I’ve had a strong interest in cannabis and pain seeing as so many of the people I’ve worked with who live with chronic pain talk about using it (it’s still illegal in New Zealand, though medical cannabis has just been legalised this year). This study is one of the growing number of studies beginning to examine the effects of cannabinoids on pain, and offers a tiny window into what might be happening. Note: the study was performed in collaboration with the cannabis producer, and one of the authors is an employee of this company. Although his role was only to comment on the protocol and final version of the paper, it’s worth noting this relationship.
The study question
In this study, the researchers were looking to understand the analgesic effect of inhaled pharmaceutical-grade cannabis as a plant rather than an extract, using four different varieties with known levels of THC and CBD. Three had active biochemicals, while one was a placebo and had neither THC nor CBD. They investigated the effects of these preparations on experimental pressure pain, electrical pain, and spontaneous pain (primary endpoints), as well as the subjective and psychotropic effects.
The participants were all women with rheumatologist-diagnosed fibromyalgia, a score on a numeric rating scale of more than 5 (where 10 = most pain imaginable), met the diagnostic criteria of the 2010 American College of Rheumatology, and therefore had a widespread pain index of greater than or equal to 7 (from 0 – 19); symptom severity score of greater than 5 (from 0 – 12), or a widespread pain index of 3 – 6, and a symptom severity score greater than 9. Participants were excluded if they had any medical, neurological or psychiatric illness, used strong opioids or other pain relief except paracetamol or ibuprofen, using benzodiazepines, or had any known allergies to the cannabis used. Other exclusion criterai included pregnancy, illicit drug or alcohol use, recent use of cannabis, breast feeding, and other pain problems apart from fibromyalgia. On the day of screening and each day of testing, urine was tested for illicit drug use. Comment: note that excluding anyone with psychiatric illness doesn’t describe whether this was current illness, illness controlled by medications – and if it doesn’t include these participants, suggests the participants are not our usual sort of person with fibromyalgia, given the high comorbidity of psychiatric illness with fibromyalgia.
Participants attended the centre five times, with the first visit being the screening session where they were also given an orientation to the experimental set-up (eg how to inhale). On subsequent visits, participants were given one of four different cannabis inhalations (in random order) with at least 2 weeks between visits. The vapour was generated using the Stroz and Brickel Volcanic Medic vapouriser which heats the plant material which is then collected in a balloon (made opaque for this study so participants couldn’t see the vapour). Participants had to inhale the vapour 3 – 7 minutes after the balloon was filled, and asked to hold their breath for 5 seconds after they’d inhaled.
Blood testing involved using an arterial line, and five ml of blood was obtained a T0 (before), 5, 10, 20, 30 , 40, 50, 60, 90, 120, and 180 minutes after the person started to inhale. This blood was analysed for CBD,THC, and its active metabolite 11‐hydroxy‐THC (11-OH-THC) plasma concentrations.
In addition, participants were asked to rate their pain on an 11 point visual analogue scale (from 0 = no pain to 10 = most severe pain imaginable), and to do this before inhaling, and at 1, 2, and 3 hours after. Two experimental pain tests were used: pressure pain test using an algometer to deliver pressure on a skin area of 1 cm square, between the thumb and index finger; pressure was applied until the person said it had become painful, and repeated three times at each time point of T 5 0 (baseline), 12, 22, 32, 42, 62, 92, 122, 152, and 182 minutes after the start of inhalation.
An electrical pain test was also used delivering a current via two electrodes placed on the tibial surface of the right leg, about 10 cm above the medial malleolus. The participants were required to indicate when they first experienced pain (threshold) and when the pain became unbearable (tolerance), and this procedure was repeated at T 5 0, 10, 20, 30, 40, 60, 90, 120, 150, and 180 minutes after the start of cannabis inhalation.
Finally, two questionnaires were also completed: the Bowdle questionnaire which is used to evaluate psychoactive aspects of cannabis use (eg psychedelic effects), and the Bond and Lader questionnaire which is used to establish the mental cloudiness and mood effects.
I won’t go into the blinding and allocation processes, but randomisation was computer-generated, and adequate steps were taken to ensure neither the investigators nor the participants were aware of the contents of the inhalation.
