CHEMISTRY & BIODIVERSITY – Vol. 4 (2007)1729

REVIEW
Cannabis, Pain, and Sleep: Lessons from Therapeutic Clinical Trials of
Sativex, a Cannabis-Based Medicine
by Ethan B. Russo* a ) b ), Geoffrey W. Guy a ), and Philip J. Robson a )a) GW Pharmaceuticals, Porton Down Science Park, Salisbury, Wiltshire SP4 OJQ, U.K.
b
) GW Pharmaceuticals, 20402 81st Avenue SW, Vashon, WA 98070, USA(phone: þ 1-206-408-7082; fax: þ 1-866-234-7757; e-mail: erusso@gwpharm.com)

Cannabis sativa L. has been utilized for treatment of pain and sleep disorders since ancient times.
This review examines modern studies on effects of D9-tetrahydrocannabinol (THC) and cannabidiol(CBD) on sleep. It goes on to report new information on the effects on sleep in the context of medical
treatment of neuropathic pain and symptoms of multiple sclerosis, employing standardized oromucosal
cannabis-based medicines containing primarily THC, CBD, or a 1 : 1 combination of the two (Sativex< ).
Sleep-laboratory results indicate a mild activating effect of CBD, and slight residual sedation with THCpredominant extracts. Experience to date with Sativex in numerous Phase I – III studies in 2000 subjects
with 1000 patient years of exposure demonstrate marked improvement in subjective sleep parameters inpatients with a wide variety of pain conditions including multiple sclerosis, peripheral neuropathic pain,
intractable cancer pain, and rheumatoid arthritis, with an acceptable adverse event profile. No tolerance
to the benefit of Sativex on pain or sleep, nor need for dosage increases have been noted in safety
extension studies of up to four years, wherein 40 – 50% of subjects attained good or very good sleep
quality, a key source of disability in chronic pain syndromes that may contribute to patientsC quality oflife.

Introduction. – Sleep disorders are important syndromes in modern medicine that
include parasomnias, or sleep-disruptive events, as well common associated afflictions
such as snoring and sleep apnea. The most common disorder is insomnia, or lack ofsleep, said by the National Institute of Neurological Disorders and Stroke to afflict
60 million Americans [1]. Insomnia is a major risk factor for associated morbidity evenin the absence of illness, and is associated with markedly increased prevalence ofdepression, anxiety, absenteeism [2], accidents [3], and utilization of health careresources [4]. Sleep disruption itself, as in shift work in nurses, may contribute notably
to anxiety and functional bowel disorders [5]. When such sleep disturbances occur
secondary to pain, they can be termed Fsymptomatic insomniaC. Pain at night at least
three times a week was identified as a significant factor in excessive daytime sleepinessin older adults [6]. When sleep disturbance accompanies chronic pain or disease,attendant treatment becomes increasingly problematic. Despite the prevalence andpervasiveness of symptomatic insomnia, very few studies have addressed it, particularly
with respect to possible effects of analgesics on sleep. For example, use of non-steroidal
anti-inflammatory drugs may be associated with gastroesophageal reflux [7] that itself
aggravates insomnia [8].
L 2007 Verlag Helvetica Chimica Acta AG, ZOrich

