experiment

An experimental study of pharmaceutical cannabis in fibromyalgia


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.

Study design

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.

The results

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.

How do you decide when to stop doing something?


ResearchBlogging.org
There are plenty of times when it’s easy to give up on doing something – just ask me to do the vacuum cleaning or do a workout at the gym! On the other hand, there are plenty of times when someone close to me sighs and asks ‘How long are you going to be?’ while rolling his eyes skyward as I take yet another photo! So, take it from me, I think how long I persist at doing something entirely depends on what it is – oh and the context. I somehow don’t think my dislike of vacuum cleaning would stop me from doing the whole house if a gun was being held to my head. I might even run if there was a fire to run from!

This paper explores an area of task persistence that I’m fascinated with – how mood and ‘stop rules’ influence whether someone stops doing something, or carries on. Stop rules are rules that people apply to whether they persist with a task, or give up – one rule could be ‘as much as can’ or ‘Am I happy with the result of my effort?’, while another could be ‘feel like stopping’ rule, or ‘Am I enjoying doing this?’.
Because our mood can influence whether we are enjoying something or not, if we are feeling a bit disgruntled or low, we’re more likely to stop if we use the latter rule because we’re more likely to feel that it’s not enjoyable to carry on. On the other hand, if we’re feeling quite chirpy, we may feel happy about how well our efforts have turned out, and stop working on the task.

This study by Karsdorp and colleagues, based at the Maastricht University, The Netherlands, manipulates mood and stop rules on task performance. Participants were people with upper limb pain, and were asked to carry out two physical tasks consisting of moving a weighted handle – one with their painful upper limb, and one with their nonpainful lower limb. Just prior to carrying out this task, pariticpants were asked to remember and give a detailed description of a positive or a negative event they had experienced in their life. Their experience was heightened by the interviewer asking for emotion-laden comments and descriptions, and lighting and music were also used to augment emotions. The stop rules were (1) ‘perform the task and ask yourself ‘have I made as many movements as I can?’ If the answer is ‘yes’ then stop, if the answer is ‘no’, then continue. Stop when you are convinced you did as many movements as you possibly could make. There is no right or wrong time to stop.’ (As many as you can rule) or (2) ‘as you perform on the task, ask yourself, ‘Am I enjoying this task?’, if the answer is ‘yes’ then continue. If the answer is ‘no’, then stop.’ Between the upper and lower limb tasks, participants were played the music that was used to heighten their emotional state during the interview section. For the detailed description of the methodology, read the paper itself – it is an elegant design, and well-described.

In addition to these variables, participants also completed a VAS (visual analogue scale) for mood and pain, and several other questionnaires were also included to measure areas such as mood, catastrophising, and pain-related fear.

What happened?
Well, firstly, it didn’t matter whether the task was upper or lower limb (ie painful or nonpainful limb), the results held true for both, and it didn’t matter whether the tasks were carried out in any order – again, the results held true. What was found was that people in a positive mood make more movements than those in a negative mood (now that’s not entirely surprising, if I’m feeling bad I really do NOT want to do the vacuum cleaning!); people who were explicitly asked to ‘do as much as you can’ made more movements than those who were asked to ‘do it as long as you enjoy it’. As well, people with high pain-related fear also performed fewer movements than others, irrespective of mood or stop rule.

What are the points raised by this study? Firstly, mood doesn’t seem to influence stop rule performance, what does influence performance is pain-related fear. Pain intensity doesn’t make a difference to performance (hence why pain reduction as a goal is not one of my priorities as I work to help people return to functional activities); but the type of stop rule itself does have an effect on performance – if I’m told to ‘do as much as I can’, I’ll probably do more than if I’m asked to do something ‘as long as I enjoy it’. This suggests that current goals – or the why am I doing this task? – might play an influential role on how long a person will persevere with a painful task. This might even over-ride the fear of pain in some people, meaning that where people feel they have less option, they may continue with a task even though they are fearful of it. But if a person is feeling low in mood, and persists with a task depending on how they’re feeling emotionally – their performance may suffer.

What does this mean?
Well, it might be an important aspect of how we might frame a goal such as returning to work. We might need to think about whether we ask the person to return to a work as ‘do as much as they can’ or ask them how they’re feeling about their return to work. Cognitive therapists among us might need to consider helping people recognise how transient mood states can be, and help people reframe their goals in the light of setting a target time or number of activities. The transient nature of mood states was highlighted in the discussion section of the paper where the authors indicate that the mood induction effect vanished rapidly – moods returned to baseline very quickly. This could be a confound in the experimental design – and there is a difference between the duration of a low mood arising from depression and that from recalling a sad experience.

