Cns drugs 2011;

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Role of Cannabinoids in Multiple SclerosisJohn P. Zajicek1 and Vicentiu I. Apostu2 1 Clinical Neurology Research Group, Peninsula College of Medicine and Dentistry, Plymouth, UK2 Clinical Neurology Research Group, Peninsula Medical School, Plymouth, UK Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Cannabis and Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1881.1 Cannabinoid Receptors and Endocannabinoids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 Neuroprotection and Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 Medical Cannabis Use and Approved Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 Route of Administration and Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 Multiple Sclerosis (MS) Clinical Course and Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 Evidence for a Therapeutic Role of Cannabinoids in Treating MS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1903.1 Anecdote and Postal Surveys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1913.2.1 Spasticity and Spasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1913.2.2 Bladder Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1943.2.3 Tremor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1943.2.4 Nystagmus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1953.2.5 Pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1953.2.6 Sleep. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 Adverse Effects of Cannabinoid Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 Although extracts from the cannabis plant have been used medicinally for thousands of years, it is only within the last 2 decades that our understandingof cannabinoid physiology and the provision of evidence for therapeuticbenefit of cannabinoids has begun to accumulate. This review provides abackground to advances in our understanding of cannabinoid receptors andthe endocannabinoid system, and then considers how cannabinoids may helpin the management of multiple sclerosis (MS).
The relative paucity of treatments for MS-related symptoms has led to experimentation by patients with MS in a number of areas including the useof cannabis extracts. An increasing amount of evidence is now emerging toconfirm anecdotal reports of symptomatic improvement, particularly formuscle stiffness and spasms, neuropathic pain and sleep and bladder dis-turbance, in patients with MS treated with cannabinoids. Trials evaluating arole in treating other symptoms such as tremor and nystagmus have notdemonstrated any beneficial effects of cannabinoids. Safety profiles of can-nabinoids seem acceptable, although a slow prolonged period of titrationimproves tolerability. No serious safety concerns have emerged.
Methodological issues in trial design and treatment delivery are now being addressed. In addition, recent experimental evidence is beginning to suggestan effect of cannabinoids on more fundamental processes important in MS,with evidence of anti-inflammation, encouragement of remyelination andneuroprotection. Trials are currently under way to test whether cannabinoidsmay have a longer term role in reducing disability and progression in MS, inaddition to symptom amelioration, where indications are being established.
G protein-coupled receptor 55[10] (GPR-55), tran-sient receptor potential vanniloid-1[11] (TRPV-1) Cannabis sativa is a flowering plant thought to and adenosine receptors.[12] CBRs are negatively have originated in the mountainous regions of the coupled to adenylate cyclase and positively cou- northwest Himalayas. It has long been used for pled to mitogen-activated protein (MAP) kinases.
fibre in rope and cloth (hemp), for medicinal pur- CB1 receptors are coupled through Gi/o proteins poses and as a recreational drug. Cannabinoids, to potassium and calcium channels and thereby terpenoids, flavonoids, carotenoids and other com- affect other neurotransmitter systems including pounds are secreted by glandular trichomes, which are most numerous in the flowers of female plants.[1] The CB1 receptor is the most common G protein- Over 60 separate cannabinoids have been identified coupled receptor within the CNS, and autoradio- from the original plant. These are low-molecular- graphic studies demonstrated high CB1 receptor weight lipophillic compounds, with a varying de- densities in the cerebellum, basal ganglia, hippo- gree of affinity at specific cannabinoid receptors campus and cerebral cortex.[14] The CB2 receptor is (CBRs). Wood, Spivey and Easterfield[2] isolated most abundant on cells of the immune system.[15] the first cannabinoid, cannabinol, in 1896, in the The discovery of endogenous CBRs led to the Agricultural Chemistry Laboratory in Cambridge, identification of endogenous cannabinoid ligands UK and Cahn[2] worked out its chemical structure or endocannabinoids, the most common of which in the 1930s. Cannabinol was later synthesized in are anandamide[16] and 2-arachidonoylglycerol.[17,18] 1940 by both Adams et al. and Ghosh et al.[3-5] Rather than being stored in presynaptic vesicles The major psychoactive cannabinoid, delta-9- as are conventional neurotransmitters, endocanna- tetrahydrocannabinol (D9-THC) or dronabinol, binoids are rapidly synthesized de novo from was isolated and characterized in 1964 by the team postsynaptic membrane-lipid precursors, act on of Raphael Mechoulam[6] in Israel. In addition to presynaptic CBRs and are then degraded or trans- D9-THC, most cannabis extracts contain cannabi- ported. There is therefore increasing interest in com- pounds that alter endogenous endocannabinoidtone, by reducing degradation – particularly using inhibitors of fatty-acid amide hydrolase.[19] This may provide a more specific method of adjustingCBR activity in those receptors most active, rather The pharmacology of cannabinoids is becom- than introducing exogenous cannabinoids that ing increasingly complex. Although most canna- may have a much wider range of activities.
