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Cannabinoids for fibromyalgia

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Abstract and Figures

Background: This review is one of a series on drugs used to treat fibromyalgia. Fibromyalgia is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue affecting approximately 2% of the general population. People often report high disability levels and poor health-related quality of life (HRQoL). Drug therapy focuses on reducing key symptoms and disability, and improving HRQoL. Cannabis has been used for millennia to reduce pain and other somatic and psychological symptoms. Objectives: To assess the efficacy, tolerability and safety of cannabinoids for fibromyalgia symptoms in adults. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE to April 2016, together with reference lists of retrieved papers and reviews, three clinical trial registries, and contact with trial authors. Selection criteria: We selected randomised controlled trials of at least four weeks' duration of any formulation of cannabis products used for the treatment of adults with fibromyalgia. Data collection and analysis: Two review authors independently extracted the data of all included studies and assessed risk of bias. We resolved discrepancies by discussion. We performed analysis using three tiers of evidence. First tier evidence was derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for drop-outs; at least 200 participants in the comparison, eight to 12 weeks' duration, parallel design), second tier evidence from data that did not meet one or more of these criteria and were considered at some risk of bias but with adequate numbers (i.e. data from at least 200 participants) in the comparison, and third tier evidence from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation). Main results: We included two studies with 72 participants. Overall, the two studies were at moderate risk of bias. The evidence was derived from group mean data and completer analysis (very low quality evidence overall). We rated the quality of all outcomes according to GRADE as very low due to indirectness, imprecision and potential reporting bias.The primary outcomes in our review were participant-reported pain relief of 50% or greater, Patient Global Impression of Change (PGIC) much or very much improved, withdrawal due to adverse events (tolerability) and serious adverse events (safety). Nabilone was compared to placebo and to amitriptyline in one study each. Study sizes were 32 and 40 participants. One study used a cross-over design and one used a parallel group design; study duration was four or six weeks. Both studies used nabilone, a synthetic cannabinoid, with a bedtime dosage of 1 mg/day. No study reported the proportion of participants experiencing at least 30% or 50% pain relief or who were very much improved. No study provided first or second tier (high to moderate quality) evidence for an outcome of efficacy, tolerability and safety. Third tier (very low quality) evidence indicated greater reduction of pain and limitations of HRQoL compared to placebo in one study. There were no significant differences to placebo noted for fatigue and depression (very low quality evidence). Third tier evidence indicated better effects of nabilone on sleep than amitriptyline (very low quality evidence). There were no significant differences between the two drugs noted for pain, mood and HRQoL (very low quality evidence). More participants dropped out due to adverse events in the nabilone groups (4/52 participants) than in the control groups (1/20 in placebo and 0/32 in amitriptyline group). The most frequent adverse events were dizziness, nausea, dry mouth and drowsiness (six participants with nabilone). Neither study reported serious adverse events during the period of both studies. We planned to create a GRADE 'Summary of findings' table, but due to the scarcity of data we were unable to do this. We found no relevant study with herbal cannabis, plant-based cannabinoids or synthetic cannabinoids other than nabilone in fibromyalgia. Authors' conclusions: We found no convincing, unbiased, high quality evidence suggesting that nabilone is of value in treating people with fibromyalgia. The tolerability of nabilone was low in people with fibromyalgia.
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Cochrane Database of Systematic Reviews
Cannabinoids for fibromyalgia (Review)
Walitt B, Klose P, Fitzcharles MA, Phillips T, Häuser W
Walitt B, Klose P, Fitzcharles MA, Phillips T, Häuser W.
Cannabinoids for fibromyalgia.
Cochrane Database of Syst ematic Reviews 2016, Issue 7. Art. No.: CD011694.
DOI: 10.1002/14651858.CD011694.pub2.
www.cochranelibrary.com
Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
10RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
13DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
28NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iCannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]
Cannabinoids for fibromyalgia
Brian Walitt1,2, Petra Klose3, Mary-Ann Fitzcharles4, Tudor Phillips5, Winfried Häuser6
1National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, MD, USA. 2National Institute
of Nursing Research, National Institutes of Health, Bethesda, MD, USA. 3Department of Internal and Integrative Medicine, Kliniken
Essen-Mitte, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany. 4Division of Rheumatology, Montreal General
Hospital, McGill University Health Centre, Montreal, Canada. 5Pain Research and Nuffield Department of Clinical Neurosciences
(Nuffield Division of Anaesthetics), University of Oxford, Oxford, UK. 6Department of Psychosomatic Medicine and Psychotherapy,
Technische Universität München, München, Germany
Contact address: Winfried Häuser, Department of Psychosomatic Medicine and Psychotherapy, Technische Universität München,
Langerstr. 3, München, D-81675, Germany. whaeuser@klinikum-saarbruecken.de.
Editorial group: Cochrane Pain, Palliative and Supportive Care Group.
Publication status and date: Stable (no update expected for reasons given in ’What’s new’), published in Issue 7, 2016.
Review content assessed as up-to-date: 26 April 2016.
Citation: Walitt B, Klose P, Fitzcharles MA, Phillips T, Häuser W. Cannabinoids for fibromyalgia. Cochrane Database of Systematic
Reviews 2016, Issue 7. Art. No.: CD011694. DOI: 10.1002/14651858.CD011694.pub2.
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
This review is one of a series on drugs used to treat fibromyalgia. Fibromyalgia is a clinically well-defined chronic condition of unknown
aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue affecting approximately 2%
of the general population. People often report high disability levels and poor health-related quality of life (HRQoL). Drug therapy
focuses on reducing key symptoms and disability, and improving HRQoL. Cannabis has been used for millennia to reduce pain and
other somatic and psychological symptoms.
Objectives
To assess the efficacy, tolerability and safety of cannabinoids for fibromyalgia symptoms in adults.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE to April 2016, together with
reference lists of retrieved papers and reviews, three clinical trial registries, and contact with trial authors.
