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Degenerative Neurological and Neuromuscular Disease 2011:1 15–23
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Open Access Full Text Article
http://dx.doi.org/10.2147/DNND.S16081
Emerging treatment options for spasticity in
multiple sclerosis – clinical utility of cannabinoids
John C Ashton
Department of Pharmacology and
Toxicol og y, Otag o Sch ool o f Med ical
Sciences, University of Otago,
Dunedin, New Zealand
Correspondence: John C Ashton
Department of Pharmacology and
Toxicology, Otago School of Medical
Sciences, University of Otago,
PO Box 913, Dunedin 9054, New Zealand
Tel +64 3 479 3040
Fax +64 3 479 9040
Email john.ashton@otago.ac.nz
Abstract: Multiple sclerosis (MS) is a widespread and common disabling autoimmune
disease of the central nervous system. The main disabling symptom is muscle spasticity, which
occurs in most patients. Treatment of spasticity with existing drugs is often poor, and there
is a need for new and additional treatments. This article reviews the use of cannabinoids for
the treatment of symptoms in MS, focusing on the pharmacology of ∆9-tetrahydrocannabinol
(∆9-THC), cannabidiol and analog drugs in various formulations, the rationale for their use, and
their efficacy and safety in the treatment of MS. It is concluded that of all currently available
formulations, only sublingual spray containing ∆9-THC has a sufficient evidence base to justify
its use in treatment of spasticity and patient quality of life, particularly in patients’ refractory
to current treatments.
Keywords: MS, ∆9-tetrahydrocannabinol, ∆9-THC, cannabis
Introduction: management issues for spasticity
in multiple sclerosis
Multiple sclerosis (MS) is a progressive or relapsing/remitting autoimmune disease
of the central nervous system. The disease is characterized by the autoimmune
destruction of myelin in the central white matter, and associated inflammation. The most
commonly reported symptom (90% of patients) for MS is spasticity, which not only
hinders movement, but can cause pain and impact on quality of life in numerous ways,
causing distress and suffering to the patient. Other symptoms include tremor, central
neuropathic pain, ataxia, and urinary incontinence. MS is the most common disabling
neurological condition in young adults, and the most common inflammatory disease
of the central nervous system worldwide.1
Spasticity is characterized by sudden involuntary movements, muscle stiffness,
or muscle spasms sufficient to cause pain, particularly in the lower back and legs.
Although the ultimate goal of therapy for MS is modification of the underlying
disease, aiming to induce remission and recovery, management of symptoms with
drugs that specifically target symptoms such as spasticity are an important part of
MS treatment. Standard drugs used to treat spasticity include centrally acting agents,
such as benzodiazepines, baclofen, tizanidine, and gabapentin, and peripherally
acting agents such as dantrolene. However, there is a very limited evidence base for
these drugs,2 and they provide only moderate relief from spasticity.3 Because many
patients are refractory to treatment with existing oral drugs, there is a clear need for
new treatments for spasticity in MS.
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Pharmacology of cannabinoids
used in the treatment of multiple
sclerosis
Cannabinoids have been identified as promising agents to
treat the symptoms of MS, particularly spasticity. The first
cannabinoids to be purified were the phytocannabinoids
derived from the cannabis plant, Cannabis sativak.4 These
include ∆9-tetrahydrocannabinol (∆9-THC) and cannabidiol,
which have been extensively studied for their medicinal
qualities. Dronabinol is the name given to the synthetically
produced (-)-trans-isomer of ∆9-THC (which is also naturally
occurring).5 Nabilone is a synthetically produced classical
cannabinoid that is a more potent analog of ∆9-THC, such
that 1 mg of nabilone is approximately equivalent to 10 mg
of dronabinol. Nabilone is the only synthetic cannabinoid
that has been licensed for use.6
Phytocannabinoids are highly lipophilic and show
extremely high levels of nonspecific binding in radioligand
binding experiments. The development of high affinity
synthetic cannabinoids was a critical step in the discovery
of cannabinoid-specific bindingsites: the cannabinoid
receptors.7,8 Identification of cannabinoid CB1 receptors and
determination of their distribution in the brain revealed that
CB1 is strongly expressed in areas of the brain relevant to
MS such as the motor regions of basal ganglia and striatum,
and in the pain pathway.9 Soon after the characterization
of cannabinoid receptors, the first endocannabinoids were
identified.4 The prototypical endocannabinoid sanandamide
and 2-arachidonylglycerol have been extensively studied
for both their biochemistry and pharmacology. These
act on CB1 receptors in neurons to inhibit the release of
classical neurotransmitters such as glutamate, dopamine,
and γ-aminobutyric acid.10,11 Activation of CB1 receptors
in the brain has potential therapeutic effects by inhibiting
spontaneous activity in the motor and pain pathways, but also
causes the characteristic intoxicating “high” of cannabis use,
along with sedation, memory impairment, mood changes,
and alterations in perception.4
The cannabinoid drugs that were first approved for clini-
cal use were synthetic analogs or stereoisomers of ∆9-THC.