binoid effects appear to be mediated throughG protein-coupled CBRs, a number of effects that are not related to binding to CBRs are beingdescribed. Two types of CBR have been identi- Genetic knockout animal studies have dem- fied, CB1 and CB2. CB1 was cloned in 1990[8] and onstrated roles for the cannabinoid system in CB2 was cloned in 1993.[9] Cannabinoids may a variety of normal responses, including mem- also show activity at other receptors including ory, learning,[20,21] emotion,[22] locomotion,[22,23] ª 2011 Adis Data Information BV. All rights reserved.
Role of Cannabinoids in Multiple Sclerosis appetite,[24] cardiovascular responses[23] and no- dronabinol (in the US) are licensed for treating ciception.[22] Neuroprotective effects have been nausea related to cancer chemotherapy, and avail- demonstrated in animal models of cranial in- ability on a named-patient basis or for off-license jury[25,26] and experimental allergic encephalo- indications varies across Europe. Nabiximols myelitis (EAE).[26,27] CB1 receptor knockout mice (SativexÒ) is licensed for treating MS symptoms demonstrate considerably more neuronal damage in Canada, and is available in parts of Europe on in EAE inflammation,[28] and CB2 receptor knock- a named-patient basis. Nabiximols was approved out mice are associated with increased excito- in UK in 2010 for treating spasticity due to MS toxicity in models of Huntington’s disease.[29] Cannabinoids may be helpful by reducing gluta-mate release[30] and calcium flux (reducing exci- totoxicity),[31,32] as well as being antioxidants,[30] thereby reducing free radical damage. In addi-tion, of significance for the disease process in Cannabinoids are notoriously difficult to work multiple sclerosis (MS), cannabinoids may re- with in the laboratory. They are highly lipophillic, duce oligodendrocyte apoptosis,[33] ameliorate the and extracts are therefore generally dissolved either inflammatory response and increase remyelina- in alcohol or some form of lipid. When ingested tion.[34] It is interesting to note that the market orally, they undergo first-pass metabolism in the liver, and there is considerable interindividual dose nabant) was largely due to its association with variation. Serum levels bear little correlation with CNS side effects, but a case of MS has been re- activity. Cannabinoids are then stored in fat, and since they may build up over time, cannabinoidscan be detected in the urine some weeks after dis-continuation. This probably explains why with- drawal responses are not a major issue.[44,45] These factors mean that it is impossible to pre- dict what dose may benefit any single person when mainly for recreational purposes, is around administered orally. Some people will experience 162 million.[36] Word-of-mouth reporting of bene- adverse events with as little as 2.5 mg of dronabinol ficial effects of smoked cannabis on MS symptoms – at night, whereas others may not notice any effects including pain, urinary disturbance, tremor and at 15 mg twice daily. These issues have led to a spasticity – led to newspaper reports and anec- search for alternative routes of administration, dotal accounts being published in the medical ranging from sublingual spray (nabiximols) to sup- literature. This caused widespread unlicensed and positories. Despite these attempts, the issue of in- often illegal use of cannabinoids in MS. A num- terindividual dose variation has not been adequately ber of varying formulations and routes of ad- investigated, and to date all preparations require ministration, ranging from use of the smoked a dose-titration phase. Although, in theory, sub- cannabis leaf to oral preparations including can- lingual preparations may be suitable for acute pain, nabis oil, extracted cannabinoids and synthetic in MS most pain tends to be more chronic, and cannabinoids (such as nabilone), have been used.
therefore single oral doses at night may both avoid The UK MS society estimates that 1–4% of the side effects and improve sleep, and work best to MS population in the UK are illegally using can- provide amelioration of chronic problems.
nabis for symptom relief (around 2750 patients).[37]This figure is thought to be higher in Canada 2. Multiple Sclerosis (MS) Clinical Course There is no cannabinoid preparation that is licensed for treating MS across Europe or North MS is the most common cause of neurological America. Nabilone (in the US and Canada) and disability in young people, with an average age of ª 2011 Adis Data Information BV. All rights reserved.
