neuropathic pain

Cannabis and cannabinoids for persistent pain?


Over the last 12 months New Zealanders have entered into the debate about cannabis and cannabinoids for medical use. In the coming year we’ll hear even more about cannabis as we consider legalising cannabis for recreational use. There is so much rhetoric around the issue, and so much misinformation I thought it high time (see what I did there?!) to write about where I see the research is at for cannabis and cannabinoids for persistent pain.

For the purposes of this blog, I’m going to use the following definitions: Cannabis = the plant; cannabis-based medication = registered extracts (either synthetic or from the plant) in standardised quantities with quality assurance; cannabinoids = substances found in cannabis that may or may not be synthesised into cannabis-based medication.

I’m going to divide this post into two: one part is about cannabis and cannabis-based medication for persistent pain; and the other is about cannabis for recreational purposes.

Recreational use

Cannabis is really popular in New Zealand. Growing up in Gisborne, one of the prime growing regions because of its long, warm summers, cannabis was common. I’ll put my hand on my heart and say I didn’t try it because I was a bit of a nerd and didn’t even try alcohol until I’d left home at 17!

Ministry of Health estimates that eleven percent of adults aged 15 years and over reported using cannabis in the last 12 months (defined here as cannabis users). Cannabis was used by 15% of men and 8.0% of women. Māori adults and adults living in the most deprived areas were more likely to report using cannabis in the last 12 months. Thirty-four percent of cannabis users reported using cannabis at least weekly in the last 12 months. Male cannabis users were more likely to report using cannabis at least weekly in the last 12 months. The NZ Drug Foundation reports that ” In the 2015/16 year, 80% of the adult population reported drinking alcohol once or more – 31% reported drinking at least twice a week.”

The harms from cannabis are real: for vulnerable people, particularly teens with developing brains, the foetus, and those with other mental health problems are more likely to experience adverse effects including psychosis. This risk increases with the greater THC content. The mix of cannabis plus alcohol is nasty… But I’m more concerned about the harms from prohibition.

Prohibition for alcohol didn’t work. Illicit stills, home brewing, fruit-based alcohol concoctions were all readily available during the prohibition era in New Zealand (see this about Hokonui Moonshine). Why would we think prohibition would be effective for cannabis? In fact, the harms from prohibition are this: limited calm and reasoned discussion about adverse effects of cannabis; disproportionate targeting of Maori for possessing cannabis; the use is underground so there is no quality control of the product; gangs use their control of cannabis to threaten purchasers; the real health and addiction problems of cannabis can’t be addressed because it’s illegal while the funding used by police and the justice system could be redirected towards helping the vulnerable. And there are undoubtedly other harms as well.

For my money, I’m quite comfortable with legalising and then controlling the quality of cannabis for sale in New Zealand. With good safeguards around the age required for purchase and redeploying the money currently spent policing and imprisoning people for cannabis crimes to health services, I think we’d do ourselves a great favour. Not quite so happy about commercialising the product because with competition there’s always an increase in efforts to sell more, but with good controls I think it will be far better than our current situation.

Now. Onto cannabis for pain, and cannabis-based medications for persistent pain.

“Pain-related use”

I’ve been reading a LOT of research exploring cannabis and cannabinoids for persistent pain. To limit the extent just a little, I’ve looked only at cannabis and cannabis-based medications for neuropathic pain. This is for a couple of reasons: cancer pain is different from non-cancer pain, and there are often different considerations for cancer pain. Most of the animal research (rats, mice) uses a neuropathic pain model. Neuropathic pain is one of the more difficult persistent pain problems to treat pharmacologically. There’s more, and better quality, research into cannabis, cannabis-based medications and cannabinoids in neuropathic pain than any other pain mechanism. BUT it’s important NOT to extrapolate from findings in rats and mice, and for neuropathic pain, to all forms of pain in humans. That being said, here’s where things are at.

In neuropathic pain, cannabis-based medications are either a combination of THC + CBD or they’re straight THC. CBD has not been studied on its own for pain. This is important because, according to a study I’ve just been involved in, and from listening to people about their experiences of using cannabis for pain, most people think a CBD-based or CBD-heavy drug is “good for pain”. Recently I reviewed a study of cannabis for fibromyalgia (here) where it was only the plant with THC or THC + CBD that gave people pain reduction. There is some thought that CBD augments the effects of THC, but only in certain proportions – there’s a reasonably small window in which THC + CBD is helpful in pain.