These are the (-)-trans-isomer of ∆9-THC, dronabinol
(Marinol®, Solvay Pharmaceuticals, Brussels, Belgium), and
the more potent CB1 agonist, nabilone (Cesamet®, Valeant
Pharmaceuticals International Inc, Mississauga, ON).12
Both of these drugs have been used in various countries
to help reduce nausea and vomiting after treatment with
anticancer medicines. Marinol is an oral form of dronabi-
nol, is available in the US, Canada, and in some European
countries. Marinol comes in the form of capsules, with the
dronabinol dissolved in sesame seed oil; these have been
available in 2.5, 5.0, and 10.0 mg.13 Nabilone is marketed
under the name Cesamet.12 Cesamet comes in the form of
crystalline powder capsules, containing 1 mg nabilone.
Cesamet is available in the United Kingdom, Canada, and
in some European countries.
Cannabis is available on a limited basis for medical use
in some countries. Oral cannabis extracts have been used for
clinical trials; Cannador® (Institute for Clinical Research,
IKF, Berlin, Germany) consists of capsules containing
cannabis extract standardized to contain 2.5 mg ∆9-THC
and 1.25 mg cannabidiol. However, Cannador has not been
licensed anywhere in the world.14 Cannabis leaf has been
approved (as an unlicensed drug) for limited medical use
in some countries including Canada. Very few clinical trial
data for smoked cannabis exist, though there are some (for
example, Abrams et al15). It is also difficult to interpret case
histories and patient or doctor testimonies, mostly because
of the lack of placebo controls, but also because habitual
cannabis users can develop tolerance to many of the effects
of the drug. Also, the amount of active cannabinoids in any
given cannabis cigarette is variable. The ∆9-THC content in
cannabis cigarettes usually ranges between 1.5% and 3.7%,
the size of the cigarettes can vary, and the amount of cigarette
smoked at any one time can vary (Pers comm; New Zealand
Ministry of Police, 2011).
Pharmacokinetics
Cannabinoids are highly lipophilic and are rapidly absorbed
and distributed around the body. When ∆9-THC enters the
body, it is quickly distributed around the blood plasma,
and then quickly moves out of the bloodstream and into
surrounding tissues. Therefore, ∆9-THC first accumulates
rapidly in those tissues that have a high throughput of
blood, including kidneys, liver, and the lungs, but also the
brain. As concentrations build, neuronal CB1 receptors
are increasingly activated, and the psychoactive effect of
∆9-THC also peaks. Following accumulation of ∆9-THC in
highly perfused tissue, concentrations in these tissues fall, but
continue to climb in poorly perfused tissues and in lipophilic
compartments.16–18
Absorption by inhalation of ∆9-THC is much faster than
for other routes of administration. The very high peak plasma
concentrations of ∆9-THC that are achieved very rapidly by
smoking cannabis may help explain why some users claim
that the medical benefits of smoked cannabis (for example
pain relief) are greater than for other ∆9-THC preparations.