onset around 30 years, and a prevalence of about date or language limits, for articles in order to 120/100 000 in most of Northern Europe and locate studies of cannabis and cannabinoid use in North America.[37] It most commonly starts as a MS. Keywords used in the search were: ‘multiple neurological event explicable by inflammation in sclerosis’, ‘cannabis’, ‘marijuana’, ‘cannabinoids’, the CNS. At the stage of a single episode, the ‘cannabinol’, ‘dronabinol’, ‘D9-THC’, ‘cannabi- disease is termed a ‘clinically isolated syndrome’.
diol’, ‘CannadorÒ’, ‘SativexÒ’, ‘trial’, ‘cannabinoid Evidence for further inflammation, demonstrat- receptors’, ‘endocannabinoids’, ‘pharmacokinetics ed either by MRI or another clinical event, con- of cannabinoids’, ‘neuroprotection’, ‘inflammation’, stitutes a diagnosis of relapsing-remitting MS ‘spasticity’, ‘spasms’, ‘treatment’, ‘pharmaco- (RRMS).[46] Around 85% of MS starts with these therapy’, ‘baclofen’, ‘tizanidine’, ‘benzodiazepines’, clinical episodes, occurring in more females than ‘dantrolene’, ‘bladder’, ‘nocturia’, ‘continence’, ‘in- males with a ratio about 3 : 1. The remaining 15% continence’, ‘antimuscarinics’, ‘oxybutinin’, ‘ tolter- of MS often starts a little later in life, occurs odine’, ‘desmopressin’, ‘tremor’, ‘nystagmus’, ‘pain’, equally in females and males, has a progressive ‘neuropathic pain’, ‘antiepileptics’, ‘antidepressants’, course from the outset and is termed primary ‘sleep’, ‘cognition’ and ‘adverse effects’. In NHS progressive disease. In patients who are initially Athens (a secure login that gives NHS professionals diagnosed with RRMS, the majority will change in England access to professional academic re- to a more progressive clinical course after a vari- sources), we used the advanced search facility and able time period, and this type of MS is termed Thesaurus mapping mainly on the EMBASE and secondary progressive disease. There is an in- MEDLINE databases. The searches have been creasing array of treatments for RRMS, almost enriched further by checking the references of all based on the assumption that MS is a primary the various articles uncovered during the initial autoimmune disease, and these treatments are work-up. We included only relevant articles pub- therefore immunomodulatory in some way.
Despite increasing optimism over the avail- ability of apparent disease-modifying treatments for RRMS, the majority of people with MS tendto accumulate symptoms over time, the most The relative paucity of treatments in MS, common being fatigue. Other prevalent symp- particularly for symptoms and progressive dis- toms include muscle stiffness and spasticity, poor ease, has led to a wide variety of treatments being mobility, pain, memory problems, tremor and used by people with MS, often without evidence balance trouble, urinary disturbance and sexual for benefit beyond anecdote. Unfortunately, when dysfunction. A major problem in determining such treatments are tested they often prove far whether any drug has efficacy in patients in MS from efficacious. Whilst such desperation is un- has been the lack of adequate means of measuring derstandable from the perspective of the person its associated symptoms beyond overly simplistic with MS, it often raises unfulfilled hopes and can visual analogue scales. In addition, the potential lead to unscrupulous exploitation. Nonetheless, for unblinding in randomized controlled trials it is incumbent on researchers to acquire as much (RCTs) in which patients are treated with can- information as possible where RCT evidence is nabinoids has also been a major problem in de- termining the efficacy of these agents.
There has been some evidence provided from postal surveys on the use of cannabinoids in MS.
One surveyed 53 UK and 59 US MS patients who had used cannabis.[47] More than 70% of patientsfound cannabis to reduce spasticity, pain, sensory We performed a search of the PubMed data- symptoms, tremor, anxiety and depression, and base and also of the NHS Evidence healthcare 60–70% reported cannabis to reduce weight loss, fatigue, double vision and sexual dysfunction.