Selection criteria
We selected randomised controlled trials of at least four weeks’ duration of any formulation of cannabis products used for the treatment
of adults with fibromyalgia.
Data collection and analysis
Two review authors independently extracted the data of all included studies and assessed risk of bias. We resolved discrepancies by
discussion. We performed analysis using three tiers of evidence. First tier evidence was derived from data meeting current best standards
and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without
imputation for drop-outs; at least 200 participants in the comparison, eight to 12 weeks’ duration, parallel design), second tier evidence
from data that did not meet one or more of these criteria and were considered at some risk of bias but with adequate numbers (i.e.
data from at least 200 participants) in the comparison, and third tier evidence from data involving small numbers of participants that
1Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
were considered very likely to be biased or used outcomes of limited clinical utility, or both. We assessed the evidence using GRADE
(Grading of Recommendations Assessment, Development and Evaluation).
Main results
We included two studies with 72 participants. Overall, the two studies were at moderate risk of bias. The evidence was derived from
group mean data and completer analysis (very low quality evidence overall). We rated the quality of all outcomes according to GRADE
as very low due to indirectness, imprecision and potential reporting bias.
The primary outcomes in our review were participant-reported pain relief of 50% or greater, Patient Global Impression of Change
(PGIC) much or very much improved, withdrawal due to adverse events (tolerability) and serious adverse events (safety). Nabilone
was compared to placebo and to amitriptyline in one study each. Study sizes were 32 and 40 participants. One study used a cross-over
design and one used a parallel group design; study duration was four or six weeks. Both studies used nabilone, a synthetic cannabinoid,
with a bedtime dosage of 1 mg/day. No study reported the proportion of participants experiencing at least 30% or 50% pain relief or
who were very much improved. No study provided first or second tier (high to moderate quality) evidence for an outcome of efficacy,
tolerability and safety. Third tier (very low quality) evidence indicated greater reduction of pain and limitations of HRQoL compared
to placebo in one study. There were no significant differences to placebo noted for fatigue and depression (very low quality evidence).
Third tier evidence indicated better effects of nabilone on sleep than amitriptyline (very low quality evidence). There were no significant
differences between the two drugs noted for pain, mood and HRQoL (very low quality evidence). More participants dropped out due
to adverse events in the nabilone groups (4/52 participants) than in the control groups (1/20 in placebo and 0/32 in amitriptyline
group). The most frequent adverse events were dizziness, nausea, dry mouth and drowsiness (six participants with nabilone). Neither
study reported serious adverse events during the period of both studies. We planned to create a GRADE ’Summary of findings’ table,
but due to the scarcity of data we were unable to do this. We found no relevant study with herbal cannabis, plant-based cannabinoids
or synthetic cannabinoids other than nabilone in fibromyalgia.
Authors’ conclusions
We found no convincing, unbiased, high quality evidence suggesting that nabilone is of value in treating people with fibromyalgia. The
tolerability of nabilone was low in people with fibromyalgia.
P L A I N L A N G U A G E S U M M A R Y
Cannabis products for people with fibromyalgia
Background
Fibromyalgia is characterised by chronic (longer than three months) widespread pain that often co-exists with sleep problems, problems
with thinking and fatigue (exhaustion). People often report severe limitations of daily functioning and poor health-related quality of
life. Therapies focus on reducing key symptoms and disability, and improving health-related quality of life. Cannabis has been used for
3000 years to reduce pain and other symptoms, such as loss of appetite and anxiety.
Key results and quality of the evidence
In April 2016 we searched for reports of clinical trials that used cannabis products to treat symptoms in adults with fibromyalgia.
We found two small, moderate quality studies, of four and six weeks long, including 72 participants. Both studies tested nabilone, a
synthetic (man-made) cannabis product, comparing it with placebo (a dummy pill) or amitriptyline (an antidepressant frequently used
in the treatment of fibromyalgia).
Nabilone did not convincingly relieve fibromyalgia symptoms (pain, sleep, fatigue) better than placebo or amitriptyline (very low
quality evidence). Compared with placebo and amitriptyline, more people experienced side effects and left the study due to side effects
(very low quality evidence). There were no serious side effects reported. We found no relevant study with herbal cannabis, plant-based
cannabinoids or other synthetic cannabinoids than nabilone in fibromyalgia.
There was not enough high quality evidence available to draw any robust conclusions. We found no studies on medical cannabis in
fibromyalgia.
2Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
B A C K G R O U N D
This review was based on a template for reviews of drugs used to
relieve fibromyalgia-associated symptoms. The aim is for all re-
views to use the same methods, based on new criteria for what con-
stitutes reliable evidence in chronic pain (Moore 2010a;Appendix
1).
Description of the condition
Fibromyalgia is defined as widespread pain that lasts for longer
than three months, with tenderness on palpation at 11 or more
of 18 specified tender points (Wolfe 1990). Chronic widespread
pain is frequently associated with other symptoms such as poor
sleep, fatigue and depression. People often report high disability
levels and poor quality of life along with extensive use of medical
care (Wolfe 2014). Fibromyalgia symptoms can be assessed by self
report of the person using the fibromyalgia criteria and severity
scales for clinical and epidemiological studies, which is a modifica-
tion of the ACR Preliminary Diagnostic Criteria for Fibromyalgia
(Wolfe 2011). For a clinical diagnosis, the 1990 American Col-
lege of Rheumatology (ACR) classification criteria (Wolfe 1990)
and the ACR 2010 preliminary diagnostic criteria (Wolfe 2010)
can be used. Lacking a specific laboratory test, a diagnosis is es-
tablished by a history of the key symptoms and the exclusion of
somatic diseases that sufficiently explain these symptoms (Wolfe
2010). How fibromyalgia is considered within the international
classification of diseases is under debate. While some rheumatol-
ogists have thought of it as specific pain disorder (Clauw 2014),
and central sensitivity syndrome (Yunus 2008), some neurologists
conceptualise fibromyalgia as a small fibre neuropathy (Oaklander
2013). In psychiatry and psychosomatic medicine, fibromyalgia
symptoms are characterised as a functional somatic syndrome, as
a bodily distress syndrome, as a somatic symptom disorder or as a
somatoform disorder (Häuser 2014a).
