This site is intended for health professionals only!

Published on 6 April 2011

Share this story:

Cannabinoids in multiple sclerosis management

teaser

Louise Dunsmure MPharm DipClinPharm MRPharmS(PIP)
Advanced Pharmacist for Neurosciences
Leeds Teaching Hospitals Trust

David Kearney MPharm DipPharmPract
Senior Neurology Pharmacist
University Hospitals of Leicester NHS Trust

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). The immunopathogenesis of MS remains unclear but the clinical manifestations of the disease are caused by a combination of inflammation, damage to myelin sheaths and axon degeneration.1

The incidence and prevalence of MS is increasing each year and the incidence varies worldwide.2 Most patients present with relapsing-remitting MS (RRMS) but 15% of patients present with primary progressive MS.3 Approximately 50% of patients that present with RRMS can subsequently develop secondary progressive (SP) MS during the first ten years of disease.

For all types of MS the aim of treatment is to provide symptomatic relief for the patient, reduce the frequency of relapses, limit the impairment caused by each relapse and prevent disability arising from disease progression. The purpose of this article is to discuss the role of cannabinoids in managing the symptoms of spasticity in patients with MS.

Spasticity in MS
Pain and spasticity are the symptoms most frequently reported by patients with MS.4 Spasticity in patients with MS occurs due to nerve conduction being interrupted by a lesion located in the brain or spinal cord. The patient may develop spasticity at any point of the disease (early or late onset) and the initial symptoms usually involve a combination of muscle stiffness, spasms, pain, weakness and fatigue. Spasticity may affect any muscle group but is most commonly associated with limbs and trunk. It can be focal, affecting only one part of the body, or generalised, affecting many parts. The symptoms may progress over time and the severity of the symptoms can become debilitating.

The management of spasticity in patients with MS requires a combination of non-pharmacological intervention (splints and serial casting) and pharmacological treatments. Initial pharmacological intervention utilises either baclofen or gabapentin but if these treatments are unsuccessful then therapeutic options include tizanidine, diazepam, clonazepam, dantrolene or intrathecal baclofen.5 The administration of botulinum toxin, or intrathecal phenol may provide a method of localised symptomatic control in patients with severe spasticity unresponsive to oral therapies. These options may each have significant adverse effects leading to patient intolerance, may involve invasive procedures, significant costs and are not effective in many patients.

Need for alternative treatment options
Until Sativex (a cannabis-based oromucosal spray) was licensed in the UK in 2010, the therapeutic options available to patients with MS that continued to experience symptoms of severe spasticity despite use of recommended non-pharmacological and pharmacological treatments were either an off-label use of nabilone (oral synthetic cannabinoid) or an unlicensed use of imported Sativex spray. The use of synthetic cannabinoids in the UK was limited due to the lack of evidence of efficacy for the products, the perceived side effect profile of these medicines and the misuse potential of these products.

Role of cannabinoids in the management of symptoms of MS
The therapeutic effects of cannabinoids are mediated through two cannabis receptors (CB1 and CB2). The receptor CB1 is expressed at high concentrations in the dorsal primary afferent spinal-cord regions, which are involved in pain pathways, and in the regions of the central nervous system (CNS) that control diverse neurological functions. The location of the CB1 receptors in the pain pathways suggests that cannabinoids may be effective in pain management and the location of the receptors in the regions that control neurological functions provide targets to manage spasticity.

The cannabis plant, Cannabis sativa, has been utilised by patients and physicians for many years in a range of conditions, including pain, nausea and sleep disturbances.  Anecdotally, despite its use being illegal in the UK, usage is thought to be widespread amongst patients with MS, who utilise it for symptomatic relief.  In a UK based study of patients with MS 43% of 254 respondents claimed to have used cannabis at one time, with 68% of these for relief of their symptoms.6 Usage was higher in those with increasing disability and the main indications were relief of pain and spasms, perhaps highlighting the inadequacy of conventional therapies in this patient group. Of those responders who had not tried cannabis 71% said they would if it were available on prescription.