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Cannabinoids for multiple sclerosis
However, the “peak and trough” pharmacokinetics of
smoked cannabis means that users experience significantly
greater psychoactivity than when using standardized
formulations.19
To improve upon the pharmokinetics of both oral and
inhaled cannabinoids, GW Pharmaceuticals (Wiltshire, UK)
developed Sativex® (GW-1000), a cannabis-plant derived
medicine. This combines ∆9-THC with cannabidiol in a
fixed ratio (1:1.08) and is administered using sublingual
spray. Sativex was first approved for sale in Canada in
2005, to help reduce neuropathic pain, and is now licensed
for use in spasticity in the UK and Spain and by special
prescription in New Zealand. In contrast to inhalation, with
Sativex, gradual dose titration to approximate steady-state
plasma concentrations is possible. To compare Sativex with
smoked cannabis, in one study inhalation of 8 mg of ∆9-THC
resulted in peak plasma concentrations 24 times higher than
10 mg of ∆9-THC delivered by sublingual spray. Also, peak
concentration was achieved 17 minutes after inhalation
but 263 minutes after sublingual spray. Smoked cannabis
providing 13 mg of ∆9-THC achieved 15.7 times the peak
plasma concentration of ∆9-THC as the Sativex, taking only
9 minutes.20–22
Another strategy recently developed for optimal
delivery of ∆9-THC, aiming for improved pharmacokinetics
and tight dosage control, has been developed. Namisol®
(Echo Pharmaceuticals, Weesp, the Netherlands) contains
dronabinol and has been tested in a Phase I trial as an oral
and as a sublingual tablet. On the basis of this trial, oral
administration appeared to be favorable,23 with the ∆9-THC
Tmax of Namisol faster and less variable compared with other
buccal/oral administrations (competitors) (Pers comm; Echo
Pharmaceuticals, 2011).
Rationale for the use
of cannabinoids in treating
multiple sclerosis
Cannabinoid receptor agonists have various effects, but the
most important medical effects can be classified more simply
into central nervous system effects and immune system
effects. In the immune system, the effects of cannabinoids are
generally immunosuppressive and anti-inflammatory, but are
more properly immunomodulatory, as in some experiments
cannabinoids can be immunostimulatory.24
The effects on the central nervous system are dose
dependent and include effects on mood such as euphoria
and dysphoria, hyperactivity, anxiolysis, and anxiety, and
sometimes a sense of enhanced well-being. Effects on
perception include a changed time sense, altered perception,
hallucinations, paranoia, psychotic states, depersonalization,
and dissociation. Cognition is altered so that thinking may
become fragmented, and short-term memory is impaired.
Body temperature is also reduced, probably through a
central nervous system mechanism. Motor control is altered,
potentially causing ataxia and loss of coordination, unsteady
gait, and slurred speech, but also reducing muscle spasms and
ameliorating tremor.25 Cannabinoids also stimulate appetite,
inhibit nausea and vomiting, and have analgesic proper-
ties. The most common neurological side effect of medical
cannabinoids is drowsiness and sedation.26
Although two cannabinoid receptors have been well
characterized, only CB1 is thought to play a major role in the
psychoactive effects of cannabinoids.7 CB1 is widespread in
the central nervous system.8 During normal functioning in
the central nervous system, endocannabinoids activate CB1
receptors on presynaptic terminals after they are released
from depolarized postsynaptic neurons. Stimulated CB1
receptors then activate G-proteins that in turn suppress
neurotransmitter release. During retrograde transmission,
CB1 receptors are well placed to regulate discharge from
hyperactive neurons during both normal neuronal functioning
and during injury.27
CB1 is most densely expressed in the basal ganglia,
limbic system, cerebral cortex, and in the cerebellum, but
in relatively low levels in both the brainstem and the spinal
cord.8,28 Importantly, there is no evidence of cannabinoid
receptors in the respiratory control centers, in contrast to
opioid receptors, so that even potent CB1 agonists do not
cause respiratory depression. CB1 receptors in the basal gan-
glia are probably the targets for cannabinoid control of tremor,
spasticity, and painful muscle spasm in MS. CB1 is densely
expressed in the output neurons of the substantia nigra pars
reticulata and globus pallidus.29 Activation of CB1 at these
neurons can suppress excessive motor output and consequent
muscle spasm.
Cannabinoids reduce pain in MS not only by reducing
painful muscle spasm, but by acting in both the central and
peripheral pain pathway and by reducing inflammation.30
The anti-inflammatory properties of cannabinoids are largely
due to activation of a second cannabinoid receptor, CB2.