Fibromyalgia is a heterogeneous condition. The definite aetiology
(causes) of this syndrome remains unknown. A model of interact-
ing biological and psychosocial variables in the predisposition to,
triggering of, and sustaining the chronicity of fibromyalgia symp-
toms has been suggested (Sommer 2012). Depression (Forseth
1999), some genes (Arnold 2013;Lee 2012), obesity combined
with physical inactivity (Mork 2010), physical and sexual abuse
in childhood (Häuser 2011), sleep problems (Mork 2012), and
smoking (Choi 2011) are risk factors for the future development of
fibromyalgia. Psychosocial stress (e.g. workplace and family con-
flicts) and physical stress (e.g. infections, surgery, accidents) might
trigger the onset of chronic widespread pain and fatigue (Clauw
2014;Sommer 2012). Depression and post-traumatic stress disor-
der worsen fibromyalgia symptoms (Häuser 2013a;Lange 2010).
Several physiological factors are associated with fibromyalgia, but
it is unclear if they cause fibromyalgia or are the result of fibromyal-
gia. Alterations in pain processing in the brain, reduced reactivity
of the hypothalamus-pituitary-adrenal axis to stress, increased pro-
inflammatory and reduced anti-inflammatory cytokine profiles
(produced by cells involved in inflammation), disturbances in neu-
rotransmitters such as dopamine and serotonin (Sommer 2012),
and small fibre pathology (Oaklander 2013;Üçeyler 2013a) have
all been demonstrated. Prolonged exposure to stress, as outlined
above, may contribute to these functional changes in predisposed
individuals (Bradley 2009).
Fibromyalgia is common. Numerous studies have investigated
prevalence in different settings and countries. One review gave
a global mean prevalence of 2.7% (range 0.4% to 9.3%), and a
mean in the Americas of 3.1%, in Europe of 2.5% and in Asia
of 1.7%. It is more common in women, with a female to male
ratio of 3:1 (4.2%:1.4%) (Queiroz 2013). The change in diagnos-
tic criteria does not appear to have significantly affected estimates
of prevalence (Wolfe 2013). Estimates of prevalence in specific
populations vary greatly, but have been reported to be as high as
9% in female textile workers in Turkey and 10% in metalworkers
in Brazil (59% in people with repetitive strain injury) (Queiroz
2013).
Fibromyalgia pain is known to be difficult to treat effectively, with
only a minority of individuals experiencing a clinically relevant
benefit from any single intervention. A multidisciplinary approach
is recommended by evidence-based guidelines, with pharmacolog-
ical interventions being combined with physical or cognitive in-
terventions, or both (Eich 2012;Fitzcharles 2013). Conventional
analgesics are usually not effective. Prescribed treatments typi-
cally include so-called pain modulators such as antidepressants like
serotonin and noradrenaline reuptake inhibitors (Häuser 2013b;
Lunn 2014), tricyclic agents such as amitriptyline (Moore 2012a),
and antiepileptics such as gabapentin or pregabalin (Moore 2011a;
Üçeyler 2013b;Wiffen 2013). The proportion of people who
achieve worthwhile pain relief (typically at least 50% pain inten-
sity reduction (Moore 2013a)) is small, generally 10% to 25%
more than with placebo, with numbers needed to treat for an ad-
ditional beneficial outcome (NNTB) usually between 4 and 10
(Kalso 2013;Wiffen 2013). Fibromyalgia is not particularly dif-
ferent from other chronic pain disorders in that only a small pro-
portion of trial participants have a good response to treatment
(Moore 2013b).
Description of the intervention
Current pharmacological treatment options for fibromyalgia af-
ford only modest benefit for most people, often with adverse ef-
fects that outweigh the benefits (Häuser 2014b). Therefore, there
is a need to explore other treatment options, with different mech-
anisms of action and from different drug categories, for treatment
of the constellation of symptoms that characterise fibromyalgia.
The cannabinoid system is ubiquitous in the animal kingdom,
with multiple functions that aid an organism in maintaining equi-
librium. These stabilising effects for the organism, including mod-
3Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ulation of pain and stress, suggest that manipulation of this system
may have therapeutic potential for the management of fibromyal-
gia (Pacher 2006). A large body of evidence currently supports the
presence of cannabinoid receptors and ligands in the peripheral
and central nervous system, but also in other tissues such as bone
and in the immune system (Pacher 2006).
The endocannabinoid system has three broad and overlapping
functions in mammals. The first is a stress recovery role, oper-
ating in a feedback loop in which endocannabinoid signalling is
activated by stress and functions to return endocrine, nervous and
behavioural systems to homeostatic balance. The second function
is to control energy balance through regulation of the intake, stor-
age and utilisation of food. The third involves immune regula-
tion; endocannabinoid signalling is activated by tissue injury and
modulates immune and inflammatory responses (Hillard 2012).
Thus, the endocannabinoid neuromodulatory system appears to
be involved in multiple physiological functions, such as antinoci-
ception, cognition and memory, endocrine function, nausea and
vomiting, inflammation and immune recognition (de Vries 2014;
Hillard 2012). The plant Cannabis sativa, commonly known as
marijuana, has been used for pain relief for millennia, and has ad-
ditional effects on appetite, sleep and mood (Kalant 2001). Data
from clinical trials with synthetic and plant-based cannabinoids
suggest a promising approach for the management of chronic neu-
ropathic pain of different origins (de Vries 2014).