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Role of Cannabinoids in Multiple Sclerosis Fewer than 60% reported reduction of bladder Table I summarizes the key efficacy data for and bowel dysfunction, vision dimness, walking cannabinoids in the treatment of MS-related disability, impaired balance and memory loss.
spasticity. The CAMS (Cannabinoids in MS) study is the largest parallel-group RCT to date to among 205 people with MS reported 34 using examine whether cannabinoids are beneficial in cannabis for medical reasons.[38] Cannabis use the treatment of MS symptoms.[56] In this study, was strongly correlated with male sex (p = 0.03), 667 patients from 33 centres in the UK were use of tobacco (p < 0.001) and recreational use of randomized to either synthetic dronabinol in cannabis (p = 0.009). The self-reported effects sesame oil (MarinolÒ), a whole-plant extract were relief of stress (moderate/complete relief vs of cannabis (CannadorÒ, containing D9-THC no/mild relief: 20 patients : 1 patient), sleep dis- 2.5 mg and cannabidiol 1.25 mg per capsule) or turbance (17 : 1), stiffness (16 : 1), mood disturbance placebo capsules for a period of 15 weeks. No (16 : 0), spasm (14 : 1), pain (10 : 2) and weight treatment effect on spasticity was found during the main study using the Ashworth score ofspasticity, although patients felt active med- ication was much more helpful than placebo inalleviating some of their distressing symptoms (spasticity, spasms, pain levels, quality of sleep) satisfactory. Current treatments include baclofen In the 12 months of follow-up there was a (a GABA agonist, given orally or intrathecally), significant decrease in the Ashworth score in tizanidine, benzodiazepines and gabapentin. The the dronabinol arm only, although both active most common side effect of these drugs is seda- treatment arms demonstrated a wider spectrum tion, which is dose dependent and dose limiting.
of symptomatic benefit than seen in the main Botulinum toxin injection in combination with short-term study.[57] There were also suggestions physiotherapy can also be useful. The evidence of improvements in some disability scores in the base behind any of these drugs is not large. Bac- follow-up study. One of the problems with inter- lofen was studied in very few limited-scale, blind- preting these data is knowing how much objec- ed studies >30 years ago.[48,49] It seemed to be tivity to place on patient-reported outcomes when better tolerated than diazepam but side effects a degree of unblinding is seen in such studies.
were common. Tizanidine was studied in a num- Whether this unblinding is due to improved ber of trials, with varying results. The UK Tiza- symptoms or unwanted side effects, or whether nidine Trial[50] showed a 21% reduction on the the unblinding matters at all, remains a matter for Ashworth score in comparison with placebo, whereas another study failed to find this.[51] The Another placebo-controlled trial in 57 MS pa- evidence for an effect from gabapentin is just tients with poorly controlled spasticity provided as limited, coming from a single double-blind, some further support for therapeutic benefit when CannadorÒ capsules were given.[58] Although Initial studies of cannabinoid use in patients they were unable to confirm benefit for spasticity, with MS were small, and some seemed to show an there was a positive effect with CannadorÒ versus improvement in spasticity with dronabinol com- placebo on spasm frequency, mobility and sleep.
pared with placebo.[53,54] Another study in 16 pa- A further recent study of CannadorÒ in people tients with MS found no effect on spasticity with with MS and significant spasticity has been re- dronabinol or a cannabis extract (CannadorÒ); ported.[59] This placebo-controlled, parallel-group however, the maximum dosage used was 5 mg study of 279 patients across 22 UK centres dem- twice daily, which is probably too low to see an onstrated very similar efficacy to the CAMS study.
effect.[55] Adverse effects were more common The primary outcome measure of a spasticity rating scale at 12 weeks showed highly significant ª 2011 Adis Data Information BV. All rights reserved.
Table I. Key efficacy data for cannabinoids in the treatment of multiple sclerosis-related spasticity in randomized studies No effect on spasticity using Ashworth scale Symptomatic benefit on spasticity, spasms, pain levels and quality of sleepTremor improvement not statistically significant Significant decrease in Ashworth score for the Statistical improvement in 7 of 9 self-ratedsymptoms No statistical difference with placebo on spasticity Symptomatic benefit on spasm frequency, mobilityand sleep Relief of muscle stiffness twice as large with cannabis extract on category rating scale, reducedpain No improvement in primary outcome measure of worst symptomImprovement of spasticity and quality of sleep No statistical significance on Ashworth scale Improvement of spasticity on numerical ratingscale Spasticity numerical rating score clearly improved Significant decrease in pain, no change in Significant reduction in incontinence episodes Not functionally significant, only subjective Reduced intensity of pain and sleep disturbance CAMS = Cannabinoids in Multiple Sclerosis study; co = crossover; db = double-blind; mc = multicentre; NNT = number needed to treat;pc = placebo-controlled; pg = parallel group; THC = tetrahydrocannabinol.
benefit with CannadorÒ compared with placebo studies used nabiximols in a 10-week, placebo- (p = 0.004), with similar results at 4 and 8 weeks.
controlled RCT in three centres involving 160 MS Nabiximols (SativexÒ) is an oromucosal spray patients with significant problems from spastic- of cannabis extract containing similar cannabinoid ity, spasms, bladder, tremor or pain.[60] The pri- proportions to CannadorÒ. One of the initial mary outcome measure was a visual analogue ª 2011 Adis Data Information BV. All rights reserved.
