment (SF-36) showed a definite improvement during the double-blind period from baseline until end of treatment in both groups (physical component summary: verum: –3.50, placebo: –3.18; mental component summary: verum: –2.69, placebo: –0.60) without significant difference.

• Safety Results:

Approx. 92.9% of patients experienced at least one AE. Patients experiencing AEs were higher in the dronabinol group than in the placebo group. The proportion of patients experiencing SAEs was low.

• Global Assessment of Tolerability:

After all the three time periods the global tolerability mostly was very good (double-blind period: verum: 84.5%; placebo: 95.6%; open-label period: 85.2%; follow-up period: 93%).

• Vital Signs, ECG:

No clinically relevant changes in the vital signs such as blood pressure, heart rate, and weight were observed. Both blood hematology and biochemistry analysis did not reveal any clinically relevant differences or trends. The presence of severe cardiac diseases could be ruled out clinically and by ECG for 90% of patients at the end of treatment.

• Signs of Withdrawal:

For most patients, no withdrawal reactions were reported after cessation of the study medication.

• Drug Dependency and Drug Abuse:

Mild signs of drug dependency were documented only for 1 patient. No patient showed any sign of drug abuse. 

This clinical trial demonstrated a significant decrease of mean pain intensities during 16-weeks dronabinol and placebo treatment. These results revealed that dronabinol is a safe long-term treatment option for neuropathic pain. The similar number of side effects have occurred in patients with MS and CNP in comparison to standard treatment. A previous clinical trial performed by Svendsen et al with dronabinol showed its efficacy superiority over placebo. Besides the analgesic effect of dronabinol, the other therapeutic effects such as sedative, spasmolytic, anti-inflammatory and anxiolytic may contribute to improving QoL of NP patients, which is the overall therapeutic goal. Patients’ QoL may also be affected by side effects, which are in general quite common for centrally acting substances. In this study, the proportion of patients with ARs was highest in the beginning and declined during the dronabinol treatment. Most AEs and ARs were non-serious and of mild to moderate. In this trial, the most frequent ARs belonged to “nervous system disorders” followed by “general disorders and administration site conditions”. The assessment of dronabinol’s potential to induce withdrawal symptoms, dependency, abuse and tolerance during long-term follow-up of our trial revealed no negative hints. Despite the long duration of dronabinol intake, only 10 patients showed transient withdrawal symptoms.

In conclusion, the dronabinol has long-lasting therapeutic potential, the good tolerability and favorable safety profile of dronabinol especially regarding drug abuse and dependency makes it a preffered choice in the treatment of neuropatihc pain.