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Fewer studies yet have employed modern methods of electroencephalography(EEG) or polysomnography to assess sleep disorders associated with chronic pain.
Results of recent investigations are sobering, as formal sleep monitoring of patientswith advanced cancers demonstrated that opioid treatment and pain disrupted
nocturnal sleep, prolonged sleep latency, and limited attainment of sleep stages 3 and4 as well as rapid eye movement sleep [9]. Further investigation indicated that such
sleep disturbances were attributable to opioid treatment itself, which contributed todepression and even enhanced pain [10]. In light of such data, it is clear that new
approaches to chronic pain and resultant sleep disorder are necessary.
Cannabis sativa L. and its derivatives have been known since ancient times for theiranalgesic, soporific, and hypnotic effects. While mentioned frequently as beneficial tosleep in a variety of pathological conditions in 19th-century sources on Indian hemp[11], modern studies on cannabinoids and their therapeutic effects on sleep havereceived little attention in modern medical literature until the last few years. As will be
noted, these are indications for which standardized cannabis-based medicine promises
palliation and symptomatic relief that may contribute greatly to patientsC global
impressions and subjective sense of relief of their condition.
The primary psychoactive ingredient of cannabis is D9-tetrahydrocannabinol(THC), many of whose actions are mediated via the CB1 G-protein coupled receptors
that cluster in nociceptive areas of the brain [12], spinal cord [13] [14], and peripheral
nervous system [15] (see [16] for an excellent review). THC Activity mimics that of thenatural endocannabinoids, anandamide (AEA, arachidonylethanolamide) and 2arachidonylglycerol (2-AG), that are likewise partial agonists on the CB1 receptor,
that modulate pain responses in integrative centers such as the periaqueductal grey
matter [17] and pain in relation to stress [18]. Another important phytocannabinoid,
the non-psychoactive cannabidiol (CBD), is not only an analgesic, anti-inflammatory,
and antioxidant in its own right [19 – 21], but it is also reported to allay various THC
adverse effects including sedation, tachycardia, and anxiety [22]. Recent work has
demonstrated that CBD antagonizes tissue necrosis factor alpha (TNF-a) in a rodent
model of rheumatoid arthritis [23], and enhances adenosine receptor A2A signaling via
inhibition of an adenosine transporter [24], suggesting an important therapeutic role invarious inflammatory and chronic pain states.
Additional cannabis components including terpenoids and flavonoids also haveanalgesic properties that may be significant [25]. Historical and scientific aspects ofcannabinoids and pain have been described for migraine [26], obstetrics andgynecology [27] , and gastroenterological conditions [28]. A clinical endocannabinoid
deficiency has been hypothesized in relation to migraine, fibromyalgia, and idiopathic
bowel syndrome [29].
In the current review, we will examine modern studies on effects of THC and CBD
on sleep, and then report new information on the effects of cannabis-based medicines
on sleep as a secondary outcome measure in the context of randomized clinical trials of
medical treatment of chronic pain states, including neuropathic pain (NP), symptoms
of multiple sclerosis (MS), and rheumatoid arthritis.
Clinical Studies of Cannabinoids and Sleep. – The soporific qualities of cannabis
were noted in the ancient Indian ayurveda tradition [30]. Subsequently, the great

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taxonomist Linnaeus recognized cannabis as narcotica and anodyna in his Materia
Medica in the 18th century [31] (p. 214). William B. O$Shaughnessy reintroduced
cannabis to Western medicine from India in the 19th century [32], wherein it produced
sleep and pain reduction for victims of rheumatism and many other conditions. Benefits
on sleep were noted in various pain states [11] throughout the 19th and early 20th
century, when cannabis medicines subsequently fell from common medical usage due tolack of standardization and daunting problems with dosing and quality control.
Scientific study of cannabinoids entered the modern era in the early 1960s with theisolation of THC [33]. Early studies revealed that THC reduced sleep latency innormal and insomniac subjects, and caused some suppression of slow wave sleep(Stages 3 and 4) [34], often with a residual FhangoverC effect the next day [35]. No
formal studies of cannabinoids to date have included electroencephalography orpolysomnography in symptomatic conditions or chronic pain states.
In a recent case report [36], treatment with Marinol< (dronabinol, synthetic THC)
effectively reversed serious insomnia in three patients afflicted with intractable pruritus
associated with cholestatic liver disease. Similarly, in a limited trial of Marinol, 2.5 mg
at night in five dementia patients, a reduction was observed in nocturnal motor activity(p ¼ 0.028) [37].
A series of experiments with cannabidiol performed in Brazil were summarized in1981 [38], with observations based on subjective sleep assessments. Of two subjects
taking CBD 300 mg twice a day (BID) for 2 d, one reported having slept more heavily,
but no performance abnormalities were evident. Ten more subjects took 200 mg CBD
vs. placebo on four separate occasions with no significant differences in subjectivefunctioning, or level of alertness. Two of four subjects taking CBD, 10 mg BID for 20 d,complained of isolated episodes of daytime somnolence on rare occasions. Anotherexperiment compared placebo to CBD, 3 mg/kg/d divided BID in eight subjects. One
reported somnolence for a week, another for the entire 30 d, and a third reported
improvement in baseline insomnia.
Subsequently, this group assessed 15 subjects with 40, 80, and 160 mg oral doses of
CBD as a hypnotic vs. nitrazepam, 5 mg, and placebo in a double-blind randomized
trial. This low dose of benzodiazepine and lower dose of CBD produced little effect on
sleep. The highest CBD dose, however, seemed to extend sleep and reduce episodic
wakening in 10/15 subjects subjectively, while also reducing dream recall. No hangover
symptoms were noted.
Cannabinoid Effects on Brain Chemistry in Sleep. – The key role of the endogenous
cannabinoid system in regulation of sleep – wake cycles was suggested by the findingthat the CB1 antagonist/inverse agonist SR 141716A produces arousal in rats at theexpense of slow-wave sleep [39]. This was further highlighted by the finding that theendocannabinoid anandamide (AEA) seems to mediate sleep induction and interacts
with oleamide in this regard [40]. Subsequently, a Japanese group demonstrated theinhibition of serotonin and ketanserin (5-HT2A antagonist) binding to the 5-T receptors
by AEA [41]. A mild but similar response has recently been demonstrated for CBD[42], and cannabis terpenoids [43], suggesting a possible synergy with the CB1 agonist,
THC. Certain terpenoid components of cannabis are sedating in their own right(reviewed in [44], particularly terpineol [45]).