Cannabis plants contain many pharmacologically active constituents, with the two most widely studied being cannabidiol and delta-9-tetrahydrocannabinol. These are usually present in a 1:1 ratio and are thought to be responsible for the majority of the effects of cannabis plants. Problems involved with patients utilising cannabis plant products directly include the plants and derivatives are currently illegal to possess in the UK, there are large variations in the concentrations of active constituents between different batches and the reliability of obtaining supplies is variable.

Developing evidence for the role of cannabinoids during the last decade
The evidence supporting the use of cannabinoids to manage the spasticity associated with MS has historically been restricted to case reports which describe the changes in a patient’s symptoms following use of illicit cannabis, plant extract cannabinoids or synthetic cannabinoids. During the last ten years there has been research conducted into the role of cannabinoids in the management of MS and this has shaped the current treatment available to MS patients with spasticity.

In 2002, Killestein et al. studied the safety, tolerability and efficacy of orally administered cannabinoids in 16 patients with progressive MS.7  The results of the study are summarised in Table 1 but this small scale study did not demonstrate that extract of Cannabis sativa plant or synthetic cannabinoid reduced spasticity in patients with MS. The findings of this study prompted further research into the therapeutic benefits of cannabinoids in this patient group.

Zajicek et al. (2003) conducted the first randomised, placebo-controlled trial to investigate the effect of cannabinoids on the spasticity associated with MS (cannabinoids in multiple sclerosis (CAMS study)).8  The trial recruited 657 patients with stable MS and muscle spasticity and the results are summarised in Table 1. The authors concluded that the results demonstrated that patients experienced a small treatment effect in the management of spasticity (assessed using Ashworth scale) when receiving cannabinoids compared to placebo. The data suggested that patients in the active treatment group believed that they had experienced an improvement in pain during the study.

These two studies did not demonstrate significant objective improvements in spasticity scores in patients with MS that received oral cannabinoids but case reports do demonstrate that nabilone, an oral synthetic cannabinoid, is effective in managing spasticity in individual patients.9

Licensed in the UK for the management of nausea and vomiting caused by chemotherapeutic agents, Nabilone is a synthetic cannabinoid which is an agonist at CB1 receptors. Nabilone is proposed to have the beneficial effects of cannabinoids in managing nausea, spasticity and pain but the psychotropic side effect profile is reduced through the structure of the molecule. Management of spasticity is an off-label use of nabilone in the UK but neurologists can offer nabilone as a treatment option for patients with MS that have failed to respond to other treatments for spasticity. Until 2010, nabilone was the cannabinoid treatment option available to most neurologists in the UK but the launch of Sativex has provided new treatment options for the management of spasticity.

Sativex was launched in the United Kingdom in 2010 as an add-on treatment for symptom improvement of spasticity due to MS. This is a cannabis-based medicine which contains delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) formulated as an oromucosal spray, in an almost 1:1 ratio that replicates that found in natural cannabis plants.

The efficacy, safety and tolerability of Sativex have been investigated in five Phase III trials which are summarised in Table 2. Four of the trials considered the mean change from baseline in MS spasticity measured on a 0–10 numeric rating scale (NRS). Secondary endpoints included reduction in spasm frequency, physician, carer and subject global impression of change (GIC), timed 10 metre walk and the Barthel Activities of Daily Living Index. Data from the four studies suggests that between 30% and 50% of the patients who received Sativex demonstrated reductions in the NRS score and this was associated with improvement in ability to walk 10 metres and engage in activities of daily living.

The adverse effects of Sativex reported by Ambler et al differed with duration of treatment.10 During the first four weeks of treatment 14% of patients reported dizziness but during the following twelve weeks the adverse effects included headache, somnolence, psychiatric disorders and gastrointestinal disorders.