These properties have lead researchers to target the CB2
receptor for the potential modification of disease progression
in inflammation and immune disorders, including MS.31 C B2-
expressing lymphocytes occur in the lymphoid, myeloid,
and monocytic lineages. These include B-cells and T-cells,
monocytes and macrophages, dendritic cells, natural killer
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cells, and neutrophils;32 cells involved in virtually all steps
in leukocyte-mediated inflammation and immune processes.
The endocannabinoid system appears to be active in diseased
white and grey matter in patients with MS. For instance,
Eljaschewitsch et al33 found that anandamide levels were
significantly increased in active lesions taken from MS
patients. Autoimmunity may be moderated by cannabinoids,
though this has yet to be determined.
Clinical evidence for the efcacy
of cannabinoids in the management
of multiple sclerosis
Survey data support the idea that many people use cannabis
to self-medicate. Because cannabis is a restricted drug,
for which possession and supply are both illegal in most
countries, these surveys have tended to often come from
Canada, where the practice of self-medication with cannabis
is most tolerated.34,35 Despite the difficulties of obtaining
reliable data, epidemiological studies have found that people
with conditions varying from chronic pain, MS, and spinal
cord injury sometimes self-medicate with cannabis.36 Some
surveys have suggested that very large numbers of patients
with MS might self-medicate with cannabis.37,38 In one
survey in the UK, 75 patients with MS were questioned.
Of these patients, 83.7% had tried cannabis to help treat
their condition, and 75.6% reported that it provided some
relief.39 In an earlier survey that targeted patients with
MS that took cannabis for self-medication some 95% of
respondents reported that cannabis improved chronic pain
to their extremities, spasticity, and some other symptoms
such as bladder and bowel dysfunction,40 Bridging the gap
between surveys of people that self-medicate with cannabis
and large-scale and well controlled clinical trials are clinical
case reports. These often suggest a therapeutic effect, but are
hard to interpret as they lack placebo controls. Fortunately,
the evidence base for the use of cannabinoid therapeutics is
rapidly becoming dominated by larger scale clinical trials.
The main benefit that cannabinoids are hoped to confer
on MS patients is reduction of spasticity and tremor, but
the effects of cannabinoids on pain, particularly centrally
generated paroxysmal pain, can also help MS patients.
In addition, cannabinoids appear to help MS patients
control their bladder function (reviewed in two papers41,42).
For example, Svendsen et al43 found that central pain was
significantly reduced by dronabinol in patients with MS.
Nabilone was tested for spasticity related pain in MS by
Wissel et al,44 who found that pain was reduced by the
drug and that adverse effects were generally mild. Similar
results were obtained in the Cannabinoids in Multiple
Sclerosis (CAMS) trial, which studied the effects of oral
administration of cannabis oil capsules (Cannador) which
contained, with other constituents of cannabis, 2.5 mg of
∆9-THC and 1.25 mg of cannabidiol.45,46 However, some
studies, such as the double-blind, placebo-controlled trial
using ∆9-THC and cannabis extract by Killestein and col-
leagues47 have found that not only did the cannabinoids
fail to reduce spasticity, but in fact worsened the patients
global impression of their condition. Fox et al48 also found
no evidence that oral Cannador reduced upper limb tremor
in MS patients. Therefore, it has been argued that there is
no compelling case for the use of cannabinoids in symptom
management in MS.49 In addition, the majority of trials have
used subjective assessments of spasticity. Only one study
confirmed this result with objective assessments.45,46
However, randomized trials using Sativex, such as by
Rog et al50 and Wade et al,51,52 have found modest but definite
improvements in MS symptoms. Ben Amar53 reviewed 12
clinical studies up to 2004 on the treatment of tremor, spastic-
ity, and pain in MS patients with cannabinoids and found that
although results were usually negative, small improvements
were seen in the trials that used Sativex. These results have
been confirmed in a more recent comprehensive review by
Karst et al.54 In a meta-analysis published in 2010, Wade
et al55 calculated that the odds ratio for improvement in spas-
ticity by Sativex is 1.67 (95% confidence interval [CI]:1.05–
2.65; P = 0.030). Due to public interest, the United Kingdom
Medicines and Health care products Regulatory Agency (UK
MRHA) issued a Public Information Report on Sativex.56 The
report concluded that “a positive risk-benefit has not been
sufficiently demonstrated at this time”. However, the report
also included responder analyses, which appear to show that
although average improvements in symptoms are small, some
patients do seem to show marked improvement and may be
designated as “cannabinoid responders”. A study by Collin
and colleagues studied the use of Sativex on MS-related
spasticity, and concluded that it may be useful for symptom
control. Specifically, 40% of patients achieved a greater than
30% benefit (21.9% of patients with placebo).