How the intervention might work
Cannabis sativa contains over 450 compounds, with at least 70
classified as phytocannabinoids. Two are of particular medical in-
terest. Delta 9-tetrahydrocannabinol (delta 9-THC) is the main
active constituent, with psychoactive and pain-relieving proper-
ties. The second molecule of interest is cannabidiol, which has
lesser affinity for the cannabinoid (CB) receptors and the potential
to counteract the negative effects of THC on memory, mood and
cognition, but also has an effect on pain modulation. The specific
roles of currently identified endocannabinoids that act as ligands
at cannabinoid receptors within the nervous system (primarily but
not exclusively CB 1 receptors) and in the periphery (primarily
but not exclusively CB 2 receptors) are only partially elucidated,
but there is abundant preclinical data to support their influence
on nociception (Owens 2015;Pacher 2006).
A clinical endocannabinoid deficiency has been hypothesised to
underlie the pathophysiology of fibromyalgia but there is no clear
evidence to support this assumption (Russo 2008). It is also hy-
pothesised that cannabinoids reduce sensitisation of nociceptive
sensory pathways and alterations in cognitive and autonomic pro-
cessing in chronic pain states (Guindon 2009). The frontal-limbic
distribution of cannabinoid receptors in the brain suggests that
cannabinoids may preferentially target the affective qualities of
pain, believed to have an important contribution to the suffer-
ing of people with fibromyalgia (Lee 2013). In addition, cannabi-
noids may attenuate low-grade inflammation, another postulate
for pathogenesis in people with fibromyalgia (Üçeyler 2011). Fi-
nally, some researchers believe that fibromyalgia is a stress-related
disorder (van Houdenhove 2004). In this context, cannabinoids
might function to buffer stress and modulate emotional and cog-
nitive functions (Hillard 2012). Therefore, taking into considera-
tion the complexity of symptom expression and the absence of an
ideal treatment, the potential for manipulation of the cannabinoid
system as a therapeutic modality is attractive.
Why it is important to do this review
Cannabinoids may be administered therapeutically as a pharma-
ceutic product that is either synthetic or derived from the plant
base, or by use of the herbal product that is not pharmaceutically
manufactured. The therapeutic use of synthetic and plant-based
cannabinoids has been widely reviewed (de Vries 2014;Guindon
2009;Pacher 2006), but clinical use so far has been conflicting.
Several practical problems, as well as ethical issues, arise in view
of the illegality of the plant Cannabis sativa in many jurisdictions,
the prevalent worldwide use of Cannabis sativa as a recreational
drug and the potential for the abuse of cannabinoid preparations
(de Vries 2014). However, various cannabinoid preparations are
legally available for some medical treatment in some parts of the
world (e.g. US, Canada, Europe, Africa) and herbal cannabis has
been recently legalised for therapeutic use in over 20 states in the
US and also in Canada and Israel. The use of synthetic cannabis
has been tested in uncontrolled trials in fibromyalgia (Schley 2006;
Weber 2009), and has been advocated by some pain specialists
(Weber 2009). Therefore, physicians will be caring for people who
may be self medicating with herbal cannabis or may request med-
ical advice about cannabis (Fitzcharles 2014). Due to this, we see
an immediate need to evaluate the efficacy, tolerability and safety
of cannabinoids in fibromyalgia in order to assist people with fi-
bromyalgia and doctors in shared decision-making on additional
pharmacological treatment options.
The standards used to assess evidence in chronic pain trials have
changed substantially, with particular attention being paid to trial
duration, withdrawals and statistical imputation following with-
drawal, all of which can substantially alter estimates of efficacy.
The most important change is the move from using mean pain
scores, or mean change in pain scores, to the number of partic-
ipants who have a large decrease in pain (by at least 50%) and
who continue in treatment, ideally in trials of eight to 12 weeks
or longer. Pain intensity reduction of 50% or more correlates with
improvements in co-morbid symptoms, function and quality of
life. These standards are set out in the reference guide for pain
studies (AUREF 2012).
This Cochrane review will assess evidence in ways that make both
statistical and clinical sense, and will use developing criteria for
what constitutes reliable evidence in chronic pain (Moore 2010a).
Trials included and analysed will need to meet a minimum of
4Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
reporting quality (blinding, randomisation), validity (duration,
dose and timing, diagnosis, outcomes, etc.), and size (ideally at
least 500 participants in a comparison in which the NNTB is four
or above (Moore 1998)). This sets high standards and marks a
departure from how reviews were done previously.
O B J E C T I V E S
To assess the efficacy, tolerability and safety of cannabinoids for
fibromyalgia symptoms in adults.
M E T H O D S
Criteria for considering studies for this review
Types of studies
We included studies if they were randomised, double-blind con-
trolled trials (RCTs) of at least four weeks’ duration. We included
studies with a parallel, cross-over and enriched enrolment ran-
domised withdrawal (EERW) design. Trials had at least 10 par-
ticipants per treatment arm. We required full journal publication,
with the exception of online clinical trial result summaries of oth-
erwise unpublished clinical trials, and abstracts with sufficient data
for analysis. We did not include short abstracts. We excluded stud-
ies that were non-randomised, studies of experimental pain, case
reports and clinical observations.
Types of participants
We included studies with adults aged 18 years and above, diag-
nosed with fibromyalgia using the 1990 or 2010 criteria (Wolfe
1990;Wolfe 2010).
Types of interventions
Cannabinoids (either phytocannabinoids such as herbal cannabis
(hashish, marihuana), plant-based cannabinoids (nabiximole) or
pharmacological (synthetic) cannabinoids (e.g. cannabidiol, dron-
abinol, levonantradol, nabilone)), at any dose, by any route, ad-
ministered for the relief of fibromyalgia symptoms and compared
to placebo or any active comparator. We did not include stud-
ies with drugs under development that manipulated the endo-
cannabinoid system by inhibiting enzymes that hydrolysed endo-
cannabinoids and thereby boosted the levels of the endogenous
molecules (e.g. blockade of the catabolic enzyme fatty acid amide
hydrolase (FAAH)) (Long 2009).