Potential future uses of cannabinoids in MS
There is ongoing research into further uses of cannabinoids in the management of patients with MS to meet patient needs relating to symptomatic relief and disease modification.

One area of investigation is the potential that cannabinoids have neuroprotective properties. This was raised following secondary observations in the CAMS study.8 A large study (Cannabinoid use in progressive inflammatory brain disease [CUPID]) is due to publish its findings in 2012.13 This study has recruited 493 patients with primary or secondary progressive MS, aged 18 years–65 years, with the ability to walk at least 20m and evidence of disease progression over the previous 12 months.  Patients are randomised to receive either tetrahydrocannabinol (THC) or placebo. The results are eagerly anticipated as patients with these forms of MS currently have little options to halt the progression of their condition.

Cannabinoids have also been studied in relation to other symptoms associated with MS. A subset analysis of the CAMS study showed patients in the active groups had significantly fewer episodes of urinary tract symptoms than those in the placebo group.14

Sativex has been licensed in Canada for the relief of pain associated with MS since 2005. Another cannabinoid, dronabinol, has been shown to provide pain relief to those with pain related to MS. This is a synthetic THC analogue that is currently licensed in the US for the relief of nausea and vomiting, and 
is available as a named patient drug in the UK.

Practical considerations
Although the availability of the licensed product Sativex presents opportunities in the management spasticity unresponsive to other treatments, it also presents a number of potential difficulties to the prescriber, pharmacist and patient.

Product choice/funding
Many hospital trusts and primary care trusts require the preferential use of a licensed product rather that an off-label use of a medicine, therefore many prescribers and pharmacists will be directed towards supplying Sativex rather than nabilone.

Currently a number of NHS Trusts have refused to fund cannabinoid therapy for MS patients and this has led to inconsistencies around availability across the country. In such areas some patients may choose to fund the costs of the medicine themselves through a private prescription.

Storage
Sativex is classed in the United Kingdom as a Schedule 1 Controlled Drug therefore safe custody requirements apply. The unopened spray containers must be refrigerated and the Home Office requires that Sativex should be stored in a locked refrigerator (where available), prior to dispensing. In the absence of a locked refrigerator, Sativex should be kept in a refrigerator out of view to the public and in an adequately secure location.

Patient should be told to store their Sativex in a fridge until in use, after which it may be stored upright, with the cap on, at room temperature for up to six weeks.

Nabilone was reclassified as a Schedule 2 controlled drug in the United Kingdom in 2009 and safe custody requirements apply.

Prescribing
In the UK, full controlled drug prescription requirements apply when prescribing either Sativex or Nabilone.

Trial period of Sativex or Nabilone
Both cannabinoids require a trial period to assess response to treatment and a hospital pharmacist should contribute to this monitoring process.

The trial period for patients prescribed Nabilone is consultant specific but the patient should be reviewed after four weeks to assess efficacy and adverse effects.

Patient should initially receive Sativex for a four week trial period to assess efficacy, highlight potential intolerance and determine their optimal dosing schedule.

After this period those without adequate response, defined in trials as a greater than 20% improvement in spasticity score on patient reported numeric rating scale, and those who experience unacceptable adverse effects should discontinue therapy.

A success rate of approximately 50% would be expected and patients should be aware of this. Those deemed to have adequate response and tolerability would continue therapy.

Dosing regimens and administration
The complicated dosing regimen and administration technique may lead to lack of adherence with the prescribed dosing regimen and a hospital pharmacist can play a key role in monitoring and supporting adherence, and optimising therapy.
Dosing is optimised according to the patient’s response and adverse effects. The appropriate dosing schedule should be determined by the patient during the 14 day initiation phase, up to a maximum of 12 sprays per day. Average daily dosing in trials was found to be 8 sprays.10 During the initiation phase the dosing should be split between morning (from waking till noon) and evening (from 4pm till bedtime), however, once titrated the patient may administer at timings to suit their symptoms and adverse effects.  Even when dosing has been optimised,  dosage requirements may vary according to factors such as level of exertion, concomitant illness.

