An Experimental Randomized Study on the Analgesic Effects of Pharmaceutical-grade Cannabis in Chronic Pain Patients With Fibromyalgia

Tine van de Donk; Marieke Niesters; Mikael A. Kowal; Erik Olofsen; Albert Dahan; Monique van Velzen


Pain. 2019;160(4):860-869. 

In This Article

Abstract and Introduction


In this experimental randomized placebo-controlled 4-way crossover trial, we explored the analgesic effects of inhaled pharmaceutical-grade cannabis in 20 chronic pain patients with fibromyalgia. We tested 4 different cannabis varieties with exact knowledge on their Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) content: Bedrocan (22.4-mg THC, <1-mg CBD; Bedrocan International BV, Veendam, the Netherlands), Bediol (13.4-mg THC, 17.8-mg CBD; Bedrocan International BV, Veendam, the Netherlands), Bedrolite (18.4-mg CBD, <1-mg THC; Bedrocan International BV, Veendam, the Netherlands), and a placebo variety without any THC or CBD. After a single vapor inhalation, THC and CBD plasma concentrations, pressure and electrical pain thresholds, spontaneous pain scores, and drug high were measured for 3 hours. None of the treatments had an effect greater than placebo on spontaneous or electrical pain responses, although more subjects receiving Bediol displayed a 30% decrease in pain scores compared to placebo (90% vs 55% of patients, P = 0.01), with spontaneous pain scores correlating with the magnitude of drug high (ρ = −0.5, P < 0.001). Cannabis varieties containing THC caused a significant increase in pressure pain threshold relative to placebo (P < 0.01). Cannabidiol inhalation increased THC plasma concentrations but diminished THC-induced analgesic effects, indicative of synergistic pharmacokinetic but antagonistic pharmacodynamic interactions of THC and CBD. This experimental trial shows the complex behavior of inhaled cannabinoids in chronic pain patients with just small analgesic responses after a single inhalation. Further studies are needed to determine long-term treatment effects on spontaneous pain scores, THC–CBD interactions, and the role of psychotropic symptoms on pain relief.


In the current opioid epidemic, there is the need for pharmaceutical alternatives to opioid treatment in patients with chronic pain. An alternative may be found in the chemicals of the cannabis plant (Cannabis sativa L.), which contains over 500 chemical components, with more than 100 of them being cannabinoids.[8] Cannabinoids, or more specifically phytocannabinoids, are the main active chemical components of the cannabis plant. They exhibit most of their pharmacological effects via cannabinoid type 1 (CB1) and type 2 (CB2) G-protein-coupled receptors. CB1 receptors are located mainly in the central nervous system, whereas CB2 receptors are mostly found on immune cells.[21] These receptors form part of the endocannabinoid system, a modulatory biological system that influences the activity of different neurotransmitters with their own ligands, the endocannabinoids, such as anandamide and 2-arachidonoylglycerol.[22] As for cannabis, its major cannabinoid is Δ9-tetrahydrocannabinol (THC), a partial CB1-receptor agonist, that produces a variety of effects including altered cognition and motor function, analgesia, and psychotropic effects (eg, drug high).[3] Another key component of cannabis is cannabidiol (CBD) that, while nonintoxicating, does affect mood and cognition.[16] It is a CB2 receptor antagonist and additionally has agonist activity at the 5HT-receptor and stimulates the vanilloid receptor type 1 with similar efficacy as capsaicin.[2,7,11,29]

In this experimental trial, we explored the effect of pharmaceutical-grade cannabis in patients with chronic pain caused by the fibromyalgia (FM) syndrome. Fibromyalgia is characterized by chronic widespread pain, often accompanied by secondary symptoms including sleep disturbance, tiredness, and cognitive symptoms such as memory deficits.[10] This condition predominantly affects women, with a worldwide prevalence of 2% to 8% and conventional pharmacologic treatment is considered only mildly effective.[5,8,17]

We explored the analgesic effects of inhaled pharmaceutical-grade cannabis using the cannabis plant with all its natural components. We tested 4 different varieties with exact knowledge on their THC and CBD content. The varieties used were Bedrocan with a high THC/low CBD content, Bedrolite with a high CBD/low THC content, Bediol with a combined high THC/high CBD content, and a placebo variety without any THC or CBD content. This approach enabled exploration of cannabis effects on pain relief relative to placebo cannabis that was similar in smell, appearance, and handling compared with the other varieties. We assessed relief of experimental pressure pain, electrical pain, and spontaneous pain (primary endpoints), as well as the subjective and psychotropic effects. We hypothesized that compared with placebo treatment, all THC-containing treatments would cause greater analgesic responses for both spontaneous pain and evoked pain models.