Where Sativex may be particularly useful is for advanced
MS patients refractory to standard treatments. In a recent
trial designed to test the efficacy of Sativex in advanced MS
patients with severe spasticity,56 73% of patients had a 30%
improvement at least once in a 4-week period.56 In a recently
reported 19-week randomized, placebo-controlled, study in
patients with MS and with spasticity refractory to current
antispasticity treatment,3 when Sativex was used as an add-on
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Cannabinoids for multiple sclerosis
therapy for 4 weeks, 48% of patients experienced a $20%
improvement. Of these, a further 241 were randomized, with
patients continuing with Sativex showing significantly better
outcomes after 19 weeks than the placebo group.
Although motor symptoms and pain have been the
primary and secondary outcome measures in most studies on
the treatment of MS with cannabinoids, other symptoms have
also been studied. Russo and colleagues57 reviewed clinical
trials using Sativex and found that sleep quality was improved
in MS patients using the drug. Also, a substudy carried out in
the CAMS trials found that the active treatments significantly
improved urge incontinence compared with placebo,58 though
a more recent trial by Kavia and colleagues59 has suggested
that the effect may be modest at best.
At the time of writing, the results of a Phase II trial using
Namisol for the treatment of spasticity in MS are nearing
completion. This is a randomized, double-blind, placebo-
controlled trial that will determine efficacy of Namisol in
MS patients, with the primary endpoints being spasticity and
pain. The trial will consist of two phases, a dose finding and
a treatment phase. Previously, a Phase I trial showed that
oral Namisol up to 8 mg is safe and well-tolerated by healthy
patients, has a short Tmax and T1/2, with quick onset of effects,
peaking at approximately 1–2 hours.23 Given the promise
shown by Sativex, further results for this new cannabinoid
formulation are awaited.
Safety and tolerability of clinical
cannabinoids
All cannabinoids in current therapeutic use have a therapeutic
index that is relatively narrow for most uses, with adverse
effects limiting dose titration. Adverse effects at the acute
stage are mostly psychoactive and due to activation of CB1
receptors in the central nervous system. Acute effects on the
cardiovascular system (postural changes in blood pressure
and tachycardia) are also mediated by CB1 receptors in the
brain.26 In clinical trials using cannabis, cannabis extracts,
∆9-THC, or analogs of ∆9-THC, adverse side effects are dose
dependent and appear to vary in intensity from trial to trial
and between individuals within trials. Possible side effects,
adverse and otherwise, include euphoria, dysphoria, anxiety,
depersonalization, sedation, and drowsiness, distorted per-
ception, mental clouding, memory impairment, impairment
on cognitively demanding tasks, fragmentation of thoughts,
and even hallucinations.60–62 Cannabinoids also stimulate
appetite, and in some contexts this might possibly be consid-
ered an undesired effect; though it is an effect that is actively
sought when cannabinoids are used to stimulate weight gain
in patients suffering from disease-induced wasting. Large
amounts of cannabis can cause psychotic episodes involving
delusions and paranoia, but this has not been reported for the
drugs in current clinical development.60 With respect to motor
function, cannabis can cause hypermotility (increased motor
activity, movement) followed by lethargy, lack of coordination
or ataxia, muscle twitches, tremors and weakness, and prob-
lems speaking (dysarthia).61 Pregnant women should avoid
cannabinoids, as this has been linked to the impairment of
fetal development,63,64 even though the evidence for this is
inconsistent.65
Most of the clinical trials also contain data on adverse
effects. These are the best source of data on side effects of
∆9-THC because they are randomized, placebo-controlled,
and use a known dose. These are mostly minor, and virtually
all the trials describe the drug as “well-tolerated”. The most
common side effects reported in the trials are drowsiness,
ataxia (loss of coordination), euphoria, and dizziness.
