Cannabis sativa, one of three species of the cannabis plant, has been used for medical purposes, including relief of pain, for thousands of years. The isolation of the principal psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol (THC), in the 1960s by Mechoulam and Gaoni sparked a search for its mechanism of action which led to the discovery of two cannabinoid receptors, the cannabinoid1 receptor (CB1) and cannabinoid2 receptor (CB2).
Endogenous ligands (endocannabinoids) which are produced by the body and exert their effects upon binding to these cannabinoid receptors were also discovered, the two best characterised being anandamide and 2-arachidonyl glycerol. The receptors, endocannabinoids, transport proteins and enzymes that synthesise or degrade the endocannabinoids and together they comprise the body’s endocannabinoid system.
A large body of pre-clinical and clinical research indicates that this lipid signalling system modulates a broad range of physiological processes and behaviours including, but not limited to, pain, mood, appetite, emesis, neuronal activity, memory, immunity, cell development and cell fate, and the cardiovascular system.
In particular, the analgesic effects of cannabinoids and endocannabinoid signalling have received a lot of attention over the past 30 years, with thousands of peer-reviewed publications reporting analgesic effects in pre-clinical and clinical studies and describing the sites and mechanisms of action. The impact of this research has gradually been seen in clinical practice, with the introduction of the Δ9-THC/cannabidiol (CBD) buccal spray nabiximols (Sativex) for the adjunctive treatment of neuropathic pain in multiple sclerosis patients and patients with severe cancer pain, initially in Canada and then in many other countries around the world (including Ireland for spasticity in multiple sclerosis). In addition, many US states and countries around the world have relaxed their laws to allow patients to use cannabis or cannabinoids for conditions including chronic pain.
<h3><strong>Compassion </strong></h3>
In February 2017, Minister for Health Simon Harris announced that he had decided to establish a compassionate access programme for cannabis-based treatments in Ireland. The announcement followed the publication of a report from the Health Products Regulatory Authority (HPRA) entitled: <em>Cannabis for Medical Use – A Scientific Review</em>. The Minister requested the HPRA report in November 2016 in order to seek expert scientific advice on the use of cannabis for medical purposes.
The HPRA report advised that, if a policy decision was taken to permit cannabis under an access programme, it should be for the treatment of patients with spasticity associated with multiple sclerosis resistant to all standard therapies and interventions whilst under expert medical supervision; intractable nausea and vomiting associated with chemotherapy, despite the use of standard anti-emetic regimes whilst under expert medical supervision; and severe, refractory (treatment-resistant) epilepsy that has failed to respond to standard anticonvulsant medications whilst under expert medical supervision.
The report also advised that patients accessing cannabis through the programme should be under the care of a medical consultant and that medical information and utilisation data should be kept on a central register. Overall, the document is a very well-researched, well-written and important contribution to the debate on medical cannabis and cannabinoids and the HPRA should be commended for preparing such a thorough report at relatively short notice.
<h3><strong>Pain </strong></h3>
Interestingly and somewhat controversially, the report recommended against the use of medical cannabis for the treatment of chronic pain. This recommendation was made despite an acknowledgement within the report that chronic pain is the most researched indication for cannabinoids and despite the fact that the majority of clinical studies, meta-analyses and systematic reviews cited in the report conclude that cannabis or individual cannabinoids afford moderate to substantial benefit to chronic pain patients.
Indeed, three of the most thorough and exhaustive scientific reviews to have been published on the subject in recent years all concluded that there is strong, high-quality evidence of a substantial or conclusive nature that medical cannabis or cannabinoids are efficacious in chronic pain in adults (Hill, 2015; The National Academies of Sciences, 2017; Barnes & Barnes (UK Barnes Report), 2016). Chronic pain conditions that were particularly responsive to cannabinoids include, but are not limited to, neuropathic pain and cancer pain.
The report was critical of some of the clinical studies of medical cannabis or cannabinoids in chronic pain, citing a moderate risk of bias in many of the studies and a paucity of long-term studies. It is well known, however, that clinical trials of analgesic medications in general carry a risk of bias, given the difficulties that the inherent psychoactivity of many classes of analgesic pose for study blinding. Certainly more long-term, large clinical studies of medical cannabis and cannabinoids would be welcome, but this is not a limitation that is unique to chronic pain (or even cannabinoids) and in fact the evidence-base for efficacy of cannabis and cannabinoids for chronic pain is at present significantly larger and stronger than that for epilepsy, a clinical indication supported within the report.