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Recently, CBD was shown to inhibit uptake of AEA, and weakly inhibit its
hydrolysis [46], making it, in effect, an inducer of AEA function, and suggesting a
modulatory role for this agent in sleep. Additionally, a functional role for endocannabinoids in regulation of respiratory stability in sleep to prevent sleep apnea has beensuggested [47]. Finally, it has recently been demonstrated that CBD administeredintracerebroventricularly in rats increased wakefulness in the lights-on period, andincreased enhancement of c-FOS expression in hypothalamus and dorsal raphe nucleus[48], supporting a clinical alerting effect for this agent [22], as discussed below.
New Data on Sleep Modulation with Cannabis-Based Medicine Extracts (CBMs). –GW Pharmaceuticals received a license from the British Home Office in 1998 tocultivate cannabis and extract it as a standardized botanical drug substance forformulation into finished pharmaceutical products. Early indications have focused on
multiple sclerosis (MS) and chronic pain, especially neuropathic, or associated withcancer and rheumatoid arthritis. Chemovars of cannabis were selected via Mendelian
genetics to express one predominant phytocannabinoid [49] [50]. Cloned plants
undergo liquid CO2 extraction to produce botanical drug substances that containpredominantly THC (Tetranabinex< ), CBD (Nabidiolex< ), or a 1 : 1 combination of thetwo (Sativex< ; Fig. 1) [51] [52]. Sativex is administered oromucosally via a pump-action
spray with each 100-ml pump-action actuation providing 2.7 mg of THC, 2.5 mg of CBDplus other phytocannabinoids, terpenoids, and phytosterols [25], in a base of 50%
EtOH and 50% propylene glycol with 0.05% peppermint flavoring. Pharmacokinetic
data on this material is available from recent publications [53]. The preparation has
onset of activity in 15 – 40 min, which allows patients to titrate dosing requirements
according to pain levels or other symptoms with an acceptable profile of adverse events.

Fig. 1. Sativex oromucosal cannabis based medicine (photo: Ethan Russo, 2003)

