Welsh health minister Mark Drakeford has announced that Wales has become the first UK country to authorize a cannabis-based medicine under its National Health Service. Sativex, a proprietary oral spray cannabinoid medicine that has been licensed in the UK to treat muscle spasms and stiffness in people with Multiple Sclerosis (MS) since 2010, has been approved by the All Wales Medicines Strategy Group (AWMSG), and will be available on prescription to treat MS patients who fail to show any response to other medicines. The active chemical agents of Sativex — Delta-9-tetrahydrocannabinol/cannabidiol — are derived from the cannabis plant.
The All Wales Medicines Strategy Group (AWMSG) is a statutory advisory Welsh Assembly-sponsored public body established under the 1977 National Health Service (NHS) Act, to provide advice on medicines management and prescribing to the Welsh Government’s Minister for Health and Social Services in an effective, efficient, and transparent manner, bringing together NHS clinicians, pharmacists, healthcare professionals, academics, health economists, industry representatives, and patient advocates. AWMSG, acting in a strategic and advisory capacity, is an authoritative and expert channel through which consensus can be reached on the use of medicines within both primary and secondary care.
Now that the AWMSG’s recommendation to approve access to the treatment has been ratified at ministerial level, Wales will become the only place in the UK where people with MS can routinely access the medicine. Mr. Drakeford is cited saying, “I hope this decision will help ease the suffering of some of those who have to live with the reality of MS every day.”
According to the U.K. MS Society there is “a very clear need for new treatments for MS symptoms.” The Society notes that “There are few effective treatments for the symptoms of MS. Most of the current drugs only benefit a minority of people and frequently have adverse side effects… this is especially true of pain control, where few treatments are effective… Available treatments for spasticity… afford partial relief and have unpleasant side effects.”
Sativex is also in development and clinical trials as a treatment for cancer pain and neuropathic pain of various origins, and has been has launched in 11 countries and approved in a further 13.
Earlier this year NICE – the body that decides what treatments should be available on the NHS in England and Wales – rejected the drug in their draft clinical guidelines for MS because it was not deemed ‘cost effective,’ but AWMSG decision overrules the NICE guideline in Wales. However, the MS Society, which contends that the NICE ruling was based on a flawed assessment of Sativex’s cost effectiveness, notes that unless local NHS bodies agree otherwise, persons living in England, Scotland, and Northern Ireland for whom Sativex is indicated an appropriate therapy and will continue to go without, or will need to fund the treatment privately. Health departments in England, Scotland, and Northern Ireland follow a different drug approval system than Wales, and the medicine is still not confirmed for use.
That may be subject to change. According to a report by The Guardian’s Nicholas Watt, U.K. drug minister Norman Baker is advocating liberalized drug laws be introduced to legalize already widespread use of cannabis to relieve symptoms of certain medical conditions, including the side effects of chemotherapy, voicing concerns that “credible people” are being obliged to break the law in order to secure the only substance that can help relieve their condition, Mr. Baker is writing to U.K. health secretary, Jeremy Hunt, to call for a review of the medicinal properties of cannabis.
Watt quotes Mr. Baker saying: “I think it is time to reconsider medicinal properties of cannabis, given what I’ve learned in my role as a minister. I’ve seen more and more evidence that cannabis can provide genuine medical benefits to treat a number of conditions. There is a growing body of research that shows the medical properties of chemical components of cannabis. I am uncomfortable that there are credible people I have met who tell me that cannabis is the only substance that helps relieve their condition but not only are they stopped from accessing it officially but have to break the law to help their health.”
MedIndia‘s Vishnuprasad reports today that the Multiple Sclerosis Trust, which supports more than 40,000 people affected by MS, has welcomed the Welsh decision saying that it will prompt England, Scotland and Northern Ireland to adopt the same approach. The article cites Sally Hughes of theMS society commenting that Sativex should be made available to all eligible people — regardless of where they live, noting: “The MS Society has campaigned for years for this treatment to be made available on the National Health Service. Muscle spasms among MS patients can be painful and distressing — and a treatment that can potentially alleviate these symptoms could be life changing, Sativex has been licensed as safe and effective for people with MS, and for many people it’s their only viable treatment option left. Despite this, NICE has rejected this medicine for use. It means people are either left with the daily battle of painful symptoms, or face financial strain as a result of funding the treatment themselves.”
According to its manufacturer, GW Pharmaceuticals, the way in which cannabinoids such as THC exert their effects on the human body is known as their “mechanism of action,” a mechanism that has recently become clearer with discovery of two cannabinoid receptors CB1 and CB2 together with that of a chemical called “anandamide.” Anandamide is an endogenous ligand, which literally means that it occurs naturally within the body (endogenous) and is a binding agent or “ligand.” The full name of anandamide is arachidonoyl ethanolamide, but it was nicknamed anandamide after the Sanskrit word for bliss “ananda” (a perhaps unfortunate association as regards prudish ideological objection to any medicine based on cannabis). Anandamide’s effect is through inhibiting cyclic AMP (part of the cellular energy generation process), through G-protein coupling in target cells, which cluster in areas of the central nervous system that mediate pain, memory, and other key functions.