The controlled studies, using reasonable methods (and believe me, there are a LOT of studies using poor methods, and even poorer reporting) show that THC or THC + CBD are the only combinations to provide pain reduction.

The question we should be asking (and always ask before adopting a new treatment) is whether this is more effective than what else is on offer, and whether the adverse effects are fewer.

At this stage I have to say the evidence is pretty skinny. Lots of studies, yes, but not well-conducted or reported, and the change in pain intensity is small. So small that the change in pain scores was a reduction of 4mm on a 1 – 100mm visual analogue scale. And the number needed to treat for one person (to achieve a 30% reduction in pain) were 27 (38.5% response to treatment, 33% response to placebo) (Campbell, Stockings & Nielsen, 2019).

Now this finding conflicts with the many people who report using cannabis (not cannabis-based medications). Again, drawing from the study I have been involved in, many of the participants indicated that they found cannabis helpful – although a good proportion also identified that cannabis didn’t actually take the pain away. And this is interesting. Why is it that people say they use cannabis for pain (and pain is the most common reason given for using “medicinal” cannabis in the US (Kosiba, Maisto & Ditre, 2019)?

Drawing from both the study I’ve been involved, and some hunches, here’s what I think might be happening (more research required):

  • Cannabis promotes a sense of euphoria. Now that doesn’t mean feeling super-high, but it does mean feeling better than before you had it. And if you’re experiencing pain that doesn’t go away, feeling good is such a contrast to what you’re feeling most of the time, I wonder if this explains some of the effect. Particularly as it’s the THC or THC + CBD combo that seems to have greatest effect in research.
  • Cannabis often promotes better sleep, and this is one consistent report from the study I’ve been involved in. Disturbed sleep is, as we know, associated with greater pain the following day, and most people with persistent pain report rotten sleep (Simpson, Scott-Sutherland, Gautam, Sethna & Haack, 2018). Maybe one effect of cannabis use is to help people sleep better – but what are the effects of cannabis on sleep architecture in the long run?
  • Using cannabis involves a ritual. A ritual either of baking, or of preparing to smoke weed. Rituals invoke a meaning response (Blease, Annoni & Hutchinson, 2018; Lindenfors, 2019). They prepare us for what is to follow. In time, we anticipate what happens next. In the case of cannabis, inhaled cannabis takes effect within seconds of inhaling, so it becomes a very potent learned expectation. In baked goods, the effect is far slower – but there’s little doubt that inhaling the scent of freshly baked goodies elicits all sorts of yummy expectations, whether the product is cannabis-laced or not! The meaning response (“placebo effect”) is an incredibly powerful product of our own nervous system – and I have no problems attributing at least part of the reported analgesic effect of cannabis to the meaning and expectations people hold towards its use. Add to the expectation some pharmacological feel-good substances, and it’s potent!
  • Cannabis can be used prn whenever the person feels the need. While some people limit their use of cannabis to an evening toke, from our study some people indicated they used cannabis repeatedly through the day and evening. Because it’s not possible to kill yourself with a dose of cannabis, and because the euphoric effects quickly drop (if they’ve even been a significant part of the experience) cannabis use can be a pick-me-up any time. There are good, and not so good effects from this: prn medication use isn’t thought to be helpful because it can promote increased use over time. That doesn’t appear to be the case for cannabis. Again, prn use of any medication is thought to perhaps address distress rather than pain intensity, so it may mean people are less inclined to use active coping than reach for cannabis. I don’t know, because the research hasn’t been carried out. What does seem clear is that because of its rapid onset and relatively mild side effects as compared with opioids or the usual drugs for neuropathic pain, people are more positive about using cannabis as needed rather than these alternative drugs.
  • Cannabis has fewer strongly sedating effects than many other medications for neuropathic pain. By this I do not mean it has no sedating effects (see above!). But participants in the study I’ve been involved in said they could function, they could participate in things that mattered to them while using cannabis, whereas with opioids or other drugs for neuropathic pain, they couldn’t because they felt groggy, spaced out, or just couldn’t think. I think this is really interesting. Maybe it’s worth being able to think straight is more important to our participants than having better pain reduction. The sedating effects of cannabis effects seem to wear off more quickly, particularly for people who use it a lot.
  • Cannabis can reduce anxiety – but so also can it increase anxiety. People living with persistent pain, particularly weird neuropathic pain, live with the uncertainty of when it will flare up, when the “electric shocks” will start up again, wondering if it will settle down or hang around. This doesn’t engender a state of calm! Some forms of cannabis can reduce anxiety (particularly CBD-heavy forms), but THC-high (see what I did again!!) increase anxiety. It’s a mixed bag especially given that establishing the precise chemical consistency of plant material is pretty difficult – particularly by growers in the illegal market of NZ.