At higher doses, dissociation and distorted perception are
infrequently reported. For example, in the trials carried out
by Berman et al66 and Rog et al,50 approximately 25 mg of
∆9-THC was used, and adverse effects were mild to moderate,
and usually spontaneously resolved. In both trials, the most
common side effects were dizziness and drowsiness. In Rog
et al,50 53% of patients experienced at least one episode
of dizziness, one of 34 patients experienced drowsiness
(“somnolence”), and one of 34 experienced dissociation and
ataxia (“feeling drunk”). It is important to note that although
this trial (which is typical) recorded at least one minor adverse
event for 88.2% of patients on the drug, to put this in context,
the figure is 68.8% for patients taking the placebo.
Tolerance and dependence
Cannabis dependence is a recognized syndrome under
Diagnostic and Statistical Manual of Mental Disorders
IV criteria and has been the subject of a number of epide-
miological studies (eg, Boden et al67 and Fergusson et al68).
The UK MRHA 2007 report on Sativex states that 1% of
cannabis users develop dependence on the drug. However,
drug-seeking behavior has many determinants,69 including
self-medication, and levels of use that are typical for one
type of drug user (eg, recreational) are not reliable guides to
levels of use for other types of users (eg, self-medication).
Therefore, the dependence on a drug used for medicinal
purposes is quite different from dependence on a drug used
for recreation.
One systematic source of data on amounts of ∆9-THC that
will be sought by people comes from clinical trials where
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the patients are allowed to “self-titrate”. This is where the
patient has ad libitum access to the drug (within an upper
limit), and takes the drug as required. In this way, the patient
finds a balance between the desired and undesired effects to
fit their individual needs. In these trials, 25 mg of ∆9-THC
is a typical amount of the drug that is taken during a day
when patients in the trials are allowed to self-titrate. This is
very similar to the doses that have found to be effective and
tolerated when given at set amounts in clinical trials, and is
therefore consistent with these patients only seeking as much
cannabinoid medication as they need for an optimal treatment
effect (source for these figures are the clinical trials cited in
sections above).
However, people who self-medicate with ∆9-THC may
raise the dose over time as they become tolerant to the
symptom-relieving effects, increasing their level of intake
well above that used by occasional recreational users, although
this has not been shown to be relevant for licensed medicinal
cannabinoids.70,71 At the same time, tolerance also occurs to
adverse effects, such as drowsiness and sedation, and therefore
the subject will function whilst receiving amounts of ∆9-THC
that may be debilitating to someone who does not regularly use
cannabis. Wade et al52 and Zajicek et al46 have both reported
on the long-term effects of ∆9-THC medication. Wade et al52
followed patients using higher amounts of ∆9-THC, and minor
adverse effects were well-tolerated.
Cannabinoids and the patient
For the patient with MS, Sativex is at the time of writing the
only cannabinoid that is widely available for treatment of
symptoms. Particularly for advanced MS patients who obtain
less than satisfactory relief from standard therapy, Sativex
is likely to provide a modest but meaningful improvement
in spasticity in particular, and in the pain associated with
muscle spasm. Sativex is indicated at present for symptom
relief of spasticity, tremor, and pain in patients with MS who
have not responded sufficiently well to standard medications,
and who show a worthwhile degree of improvement during
a 4-week trial period. Sativex is contraindicated in patients
with known or suspected allergy to cannabinoids or any of
the other ingredients. Like oral cannabinoid drugs, Sativex is
also contraindicated for patients with significant psychiatric
disorders other than illness-associated depression. Use is not
advised for nursing mothers, and also not recommended for
adolescents or children under 18, as these groups have not
been adequately studied. Elderly patients have been poorly
studied as a group, but some clinical trials have included
patients up to 90 years of age. Elderly people are more prone
to psychoactive adverse reactions and special care should be
made for personal safety; for example, to avoid falls or burns
whilst cooking or preparing hot drinks.
In addition to spasm, in the most recent trials,3 such
patients have shown additional improvements in bladder
control, global impressions of their condition, sleep, quality
of life, and patient satisfaction with the treatment regimen.