25 people were recruited, but five withdrew after the first study visits, and interestingly three did so because of dizziness and nausea (3/5) . These participants were replaced with another patient according to the protocol. Participanats were women, around 39 years old (+/- 13 years), weighing about 82kg +/- 20kg, and 169 cm (+/- 7cm). Their NRS pain score was 7.20 +/-1.24; and all had their fibromyalgia diagnosis confirmed. Widespread body pain of 13.9 =?-2.6, symptom scale of 9.2 +/-1.3, and 14.9 +/- 2.9 tender points. (note that tender points are still difficult to identify reliably, so this continues to be an area of discussion).
All three active preparations resulted in adverse effects. Yes – all three! These effects included coughing, sore throat and bad taste, feeling high, dizzy, and nauseous. Of course, two also reported feeling high after placebo, but there were no differences in the frequency of adverse effects between the active treatments, and it should be noted, no serious adverse effects.
Interestingly, none of the treatments had an effect greater than placebo on spontaneous pain scores or electrical pain responses. So it doesn’t look like cannabis is much help with the general spontaneous pain many people with fibromyalgia experience, and I hope we don’t go around electric shocking each other!!
BUT two preparations caused a significant increase in tolerance to the pressure applied to the skin over the adductor pollicis muscle for the duration of the study. The largest effect was observed for the cannabis variety that contained high doses of both THC and CBD, allowing an additional 11kgf at 20 – 90 minutes. Active treatments vs placebo showed significantly more patients (n = 18) responded to the CBD + THC preparation with a decrease in spontaneous pain by 30%, but only N = 9 achieved 50% which is not statistically significant. At both responder rates, all other treatments had response profiles not different from placebo. Spontaneous pain scores were strongly correlated with the magnitude of drug high.
Study author’s discussion
The authors point out that none of the treatment had an effect greater than placebo on spontaneous pain, but that compared with placebo, more people responded to the combined THC + CBD preparation than the other forms – and these others had response rates no different from placebo. The pain reduction scores for spontaneous pain correlated with how high participants felt. For pressure pain threshold, an increase in pressure was tolerated by people with two preparations with THC content, while the form with CBD did not have any analgesic effect.
What do I think?
As someone living with fibromyalgia, I’m always curious about treatments that may help reduce the burden of this disorder. Unfortunately, I don’t think cannabis, at least in these forms, is going to cut the mustard. While pressure pain threshold reduced, it didn’t reach the 50% reduction in pain that we really want, and I’m not sure pressure pain is the one I’m most concerned about. I’d love for my spontaneous pain to reduce and unfortunately this study suggested that I’d have to get high to do so. Might be great for pain, but not so great for being able to DO anything! The authors point out that “the pressure pain test seems especially suited for exploring treatment effects in FM pain, as it elicits mechanical muscle stimulation through A delta- and C fibre activation and better reflects the symptoms of patients with FM, but I’m not entirely convinced myself.
The numbers needed to treat for cannabis preparations are greater than 20 – what this means is that more than 20 people need to try cannabis for ONE person to obtain a benefit. Not only that, but from this study, 5 of the original 20 people withdrew because of adverse effects, with adverse effects being very common. You’d have to be prepared to cope with coughing, dizziness, nausea, and feeling high if you wanted to use cannabis in this way.
So, at this point I’m not an advocate of cannabis for the purpose of relieving the pain that people with fibromyalgia experience. While it’s appealing, the numbers needed to treat are very high, adverse effects common, and the fact that the analgesic effects were only experienced alongside feeling high makes me very cautious. More studies are needed!
van de Donk, T., Niesters, M., Kowal, M. A., Olofsen, E., Dahan, A., & van Velzen, M. (2019). An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia. Pain, 160(4), 860-869.
Bronnie, since we wrote our article (see below) there has been increasing evidence that the endocannabinoid system is involved in the regulation of systems of stress response. In view of the possibility that the “polysymptomatic distress” that typifies the fibromyalgia phenotype reflects activation of these systems, there may be an important therapeutic role for exogenous cannabinoids in these conditions. Worth a thought? https://blog.apsoc.org.au/…/if-cannabis-should…/amp/
Thank you for a thorough summary and evaluation of the meaning of the clinical scope, trial considerations and results of this study. I rarely see someone make studies intelligible in this way.