<h3><strong>Trials </strong></h3>
There are at least 27 randomised controlled trials of cannabinoids in chronic pain, the majority of which support efficacy. Certainly there is a strong case for recommending cannabinoids for epilepsy and I am supportive of this, on the basis of very positive anecdotal reports and patient and caregiver testimonies on efficacy, particularly for cannabidiol (CBD) in childhood epilepsy conditions such as Dravet syndrome and Lennox-Gastaut syndrome. Such conditions represent a major unmet clinical need. But so, too, does chronic pain.
However, the report stated of chronic pain: “The HPRA does not consider that there is an unmet medical need as a large number of authorised medicines and other treatments are available to treat the many factors involved in chronic pain.” The second part of this sentence is of course correct – a large number of authorised analgesics and non-pharmacological treatments are currently available to manage chronic pain.
But the striking fact and reality is that despite the availability of these treatments, 13-to-35 per cent of the population still suffer from chronic pain (Breivik <em>et al</em>, 2006; Raftery<em> et al</em>, 2011), at a cost of €5.34 billion per year to the Irish economy (2.86 per cent of GDP; Raftery <em>et al</em>, 2012) and, in the largest study ever to look at the prevalence and impact of chronic pain in Europe (46,394 patients), 40 per cent of patients reported that the management of their pain was inadequate (Breivik <em>et al</em>, 2006).
Moreover, in addition to their lack of efficacy in a significant number of patients, all of the currently available analgesics are associated with significant adverse effects, particularly during chronic/repeated administration. These include constipation, respiratory depression and dependency on opioids, gastrointestinal ulceration with NSAIDs, and cognitive effects with gabapentinoids, anticonvulsants and tricyclic antidepressants.
Other interventions such as spinal cord stimulation, psychological therapy and physiotherapy, while effective as part of a multidisciplinary treatment plan, can be very difficult and costly for many patients to access within the Irish healthcare system. Thus, chronic pain represents a very significant unmet clinical need, particularly conditions such as low back pain, neuropathic pain, fibromyalgia, post-surgical pain, arthritic pain and severe cancer pain, and there is no basis for citing the absence of unmet clinical need as a reason for not recommending medical cannabis or cannabinoids for treatment of chronic pain.
<h3><strong>Reasons </strong></h3>
There are four reasons cited by the report for not supporting the inclusion of chronic pain as a specified medical indication for medical cannabis and cannabinoids.
The report stated that the causes of chronic pain are diverse and a suitable patient population or clinical indication for treatment with cannabis cannot be defined, due to the complexity and variety of chronic pain syndromes.
The physical, emotional, social, spiritual and other subjective factors that inform the individual pain experience, makes it difficult for a doctor to objectively assess the effectiveness of treatment, the report stated.
The report added that there are a large number of authorised medicines that are of proven effectiveness and other non-pharmacological treatments available to treat the many factors involved in chronic pain.
The report further stated that chronic pain is common and the potential use of cannabis-based medicines by a large number of patients, raises concerns about misuse and diversion into the wider community.
I understand these concerns and I can appreciate that chronic pain, with its complexity and high prevalence, presents a challenge for regulatory authorities such as the HPRA when deliberating over medical cannabis and cannabinoids.
However, I think there is value in looking at and debating these four reasons in more detail.
Regarding the first reason, the causes of chronic pain can be diverse, but we now know from the last 25 years of research into the neurobiology and pathophysiology of chronic pain that peripheral and central sensitisation are the neurobiological mechanisms underlying most types of chronic pain and these mechanisms are reduced by cannabinoids. Moreover, some clinical studies have actually shown efficacy of cannabis or cannabinoids in specific chronic pain indications or syndromes (for example, specific types of neuropathic pain, cancer pain and others).
Furthermore, the THC/CBD oromucosal spray nabiximols (Sativex) is licenced in Canada for adjunctive treatment of neuropathic pain in multiple sclerosis, not just spasticity, and also for severe cancer pain. Many other countries around the world, including a number of European countries and a majority of US states over the past five years, have now authorised medical cannabis for chronic pain. Moreover, the current evidence base in support of efficacy of cannabinoids in chronic pain is without doubt stronger for chronic pain than for some of the other indications recommended within the report.
Regarding point two, it is certainly the case that many factors can influence the individual pain experience, as is true for many disorders (including the three indications recommended within the report). However, a highly trained pain specialist or consultant would be able to assess the effectiveness of a particular treatment. If that were not the case, and we could not have confidence in the ability of our medical experts to objectively assess the effectiveness of treatment, then it would not be possible to justify prescribing any pain medications to chronic pain patients.