Summary – and a bit of science

Writing this blog I’m sure will bring out a heap of pro-cannabis people who will argue that I’m ignoring the “strong evidence” for cannabis for pain relief. Before anyone does – believe me, I’ve read a heap of papers, and to be perfectly honest, I’m alarmed at the state of the research. Not only are many studies failing to identify the pain mechanisms addressed (neuropathic pain is the most commonly studied, but it’s also common to find studies with mixed cohorts); studies are often short – for a chronic, ongoing problem like persistent pain, we need to have studies carried out over 12 months or more, 8 weeks or less is completely insufficient; the outcome measures used are primarily pain intensity using a unidimensional index like a numeric rating scale – come on guys, pain is NOT a unidimensional problem, and surely we’ve learned from opioid trials that pain intensity isn’t the best outcome measure for a long-term problem? What about participation in life? What about disability reduction? What about sleep? What about reduced use of healthcare? Many of the studies are in rats and mice and last time I checked, I’m not a rat or a mouse, and my physiology is a little different; the analysis of studies is often awful with no mention of dropout rates, no responder analysis, no description of adverse effects and tiny, tiny sample sizes. Worse, the small sample sizes exclude people with comorbid problems like depression, anxiety, insomnia, drug and alcohol use (and yet these are characteristics of many people seeking help for persistent pain). Additionally, most studies don’t indicate whether the people taking part in the study are naive to cannabis – people who use cannabis regularly are less likely to be bothered by adverse effects, so studies aren’t describing what may happen in people who are new to the effects of cannabis.

I could go on, but I think there are enough questions about the state of the research into cannabis for pain for us to be pretty cautious about asking medical practitioners (who may not have the time I’ve dedicated to reading the research) to sign their name to a prescription for a cannabis-based treatment, or cannabis itself. Doctors should think carefully before prescribing because, in health, we expect that medical practitioners know what substance they’re prescribing, the effects of that substance, what it should be used for, what harms might come from it, what interactions it might have with other medications, and that the product available has consistent quality-assured content.

As for understanding why people continue to use cannabis for pain – I’m keen to study this in more detail. Why is there such a disparity between what research shows and what people tell us? What might explain this? I’m absolutely not doubting the experience of people who say that cannabis helps – I’m just curious about how this is coming about, because it doesn’t look like it’s purely from the pharmacological effects of the plant.

References

Blease, C., Annoni, M., & Hutchinson, P. (2018). Editors’ Introduction to Special Section on Meaning Response and the Placebo Effect. Perspectives in biology and medicine, 61(3), 349-352.

Campbell, G, Stockings, E, Nielsen, S. (2019). Understanding the evidence for medical cannabis and cannabis-based medicines for the treatment of chronic non-cancer pain. European Archives of Psychiatry and Clinical Neuroscience, 269. pp 135 – 144. https://doi.org/10.1007/s00406-018-0960-9

Kosiba, J, Maisto, S, Ditre, J. (2019). Patient-reported use of medical cannabis for pain, anxiety, and depression symptoms: Systematic review and meta-analysis. Social Science & Medicine, 233, pp 181-192. https://doi.org.10.1016/j.socscimed.2019.06.005

Lindenfors, P. (2019). Divine Placebo: Health and the Evolution of Religion. Human Ecology, 47(2), 157-163.

Simpson, N. S., Scott-Sutherland, J., Gautam, S., Sethna, N., & Haack, M. (2018). Chronic exposure to insufficient sleep alters processes of pain habituation and sensitization. Pain, 159(1), 33-40.

How well do people understand their neuropathic pain?


ResearchBlogging.org
When coming to terms with a chronic pain problem, one of the important steps involves obtaining a diagnosis that fits with both the individual’s personal experience of their pain, and also their knowledge (drawn from what is available in the general population). If the label doesn’t square with their experience, people continue searching until they find something that does.