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A total of 1000 patient years of Sativex exposure in over 2000 experimental subjects has
been amassed in Phase-II and -III clinical trials. A slight majority of subjects had no
previous recreational or medicinal cannabis exposure, but comparative efficacy results
have been identical in cannabis-experienced and cannabis-naQve cohorts with noevidence of inadequacy of subject blinding [54] [55]. Patients are generally able to finda stable dose at which they obtain therapeutic relief without unwanted psychoactive
effects. All randomized controlled trials (RCTs) were performed with Sativex added as
an adjunct to existing drug regimens in patients with intractable symptoms, i.e., patients
considered treatment-resistant and remained on best available analgesic therapy andhypnotic medication, if prescribed. A concerted effort has been made in this review toinclude data from all available Sativex clinical trials; no negative data were excluded.
Sativex was approved in June 2005 for marketing as a prescription medicine in
Canada under a Notice of Compliance with Conditions (NOC/c) for central neuropathic pain in multiple sclerosis (MS). An Investigational New Drug (IND) application
to study Sativex in intractable cancer pain patients in the USA was approved by the
FDA in January 2006. Two independent reviews of Sativex have recently been
published [56] [57].
The effects of oromucosal high-THC extract (Tetranabinex< ), 15 mg, and THCCBD extract doses of 5 and 15 mg of THC-equivalent were assessed by Nicholson et al.
in eight subjects with respect to nocturnal sleep, early morning performance, memory,and residual sleepiness in a double-blind placebo-controlled four-way cross-over study
with EEG monitoring [58]. While the THC extract, 15 mg, alone produced little effecton sleep architecture, sleep latency was reduced, memory was impaired, and residual
sleepiness and mood changes were observed (p < 0.05). Both dose levels of combined
THC-CBD extract decreased Stage 3 sleep (p < 0.05) over placebo, and the 15-mg
doses increased wakefulness (p < 0.05) compared to 5-mg doses. The 5-mg doses of
THC-CBD extract actually produced faster reaction times on the digit recall test (p <0.05) over placebo. The authors noted that whereas impaired memory was observed thenext day when 15-mg THC extract was given alone overnight, there were no such
effects when THC was concomitantly accompanied by 15 mg of CBD, as in Sativex.
Conclusions were that THC was sedative, while, in contrast, the presence of CBD wasalerting, tended to counteract THC adverse effects on cognition, and impaired
wakefulness.
In subsequent Phase-II and -III clinical trials, sleep quality was assessed withquestionnaires completed by clinical trial subjects. Visual Analogue Scales (VASs) andNumerical Rating Scales (NRSs) are familiar instruments to many clinicians and havetraditionally been used to quantify patient-rated subjective experiences. The two typesof scale have similar sensitivity and reliability, but NRS is generally preferred bypatients for ease of use. NRS and VAS are well-established and validated for themeasurement of pain [59]. As is the case with pain, there is no objective gold standard
by which to quantify the quality and quantity of sleep in patients participating in clinical
trials. For this reason, most of the studies included in this review utilized NRSs or VASs
to measure sleep and sleep disturbance. For example, Wade et al. [60] used VASs
attached to the following questions: FHow was your quality of sleep last night?C/FHow
much sleep did you get last night?C/FHow did you feel when you awoke this morning?CThe anchors at each extremity of the 10-cm line were Fbest imaginableC and Fworst

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imaginableC for the first two questions, and Ftotally refreshedC or Ftotally unrefreshedC for
the third. As an example of NRS, Rog et al. [61] used an 11-box (0 – 10) scale attached to
the following instruction: FOn a scale of 0 – 10 please indicate how your nerve pain
disrupted your sleep last night. Please tick one box onlyC. The anchors were Fdid not
disrupt sleepC and Fcompletely disrupts (unable to sleep due to pain)C. Such measuresappear to have good face validity.
These and other studies of cannabis-based medicines on pain and sleep aresummarized in the Table.
In a Phase-II study in 24 patients with intractable neurogenic symptoms including
MS and chronic pain, Tetranabinex, Nabidiolex, and Sativex were tested in a doubleblind-N-of-1 RCT vs. placebo by Wade et al. [66]. Significant improvement was seen
with both Tetranabinex and Sativex on pain (especially neuropathic) (p < 0.05), but
post-hoc analysis showed symptom control was best with Sativex (p < 0.0001), withslightly less intoxication than with THC-predominant extract. Sativex significantly
improved sleep quality (p ¼ 0.041; Study GWN19902; Fig. 2) [66]. The authors noted
that, compared to placebo, the CBD-predominant extract significantly improved pain,
the THC-predominant extract yielded significant improvements in pain, muscle spasm,
spasticity, and appetite, and combined THC:CBD extracts (Sativex) significantly
improved muscle spasm and sleep. They also observed that the visual analogue scale for
Sativex was significantly improved over baseline for 20 subjects in the sleep category(p < 0.05). Of particular note in this trial was the confirmation of the CBD component
as alerting, while high THC extract (Tetranabinex) improved sleep parameters(although not statistically significantly over placebo in this trial), while the combinationof the two (Sativex) improved sleep synergistically.