Role of Cannabinoids in Multiple Sclerosis score for each patient’s most troublesome symp- well as spasms, sleep and Barthel activities of tom. Although there was no overall improvement daily living (ADL) in recipients of nabiximols.
in the primary outcome measure of a visual ana- The synthetic cannabinoid nabilone (1 mg/day) logue score of the worst symptom, in those has been investigated in a small placebo-controlled patients whose main symptoms was spasticity, RCT in 13 patients with MS with disabling spasticity- there was a significant reduction with nabiximols related pain, and showed a significant decrease in (p = 0.001). There were no significant adverse ef- pain using the 11-point box test but no change in fects in recipients of nabiximols on cognition and mood, and intoxication was generally mild. A There seems to be a discrepancy between the further RCT using nabiximols in 189 patients with favourable symptomatic effect of cannabinoids MS[61] reported marginal benefits of this agent on on spasticity and the lack of change in the Ash- the subject-recorded numerical rating scale of worth scale from most class I level of evidence spasticity (p = 0.048), but the Ashworth scale and studies. A potential explanation might be that the other secondary outcomes did not achieve statis- follow-up is too short.[57] Another explanation tical significance. Another recent phase III study would be that the beneficial effect is more subtle investigated the use of nabiximols.[62] This study than the detection range of the Ashworth scale, was not a conventional parallel-group RCT, but probably mediated through the relief of pain an ‘enriched study’, where all participants were caused by spasms. The symptomatic benefit, with initially provided active drug for 4 weeks, and modest side effects, in recipients of cannabinoids responders (>20% reduction in spasticity visual is nonetheless clear from studies yielding class I analogue score) were then enrolled in a longer level of evidence. On the basis of this evidence, (12-week) placebo-controlled study. Significant there is a strong case for cannabinoids to be used benefit was reported in spasticity rating scores as as add-on treatment for MS-related spasticity.
Table II. American Academy of Neurology classification scheme requirements for therapeutic questions (reproduced from Frenchand Gronseth,[72] with permission) A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in arepresentative population. Relevant baseline characteristics are presented and substantially equivalent among treatmentgroups or there is appropriate statistical adjustment for differences The following are also required:a. Concealed allocationb. Primary outcome(s) clearly definedc. Exclusion/inclusion criteria clearly definedd. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias e. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required:a 1. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g. for a drug, the mode of administration, dose and dosage adjustments are similar to thosepreviously shown to be effective) 2. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are substantially equivalent to those of previous studies establishing efficacy of the standard treatment 3. The interpretation of the results of the study is based on an observed-cases analysis A randomized, controlled clinical trial of the intervention of interest in a representative population with masked or objectiveoutcome assessment that lacks one criterion a–e class I, above, or a prospective matched cohort study with masked or objectiveoutcome assessment in a representative population that meets b–e class I, above. Relevant baseline characteristics arepresented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences All other controlled trials (including well defined, natural history controls or patients serving as their own controls) in arepresentative population, where outcome is independently assessed, or independently derived by objective outcomemeasurements Studies not meeting class I, II or III criteria including consensus or expert opinion Note that numbers 1–3 in class Ie are required for class II in equivalence trials. If any one of the three is missing, the class is automaticallydowngraded to a class III.
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largest cannabinoid study to date, the level of As is the case with many symptom treatments evidence being class II (unintentional dropouts, in patients with MS, evidence for the use of commonly prescribed drugs for treating bladdersymptoms is sparse. The most common bladder problems in MS are detrusor hyper-reflexia, with One of the most disabling symptoms in MS is symptoms of urinary urgency and frequency, and a coarse tremor, which is usually very resistant detrusor/sphincter dys-synergia, where relaxation to pharmacological treatment. Traditional drugs of the external sphincter and bladder contrac- include b-adrenoceptor antagonists and primidone.
tion are not coordinated. Presently, detrusor Other drugs used include carbamazepine, clonaz- hyper-reflexia is treated non-invasively with anti- epam, isoniazid and buspirone.[77-79] Levetiracetam muscarinics, including oxybutinin or tolterodine.