Types of outcome measures
We anticipated that studies would use a variety of outcome mea-
sures, with the majority of studies using standard subjective scales
(numerical rating scale (NRS) or visual analogue scale (VAS) for
pain intensity or pain relief, or both. We were particularly inter-
ested in Initiative on Methods, Measurement, and Pain Assess-
ment in Clinical Trials (IMMPACT) definitions for moderate and
substantial benefit in chronic pain studies (Dworkin 2008). These
were defined as at least 30% pain relief over baseline (moderate),
at least 50% pain relief over baseline (substantial), much or very
much improved on Patient Global Impression of Change (PGIC)
(moderate) and very much improved on PGIC (substantial). These
outcomes are different from those used in most earlier reviews,
concentrating as they do on dichotomous outcomes where pain
responses do not follow a normal (Gaussian) distribution. People
with chronic pain desire high levels of pain relief, ideally more than
50%, and with pain not worse than mild (Moore 2013a;O’Brien
2010).
We planned to include a ’Summary of findings’ table as set out
in the author guide (AUREF 2012). The ’Summary of findings
table was planned to include outcomes of at least 50% pain re-
duction, PGIC, adverse event withdrawals, serious adverse events
and death.
Primary outcomes
1. Participant-reported pain relief of 50% or greater.
2. PGIC much or very much improved.
3. Withdrawal due to adverse events (tolerability).
4. Serious adverse events (safety). Serious adverse events
typically include any untoward medical occurrence or effect that
at any dose results in death, is life-threatening, requires
hospitalisation or prolongation of existing hospitalisation, results
in persistent or significant disability or incapacity, is a congenital
anomaly or birth defect, is an ’important medical event’ that may
jeopardise the person, or may require an intervention to prevent
one of the above characteristics/consequences.
Secondary outcomes
1. Participant-reported pain relief of 30% or greater.
2. Sleep problems.
3. Fatigue.
4. Depression.
5. Anxiety.
6. Health-related quality of life (HRQoL).
7. Disability.
8. Withdrawals due to lack of efficacy.
9. Participants experiencing any adverse event.
10. Other specific adverse events, particularly somnolence,
dizziness and drug prescription abuse (addiction).
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Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Search methods for identification of studies
Electronic searches
We searched the following databases, without language restric-
tions:
1. Cochrane Central Register of Controlled Trials
(CENTRAL) (Issue 3 of 12, 2016);
2. MEDLINE (via Ovid) (to 26 April 2016);
3. EMBASE (via Ovid) (to 26 April 2016).
See Appendix 2 for the CENTRAL search strategy, Appendix 3 for
the MEDLINE search strategy and Appendix 4 for the EMBASE
search strategy.
Searching other resources
We reviewed the bibliographies of any randomised trials identified
and review articles, contacted the authors and known experts in
the field, and searched clinical trial databases (ClinicalTrials.gov
(ClinicalTrials.gov), International Association for Cannabinoid
Medicines (IACM) databank (www.cannabis-med.org/studies/
study.php), and the World Health Organization (WHO) Interna-
tional Clinical Trials Registry Platform (ICTRP) (apps.who.int/
trialsearch/) to identify additional published or unpublished data
and ongoing trials.
Data collection and analysis
Selection of studies
Two review authors (WH, BW) determined eligibility by reading
the abstract of each study identified by the search. We eliminated
studies that clearly did not satisfy the inclusion criteria, and ob-
tained full copies of the remaining studies. Two review authors
(MAF, WH) independently read these studies and reached agree-
ment by discussion. We did not anonymise the studies before as-
sessment. We created a PRISMA flow chart of the screening pro-
cess (see Figure 1).
6Cannabinoids for fibromyalgia (Review)
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Figure 1. Study flow diagram.
7Cannabinoids for fibromyalgia (Review)
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Data extraction and management
Two review authors (MAF, WH) independently extracted data
using a standard form and checked for agreement. One review
author (WH) entered suitable data Review Manager 5 (RevMan
2014). We included information about the pain condition and
number of participants treated, drug and dosing regimen, study
design (placebo or active control), inclusion and exclusion criteria,
study setting, study duration and follow-up, outcome measures
and results, withdrawals and adverse events (participants experi-
encing any adverse event or serious adverse event).
Assessment of risk of bias in included studies
We used the Oxford Quality Score as the basis for inclusion (Jadad
1996), limiting inclusion to studies that were randomised and
double-blind as a minimum.
Two review authors (WH, MAF) independently assessed risk of
bias for each study, using the criteria outlined in the Cochrane
Handbook for Systematic Reviews of Interventions (Higgins 2011),
and adapted from those used by the Cochrane Pregnancy and
Childbirth Group, with any disagreements resolved by discussion.
We assessed the following for each study.
1. Random sequence generation (checking for possible
selection bias). We assessed the method used to generate the
allocation sequence as: low risk of bias (any truly random
process, e.g. random number table; computer random number
generator); unclear risk of bias (method used to generate
sequence not clearly stated). We excluded studies at high risk of
bias that used a non-random process (e.g. odd or even date of
birth; hospital or clinic record number).
2. Allocation concealment (checking for possible selection
bias). The method used to conceal allocation to interventions
prior to assignment determines whether intervention allocation
could have been foreseen in advance of, or during, recruitment,
or changed after assignment. We assessed the methods as: low
risk of bias (e.g. telephone or central randomisation;
consecutively numbered, sealed, opaque envelopes); unclear risk
of bias (method not clearly stated). We excluded studies that did
not conceal allocation and were therefore at a high risk of bias
(e.g. open list).