What this study does do is highlight the effect that contextual factors like mood and stop rules strongly influence task performance. We may need to keep this in mind as we look at how people we structure activity experiences for people participating in rehabilitation.

Karsdorp, P., Nijst, S., Goossens, M., & Vlaeyen, J. (2009). The role of current mood and stop rules on physical task performance: An experimental investigation in patients with work-related upper extremity pain European Journal of Pain DOI: 10.1016/j.ejpain.2009.07.003

Placebo and social observational learning


ResearchBlogging.org
One of the greatest enigma in health is the human response to placebo. Placebo itself is an inert substance or treatment that has no effect – yet humans can respond with physiological changes as if the substance was active. For years some unscrupulous medical practitioners have used this response in people experiencing chronic pain as evidence that their pain is ‘all in the head’, or that their problem is ‘psychosomatic’, whereas other even less scrupulous snake oil merchants have used this as a way to sell things like crystals, colour therapy and even coloured lotions for the ‘healing’ of pain and other assorted symptoms.

Colloca and Benedetti are two of the most respected researchers into the phenomenon of human response to placebo. They have used a wide range of experimental methodologies to investigate placebo, and this one is yet another to add to their extensive repertoire.

In this study, hoping to investigate the effect of learning through observing someone experience placebo analgesia as compared with first-hand experience and verbal suggestion alone. The premise is that some placebo analgesia is influenced by expectancy, some by conditioning, some by reinforcement – and in this experiment, by social observational learning.

Social observational learning is where an individual watches another person and learns through ‘vicarious learning’.
In this experiment, the participants were asked to sit beside a person who had been trained to simulate the
experimental session. This person ‘always rated as painful the stimuli paired to red light and as non-painful the stimuli paired to green light. In this way, he simulated an analgesic benefit following the presentation of the green light.’ After observing this, the participant underwent his or her own experimental session.

The other two conditions were – one in which the person was conditioned using an electric shock paired with the red light, and were told a ‘sub-threshold’ electric shock would be delivered paired with a green light. An electric shock was never paired with the green light at all, leading to a conditioned response where the green light produced an analgesic effect. As the authors state: ‘It is important to stress that the stimulus intensity was surreptitiously reduced, so that the subjects believed that the green light anticipated analgesic effects’. This is a standard conditioning process used in Colloca and Benedetti’s placebo experiments.

The final condition was one in which the participants were told that the green light would be paired with an analgesic just before the shock was delivered – the subjects were told ‘that a green light would anticipate a stimulus that was made analgesic by delivering a sub-threshold electrical shock on their middle finger. Conversely, a red light would anticipate the deactivation of this electrode and thus a painful stimulation on the dorsum of the hand. Actually, all the stimuli were set to go off at the same time as the light.’

What were the results? Quite startling, actually! The subjects who had observed the analgesic effect in the demonstrator rated the green-stimuli consistently less painful than the red-stimuli. And every single green-stimulus was rated lower than the red. This effect simply from watching someone else apparently receiving an analgesia – when actually nothing was being delivered.

The experiential group, those that went through the conditioning procedure themselves, also reported reduced pain when the electric shock was paired with a green light. And finally those who were given a verbal instruction that they would experience analgesia paired with the green light also reported lower pain, but this dropped off fairly quickly after the initial instruction.

So there you have it – somehow by watching someone else obtain an effect, these participants developed a strong and sustained analgesic effect. What is it they were seeing? We’re not sure yet – but Colloca and Benedetti suggest that empathy has something to do with it, because there was a relationship between empathy and the response as measured on the Empathic Concern subscale of the Interpersonal Reactivity Index, a measure often used to investigate trait empathy. This wasn’t demonstrated for other subscales of the IRI.

What can we learn from this? Well, firstly it’s important to recognise that this is an experimental situation in a lab with volunteers – all female – who may not be like you or me! But findings like this can suggest that when we observe someone else reporting and behaving as if a treatment provides good results, we are likely to have a similar effect, provided of course we’re high in empathy. Similarly, but not quite as strongly, we respond to being conditioned ourselves to experience analgesia through a placebo.

Maybe an experiment like this will see the end of celebrity endorsement of magnetic underlays for the bed?!

Colloca, L., & Benedetti, F. (2009). Placebo analgesia induced by social observational learning Pain DOI: 10.1016/j.pain.2009.01.033
Colloca L, Benedetti FPlacebo analgesia induced by social observational learning, PAIN (2009),
doi:10.1016/j.pain.2009.01.033