seemed to work in a class III level of evidence Nocturia is treated with desmopressin.[73] A class III study but not according to a class I level of evi- study showed symptomatic response to oxy- butinin in 67% of patients, but 21% of patients The evidence for beneficial effects of cannabi- had to stop the trial because of side effects.[74] noids on MS-related tremor is weak. There was Tolterodine proved superior to placebo and com- a single case report of an MS patient with acute parable to oxybutinin in enhancing bladder vol- improvement of chronic motor handicap while ume and improving continence in a very small smoking marijuana.[82] Another uncontrolled study used oral D9-THC in eight patients with severe In patients with MS, fewer studies have in- ataxia and tremor, two of whom demonstrated vestigated the effect of cannabinoids on urinary symptoms than on spasticity or pain. A small Data from the CAMS study revealed CannadorÒ open-label pilot study of 15 MS patients used improved tremor in 48% of patients, MarinolÒ in nabiximols or a D9-THC spray for 8 weeks fol- 40% and placebo in 33%, according to patient lowed by a long-term extension. Urinary incon- reports; the difference between active treatments tinence, number and volume of incontinence episodes, frequency of urination and nocturia all A double-blind, placebo-controlled, crossover decreased in recipients of both agents versus base- RCT investigated the effect of 4 weeks of treat- line (p < 0.05).[76] Patient self-assessment of pain, ment with oral CannadorÒ in 14 patients with spasticity and sleep also improved significantly.
MS and upper limb tremor.[65] The primary out- Pain improvement continued up to a median of come was a validated tremor rating scale. Sec- 35 weeks and side effects were mild.
ondary outcomes were accelerometry, ataxia scale, A sub-study of the main CAMS study looked spiral drawing, finger tapping and the nine-hole specifically at lower urinary tract symptoms.[64] pegboard test. Although there was no improve- ment in any of the objective measures of upper to receive CannadorÒ, MarinolÒ or placebo, it limb tremor, finger tapping was faster in placebo was primarily aimed at evaluating spasticity, and recipients (p < 0.02) and five patients felt a sub- there were considerable missing data from the jective improvement of tremor whilst on active incontinence charts used to assess episodes of urge incontinence. Nevertheless, all three groups Data from a 10-week, placebo-controlled RCT in showed a significant reduction (p < 0.01) in ad- 160 MS patients treated with nabiximols cited in justed episode rate (38% cannabis extract, 33% section 3.2.1 failed to show any improvement in a THC, 18% placebo), with both active treatments visual analogue scale for tremor between the baseline showing significant reduction over placebo.
2 weeks and the final 2 weeks of the trial.[60] There is therefore limited evidence for canna- Overall, there is no evidence for objective im- binoid action in reducing incontinence episodes provement of tremor in the class I evidence stud- in comparison with placebo in a sub-study of the ª 2011 Adis Data Information BV. All rights reserved.
Role of Cannabinoids in Multiple Sclerosis Nystagmus treatment in patients with MS is patients.[92,93] No other double-blind RCTs have disappointing. There are isolated reports of a been conducted to support the use of antiepileptic potential effect of gabapentin on nystagmus drugs for pain in MS. One follow-up study (class (class IV, class II and again class II level of evi- III evidence) reported a significant incidence of dence in three trials, respectively).[84-86] side effects in patients with MS prescribed anti- There is a case report on an MS patient with epileptic drugs for pain, especially after the use of severe pendular nystagmus who took cannabis in carbamazepine.[94] Gabapentin seemed to be ef- several preparations, some of them in a blinded fective in treating painful spasms in MS in an fashion.[87] A dramatic suppression of the nys- open-label unblinded trial (class III evidence).[95] tagmus was documented by video and infrared Pregabalin was investigated in an open-label, pilot oculography after smoking cannabis, whilst both study in a small number of patients with MS and nabilone tablets and cannabis oil-containing cap- was found to reduce paroxysmal painful phe- sules (up to 40 mg of THC per day) had no effect.