3. Blinding of participants and personnel/treatment providers
(systematic performance bias). We assessed the methods used to
blind participants and personnel/treatment providers from
knowledge of which intervention a participant received. We
assessed the methods as: low risk of bias (study stated that it was
blinded and described the method used to achieve blinding, e.g.
identical tablets; matched in appearance and smell); unclear risk
of bias (study stated that it was blinded but did not provide an
adequate description of how it was achieved); high risk of bias
(blinding of participants was not ensured, e.g. tablets different in
form or taste).
4. Blinding of outcome assessment (checking for possible
detection bias). We assessed the methods used to blind study
participants and outcome assessors from knowledge of which
intervention a participant received. We assessed the methods as:
low risk of bias (study stated that it was blinded and described
the method used to achieve blinding, e.g. identical tablets,
matched in appearance and smell); unclear risk of bias (study
stated that it was blinded but did not provide an adequate
description of how it was achieved). We excluded studies at a
high risk of bias that were not double-blind.
5. Incomplete outcome data (checking for possible attrition
bias due to the amount, nature and handling of incomplete
outcome data). We assessed the methods used to deal with
incomplete data as: low risk of bias (i.e. less than 10% of
participants did not complete the study or used ’baseline
observation carried forward’ analysis, or both); unclear risk of
bias (used last observation carried forward (LOCF) analysis); or
high risk of bias (used completer analysis).
6. Reporting bias due to selective outcome reporting
(reporting bias). We checked if an a priori study protocol was
available and if all outcomes of the study protocol were reported
in the publications of the study. There was low risk of reporting
bias if the study protocol was available and all of the study’s pre-
specified (primary and secondary) outcomes that were of interest
in the review were reported in the pre-specified way, or if the
study protocol was not available but it was clear that the
published reports included all expected outcomes, including
those that were pre-specified (convincing text of this nature may
be uncommon). There was a high risk of reporting bias if not all
of the study’s pre-specified primary outcomes were reported; one
or more primary outcomes was reported using measurements,
analysis methods or subsets of the data (e.g. subscales) that were
not pre-specified; one or more reported primary outcomes were
not pre-specified (unless clear justification for their reporting was
provided, such as an unexpected adverse effect); one or more
outcomes of interest in the review were reported incompletely so
that they could not be entered in a meta-analysis; the study
report did not include results for a key outcome that would be
expected to have been reported for such a study.
7. Group similarity at baseline (selection bias). We assessed
similarity of the study groups at baseline for the most important
prognostic clinical and demographic indicators. There was low
risk of bias if groups were similar at baseline for demographic
factors, value of main outcome measure(s) and important
prognostic factors. There was unclear risk of bias if important
prognostic clinical and demographic indicators were not
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reported. There was high risk of bias if groups were not similar at
baseline for demographic factors, value of main outcome
measure(s), and important prognostic factor.
8. Size of study (checking for possible biases confounded by
small size). We assessed studies at low risk of bias (i.e. 200
participants or more per treatment arm); unclear risk of bias (50
to 199 participants per treatment arm); or high risk of bias
(fewer than 50 participants per treatment arm).
Two review authors (WH, MFA) made quality ratings separately
for each of the seven methodology quality indicators as defined by
the ’Risk of bias’ tool. We defined a study to be of high quality
when it fulfilled six to eight of the indicators (no risk of bias), to be
of moderate quality when it fulfilled three to five of the indicators
and to be of low quality if it fulfilled zero to two of the quality
indicators (Schaefert 2015).
Measures of treatment effect
We planned to calculate numbers needed to treat as the reciprocal
of the absolute risk reduction (ARR) (McQuay 1998). For un-
wanted effects, the number needed to treat for an additional ben-
eficial outcome (NNTB) became the number needed to treat for
an additional harm outcome (NNTH) and was calculated in the
same manner. We planned to use dichotomous data to calculate
risk ratio (RR) with 95% confidence intervals (CI) using a fixed-
effect model unless we found significant statistical or clinical het-
erogeneity (see below). We planned to calculate standardised mean
differences (SMD) with 95% CI for continuous variables using a
fixed-effect model unless we found significant statistical or clinical
heterogeneity. We planned to calculate NNTBs for continuous
variables (fatigue, sleep problems, HRQoL) using the Wells cal-
culator software available at the Cochrane Musculoskeletal Group
editorial office, which estimates, from the SMDs, the proportion
of participants who will benefit from treatment (Norman 2001).
We planned to use a minimal clinically important difference of
15% for the calculation of the NNTB from SMDs for all continu-
ous outcomes. This approach has been used by previous Cochrane
reviews in drug therapies for fibromyalgia (Häuser 2013b;Üçeyler
2013b).
Where means or standard deviations (SDs) were missing, we at-
tempted to obtain these data through contacting trial authors.
Where SDs were not available from trial authors, we calculated
them from t values, P values, CIs or standard errors, where reported
in articles (Higgins 2011). Where 30% and 50% pain reduction
rates were not reported or provided on request, we planned to
calculate them from means and SDs using a validated imputation
method (Furukawa 2005).
Unit of analysis issues
We intended to split the control treatment arm between active
treatment arms in a single study if the active treatment arms were
not combined for analysis. We included studies with a cross-over
design where separate data from the two periods were reported,
where data were presented that excluded a statistically significant
carry-over effect, or where statistical adjustments were carried out
in case of a significant carry-over effect.
Dealing with missing data
We planned to use an intention-to-treat (ITT) analysis where the
ITT population consisted of participants who were randomised,
took at least one dose of the assigned study medication and pro-
vided at least one post-baseline assessment. We would have as-
signed missing participants zero improvement wherever possible.