Regarding the third cited reason, the fact that 40 per cent of 46,394 chronic pain patients in the landmark <em>Pain in Europe</em> study reported that the management of their pain was inadequate (Breivik <em>et al</em>, 2006), coupled with the significant adverse side-effects of currently available analgesics, difficulty in accessing non-pharmacological treatments, and the epidemic scale of the chronic pain problem (one-in-five people in European countries, including Ireland), means that chronic pain remains a major unmet clinical need.
Finally, regarding point four, surely the fact that chronic pain is so prevalent is all the more reason to try and do what we can to make new treatments such as cannabinoids with proven efficacy and fewer serious adverse effects available to patients. The concerns about misuse and diversion into the wider community, while understandable, are not unique to cannabis/cannabinoids – they also apply to opioids which have been mainstays in pain treatment for decades. In fact, cannabis has significantly less abuse potential than many opioids and significantly less risk of overdose. Moreover, these concerns could be mitigated to a large degree if the authorisation stipulated that only consultants could prescribe cannabis medicines for chronic pain (as the report recommends for multiple sclerosis, epilepsy and chemotherapy-induced nausea).
<h3><strong>Further research</strong></h3>
As we continue down the path towards authorisation of medical cannabis, we should ensure that the concept of cannabis as medicine is kept separate from its recreational use, and take measures to ensure that use of cannabis among adolescents in particular does not increase – a time when the brain is still developing and more vulnerable. We should also ensure that if or when cannabis and cannabinoids are authorised for medical use in Ireland, we have proper regulation and testing in place to ensure their standardisation in terms of precise composition and THC content given the significant variability in plant strains, and testing for impurities and pesticides, so that patients and doctors can feel secure in what they are taking or prescribing.
Importantly, the report was very supportive of further research within Ireland and internationally on medical cannabis and cannabinoids, including for chronic pain, and this support is very welcome. However, if cannabinoid-based medication is not authorised for chronic pain in Ireland then there will be no Irish pain patients taking it and that will remove a very large and important source of potential data for Irish researchers. In a recently published national survey, over half of Irish GPs supported the legalisation of cannabis for medical use (58.6 per cent), with over 60 per cent agreeing that cannabis can have a role in palliative care, pain management and multiple sclerosis (Crowley <em>et al</em>, 2017).
Over the past 12 years at NUI Galway, we have established a very active research group within our Centre for Pain Research and Galway Neuroscience Centre with a focus on cannabinoids and the endocannabinoid system. In work funded from a variety of peer-reviewed grant sources including Science Foundation Ireland, the Health Research Board, the Irish Research Council, the International Association for the Study of Pain and others, we have published 50 peer-reviewed scientific publications demonstrating a key role for the endocannabinoid system in stress-induced modulation of pain, descending control of pain, cognitive and affective aspects of pain, and neuroimmune signalling and its relevance to pain, affective disorders and neurodegenerative disease.
Continued support of such research into cannabinoids and the endocannabinoid system alongside the careful, controlled and regulated introduction of medical cannabis in Ireland for chronic pain will be key to ensuring that we move forward in an informed manner and can lead internationally in this area.
<strong>References: </strong>
Barnes, Michael P and Jennifer C Barnes. The Evidence For Medical Use. 2016. Web. 10 Nov. 2016.
Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D (2006). Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. <em>European Journal of Pain</em>, 10(4): 287-333.
Crowley, D, Collins, C, Delargy, I, Laird, E and Van Hout, M C (2017). Irish general practitioner attitudes toward decriminalisation and medical use of cannabis: results from a national survey. <em>Harm Reduct J</em>, 14: 4.
HPRA Report, Cannabis for Medical Use – A Scientific Review. (2017). http://health.gov.ie/wp-content/uploads/2017/02/HPRA-Report-FINAL.pdf.
Hill, K P, (2015). Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: a clinical review. <em>JAMA</em>, 313(24), pp.2474-2483.
Raftery MN, Sarma K, Murphy AW, De La Harpe D, Normand C and McGuire BE (2011). Chronic pain in the Republic of Ireland – community prevalence, psychosocial profile and predictors of pain-related disability: Results from the Prevalence, Impact and Cost of Chronic Pain (PRIME) study, part 1. Pain, 152: 1096-103.
Raftery MN, Ryan P, Normand C, Murphy AW, de la Harpe D, McGuire BE (2012). 4. The economic cost of chronic noncancer pain in Ireland: results from the PRIME study, part 2. <em> Journal of Pain.</em> 13(2):139-45.
The National Academies of Sciences, Engineering and Medicine. The Health Effects Of Cannabis And Cannabinoids: The Current State Of Evidence And Recommendations For Research. National Academies Press, 2017. Web. 25 Jan. 2017.