Fig. 2. Compendium of results of Sativex on sleep in earlier Phase II – III RCTs in multiple sclerosis (MS)and intractable chronic pain

In a Phase-II double-blind crossover N-of-1 study of intractable chronic pain in 34
subjects by Notcutt et al. [67], visual analogue scales for pain were significantly
improved for Tetranabinex and Sativex extracts over placebo (p < 0.001). Sativex

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produced best results for pain in MS subjects (p < 0.0042). Marked improvement wasobserved on sleep duration (p ¼ 0.0001) and quality (p ¼ 0.0001; Study GWN19901A;
Fig. 2). The authors commented that Sativex, while having little effect on the recorded
sleep hours, rather produced marked changes in reported sleep quality from the FpoorCor FfairC to FgoodC categories. The sleep quality measure represented a global assessmentby the subject of sleep duration, depth, and relative degree of sleep disruption. Finally,
they posited that improvement of sleep by the drug might prove to be one of its major
benefits in chronic pain and MS.
In a Phase-III randomized placebo-controlled clinical trial in central neuropathic
pain due to MS over 5 weeks in 66 patients by Rog et al., subjects showed mean NRS
analgesia favoring Sativex over placebo (p ¼ 0.009), and significant benefit of Sativex
over placebo was observed in sleep disturbance (p ¼ 0.003) [61] (Study GWMS0107;
Fig. 2).
In another Phase-III RCT in intractable pain in 79 subjects with MS, diabetic
neuropathy, or other conditions by Notcutt et al. [72], the Sativex cohort utilized escapeanalgesia a mean of 20.57% of days vs. 50.12% for placebo (p ¼ 0.002). Sleep
disturbance was also reduced by Sativex vs. placebo (Study GWPS0105; Fig. 2), with atreatment difference favoring the former (p ¼ 0.045).
In a Phase-III double-blind placebo-controlled trial of peripheral neuropathic painwith allodynia in 125 subjects by Nurmikko et al. [73], Sativex produced highly
statistically significant improvements in pain levels (p ¼ 0.004) and dynamic allodynia(p ¼ 0.042). Marked reductions in sleep disturbance were observed (p ¼ 0.001; StudyGWNP0101; Fig. 2) [73].
In the largest clinical study of brachial plexus avulsion and central neuropathic pain
to date by Berman et al. [68] in 48 subjects in a double-blind cross-over design assessing
oromucosal Tetranabinex, Sativex, and placebo, comparable benefits were noted in Box
Scale-11 pain scores with Tetranabinex (p ¼ 0.002) and Sativex extracts (p ¼ 0.005).
Sleep disturbance scores favored Sativex over placebo (p ¼ 0.017) [68] (StudyGWBP0101; Fig. 2), with sleep quality scores also favoring Sativex (p ¼ 0.019).
In another Phase-III RCT focusing on mixed neurogenic symptoms in MS by Wadeet al. [60], the greatest improvement following Sativex was noted in spasticity (p ¼0.001). Subjects also demonstrated benefit on sleep disturbance (p ¼ 0.047; Study
GWMS0001; Fig. 2). From this cohort, 137 patients elected to continue on Sativex insafety-extension (SAFEX) studies [74]. Rapid reductions were noted in the first twelve
weeks in pain VAS in 47 affected patients with sustained improvements for more than
one year. During that time, there was no escalation of dose indicating an absence oftolerance to analgesic or other therapeutic benefits of the preparation. Similarly, no
withdrawal syndrome (as defined by Budney et al. [75]) was noted in a subset of 25
patients who voluntarily stopped the medicine abruptly. Upon resumption, benefits
resumed at the prior established dosages. Improvements in sleep were also maintained[74].
Additional data from patients with central and peripheral neuropathic pain who
completed these RCTs have been collected in a second SAFEX study of some 507
subjects taking Sativex for at least one, and up to four years. These data confirm thecontinued efficacy of Sativex in maintaining improvements in subjective sleep
parameters. As in the prior SAFEX in MS subjects with mixed symptoms [74], no1736

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Table. Clinical Studies of Cannabis Based Medicines on Pain and Sleep
Drug

Clinical indication

Subject Trial duration
number(N)

Results/reference

Cannabis HIV neuropathy(smoked)50

5 days> 30% pain reduction vs. placebo(p ¼ 0.04), sleep NA [62]Cannador Spasticity in MS419