GW Pharmaceuticals reports that preliminary tests of pharmacology and behavioral activity support the similarity of anandamide to THCiv. Both anandamide and THC bind weakly to the cannabinoid type one (CB1) receptors, which are found in the brain and are called partial agonists. In contrast, cannabidiol (CBD) has little activity at CB1 but greater activity at the cannabinoid type 2 receptors (CB2) that are mostly located in the periphery, in lymphoid tissues. CB1 receptor distribution and THC binding affinity at CB1 differ between humans and rodents, which underscores the importance of conducting human clinical trials. Both THC and CBD are neuroprotective antioxidants that have been shown to inhibit NMDA-mediated excitotoxicity under conditions of traumatic head injury, stroke and degenerative brain diseases.
GW says the discovery of the endocannabinoid system has provided new insights into a neuromodulatory scheme that may provide better explanations of, and treatments for, a wide variety of previously poorly treatable, often painful disorders, and it has recently been demonstrated that CBD also stimulates vanilloid pain receptors (VR1), inhibits uptake of the anandamide, and weakly inhibits its breakdown. These new findings have important implications in elucidating the pain-relieving, anti-inflammatory, and immunodulatory effects of CBD, and that combining THC, CBD and essential oils in cannabis-based medicinal extracts may produce a therapeutic preparation whose benefits are greater than the sum of its parts.
The company notes that neuropathic pain is a chronic, debilitating and widespread condition with an estimated prevalence of one per cent of the general population. It arises as a consequence of damage to or dysfunction in the nervous system, either peripheral, central or both, and is usually accompanied by unpleasant burning or shooting sensations, or extreme sensitivity to touch.
Neuropathic pain may be triggered by a variety of diseases and conditions, but the mechanism that establishes and maintains neuropathic pain is specific to the characteristics of the damage and/or dysfunction of the nervous system, and is not necessarily related to the triggering disease. The list of conditions with which neuropathic pain can be associated include MS, stroke, cancer, spinal cord injury, physical trauma and peripheral neuropathy resulting from diabetes or other causes. It can also occur in patients who have previously suffered from shingles, a condition known as post-herpetic neuralgia.
Neuropathic pain is also one of the most difficult types of chronic pain to treat, and relief is often unsatisfactory or short-term. OTC and even strong opioid narcotic painkillers tend to have little helpful effect, and plenty of unhelpful ones. Because treatment options are so limited, doctors often prescribe a combination of therapies in an attempt to relieve symptoms using available therapies come from the drug classes of tricyclic and related antidepressants, antiepileptic agents and opioids. Currently in the UK, amitriptyline is prescribed most frequently for neuropathic pain, although it is unlicensed in this indication. The tricyclic Nortriptyline is also sometimes used, with reportedly mixed results.
Sativex is approved in Canada for the treatment for central neuropathic pain due to MS, and the drug has also been used in a number of Phase II and III clinical trials in various models of peripheral neuropathic pain, from which a body of positive data has been generated.
GW observes that ninety percent of people with multiple sclerosis (MS) develop lower urinary tract symptoms after 10 years of disease activity, and says the company has completed two trials of Sativex in treating bladder dysfunction in people with MS.
They report that the first study incorporated 135 patients with advanced MS who were experiencing bladder dysfunction (“Detrusor Overactivity”) that was not responding adequately to currently available treatment. In the trial, Sativex achieved statistically significant improvements in a range of bladder symptoms, including nocturia (p= 0.01), daytime frequency (p=0.044), frequency per 24 hours (p=0.001), bladder symptom severity (p=0.001). A significant effect was also seen in the patient’s global impression of change (p=0.005). There was also a strong trend in favor of Sativex in urgency (p=0.07). There was no significant effect on incontinence, the primary endpoint of the study. The adverse event data showed the medicine to be generally well tolerated.
Professor Clare Fowler, Professor of Uro-Neurology at the Institute of Neurology, UCL and Consultant in Uro-Neurology, National Hospital for Neurology & Neurosurgery, is cited by GW commenting: “This study demonstrates that in patients with MS who have exhausted other pharmacological treatments, Sativex improved some of their most troublesome symptoms of bladder dysfunction. The impact that Sativex had, particularly on frequency and nocturia in these patients was of significant benefit for them and was maintained in long-term use. The results suggest that Sativex will have a useful place in the management of these distressing problems.”
A 2011 study published in the Multiple Sclerosis Journal entitled “A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex (nabiximols)” (2012 Feb;18(2):219-28. doi: 10.1177/1352458511419700) by W. Notcutt, R. Langford, P. Davies, S. Ratcliffe, and R. Potts of the James Paget University Hospital Pain Management Department at Gorleston on Sea, UK evaluated the maintenance of efficacy of Sativex in subjects who had gained long-term symptomatic relief of spasticity in multiple sclerosis (MS), and to assess the impact of sudden medicine withdrawal.
The researchers report that the primary outcome of time to treatment failure was significantly in favor of Sativex (p = 0.013). Secondary endpoints showed significant changes in the Carer and Subject’s Global Impression of Change scales in favor of Sativex, and conclude that maintenance of Sativex efficacy in long-term symptomatic improvement of spasticity to a group of subjects with MS has been confirmed using this study design.
U.K. MS Society
U.K. Multiple Sclerosis Trust
Multiple Sclerosis Journal
National Assembly for Wales
National Assembly for Wales