There should be a 15 minute gap between each spray of Sativex, therefore, patients should be counselled to administer in such a manner rather than all sprays at the same time. The administration site, under the tongue or inside the cheek, should be rotated between each administration to reduce the risk of mucosal irritation.

Each vial of Sativex contains 90 doses and must be primed by administering into a tissue until full doses dispensed.  The noise made by the pump during administration changes when the vial comes to an end. If there is doubt as to whether a full spray has been administered it should be assumed that it has.

Adverse effects
All of these drugs will be associated with adverse effects and the hospital pharmacist must be aware of these adverse effects and be able to advise the patient about how to manage these effects.

Patients experiencing adverse effects may find that adjusting the number of sprays or extending the interval between doses may reduce their occurrence.  Adverse effects are more common upon initiation so to aid tolerability patients should be advised to commence therapy in the evening and that tolerance often develops to adverse effects.

Patients may have concerns regarding ‘getting high’ when taking cannabinoids. They can be reassured that less than 2% of patients in trials reported feelings of euphoria.

Travel
The legal status of cannabinoid containing medications varies between countries. Patients planning on travelling with their medication should consult the relevant authorities in their destination country to determine the requirements for importation of their medication.
It may also be illegal in some countries to drive whilst taking cannabinoids.

Pregnancy and breastfeeding
It is recommended that patients avoid becoming pregnant whilst taking Sativex and for three months after discontinuing. Breastfeeding should also be avoided as significant amounts of cannabinoids are passed into breast milk. There is some evidence that exposing the developing central nervous system to cannabinoids can have long lasting effects.15

Alcohol
Alcohol may enhance the adverse effects of Sativex and patients should be counselled to only ingest moderate amounts. In addition, Sativex is formulated as a 50% ethanol solution so patients should be advised of this if cultural or personal reasons prohibit consumption of alcohol, even in minimal amounts.

Drug interactions
Although both components of Sativex are metabolised via the cytochrome p-450 enzyme system there have been no reports of drug-drug interactions with concomitantly administered drugs that affect or are metabolised via this system.
Synergistic interactions may occur with drugs that have similar adverse effects, e.g. hypnotics, leading to excessive sedative effects.

Conclusions
The availability of a licensed cannabinoid product, Sativex, offers a further option in the management of spasticity related to MS, but also presents a number of challenges to clinicians, pharmacists and patients. l

References
1.    
Compston A. and Coles A. Lancet 2008;372(9648):1502-17
2.    Koch-Henriksen N. and Soelberg Sørensen P.
3.    Lancet Neurology 2010;9(5):520-32.
4.    Leary SM et al. Neurology 2003;60:44–51.
5.    Beard S et al. Health Technol Assess 2003;7(40).
6.    
National Institute for Clinical Excellence. 2003 accessed at www.nice.org.uk/nicemedia/live/10930/29199/29199.pdf
7.    
Chong et al. Mult Scler 2006;12(5) :646-651
8.    
Killestein et al. Neurology 2002;58:1404-07
9.    Zajicek et al. Lancet 2003;362 :1517-26
10.    
Martyn et al. Lancet 1995;345:579
11.    
Ambler et al. Poster 844 presented at 25th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis
12.    
Collin et al. Eur J Neurol 2007;14:290-296
13.    
Notcutt et al. Poster 845 presented at 25th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis http://sites.pcmd.ac.uk/cnrg/cupid.php
14.    
Freeman et al.  Int Urogynecol J Pelvic Floor Dysfunct. 2006;17:636-41
15.    
Campolongo et al.  Int Rev Neurobiol. 
2009;85:117-33



Most read




Latest Issue

Be in the know
Subscribe to Hospital Pharmacy Europe newsletter and magazine
Share this story: