TITLE: Nabilone for Chronic Pain Management: A Review of Clinical Effectiveness, Safety,

and Guidelines

DATE: 11 November 2011

CONTEXT AND POLICY ISSUES

Cannabis sativa is a flowering plant that has long been used as a recreational drug, and for
medicinal purposes.1,2 The main psychoactive component of cannabis is delta-9-
tetrahydrocannabinol (∆9-THC).2 Nabilone (Cesamet®) is an oral synthetic cannabinoid, which is
licensed in Canada for treating patients with severe nausea and vomiting related to
chemotherapy for cancer and who have failed to respond adequately to conventional antiemetic
treatments.2-4 Clinical trials and anecdotal reports have suggested that the use of nabilone in
other medical conditions, such as appetite stimulation, anxiety, spasticity, and pain.1,5

Chronic pain affects approximately one in five people in developed countries and two in five in
less well-resourced countries. In many circumstances, the patient’s quality of life is poor due to
persistent pain caused either by an ongoing illness or nerve damage caused by the disease
after resolution or cure of the disease.6

Multiple sclerosis (MS) is a neurodegenerative disease, and is the most common cause of
neurological disability in young people, with an average age of onset around 30 years and a
prevalence of about 120 per 100,000 individuals in North America. The majority of patients with
MS display symptoms, such as fatigue, muscle stiffness or spasticity, pain, memory problems,
balance trouble, tremors, urinary disturbance, and sexual dysfunctions.2,7

The purpose of this review is to assess the evidence of benefits and harms related to the use of
nabilone in management of chronic pain, including patients with MS. Evidence-based guidelines
and recommendation for the dosing of nabilone in adults for chronic pain management will also
be discussed. This report is an update of a CADTH rapid review published in 2007.

Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid
responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and
a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses
should be considered along with other types of information and health care considerations. The information included in this response is not
intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health
technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in
the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While
CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not
make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report.

Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is
given to CADTH.

Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have
control over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions.
RESEARCH QUESTIONS

1. What is the clinical effectiveness of nabilone in adults for chronic pain management?

2. What is the clinical effectiveness of nabilone in adults with multiple sclerosis for chronic
pain management?

3. What is the clinical evidence on the safety of nabilone in adults for chronic pain
management?

4. What is the clinical evidence on the safety of nabilone in adults with multiple sclerosis for
chronic pain management?

5. What are the evidence-based guidelines and recommendations for the dosing of nabilone
in adults for chronic pain management?

KEY MESSAGE

Limited evidence suggests that nabilone may be better than placebo in relieving chronic pain
but its relative benefits compared to other analgesics have not been proven. Current guidelines
recommend the dosage of nabilone for treating neuropathic pain be titrated gradually until target
relief is obtained.

METHODS

Literature Search Strategy

A limited literature search was conducted on key resources including Medline, Embase,
PubMed, The Cochrane Library (2011, Issue 11), University of York Centre for Reviews and
Dissemination (CRD) databases, Canadian and major international health technology agencies,
as well as a focused Internet search. No methodological filters were applied. The search was
also limited to English language documents published between January 1, 2006 and October
13, 2011.

Selection Criteria and Methods

One reviewer screened the titles and abstracts of the retrieved publications and evaluated the
full-text publications for the final article selection, according to selection criteria presented in
Table 1.

Table 1: Selection Criteria

Population Adult patients with chronic pain; adult patients with multiple sclerosis
Intervention Nabilone
Comparator Active control or placebo
Outcomes Benefits related to chronic pain (e.g. reduction in pain and improvement in QOL);
Harm (e.g. adverse events, serious adverse events, and withdrawal due to adverse
events);
Dosages in chronic pain.
Study Designs Health technology assessments, systematic reviews, meta-analyses, RCTs, non-
RCTs, evidence-based guidelines.

QOL=quality of life; RCTs=randomized controlled trials

Nabilone for Chronic Pain Management 2

Exclusion Criteria

Studies were excluded if they did not meet the selection criteria, were duplicate publications,
were abstracts/conference proceedings, were included in a selected systematic review, or were
published prior to 2006.

Critical Appraisal of Individual Studies

The quality of the included systematic reviews was assessed using the Assessment of Multiple
Systematic Reviews (AMSTAR) tool.8 RCT and non-randomized study quality were evaluated
using the Downs and Black instrument.9 The AGREE (Appraisal of Guidelines for Research and
Evaluation) instrument was used to evaluate the quality of evidence-based guidelines.10 A
numeric score was not calculated for each study. Instead, the strengths and weakness of each
study were summarized and described.

SUMMARY OF EVIDENCE:

Quantity of Research Available

The literature search yielded 167 citations. Upon screening titles and abstracts, 142 citations
were excluded, and 25 potentially relevant articles were retrieved for full-text review. Of the 25
potentially relevant reports, 14 did not meet the inclusion criteria, and thus 11 publications were
included in this review. The study selection process is outlined in a Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) flowchart (Appendix 1). Four systematic
reviews, two RCTs, two non-RCTs and three evidence-based guidelines met the inclusion
criteria. No health technology assessments were identified.

Summary of Study Characteristics

Two of the SRs and all RCTs and non-RCTs were conducted in Canada. Three evidence-based
guidelines were developed in Canada, Latin America and the UK, respectively. Details of
selected SRs, RCTs and non-RCTs are presented in Appendices 2 and 3. A list of instruments
used to measure pain and other outcomes is provided in Appendix 4.

Systematic reviews

A systematic review by Lynch and coworkers evaluated the efficacy of cannabinoids for the
treatment of chronic non-cancer pain.6 Cannabinoids examined in this review included smoked
cannabis, extracts of cannabis based medicine that are applied to the buccal mucosa, nabilone,
dronabinol and a novel THC analogue. Chronic non-cancer pain conditions included
neuropathic pain (NP), fibromyalgia, rheumatoid arthritis, and mixed chronic pain. Literature
search for RCTs was performed up to October 7, 2010, without a limit on language or
publication date. Eligible studies were RCTs comparing cannabinoid with a placebo or active
control group where the primary outcome was pain measured by various assessment scales in
subjects with chronic non-cancer pain. The methodological validity of the included studies was
assessed using the modified Oxford Scale. Eighteen studies involving 776 patients met the
inclusion criteria. The quality of these studies was high with a mean score of 6.1 on the 7-point
modified Oxford Scale. Amongst the 18 RCTs, four compared nabilone with placebo (in 3 trials)
or active control (in 1 trial). Treatment durations ranged from four to six weeks and total trial
duration was up to 14 weeks. The four studies examined the effect of nabilone in various

Nabilone for Chronic Pain Management 3

populations, including fibromyalgia,11 spasticity-related pain resulting from MS,12 chronic
neuropathic pain13 and spinal pain14. The details of the four RCTs are presented in Table 2.

The four RCTs on nabilone identified in Lynch were included in earlier systematic reviews
conducted by Zaijicek et al.,2 Watson et al.,15 and Martin-Sanchez et al.,16 where different
selection criteria were applied: the Zajicek review focused on MS patients, the Watson review
was limited to head-to-head trials, while the Martin-Sanchez review was limited to placebo-
controlled studies. Because the three reviews did not provide additional information, we
summarized the evidence from the Lynch review in this report.

Randomized controlled trials

Pooyania et al. conducted a double-blinded, crossover study to assess the effect of nabilone on
spasticity in patients with spinal cord injury.17 The inclusion criteria were patients aged between
18 and 65 years, with the level of injury at C5 or below, and in whom the injury occurred more
than one year ago. The patients had to have demonstrated stable neurologic level in the last six
months, with moderate spasticity (Ashworth ≥3), unchanged spasticity medications (concomitant
medications were not specified) for at least 30 days before enrollment, and no botulinum toxin
injections for more than four months. The exclusion criteria were as follows: presence of heart
disease; a history of psychotic disorders, schizophrenia or any active psychologic disorder;
previously documented sensitivity to marijuana or other cannabinoid agents; severe liver
dysfunction; cognitive impairment; a major illness in another body area; being pregnant or
nursing mother; a history of drug dependency, having smoked cannabis less than 30 days
before the onset of the study or unwilling to give up smoking during the study; or fixed tendon
contractures. Twelve patients were recruited. The participants were randomized using a
computerized randomization system, to receive either nabilone (0.5 mg once daily to 0.5 mg
twice daily depending on the tolerance of drug/placebo-related side effects) or placebo in the
first 4-week period. After a 2-week washout period, the patients were crossed over to the
opposite arm. The total study duration was 10 weeks. One patient dropped out of the study from
the placebo arm because of unrelated causes. The primary outcome was the Ashworth Scale
for spasticity in the most involved muscle group of the body. The secondary outcome measures
included the sum of the Ashworth Scale in the eight muscle groups bilaterally, and the visual
analog scale (VAS) for spasticity.

Another double-blinded, crossover RCT was conducted by Ware et al.18. Nabilone was
compared with an active control, amitriptyline in patients with fibromyalgia. Eligible patients were
adult men and nonpregnant women aged 18 or older with a diagnosis of fibromyalgia. They
remained on stable analgesic therapy (no details were provided) but were required to have a
negative urine screen for cannabinoids at baseline. Patients were excluded if they had cancer
pain, unstable cardiac disease, a history of psychotic disorder, seizure disorder, glaucoma,
urinary retention, hypersensitivity to the study drugs, or were taking monoamine oxidase
inhibitors. Thirty-two patients were enrolled and 29 completed the study. The study used a 2-
period crossover design. Each period was of two weeks duration separated by a 2-week
washout period. The primary outcome was the quality of sleep measured by the Insomnia
Severity Index (ISI). The secondary outcomes included pain, which was assessed by the McGill
Pain Questionnaire (MPQ).

Nabilone for Chronic Pain Management 4

Non-randomized controlled trials

Bestard et al. conducted a non-randomized trial of nabilone and gabapentin in the management
of NP in patients with peripheral neuropathy.19 Patients were excluded if they had an alternative
diagnosis that could explain their symptoms or if an alternative source of pain made it
impossible for the patients to differentiate their NP from other causes of pain. The patients
without prior medications for pain 30 days before initial assessment received monotherapy of
nabilone or gabapentin. Flexible dosing was used for all patients, and medication doses were
titrated up gradually. The primary outcome was the degree of NP which was evaluated using a
10-cm VAS. Secondary outcomes were quality of life measured by various assessment tools,
such as the Brief Pain Inventory (BPI), EuroQol 5 Domains (EQ-5D), Medical Outcomes Sleep
Study Scale (MOSSS), Hospital Anxiety and Depression Scale (HADs), and Short-Form 36
Health Survey (SF-36). The patients were followed for six months. A total of 101 patients were
included.

Another non-randomized prospective study was conducted by Maida et al., to evaluate the
effectiveness of adjuvant nabilone therapy for pain management in patients with advanced
cancer.20 Data were collected between January 2005 and October 2006. Eligible patients had a
diagnosis of cancer and survived for at least 48 hours after the initial consultation. The
Edmonton Symptom Assessment System (ESAS) questionnaire was completed at baseline and
at least once within 60 days of baseline. Treatment had to start on the day of initial assessment
and continued for at least 48 hours. The decision to prescribe nabilone was based on the
presence of severe symptom-related distress at the initial consultation. The nabilone dosage
ranged from one to two mg per day. Two primary outcomes evaluated were the differences
between treated and untreated patients at one month follow-up in ESAS pain scores and the
differences between treated and untreated patients at one month follow-up in total morphine-
sulfate-equivalent (MSE) use. When using MSE, all opioid dosages were converted to morphine
sulfate equivalents according to generally accepted conversion ratios, and these calculations
were summed. Statistical methods were adopted to adjust for the unbalanced baseline patient
characteristics. In total, 112 patients were enrolled in the study, with 47 patients treated with
nabilone and 65 untreated patients. Among the 47 patients receiving nabilone, 51% of patients
were prescribed nabilone for pain relief, 26% to relieve nausea, and 23% for anorexia. The
mean daily dose of nabilone was 1.79 mg. The mean duration from baseline to patient’s one-
month assessment was 23.8 days in the treated group and 23.2 days in the untreated group.

Guidelines

Three sets of guidelines were found. Two of these included recommendations on dosing.

Namaka and coworkers from Canada updated a treatment algorithm for NP that was developed
in 2004.21 A comprehensive search was performed to include studies published between 1980
and 2009. The authors did not describe the methods of evidence grading.

A group of Latin American experts developed guidelines for the diagnosis and management of
NP.22 Publications of management guidelines of NP were identified through multiple databases
since 2003 onwards, with a special interest in those published in Latin American countries. In
total, four documents from Mexico, Colombia, Ecuador and Venezuela were retrieved from the
literature search. There were 17 specialists in the workgroup. They reviewed the selected
reference material and presented and discussed the recommendations in a plenary session.
With regards to the comments received and for the changes proposed by the plenary group, a

Nabilone for Chronic Pain Management 5

final report was initiated and voted on. Consensus was reached when 80% of the participants
agreed. If voting for the item in consideration did not achieve the necessary 80%, new opinions
and comments were incorporated until the ≥80% limit was agreed upon.

The Scottish Intercollegiate Guidelines Network (SIGN) published guidelines on the control of
pain in adults with cancer in 2008.23 Multidisciplinary guideline development groups with
representation from across Scotland were involved during the process, and the groups
comprised representatives from various health care areas. Literature searches were carried out
from 1997 to June 2007. The guidelines will be considered for review in three years. The
guideline recommendations are based on a systematic review of best available evidence. The
grade of recommendation relates to the strength of the supporting evidence on which the
evidence is based (Grade A: at least one high quality meta-analysis, systematic review of
randomized controlled trials, or randomized controlled trial with a very low risk of bias and
directly applicable to the target population; or a body of evidence consisting principally of well
conducted meta-analyses, systematic reviews of randomized controlled trials, or randomized
controlled trials with a low risk of bias directly applicable to the target population, and
demonstrating overall consistency of results. Grade B: a body of evidence including studies
rated as high quality systematic reviews of case-control or cohort studies, and high quality case-
control or cohort studies with a very low risk of confounding or bias and a high probability that
the relation is causal and which are directly applicable to the target population, and with overall
consistency of results; or extrapolated evidence from studies described in A. Grade C: a body of
evidence including well conducted case-control or cohort studies with a low risk of confounding
or bias and a moderate probability that the relation is causal and which are directly applicable to
the target population and with overall consistency of results; or extrapolated evidence from
studies described in B. Grade D: non-analytic studies, such as case reports, case series, expert
opinion; or extrapolated evidence from studies described in C).

Summary of Critical Appraisal

Details on the critical appraisal of individual studies are presented in Appendix 5.

Systematic review

The systematic review by Lynch et al. described the research questions and selection criteria.
Multiple databases were searched without limits to publication date or language. It declared
conflicts of interest and funding sources. However, the identified individual RCTs had sample
sizes that ranged from 13 to 96 patients and trial durations of less than 14 weeks. The number
of included RCTs of nabilone was four.

Randomized controlled trials

The included RCTs described the objectives, inclusion criteria, and outcome measures of the
study. Also, conflicts of interest and funding sources were reported.

The quality of the results from these RCTs may be compromised due to their sample sizes. One
trial included 12 patients with pain due to spasticity and the other included 32 patients with
fibromyalgia. Patients in both trials were allowed to take concomitant analgesics or medications
for breakthrough pain, however no details were provided.

Nabilone for Chronic Pain Management 6

Non-randomized controlled trials

Both studies declared the funding sources and conflicts of interest.

Data in one of the prospective study20 showed that patients treated with nabilone were
physically weaker, with more severe pain and other symptoms. The authors adjusted the
baseline differences between the groups using two statistical methods. Another limitation
identified by the authors was that the investigator was not blinded to patient status when
evaluating outcomes at baseline and at follow-up.

Guidelines

The guideline of the treatment for NP21 by Namaka et al. was an update of an earlier evidence-
based guideIine (2004) developed by the same authors. It did not specify whether the evidence
was graded and how the recommendations were generated. The evidence identified through the
literature search did not find RCTs of nabilone on pain management. Their recommendations
were based on existing guidelines and non-randomized controlled trials. The document was
supported by manufacturer.

The Latin American guidelines22 took into account the particular conditions of medical practice in
this region, since the available North American guidelines or European guidelines do not
necessarily reflect the clinical practice in Latin America. The guidelines described how the
recommendations were developed.

For the SIGN guidelines, one of the coauthor received research grants from industry for writing
the summary of the recommendation.23 Details with regards to the methods and process of the
development of the SIGN guidelines are not available; therefore, it was not possible to
thoroughly examine the quality of these guidelines.

Summary of Findings

Details of the main study findings and authors’ conclusions are presented in Appendix 6.

Clinical effectiveness of nabilone in adults for chronic pain management

Pain management

Systematic review

The systematic review by Lynch et al.6 included four RCTs that examined the efficacy of
cannabinoids in chronic non-cancer pain: one was a head-to-head trial comparing nabilone with
dihydrocodeine, and three were placebo-controlled trials. The head-to-head trial indicated that
for patients with chronic NP, nabilone has similar effects as dihydrocodeine on pain relief
measured by pain scores in a 10 cm-VAS, even though significantly more patients treated with
dihydrocodeine had a drop of more than 10 mm in the VAS. The results should be interpreted
with cautions due to the high dropout rates in the study population (about one third of patients
did not complete the study). When compared with placebo, nabilone significantly decreased the
pain measured by VAS or 11-Point-Box-Test in patients with fibromyalgia, spasticity-related or
spinal pain.

Nabilone for Chronic Pain Management 7

Randomized controlled trials

All participants in the Pooyania study17 were men, with an average age of 42 years. Baseline
characteristics were balanced between groups except a significantly higher baseline sum of
Ashworth observed in the active treatment period than the placebo period (35.6 versus 25.1,
p<0.005). This was deemed as “occurred by coincidence” by the authors. Spasticity improved
significantly in the most spastic muscle group when patients were treated with nabilone, as
measured by the Ashworth scale (p=0.003). It found no significant difference between the
treatment and placebo periods with regards to pain relief measured by VAS (p=0.076).

In total, 32 patients were enrolled in the Ware study18, and 29 of them completed it. The mean
age in the study group was 49.5 years. Nabilone was found to have a greater effect on sleep
than amitriptyline on the ISI (p<0.05); no difference was detected between treatments for pain,
measured with MPQ (p>0.05).

Non-randomized controlled trials

One non-RCT compared the effectiveness of nabilone with gabapentin in patients with NP.19
Patients in each treatment group were similar with regards to age, sex and severity of NP prior
to the study initiation. Significant improvement in VAS pain scores after six months of treatment
was observed for both nabilone- and gabapentin-treated patients. In the nabilone group, the
VAS pain score was reduced from 45.8±11.3 (mean ± standard deviation) to 28.0±10.5; for
gabapentin, the VAS pain score was reduced from 50.2±13.5 to 33.8±11.6. The authors
indicated that the differences were statistically significant, but the p values were not reported.
Some improvement was observed in the domain of average pain in BPI in either group as well
(nabilone, decreased from 4.7±2.3 at baseline to 4.1±1.9 at 6-month; gabapentin, decreased
from 4.8±2.4 at baseline to 4.2±2.0 at 6-month. P values were not provided). The results implied
that the benefits (pain relief and improved QOL) of nabilone in the management of NP were
comparable to gabapentin. However, there was no direct comparison between nabilone and
gabapentin regarding the clinical effectiveness in pain or QOL.

Results from another non-RCT20 indicated that cancer pain was reduced significantly in patients
treated with nabilone (ESAS symptom score 3.0 versus 5.5, p<0.001) as adjunct therapy
compared to no nabilone. Medication use measured by MSE was significantly reduced in
treated patients (total MSE 3.7 versus 4.3, p <0.001).

Quality of Life

Systematic review

Compared with placebo, the results from the systematic review indicated that nabilone
significantly improved the QOL measured by FIQ and the Mezzich & Cohen QOL-score, in
patients with fibromyalgia or chronic therapy-resistant pain related to skeletal and locomotor
system disorders.6

Non-randomized controlled trials

In one non-RCT19 that examined the effects of nabilone in patients with NP, there were no
significant improvements in EQ-5D scores, EQ health status scores, or total HADS scores at six
months follow up from baseline for either nabilone or gabapentin; however, significant

Nabilone for Chronic Pain Management 8

improvement was observed for the domains of pain or discomfort within the EQ-5D (data not
shown in the article). When assessed by SF-36, both nabilone and gabapentin therapy led to
significant improvement in domains of Physical Functioning, and Bodily Pain from baseline to 6-
month follow up (Physical Functioning: nabilone, increased from 35.6±25.5 to 43.7±26.4;
gabapentin, increased from 35.4±25.4 to 42.6±23.4. Bodily Pain: nabilone, increased from
26.9±20.3 to 39.6±14.4; gabapentin, increased from 26.2±22.0 to 38.3±19.1. P values were not
provided).
Clinical effectiveness of nabilone in adults with multiple sclerosis for chronic pain
management

Randomized controlled trials

One double-blind, placebo-controlled, crossover RCT12 was included in the Lynch review6. It
enrolled 13 patients with spasticity-related pain resulting from MS. The data in this study
showed that nabilone significantly decreased pain, while spasticity, motor function and activities
of daily living did not change.

Safety of nabilone in adults for chronic pain management

Systematic reviews

The Lynch review6 found that there were no serious adverse effects in treatment with
cannabinoids. Adverse effects most commonly reported were generally well tolerated, mild to
moderate in severity, and led to withdrawal from the studies in only a few cases.

Randomized controlled trials

In the Pooyania study,17 nabilone was tolerated by all the patients. Adverse events occurred in
eight out of 11 patients in the nabilone-treated period, while no patients in the placebo-treated
period reported such events. No serious adverse events emerged and no dropouts due to
adverse events occurred during the trial. The reported adverse events included drowsiness, dry
mouth, asthenia, vertigo, mild ataxia, headache and lack of motivation.

In the Ware study,18 a total of 187 adverse events were observed during the trial, of which 120
were mild and 64 were moderate. Two severe adverse events were reported with amitriptyline
and one severe adverse event (drowsiness) occurred during nabilone therapy. It is unclear if
this was treatment-related. Fifty-three adverse events were considered possibly related to
amitriptyline therapy, while 91 adverse events were considered possibly related to nabilone
therapy. The most common adverse events occurred in the nabilone period were dizziness
nausea, dry mouth and drowsiness.

Non-Randomized controlled trials

In the Bestard study,19 nabilone-treated patients tended to have fewer overall adverse events
when compared with those treated with gabapentin (38% versus 48%). Sedation occurred in 6%
of nabilone-treated patients and 15% of gabapentin-treated patients; dizziness occurred in 4%
of nabilone-treated patients and 8% of gabapentin-treated patients. Patients in the nabilone
group were less likely to discontinue the treatment due to drug intolerance compared with
gabapentin at 6-month follow up (n=5 versus n=12). Statistical comparisons were not performed
between the two treatment groups.

Nabilone for Chronic Pain Management 9

Clinical evidence on the safety of nabilone in adults with multiple sclerosis for chronic
pain management

The Wissel study12 which was included in the Lynch review6 reported adverse events in five
patients: one patient with moderate transient weakness of the lower limbs (nabilone phase,
patient dropped out), three patients with mild drowsiness (2 in nabilone phase, 1 in placebo
phase) and one patient with mild dysphagia (placebo phase). One patient was excluded from
the study due to an acute relapse of MS in the nabilone phase.

Evidence-based guidelines and recommendations for the dosing of nabilone in adults for
chronic pain management

The literature search identified three evidence-based guidelines.21-23

In the treatment algorithm developed by Namaka et al.,21 based on the findings from the
literature search, the authors indicated nabilone should be reserved as adjunctive combination
therapy for breakthrough episode of NP. The dosage should be titrated gradually at weekly
increments of 0.5 mg until target relief is obtained or maximal dosing of 1 mg twice daily is
achieved.

The main recommendations provided by a group of Latin American experts22 on neuropathic

pain were as follows:

1) Multimodal treatment is preferred when starting therapy, in that drugs are loosely
classified into four groups: A (for example, lidocaine patch), B (for example, gabapentin
and fast-acting opioids), C (for example, duloxetine and slow-released opioids), and D (for
example, cannabinoids); therapeutic groups show preference levels in descending order,
which means that Group A is considered first, and in case of unsatisfactory response with
monotherapy or combination therapy with Group A drugs, it is recommended to replace or
combine with drugs from Group B, C or D.

2) For most patients, a combination of medications is recommended in cases of inadequate

response from monotherapy.

3) For localized peripheral neuropathies (such as postherpetic neuralgia and diabetic

neuropathy), diffuse peripheral neuropathies (such as nutritional/metabolic disorders and
adverse effects related to chemotherapy), and central neuropathic pain (injury of spinal
cord or brain due to trauma, inflammation, or multiple sclerosis), cannabinoids may be
used when an inadequate treatment effect from drugs in Group C is observed.
Recommended dose of nabilone is 0.5 mg twice daily to 1 mg twice daily.

4) No recommendation of the use of drugs in Group D for patients with mixed nonmalignant
pain (such as chronic back pain caused by osteoarthritis, or herniated disc), cancer pain,
or trigeminal neuralgia is provided.

The SIGN guidelines do not recommend cannabinoids for the treatment of cancer pain (Grade A
recommendation).23

Nabilone for Chronic Pain Management 10

Limitations

Although most of the included individual studies were double-blind RCTs, several of these
compared nabilone with placebo; therefore, the effectiveness of nabilone relative to an existing
active treatment has not been adequately assessed. Quality of the individual studies varied.
Methods of allocation concealment were not reported in many of the trials. The sample size of
these trials (range of 13 patients to 96 patients in RCTs) does not allow us to make solid
conclusions from the study findings. The duration of the trials ranged from four weeks to 14
weeks. Evidence of longer-term benefits and harms of nabilone in chronic pain management is
lacking.

The etiologies of chronic pain evaluated in this review were different (for example, neuropathic
pain, cancer pain, spasticity, fibromyalgia etc.). It, therefore, is a challenge to synthesize data
from the varied populations. Moreover, the evidence of effectiveness of nabilone on MS patients
is sparse. The only available data were identified from one RCT that recruited 13 patients.

CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING:

In total, four SRs, two RCTs, two non-RCTs and three evidence-based guidelines are included
in this review. The conditions examined in these studies include non-cancer pain, such as NP,
fibromyalgia, spasticity-related pain resulting from MS and spinal pain, and cancer pain.

Evidence from these placebo-controlled trials indicated that nabilone statistically significantly
reduces severity of pain in patients with chronic non-cancer pain. Limited evidence from head-
to-head trials suggests that nabilone was not better than an existing analgesic agent
(dihydrocodeine and amitriptyline) in pain management. An RCT of 13 MS patients found that
nabilone was more efficient in spasticity-related pain. A solid conclusion regarding the clinical
effectiveness of nabilone on chronic pain management cannot be made based on the available
evidence. Overall, nabilone was well-tolerated among the study populations, where the most
common adverse events included dizziness, nausea and dry mouth.

The current evidence-based guidelines recommend the dosage of nabilone for treating
neuropathic pain should be titrated gradually at weekly increments of 0.5 mg until target relief is
obtained or maximal dosing of 1 mg twice daily is reached.

The majority of the studies were conducted in Canada, which may be more helpful in guiding
the use of nabilone in chronic pain management in the Canadian population. Additional well-
designed, large-scale randomized trials with longer-term follow-up are required to evaluate the
clinical effectiveness and safety of nabilone in patients with chronic pain.

PREPARED BY:
Canadian Agency for Drugs and Technologies in Health
Tel: 1-866-898-8439
www.cadth.ca

Nabilone for Chronic Pain Management 11

References

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treatment of chronic pain. Ann Pharmacother. 2006 Feb;40(2):251-60.

2. Zajicek JP, Apostu VI. Role of cannabinoids in multiple sclerosis. CNS Drugs.
2011;25(3):187-201.

3. Martin CW, WCB Evidence Based Practice Group (EBPG). Efficacy of marijuana in
treating chronic non cancer pain: a short review [Internet]. [place unknown]: WorkSafeBC;
2006 Jun 22. [cited 2011 Oct 28]. Available from:
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5. Turcotte D, Le Dorze JA, Esfahani F, Frost E, Gomori A, Namaka M. Examining the roles
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Nabilone for Chronic Pain Management 13

APPENDIX 1: Selection of Included Studies

167 citations identified from

electronic literature search and
screened

142 citations excluded

25 potentially relevant articles

retrieved for scrutiny (full text, if
available)

0 potentially relevant
reports retrieved from
other sources (grey
literature, hand
search)

25 potentially relevant reports

14 reports excluded:
irrelevant population (2)
irrelevant intervention (4)
already included in at least
one of the selected
systematic reviews (4)
published in language other
than English (1)
other (review articles,
editorials)(3)

11 reports included in review

4 SRs
2 RCTs
2 non-RCTs
3 clinical practice
guidelines

Nabilone for Chronic Pain Management 14

Appendix 2. Summary of Study Characteristics for Systematic Review

First Study Design Patient Intervention Comparator Clinical

Author, Characteristics Outcomes
Publication Measured
Year,
Country
Lynch, SR Chronic non- Nabilone Dihydrocodeine* Pain score in
2011, Included 18 cancer pain: 0.25- 240mg/day VAS or other
Canada6 RCTs of NP, 2mg/day scales
cannabinoids; fibromyalgia, Or placebo
nabilone was spasticity QOL
examined in 4 related pain,
DB crossover and pain related
or parallel to skeletal and
RCTs locomotor
(described system
below) diseases

RCTs included in the Lynch review

Frank et al., DB, crossover, Chronic NP Nabilone Dihydrocodeine‡ Pain score in

200813 active- 2mg/day 240mg/day VAS
controlled, 96
patients + + concomitant QOL
enrolled concomitant analgesics measured
analgesics with SF-36
Trial duration:
14 weeks,
including two
6-week
treatment
periods and
one 2-week
washout
period

Skrabek et DB, placebo- Fibromyalgia Nabilone Placebo Pain score on

al., 200811 controlled, 1-2mg/day VAS
parallel, 40 + other oral
patients + other oral medications for QOL
randomized medications fibromyalgia measured
for with FIQ
Trial duration: fibromyalgia
4 week
treatment and
4 week follow-
up

Wissel et DB, crossover, Spasticity- Nabilone Placebo Pain score in

Nabilone for Chronic Pain Management 15

First Study Design Patient Intervention Comparator Clinical
Author, Characteristics Outcomes
Publication Measured
Year,
Country
al., 200612 placebo- related pain 1mg/day 11-Point-Box-
controlled, 13 resulting from + concomitant Test
patients MS + analgesic
randomized concomitant therapy
analgesic
Trial duration: therapy
9 weeks,
including two
4-week
treatment
periods and 1-
week washout
period

Pinsger et DB, crossover, Chronic Nabilone Placebo Spinal pain

al., 200614 placebo- therapy- 0.25- intensity in
controlled, 30 resistant pain 1mg/day + standard VAS
patients related to therapy
randomized skeletal and + standard QOL
locomotor therapy measured
Trial duration: system disorder with Mezzich
14 weeks, & Cohen
including two QOL-score
4-week
treatment
periods and
washout
period

DB=double-blind; FIQ=Fibromyalgia Impact Questionnaire; MS=multiple sclerosis; NP=neuropathic pain;

QOL=quality of life; RCT=randomized controlled trial; SF-36=Short Form-36 Health Survey;
SR=systematic review; VAS=visual analogue scale
* a codeine derivative not available in Canada

Nabilone for Chronic Pain Management 16

Appendix 3. Summary of Study Characteristics for RCTs and non-RCTs

First Study Patient Intervention Comparator Clinical

Author, Design Characteristics Outcomes
Publication Measured
Year,
Country
Pooyania, DB, placebo- Spasticity Nabilone Placebo Spasticity
2010, controlled related to spinal 0.5-1mg/day measured by
Canada17 crossover cord injury + concomitant Ashworth scale
RCT + medications for
concomitant spasticity Pain score in
12 patients medications VAS
enrolled, for spasticity
study
duration 10
weeks
Ware, DB, active- Fibromyalgia Nabilone Amitriptyline Sleep quality
2010, controlled 0.5-1mg/day 10-20mg/day measured by ISI
Canada18 crossover
RCT + + concomitant Pain measured
concomitant analgesic with MPQ
32 patients analgesic therapy
enrolled, therapy
study
duration 10
weeks
Bestard, Non-RCT, NP Nabilone Gabapentin VAS pain
2011, prospective 3mg/day 2.3mg/day scores
Canada19 study (mean)
49 patients QOL measured
101 patients 52 patients by various tools
enrolled
Maida, Non-RCT, Cancer pain Nabilone No nabilone ESAS pain
2008, prospective 1-2mg/day score
Canada20 study + concomitant
+ palliative care Medication use
112 patients concomitant measured by
enrolled palliative 65 patients MSE
care

47 patients
DB=double-blind; ESAS=The Edmonton Symptom Assessment System; ISI=Insomnia Severity Index;
MPQ=McGill Pain Questionnaire; MSE=morphine-sulfate-equivalent; NP=neuropathic pain; QOL=quality
of life; RCT=randomized controlled trial; VAS=visual analogue scale

Nabilone for Chronic Pain Management 17

APPENDIX 4: Instruments Used in the Studies Reviewed in this Report

Ashworth scale
This is a common clinical approach to the routine measurement of levels of spasticity, higher
score indicates more severe spasticity.17

ESAS
The Edmonton Symptom Assessment System is a 10-item, patient- or caregiver-rated, validated
tool to assess the most prevalent symptoms in palliative care patients. The severity of the 10
items, including pain, was rated on a 10-point scale, with 0=absence of the symptom and
10=the worst possible severity.20

FIQ
Fibromyalgia Impact Questionnaire is a validated, self-administered test, scored out of 100, that
evaluates physical function, work status, depression, anxiety, sleep, pain, stiffness, fatigue, and
well-being in patients with fibromyalgia. Higher score indicates greater impact of fibromyalgia on
the patient’s quality of life.11

ISI
Insomnia Severity Index is a reliable and valid instrument used to quantify perceived insomnia
severity and is used as an outcome measure in insomnia treatment research. Higher score
indicated poorer sleep quality.18

MPQ
McGill Pain Questionnaire is a validated instrument frequently used in clinical trials of analgesic
medications.18

VAS
Visual analog scale is an unmarked 10 cm line between anchors of “no pain” on the left (0) and
“worst possible pain” on the right (10). It was demonstrated as valid and reliable in rating pain
intensity.19

11-Point-Box-Test
This is a measure of spasticity-related pain, in which patients rated their pain from 0 to 10 (11-
point scale), with 0 representing no pain and 10 representing the other extreme of pain
intensity.12

Nabilone for Chronic Pain Management 18

APPENDIX 5: Summary of Critical Appraisal

First Author, Strengths Limitations

Publication Year
Systematic review

Lynch, 2011, Research questions and Included RCTs were small,

Canada6 selection criteria clearly with short trial durations
provided List of excluded studies not
Comprehensive literature provided
search based on pre-defined List of study characteristics
criteria, no limits on date or lacked detail
language
Methods were used to
minimize reviewer errors and
bias in the selection of studies,
assessment of validity, and
data extraction
List of included studies
provided
Conflicts of interest stated
Randomized controlled trials

Pooyania, 2010, Objectives, inclusion criteria, No power calculation

Canada17 and outcome measures clearly Small sample size (n=12)
described makes it difficult to reach
Patients and clinicians were firm conclusion
blinded to the treatment Number of loss to follow-up
Adequate method of unable to determine
randomization Study mostly focused on
Results were appropriately spasticity; pain was a
reported secondary outcome
Compliance with the
intervention was reliable
Ware, 2010, Objectives, inclusion criteria, Small sample size (n=32)
Canada18 and outcome measures clearly makes it difficult to reach
described firm conclusion
Allocation concealment Pain was not primary
unclear outcome
Adequate method of
randomization Patients,
nurses and clinicians were
blinded to the treatment
Results were appropriately
reported
Loss to follow-up was reported
Sample size estimation
provided
Non-Randomized controlled trials

Nabilone for Chronic Pain Management 19

First Author, Strengths Limitations
Publication Year

Bestard, 2011, Objectives, inclusion criteria, Non-randomized study

Canada19 and outcome measures clearly design led to unbalanced
described baseline characteristics,
Statistical methods to adjust even if statistical methods
for baseline differences were were used to adjust the
adopted unbalance
Results were appropriately No sample size calculation
reported
Potential confounders
identified
Maida, 2008, Objectives, inclusion criteria, Patients had cancer and
Canada20 and outcome measures clearly used nabilone as adjuvant
described treatment (only 50% of
Results were appropriately nabilone patients were
reported treated for pain; the
remainder were treated for
nausea or anorexia)
No sample size calculation
Potential confounders not
identified

Nabilone for Chronic Pain Management 20

APPENDIX 6: Summary of Findings for Chronic Pain Management from SRs and RCTs

First Author, Main Study Findings Conclusions

Publication Year
Systematic review

Lynch, 20116 4 RCTs compared nabilone with placebo or Nabilone may be better
(results from 4 active control. Number of patients ranged than placebo in
primary studies11-14) from 13 to 96. Trial durations were less relieving chronic pain;
than 14 weeks, and treatment duration of its relative benefits
the study drug ranged from 4 to 6 weeks. compared to other
analgesics (e.g.
Compared to placebo: dihydrocodeine) were
-Significant decrease in pain measured by not proven.
VAS or 11-Point-Box-Test in patients with
fibromyalgia, spasticity-related or spinal
pain.
-QOL measured by FIQ:
Decreased from baseline for nabilone:
-12.7, p<0.02
-QOL measure by Mezzich & Cohen QOL-
score:
Increased from baseline:
Nabilone:
5.0(0.8;10.8)(median[interquartile])
Placebo: 2.0(-2.3,8.0)

Compared to dihydrocodeine13 in patients

with NP:
- Both agents resulted in approximately a
10mm reduction in VAS:
Baseline 69.6mm (range 29.4-95.2);
Study end:
Nabilone 59.9±24.4 (mean±SD)mm,
Dihydrocodeine 58.6±24.1 mm.
-Number of patients with ≥10mm drop in
VAS:
Nabilone: 3/64*
Dihydrocodeine: 12/64*, significant
difference
-QOL measured by SF-36:
SF-36 data better with dihydrocodeine.
Randomized controlled trials

Pooyania, 201017 Ashworth in most involved muscle group: Nabilone reduced

Mean at baseline: 7.63 spasticity in people
Mean after placebo period: 7.45 with spinal cord injury.
Mean after treatment period: 6.54 No significant
Mean difference±SD between treatment difference in pain relief
and placebo: 0.91±0.85, p=0.003 with compared with

Nabilone for Chronic Pain Management 21

First Author, Main Study Findings Conclusions
Publication Year
placebo.
VAS:
Mean at baseline: 46.18
Mean after placebo period: 53.18
Mean after treatment period: 44.09
Mean difference±SD between treatment
and placebo: 9.09±16.97, p=0.076

Ware, 201018 ISI: Nabilone was effective

Difference between groups: in improving sleep in
-3.25 (95%CI -5.26, -1.24) patients with
fibromyalgia and well
MPQ: tolerated.
Difference between groups:
-0.1 (95%CI -0.3, 0.2) Nabilone had no
effects on pain relief.

CI=confidence interval; FIQ=Fibromyalgia Impact Questionnaire; ISI=Insomnia Severity Index;

MPQ=McGill Pain Questionnaire; NP=neuropathic pain; QOL=quality of life; RCT=randomized controlled
trial; SD=standard deviation; SF-36=Short-Form 36 Health Survey; SR=systematic review; VAS=visual
analog scale
*Per protocol dataset

Nabilone for Chronic Pain Management 22