15 weeks

Improvement over placebo insubjective pain associated withspasm (p ¼ 0.003), sleep(p ¼ 0.025) [63]Cannador Post-herpetic
neuralgia

65

4 weeks

No benefit observed on pain,
sleep NA [64]Cannador Post-operative pain

30

Single doses, 1 day Decreasing pain intensity witheach
increasing dosage (p ¼ 0.01).
Sleep NA formally. One complaintof sleep disturbance [65]Sativex

Neurogenic pain

20

Series of 2-week
N-of-1crossover blocks

Improvement with Tetranabinex
and Sativex on VAS pain vs. placebo(p < 0.05), symptom control bestwith Sativex (p < 0.0001). Sativex
improved sleep quality (p ¼ 0.041) [66]

Sativex

Chronic intractable pain 24

12 weeks, seriesof N-of-1
crossover blocks

VAS pain improved over placebo(p < 0.001) especially in MS(p < 0.0042). Sleep duration andquality both improved (p ¼ 0.0001) [67]SativexBrachial plexus avulsion 48

6 weeks in 3
two-week
crossover blocks

Benefits noted in Box Scale-11
pain scores with Tetranabinex(p ¼ 0.002) and Sativex (p ¼ 0.005)
over placebo. Sativex improved sleep
disturbance (p ¼ 0.017) and sleep
quality scores (p ¼ 0.019) [68]

SativexCentral neuropathic
pain in MS66

5 weeks

Numerical Rating Scale ( NRS)
analgesia improved (p ¼ 0.009),
sleep disturbance (p ¼ 0.003)
vs. placebo [61]Sativex

Peripheral neuropathic 125
pain

5 weeks

Improvements in NRS pain levels(p ¼ 0.004), dynamic allodynia(p ¼ 0.042), sleep disturbance(p ¼ 0.001) vs. placebo [69]Sativex

Rheumatoid arthritis

5 weekImprovements over placebo
morning pain on movement(p ¼ 0.044), morning pain at rest
(p ¼ 0.018), DAS-28 (p ¼ 0.002),
and SF-MPQ pain at present(p ¼ 0.016), sleep quality(p ¼ 0.027) [70]56CHEMISTRY & BIODIVERSITY – Vol. 4 (2007)

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Table (cont.)
Drug

Clinical indication

Subject
number(N)

Trial duration

Results/reference

Sativex

Pain after spinal injury

117

10 days

NSD in sleep disturbance and NRS
pain scores, but improved Brief
Pain Inventory (p ¼ 0.032) andPatients Global Impression of
Change (p ¼ 0.001, odds ratio 3.4).

Sativex

Intractable cancer pain

177

2 weeks

Improvements in NRS analgesia
vs. placebo (p ¼ 0.0142),
Tetranabinex NSD. Sleep quality
NSD [71]

Sativex

Intractable lower urinary
tract symptoms in MS

135

8 weeks

Improvement in bladder severity
symptoms (p ¼ 0.001) and nocturia
episodes (p ¼ 0.01) over placebo.

dose escalation over time was necessary to maintain efficacy, supporting a lack oftolerance to this clinical benefit. Specifically, in an initial combined cohort of 287
subjects with central or peripheral neuropathic pain (Fig. 3), ca. 40% of subjects
attained good-to-very-good sleep quality with maintenance of up to two years. Fewerthan 20% of subjects had less than satisfactory results in their assessments of sleep
quality.

Fig. 3. Cumulative data on sleep disturbances (sleep quality scores) in a long-term safety-extension(SAFEX) study of central and peripheral neuropathic pain patients treated with Sativex (StudyGWEXT0102)

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An examination of adverse event profiles from the two SAFEX studies (137 and537 subjects, resp.) reveals that complaints attributed to poor sleep or residual fatigue
are infrequent after regular use of Sativex (Fig. 4).

Fig. 4. Graph of fatigue and other adverse events attributable to sedation or sleep disturbance in safetyextension studies of mixed symptoms of multiple selerosis (MS) (SAFEX GWMS0001, N ¼ 137), andperipheral and central neuropathic pain (SAFEX GWNP0102, N ¼ 507) taking Sativex for greater than
one and up to four years. Rates of associated complaints are all less than 10%.

In a Phase-II double-blind, randomized placebo-controlled five-week study of 56
rheumatoid arthritis patients with Sativex by Blake et al. [70], employing nocturnal
treatment only, subjects received a maximum of 6 sprays each evening (16.2 mg THC þ
15 mg CBD). In the final treatment week, many study measures favored Sativex overplacebo: morning pain on movement (p ¼ 0.044), morning pain at rest (p ¼ 0.018), 28joint disease activity score (DAS-28; p ¼ 0.002), and Short Form McGill Pain
Questionnaire (SF-MPQ) pain at present (p ¼ 0.016). Sleep quality favored Sativex
over placebo (p ¼ 0.027) (Fig. 5, a).
Results of a Phase-III study (N ¼ 177) comparing Sativex, Tetranabinex, andplacebo in intractable pain due to cancer unresponsive to opiates by Johnson and Potts[71] demonstrated that Sativex produced highly statistically significant improvements
in analgesia (p ¼ 0.0142), while Tetranabinex was not significantly different fromplacebo, suggesting that the presence of CBD in the Sativex preparation contributed topain control. Sleep quality in this study was not significantly improved over placebo,
perhaps due to its short duration of only three weeks.
Similarly, in a Phase-II study of neuropathic pain after spinal injury, whereas no
significant difference was noted in the primary outcome measure of average daily pain
due to a large placebo response, the Brief Pain Inventory (BPI) did improve (p ¼
0.032), as did the Patients Global Impression (PGI) of change (p ¼ 0.001, odds ratio
3.4). No changes in sleep over placebo were noted in this brief ten-day trial(unpublished findings).
In a Phase-III RCT of MS patients with intractable lower urinary tract symptoms
and frequent accompanying pain in 135 subjects, Sativex produced a significant

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Fig. 5. a) Effect of Sativex vs. placebo on rheumatoid arthritis sleep quality GWCRI016 (N ¼ 58; 0 – 10
NRS, 0 ¼ Fvery goodC and 10 ¼ Fvery badC). b) Effect of Sativex vs. placebo on nocturia in intractable lower
urinary tract symptom patients with multiple sclerosis (N ¼ 135).

improvement over placebo in bladder symptom severity (p ¼ 0.001) and in nocturia
episodes (p ¼ 0.010) affecting sleep (Fig. 5, b) (Fowler et al., GW Pharmaceuticals dataon file, manuscript in preparation).
Common Adverse Events (AE) of Sativex acutely in RCTs have included
complaints of bad taste, oral stinging, dry mouth, dizziness, headache, nausea, or
fatigue, but do not generally necessitate discontinuation, and proved less common overtime. Cumulative subject withdrawals from the RCTs secondary to AEs attributable to
Sativex have occurred in 10.7% of all subjects, and in 10.8% of MS subjects (data on file,
GW Pharmaceuticals, May 24, 2006). Figures ranged from 12.5% in the first Phase-II
trial [60], while 0% of Sativex subjects withdrew due to attributable AEs in studies oflower urinary tract symptoms in MS [76] and brachial plexus avulsion [68].
Placebo-controlled trials have also been conducted with an oral plant-derived
cannabis-based medicine, Cannador, which contains variable THC:CBD ratios [22].
This was examined in a large trial alongside Marinol (synthetic THC) and placebo in
MS patients (Table). In neither the acute trial (CAMS) reported by Zajicek et al. [63],nor its 12-month long-term follow-up [77], were significant improvements noted insleep with Cannador or Marinol. These data would support the proposition that
benefits of cannabis-based medicines on sleep in the context of symptomatic treatment
may be specific to a preparationCs formulation and/or delivery system, and theimprovement with one preparation cannot necessarily be extrapolated to another.
Another study of Cannador in post-operative pain (Table) showed decreased pain withincreasing dosage, but sleep was not assessed formally (NA) [65]. One subject noted
sleep disturbance. Finally, Cannador was utilized in a four-week study of post-herpetic
neuralgia (Table), but no benefit was observed on pain, and sleep was NA formally
[64].