Assessment of heterogeneity
We assessed clinical heterogeneity by analysing the inclusion and
exclusion criteria of the studies included. We assessed statistical
heterogeneity visually (L’Abbé 1987), and with the use of the I2
statistic. When the I2value was greater than 50%, we would have
considered possible reasons for this.
Assessment of reporting biases
We aimed to use dichotomous outcomes of known utility and of
value to participants as primary outcomes (Moore 2010b;Moore
2013a). We extracted and used continuous data, which probably
reflect efficacy and utility poorly, for illustrative purposes only.
Data synthesis
We planned to analyse data in three tiers, according to outcome
and freedom from known sources of bias (Moore 2010a).
1. The first tier used data meeting current best standards,
where studies reported the outcome of at least 50% pain intensity
reduction over baseline (or its equivalent), without the use of
LOCF or other imputation method for drop-outs, reported an
ITT analysis, lasted eight or more weeks, had a parallel-group
design and had at least 200 participants (preferably at least 400)
in the comparison (Moore 1998;Moore 2010a;Moore 2012a;
Moore 2012b). We planned to report these first-tier results first.
2. The second tier used data from at least 200 participants but
where one or more of the first-tier conditions were not met (e.g.
reporting at least 30% pain intensity reduction, using LOCF or a
completer analysis, or lasting four to eight weeks).
3. The third tier of evidence related to data from fewer than
200 participants, or where there were significant problems
because, for example, of very short duration studies of fewer than
four weeks, where there was major heterogeneity between
studies, or where there were shortcomings in allocation
concealment, attrition or incomplete outcome data. For this
third tier of evidence, no data synthesis was reasonable and may
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be misleading, but an indication of beneficial effects might be
possible.
There was only third-tier evidence available. For this third-tier
evidence, no data synthesis was reasonable and may have been
misleading. Therefore, we did not conduct the planned meta-
analysis.
We used the Grading of Recommendations Assessment, Devel-
opment and Evaluation (GRADE) to assess the overall quality of
evidence (Balshem 2011;GRADEpro GDT 2015), defined as the
extent of confidence in the estimates of treatment benefits and
harms. We downgraded the quality of evidence by one level for
each of the following factors that we encountered.
1. Limitations of study design: greater than 50% of the
participants in low quality studies.
2. Inconsistency of effect size: I2greater than 50%.
3. Indirectness: we assessed whether the question being
addressed in this systematic review was different from the
available evidence regarding the population in routine clinical
care, if people with inflammatory rheumatic diseases or
depressive disorders (or both) were excluded in greater than 50%
of participants.
4. Imprecision: there was only one trial or when there was
more than one trial, the total number was fewer than 400
participants or when 95% CI of the effect size included zero.
5. High probability of reporting bias: all studies were
sponsored by the manufacturer of the drug.
We categorised the quality of evidence as follows.
1. High: we were very confident that the true effect lay close
to that of the estimate of the effect.
2. Moderate: we were moderately confident in the effect
estimate; the true effect was likely to be close to the estimate of
the effect, but there was a possibility that it was substantially
different.
3. Low: our confidence in the effect estimate was limited; the
true effect may be substantially different from the estimate of the
effect.
4. Very low: we had very little confidence in the effect
estimate; the true effect was likely to be substantially different
from the estimate of effect; any estimate of effect was very
uncertain.
We planned to present the main findings of the review in ’Sum-
mary of findings’ tables in a transparent and simple tabular format.
Due to the scarcity of data, we were unable to create a GRADE
’Summary of findings’ table.
Subgroup analysis and investigation of heterogeneity
We planned subgroup analyses (studies with and without strati-
fication for co-morbid mental disorders; different cannabinoids;
different routes of administration) if there were at least two studies
available.
The planned subgroup analyses were not possible due to the lack
of a sufficient number of studies.
Sensitivity analysis
We did not perform sensitivity analysis because we did not identify
individual peculiarities of the studies under investigation during
the review process that were suitable for sensitivity analyses.
R E S U L T S
Description of studies
Results of the search
Searches identified three potentially relevant studies in CEN-
TRAL, 20 in MEDLINE and 47 in EMBASE. In addition, we
identified two study protocols in clinicaltrials.gov. After reading
the full reports, we included two studies into the review (Skrabek
2008;Ware 2010). We excluded two studies (NCT00176163;
NCT01149018) (see Figure 1).
Included studies
We included two studies with 72 participants using nabilone in
people with fibromyalgia (Skrabek 2008;Ware 2010). Study re-
cruitment was from a chronic pain specialist clinic (Ware 2010),
and from a Musculoskeletal Rehabilitation clinic (Skrabek 2008)
(single centre studies). Both studies were conducted in Canada.
Studies enrolled adults with aged between 26 and 76 years, with
no upper age limits in one study (Ware 2010), and upper limit
of 75 years in the other study (Skrabek 2008). In both studies,
there was a preponderance of women (ca 90%). Inclusion crite-
rion was continued pain despite the use of other oral medications
(Skrabek 2008), or self reported chronic insomnia (Ware 2010)
(see Appendix 5). Diagnosis of fibromyalgia was established by
the ACR 1990 classification criteria in both studies (Wolfe 1990).
Exclusion criteria in both studies included a history of substance
abuse, current psychotic disorders and unstable cardiac disease.
The extent of other exclusion criteria varied between studies. One
study with the majority of participants in the review excluded peo-
ple with “History of untreated non-psychotic emotional disorders”
(Skrabek 2008) (see Appendix 5). Nabilone was compared with
placebo (Skrabek 2008) and with amitriptyline (Ware 2010). One
study used a parallel group design (Skrabek 2008); the other was
a cross-over study (Ware 2010). Study duration was four weeks
(Skrabek 2008) and six weeks (two weeks each for each period,
separated by a two weeks’ wash-out phase) (Ware 2010). Ware
2010 reported data from the first phase separately only for the
main outcome sleep problems. To assess potential carryover e ffects,
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examination of treatment by period interactions was conducted.
