Clinical Drug Experience Knowledgebase

A Phase II, Randomized, Open-label, Double-blind, Two-center Study to Evaluate the Tolerability, Safety and Dose-finding of Oil Cannabis Preparation for Pain in Parkinson's Disease

BACKGROUND AND RATIONALE Pain is a common symptom in PD and is reported in up to 50 % of patients. Pain in PD has been classified as musculoskeletal, dystonic (particularly in OFF-periods), radicular and central pain, and is frequently associated with muscle rigidity, postural abnormalities and bradykinesia. Often, the presence of pain in PD is associated with the daily fluctuations in the motor symptoms of PD. In addition, some patients experience 'off-dystonia' which affects the toes and feet, with painful cramps and posturing. The treatment of pain in PD patients with such fluctuating symptoms involves optimizing the dose of levodopa or other dopaminergic drugs to treat the OFF periods. Frequently, the pain does not resolve on altering the PD medication and remains difficult to treat.

Cannabis Sativa (marijuana) and its major psychoactive constituent, delta-9- tetrahydrocannabinol(Δ9THC) have been used for centuries to treat pain. The mechanism of action is likely mediated via cannabinoid receptors (CB1 and CB2) in basal ganglia and spinal circuits. Because of these potential therapeutic properties, several synthetic and naturally occurring cannabinoid preparations have been manufactured. Cannabinoids have been demonstrated to alleviate allodynia or hyperalgesia in animal models of pain; the effect on pain modulation may be secondary to CB1 receptors in the amygdala, thalamus, spinal cord and dorsal root ganglion. Several recent clinical studies have demonstrated the potential efficacy of synthetic and naturally occurring cannabinoids in pain. Synthetic cannabinoids such as nabilone and nabiximols are now licensed as add-on therapy in multiple sclerosis and advanced cancer for relief of pain. A Canadian systematic review of randomized clinical trials of cannabinoids (cannabis, nabilone, dronabinol and nabiximols) for the treatment of chronic non-cancer pain (neuropathic pain, mixed chronic pain, rheumatoid arthritis, fibromyalgia) concluded that cannabinoids are modestly effective. Other cannabinoids found in cannabis sativa include cannabidiol (CBD). CBD potentially lacks a psychoactive effect, and appears to act via non-CB receptor-mediated actions including ion channels and enzymes. Pre-clinical studies suggest anti-inflammatory, analgesic, anti-nausea, anti-emetic, anti-psychotic, anti-ischemic, anxiolytic, and anti-epileptiform actions. Thus, the advantage of CBD in PD is a potentially lesser risk of cognitive dysfunction and psychosis.

Currently, there is an oil preparation (CanniMed® Oil) in Canada, with the advantage of ease of administration. CanniMed® Oil is a mixed oil preparation that contains both Δ9THC and CBD, of varying proportions of Δ9THC (more psychoactive component) and CBD (18:0; 10:10; 1:20 respectively). Investigators of this study have experience in conducting trials using synthetic cannabinoids in movement disorders, including PD. Investigators have demonstrated tolerability, but limited efficacy, of short-term administration of clinically available oral tablet cannabinoids in idiopathic dystonia. More specifically in PD, investigators have assessed nabilone for the treatment of levodopa-induced dyskinesia with documented efficacy. Of interest to the current proposal, in this study, investigators also found an improvement in painful OFF-period limb dystonia in 2 out of 7 subjects. It is unknown if this effect is a specific analgesic effect or related with an anti-dystonia effect.

STUDY HYPOTHESIS Despite the major advances in understanding the pathophysiology of the endocannabinoid system, there are many unknowns in the use of cannabinoids for medical purposes. To date, clinical studies with cannabinoids in PD have been inconclusive and the use of cannabinoids remains controversial due to a lack of well-powered confirmatory clinical studies and obvious safety concerns. However, the known efficacy of cannabinoids in reducing pain suggests that PD-related pain may also be a reasonable target for cannabinoids. Combined with the potential rationale for reducing dystonia, we hypothesize that cannabinoids could reduce pain in PD, regardless of the PD-specific pain cause.

Primary Outcome

Safety:

Incidence and severity of adverse events
Maximum tolerated dose (MTD)

Tolerability:

Ability to remain on assigned treatment
Withdrawal rates due to adverse events

Secondary Outcomes: Assess change from baseline in the King's Parkinson Disease Pain scale (KPPS).

Other Outcomes: Assess change from baseline in frequency and severity of pain, sleep, dystonia and PD motor symptoms, using the following measurement tools:

Visual Analogue Scale for Pain
MDS-UPDRS part III
UDysRS - Dystonia part 2 subscores
Clinical Global Impression of pain severity (severity and improvement)
Epworth Sleepiness Scale