nomena with mild side effects.[96] Levetiracetam We cannot recommend cannabinoids for nys- was effective and well tolerated according to a tagmus treatment based on the present class IV small single-blinded, preliminary study.[97] Nortriptyline seemed to be effective in sensory complaints and pain in a randomized trial in 59 MS patients that compared transcutaneous Pain is very common in MS, affecting up to electrical nerve stimulation with nortriptyline 70% of patients, and treatment is often un- satisfactory.[88] Many patients with MS experience Misoprostol seemed to be effective in pain due more than one pain syndrome; combinations of to trigeminal neuralgia in patients with MS in an dysaesthesia, headaches and/or back or muscle and open-label prospective trial (class III evidence).[98] joint pain are frequent. The most common pains Pain is another area of MS-related symptoms are either central chronic neuropathic pain (often where there is stronger evidence for an effect described as a burning, dragging or aching in as- of cannabinoids. A crossover, double-blind RCT sociation with spasticity) or paroxysmal neuralgias evaluated oral synthetic dronabinol on central (usually lancinating and sometimes difficult to dis- neuropathic pain in 24 MS patients treated for tinguish from nerve root irritation when outside the 3 weeks with a maximum 10 mg of dronabinol or cranial nerves). However, the definition of, and con- placebo, separated by a 3-week period of wash- ditions encompassing ‘neuropathic pain’ remain con- out.[66] Median spontaneous pain intensity was troversial. No universally accepted and validated measured with a numerical scale in the last week clinical diagnostic criteria for neuropathic pain exist of treatment. The pain intensity was significantly and assessment of patients based on clinical exam- lower (p = 0.02) and the pain relief score higher ination and bedside test to decide what is, and what (p = 0.035) with dronabinol versus placebo.
is not, neuropathic is difficult, even for experts.
A similar crossover RCT in 24 patients of Current options for treating central pain condi- whom 18 had MS found that pain levels were tions remain limited and are based mostly on the significantly lowered versus baseline when either use of CNS drugs with known problems of toler- ability, particularly antiepileptic drugs (e.g. carba- A larger single-centre, double-blind RCT over mazepine, oxcarbazepine, gabapentin, pregabalin, 5 weeks in 66 MS patients with central pain states lamotrigine and levetiracetam), and tricyclic anti- (59 dysaesthetic, 7 painful spasms) treated with depressants (TCAs) such as amitriptyline, short-term nabiximols as adjunctive treatment was subse- non-steroidal anti-inflammatory drugs (NSAIDs) quently conducted.[68] Patients could self-titrate up to 48 sprays in 24 hours. Nabiximols was su- In two double-blind RCTs, lamotrigine failed perior to placebo in reducing the mean intensity to show any difference versus placebo as stand- of pain (p = 0.005) and sleep disturbance (p = 0.003).
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Most adverse effects in nabiximols recipients Greenberg et al.[101] evaluated the effect of smok- were minor, but were intense enough in two ing marijuana on balance in ten patients with MS patients to warrant withdrawal from the study.
and described postural reflexes being affected The 2-year open-label follow-up study found that more than in normal subjects. Interestingly, pa- nabiximols was effective, with no evidence of tients perceived an improvement despite evidence tolerance in the 28 patients who completed the A follow-up, open-label study with nabiximols reported on safety and tolerability in 137 patients strated significant patient-reported effects on with MS.[102] Patients reported 292 side effects, of pain with both dronabinol and CannadorÒ using which 86% were mild to moderate including oral category rating scales. These results were con- pain, dizziness, diarrhoea, nausea and oromucosal firmed in the recent MUSEC (MUltiple Sclerosis disorder. Three patients had five serious side ef- and Extract of Cannabis) study using CannadorÒ fects: two seizures, one fall, one aspiration and conducted from 2006 to 2008 on 279 patients one gastroenteritis. Four patients had first-ever seizures. Planned, sudden interruption of nabix- A meta-analysis of nabiximols, cannabidiol imols in 25 patients for 2 weeks failed to demon- and dronabinol in neuropathic and MS-related strate any evidence for a consistent withdrawal pain found a statistically significant effect of syndrome, although 11 reported tiredness, inter- these agents on pain relief across studies. Side rupted sleep, hot and cold flushes, mood alteration, effects were generally mild, and the most com- reduced appetite, emotional lability, intoxication Evidence from these studies strongly suggests A systematic review of the published data over that cannabinoids (in the form of an oral canna- the last 40 years on cannabinoids, which excluded bis extract,[56,59] synthetic D9-THC[66] or nabix- those studies referring to recreational use, re- imols) are effective in pain relief.[68] The numbers tained 31 studies, from which 23 were RCTs and needed to treat are very low at 3.5 or 3.7.[66,68] eight were observational studies.[103] In the RCTs The side effects of these agents were rare, mild the median exposure was 2 weeks and 96.6% of and well documented in the class I studies.
the adverse effects were not serious, the mostcommon one being dizziness if receiving active treatment (15.5%). Serious side effects listed were Sleep disturbance in MS patients is improved relapse of MS (12.8%), vomiting (9.8%) and with cannabinoid treatment. In the CAMS study, urinary tract infection (9.1%), and non-serious MS patients reported improved sleep with both side effects were more frequent if receiving active CannadorÒ and dronabinol compared with pla- treatment (95% CI 1.57, 2.21). The rate of serious cebo (p = 0.025).[56] Other already cited studies adverse effects did not differ significantly be- (see section 3.2.1 and 3.2.5) demonstrated a ben- tween the treated patients and the controls.
eficial effect of nabiximols on pain-related sleep Chronic use of cannabinoids for symptom re- disturbance (p = 0.003)[68] and on the quality of lief by people affected by MS has raised the con- cern of potential cognitive side effects. Severalstudies have quantified the neuropsychological effects of cannabinoids, with conflicting results.