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Results are recently available from the first RCT of smoked cannabis on pain, insensory neuropathy due to HIV/AIDS or its treatment (Table) [62]. A greater than
30% reduction in pain vs. placebo was noted in this five-day trial, but sleep effects were
not reported. An additional study is planned in California to assess effects of cannabis
on sleep disturbance in similarly affected patients (http://www.cmcr.ucsd.edu/geninfo/
drummond_abs.htm). The FDA has recently published guidelines for botanicalmedicines that mandate parameters required for New Drug Approval [78]. The
difficulties inherent in standardizing herbal cannabis, and pulmonary issues associatedwith its inhalation [79], make it unlikely that regulatory approval would be attainablein most nations of the world [54].
No head-to-head trials of Sativex vs. smoked cannabis have been performed, but acomparison of AE profiles from self-selected SAFEX study subjects on Sativex withthose of smoked-cannabis patients utilizing standardized cannabis in government
programs in Canada [80] and the Netherlands [81] [82] supports the concept that
Sativex was much better tolerated, especially with respect to mental status andcognitive issues [54].
Discussion. – Chronic pain, neurological illness, and sleep disorders are clearly comorbid conditions. Upwards of 80% of MS patients suffer from debilitating fatigue
symptoms and complain of significant sleep disturbance. Additionally, chronic pain
accompanies MS in up to 60% in some surveys, with a citation of 48% in a recent study[83], further compromising the ability of patients to attain rest. Tachibana et al. [84]noted that such problems in MS arise from legion sources: pain, spasticity, muscle
spasm, restless legs syndrome, myoclonus, and lower urinary tract symptoms, resulting
in sleep disturbance in 80% of 28 subjects. It was felt by these authors that these
problems were rarely addressed therapeutically. MS may also be associated with sleep
apnea, a condition that has recently been demonstrated to respond favorably totreatment with THC in an animal model [47].
A recent study of sleep and fatigue in 60 MS subjects is quite germane [85], with overhalf noting difficulty with sleep disturbance at least two nights per week. Fatigue andexcessive daytime sleepiness affected 64 and 32% of subjects, respectively. Those problems
correlated best to difficulties with middle-of-the-night insomnia that subjects attributed
most often to pain/discomfort (21.7%) or nocturia symptoms (72.5%). These symptoms
were improved by Sativex treatment in the above discussed RCTs. Comparison of rates offatigue, lethargy, somnolence, and insomnia in Sativex SAFEX subjects (Fig. 4) supports
very remarkable amelioration compared to MS patients in the Stanton study [85], many ofwhom were already taking pharmacotherapy for such symptoms. The authors of the latterstudy specifically recommended symptomatic treatment of pain and nocturia as strategies
to minimize sleep disturbance and its diurnal sequelae.
Similar sleep complaints affect patients with other etiologies of neuropathic pain. A
current review article strongly suggested treatment of chronic pain with agents thatconcomitantly improve sleep [86]. A survey of 173 adults with neuropathic pain
reported significantly higher rates of sleep disturbance and daytime somnolence vs.
controls [87], with improvement after institution of specific treatment. Unfortunately,
sleep disturbance continued in 43% of 140 subjects suffering from diabetic neuropathy
despite treatment [88].

CHEMISTRY & BIODIVERSITY – Vol. 4 (2007)

1741

In a recent review [89], the authors state, FThe alterations of THC on sleep EEG and
its rebound effect, its side effects before sleep induction, and its residual effects after
awakening have contraindicated its clinical use as a sedative hypnoticC. Data from theclinical research on Sativex reviewed in this article are not consistent with thisconclusion. Rather, the available evidence to date would suggest that Sativex
improvement in subjective sleep parameters, and satisfaction in patients with MS
and neuropathic pain, with symptomatic relief of pain, spasms, nocturia, and related
complaints. From limited sleep-laboratory information, it seems unlikely that its use
will result in significant change in sleep architecture. Sativex does not benefit all
patients, but in those who do respond, the beneficial effects are maintained consistently
over time without evidence of tolerance, and are not accompanied by unusual cognitive
sequelae [54]. Of course, additional in-depth studies are needed to confirm thesecontentions and might include formal neuropsychological testing and polysomnography.
Sativex patients and their caregivers have remarked to their physicians how the
medicine had transformed their lives through its ability to allow them more restful
sleep, increase their daytime level of function, and markedly improve their quality oflife. Its addition to the pharmacopoeia may be welcomed by patients, families, andphysicians.

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