There has been an enormous wave of excitement about giving people good “pain education”. I’ve always been a bit anxious about the term “education”, because it can so often mean giving an information dump, leaving the person being “educated” with little or no relevant knowledge about their personal concerns – and it’s the individual and unique concerns that influence how a person interprets what is happening, and how they respond. As a result, I prefer “helping people to develop a personal pain formulation” or “reconceptualising” their pain. Putting the pedantics aside, it seems really important for health professionals to not only understand what people with pain already know about their health condition, but also to understand how people interpret what they’re told – if they’re told anything.

In this study, 75 people with neuropathic pain were asked to sort a series of statements about neuropathic pain according to their level of agreement with them. This is known as Q-methodology. The sorted statements are then analysed to identify common features amongst them. Four factors were identified:

  1. Neuropathic pain is a nervous system problem, psychology influences the pain experience and acceptance, and being open to psychological interventions – this group of respondents had tried psychological treatments, their pain was on average about 6 – 7 years.
  2. Neuropathic pain is nerve damage, psychology is irrelevant in pain experience, neutral about psychological treatments – this group of people had not tried psychological treatments, but had tried surgery and medications.
  3. Neuropathic pain is irreparable nerve damage, symptom management is needed, psychological factors play a part in pain perception but psychological treatment is not OK – this group of individuals had pain for an average of 10 years, and they had used breathing, positive thoughts, medications and physical treatments.
  4. Neuropathic pain cause should be identified, psychological influences may play a part, and treatment can include both medical and psychological – this group had pain for an average of 1 -2  years, and they had tried a range of medications, physical methods, yoga, meditation and complementary therapies.

The authors point out several limitations of this study – people were not recruited on the basis of an particular characteristics, there could be a number of recruitment biases, and they were all identified via online recruitment processes, therefore it’s hard to generalise. What it does indicate is that there is no coherent biopsychosocial explanation put forward by participants, they appeared to have received very little explanation about their problem, and this affected their readiness for psychological or self management interventions.

Another interesting point is how many of these participants, across all the four factor groups, described experiencing being given psychosomatic explanations of their pain. The authors write :”Across all accounts, participants’ comments indicated that they had received psychosomatic explanations of their pain and had been distressed and offended, consistent with other studies which use open-ended methods to sample patients’ experiences. (p. 353).” The influence of psychological factors was found to be associated more with adjusting to chronic pain, rather than to developing an integrated model of pain. Factor 1 were the only group to endorse the notion of acceptance, or learning to live with pain – and the groups in Factors 3 and 4 were strongly against the idea that pain could be lived with.

I find this study interesting, not so much in what it has discovered, but rather more in terms of the discussion about psychological factors and medical factors – but nothing on social factors. I find myself wondering again whether we have a biopsychological model of pain, rather than a more complex biopsychosocial model.

That being said, I agree with a point made in the conclusion: people with chronic pain value a coherent explanation for their pain, it helps resolve their worry and enables them to approach their pain differently.  The problem facing people with chronic pain is how to access evidence-based and accessible information about neuropathic (or indeed any type of) pain. Often people find out about neuropathic via biomedical models, and they rarely get exposed to the complexity of a biopsychological model, let alone a biopsychosocial one.

We desperately need to understand the best ways to personalise an explanation for an individual with chronic pain. I think a case formulation approach is the most useful, but I’ve found that many clinicians think this takes “too long” and is “too complex”. I wonder about this. A formulation might take a couple of sessions, but it’s a lot less expensive and has lower risk than surgery.

In light of the very limited range of interventions for people with neuropathic pain, perhaps taking the time to respond to the person’s unique questions about their pain would be time and money well spent.

 

People who have chronic pain are often very reluctant to consider the influence of psychological factors on their pain, reflecting their fear that by accepting this, their pain is being dismissed as “not real”, or not legitimate. This means people may not accept (or indeed be referred for) psychological interventions. Treatment approaches based on a cognitive behavioural approach have good evidence to support them, but they don’t do much good if people are not ready for them, or even referred for them.

 

Martin, S., Daniel, C., & Williams, A. (2014). How do people understand their neuropathic pain? A Q-study PAIN®, 155 (2), 349-355 DOI: 10.1016/j.pain.2013.10.021