CAMS-PEC, a substudy on 89 patients whocompleted psychological tests from the original CAMS study, found a significant reduction in when used medicinally. Side effects appear to be performance on the California Adult Verbal generally mild, and most serious adverse events Learning Test (verbal learning and memory) in from clinical trials appear to be either unrelated, those patients receiving cannabis extracts com- or expected from the complications of MS.
pared with placebo.[104,105] Another trial reported ª 2011 Adis Data Information BV. All rights reserved.
Role of Cannabinoids in Multiple Sclerosis on a worse performance in the Selective Remind- detecting meaningful symptom change from the pa- ing Test (long-term memory storage capacity).[68] tient perspective. There is still a considerable way to Other studies have not demonstrated adverse ef- go to fully understand how symptoms interact with disability, and how we can take account of placebo Most concern with cannabinoids has been di- effects (evidence from the CAMS study suggests that rected towards potential psychiatric side effects, these may last at least 12 months), together with particularly in light of the association between ways of accommodating potential unblinding.
excess recreational cannabis abuse during ado- Advances need to be made in reducing can- lescence and subsequent schizophrenia. Although nabinoid side effects, including unwanted psy- there have been occasional cases of toxic psy- choactivity. This may result from developing chosis associated with clinical trials of cannabi- peripherally active compounds that may affect noids, to date all of these have been reversible and peripheral receptors or blood flow for symp- dose related.[54,68] Indeed, some cases of psy- toms such as pain and spasticity. Newer com- chosis have occurred in placebo-treated patients.
pounds altering endocannabinoid tone may also Nevertheless, caution must always be exercised, not have the same degree of psychoactivity.
and slow titration is usually the best method of Drug availability may be altered by developing obtaining symptom relief and compliance.
water-soluble compounds and newer methodsof administration.
Perhaps most exciting is the possibility that cannabinoids may be neuroprotective and have a Considerable effort has been expended in the much wider role than symptom alleviation. There last decade to conduct clinical trials using can- is considerable experimental evidence for canna- nabinoids and to start to test which cannabinoids binoids being associated with reduced excito- may be therapeutically beneficial. At present toxicity secondary to reduced neurotransmitter there are a number of trials providing class I release, synaptic modulation, reduced free radical evidence demonstrating a beneficial effect of damage, improved mitochondrial function and cannabinoids on pain and sleep disturbance, and reduced inflammation together with increased re- a class II large follow-up study that has shown pair and remyelination. One of the long-term a significant reduction in incontinence episodes.
follow-up studies has also suggested a role for The side effects were carefully reported and cannabinoids in possibly reducing disease pro- deemed to be mild. Evidence for a beneficial ef- gression that was not seen in the short-term, fect of cannabinoids on symptomatic spasms and 15-week, main study.[57] A further pivotal study is spasticity is persuasive from a number of trials now under way, expected to report in 2012, where providing class I evidence – often considerably 500 people with progressive MS have been re- better than the evidence on which current treat- cruited to a UK 3-year, randomized, placebo- controlled, follow-up study to see whether disability This evidence for the therapeutic benefit of progression can be slowed with cannabinoids cannabinoids has been slow to gather, although (CUPID [Cannabinoids Use in Progressive In- most clinicians with experience of these drugs will flammatory brain Disease] study). We await generally vouch for their effectiveness. The num- ber of positive studies is now accumulating, inparallel with developments in trial methodology, including improved symptom measurement (e.g. thenew patient report spasticity scale, MSSS-88)[107] No funding has been provided to prepare this review.
and newer trial designs. Licensing authorities tend to There has been no involvement of any funding organisation or believe ‘objective’ measurements more than patient sponsor in any of the following: collection, management,analysis and interpretation of the data; and preparation, re- report, even when older ‘objective’ measures such as view or approval of the manuscript. Prof. J.P. Zajicek has pre- the Ashworth scale of spasticity are inadequate for viously received consultancy fees from IKF and Bayer-Schering.
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