In particular, sleep is an essential aspect of quality of life, and
patients with chronic-pain MS often have difficulty sleeping.
Sleep disturbance is itself disturbing and unpleasant, and lack
of sleep contributes to fatigue during waking hours. Insomnia
is generally treated with central nervous system depres-
sants, which have a number of problems with long-term use,
including the development of tolerance and dependence,
rebound anxiety and insomnia (as well as more severe with-
drawal effects), and problems with cognition. Cannabinoids
have soporific effects, and the possibility that cannabinoids
can help improve sleep when given to patients with chronic
pain has been the subject of clinical trials, generally as a
secondary outcome measure. In particular, Russo and col-
leagues57 reviewed the effects of Sativex in nine clinical
trials where sleep disturbance, duration and/or quality were
recorded as the secondary outcome measure. Seven out of
nine trials found that sleep was improved in patients receiving
Sativex compared with patients receiving placebo.
Patient use of Sativex
An essential part of the therapeutic use of Sativex is patient-
directed dose-optimization through self-titration. Sativex
is administered by escalating doses during a self-titration
period, and it may take up to 2 weeks to find the optimal dose.
Adverse reactions can occur during this period, although they
are generally mild and resolve in several days. If Sativex is
sufficiently well-tolerated, patients should then continue the
drug for 4 weeks to determine efficacy, and a decision on
ongoing use then made.56
On the first day of the titration period, one spray in the
morning and one spray in the afternoon/evening should be
administered. This should be increased by one spray each
day depending on efficacy and adverse effects. Following
titration, patients are advised to maintain the optimal
dose. The average effective dose is 8–9 sprays per day,
up to a maximum of 24 sprays per day. Re-titration can be
considered if there are any changes in the patient’s condition,
concomitant medication, or if adverse reactions occur.56
Each spray of Sativex delivers 100 µL of the drug and
contains 2.7 mg ∆9-THC and 2.5 mg cannabidiol. Each spray
also contains up to 0.04 g alcohol (ethanol anhydrous) as well
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Cannabinoids for multiple sclerosis
as propylene glycol and peppermint oil. Because of concerns
over irritation to the sublingual membranes, occurring in
over 20% of patients in the trial,52 each spray should be
delivered to a different area of the sublingual surface. Sativex
is absorbed through the sublingual membranes, after which
peak concentrations of both ∆9-THC and cannabidiol are
usually reached within 2 hours.
Conclusion: the place
of cannabinoids in multiple
sclerosis therapy
Although there is no convincing evidence that treatment
with oral cannabinoids can improve the symptoms or
quality of life for patients with MS, there is evidence that a
cannabinoid formulation containing ∆9-THC delivered by
sublingual spray has a role in MS management, particularly
in patients who fail to gain adequate relief from standard
treatments. A meta-analysis of data gathered in randomized
clinical trials up to 201055 showed that the odds ratio for
improvement in muscle spasticity in MS patients is 1.67, and
in patients with advanced MS and severe spasticity refrac-
tory to standard treatment, close to half of all patients treated
experience a 20% or greater improvement in symptoms.
Despite this, the randomized clinical trials used in the
assessment of cannabinoids have been of inconsistent quality.
A high risk of unblinding of subjects to treatment group has
been an issue in several trials. For example, some trials have
included an open phase prior to randomization, and others have
included a high proportion of subjects with prior exposure to
cannabis and its effects. In addition, there has been considerable
heterogeneity of outcome measures and patient groups across
different trials. There have also been concerns with respect to
uncertainty about the quality of analysis in some trials.
The adverse effects of cannabinoid sublingual spray are
sufficiently common that it should not be considered a front-
line treatment but as a secondary or tertiary treatment, used
as an add-on to existing therapy in patients who require more
relief than they are able to get from other available treatments.
Apart from reducing spasticity, cannabinoid sublingual spray
also has moderate effects on the pain associated with muscle
spasm and also with centrally generated neuropathic pain.
Quality of life, particularly with respect to sleep, is improved
for patients taking the drug, and urinary incontinence is
moderately reduced.
Disclosure
The author has no financial or commercial interests in any of
the drugs or companies discussed in this article.
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