Other stable medication (including pain medication) was contin-
ued unchanged in both studies. There was a two-week washout
between phases in the cross-over study (Ware 2010). The dosage
of nabilone was progressively increased from 0.5 mg/day to 1 mg/
day at bedtime in both studies.
See Characteristics of included studies table.
Excluded studies
We excluded two studies after reading the full reports (
NCT00176163;NCT01149018). Reasons for exclusion of indi-
vidual studies are listed in the Characteristics of excluded studies
table.
Risk of bias in included studies
Each study had at least two high risks of bias (Assessment of risk
of bias in included studies). See Figure 2;Figure 3. The reported
methodology quality of the trials was moderate according to the
pre-defined criteria.
Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
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Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.
Allocation
Both studies were randomised. Random sequence generation and
allocation concealment were of low risk in Ware 2010. In Skrabek
2008, the details of randomisation were unclear.
Blinding
Both studies were double blind. Both studies adequately described
the method used to achieve double blinding.
Incomplete outcome data
Both studies did not perform ITT, but completer analysis.
Selective reporting
A study protocol was not available for either study.
Other potential sources of bias
The demographic characteristics of the study groups were not
different in both studies. The sample size of both studies were
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small. Both studies were partially funded by the manufacturer of
nabilone.
Effects of interventions
Both included studies reported at least one pain-related outcome.
Due to the scarcity of data, we did not create a ’Summary of
findings’ table. See Appendix 6 and Appendix 7 for details of data
from individual studies. There was no first- or second-tier (high
to moderate quality) evidence of efficacy, tolerability and safety.
The studies did not report outcomes for proportion of participants
experiencing at least 30% or 50% pain relief or who were very
much improved. The quality of evidence for all outcomes was
downgraded by three levels because of indirectness, imprecision
and potential reporting bias to very low.
Third-tier evidence
Efficacy
The quality of evidence for all outcomes of efficacy was very low.
Using a responder analysis, Skrabek 2008 reported that statisti-
cally significant improvements were detected in pain, anxiety and
HRQoL. However, calculating SMDs by the means and SDs ex-
tracted from figures, we did not find a significant difference be-
tween nabilone and placebo. There were no significant differences
between nabilone and placebo noted for fatigue and depression.
The outcome disability was not reported. No participant dropped
out due to lack of efficacy in the nabilone or placebo group.
Nabilone had better effects on sleep than amitriptyline (adjusted
difference -3.25, 95% CI -5.26 to -1.24; P value < 0.05) on a 0
to 28 scale (Insomnia severity index). There were no significant
differences between the two drugs for pain and HRQoL. There
were no data for the Fibromyalgia Impact Questionnaire (FIQ)
subscales anxiety, disability, fatigue and depression. There were
no significant differences between the two drugs in the Profile
of Mood States. One participant dropped out due to the lack of
efficacy.The authors did not report if the drop-out due to the lack
of efficacy was in the nabilone or amitriptyline group. All results
were based on a responder analysis (Ware 2010).
Neither study assessed the outcomes participant-reported pain re-
lief of 30% or 50% or greater, or PGIC much or very much im-
proved. The data provided by both studies did not allow the use of
the planned imputation method to calculate 30% and 50% pain
responder rates (Furukawa 2005).
Tolerability
The quality of evidence for all outcomes of tolerability was very
low.
Both studies did not report the numbers of participants who ex-
perienced any adverse event. Skrabek 2008 did not report the to-
tal number of adverse events. Ware 2010 reported 187 adverse
events. Fifty-three adverse events were possibly or probably related
to amitriptyline therapy and 91 AEs to nabilone therapy.
Three out of 20 participants in the nabilone group and 1/20 par-
ticipant in the placebo group dropped out due to adverse events
in the Skrabek 2008 study. Ware 2010 reported that 1/32 partici-
pant dropped out in the nabilone group and no participants in the
amitriptyline group dropped out due to adverse events. The most
frequent adverse events were drowsiness (seven participants with
nabilone, one participant with placebo), dry mouth (five partic-
ipants with nabilone, one participant with placebo) and vertigo
(four participants with nabilone, no participants with placebo) in
Skrabek 2008. The most frequent adverse events were dizziness
(10 participants with nabilone, four participants with amitripty-
line), nausea (nine participants with nabilone, one participant with
amitriptyline), dry mouth (seven participants with nabilone, three
participants with amitriptyline) and drowsiness (six participants
with nabilone, one participant with amitriptyline) in Ware 2010.
Neither study reported on abuse of prescribed nabilone.
Safety
The quality of evidence for all outcomes of safety was very low.
Both studies reported no serious adverse events during the study
period.
D I S C U S S I O N
Summary of main results
The review found two studies testing the synthetic cannabinoid
nabilone in 72 participants with FM. No first- or second-tier evi-
dence was available.
There was no unbiased evidence of a superiority of nabilone over
placebo to reduce fibromyalgia symptoms. Third-tier evidence in-
dicated a superiority of nabilone over placebo in pain relief and
HRQoL, but not in fatigue, but this was derived from group mean
data and completer analysis in a small, short duration study, where
major bias was possible. Third-tier evidence indicated a superi-
ority of nabilone over amitriptyline in improving sleep quality,
but not for pain and HRQoL, but this was derived from group
mean data and completer analysis in a small, short duration study,
where major bias is possible. Participants taking nabilone experi-
enced more adverse events (but not serious adverse events) than
did participants taking placebo or amitriptyline. More participants
dropped out due to adverse events in the nabilone than in the
control groups. The most frequent adverse events with nabilone
were dizziness/drowsiness, dry mouth and vertigo. We found no
RCTs with other cannabinoids than nabilone.
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Overall completeness and applicability of
evidence
Overall completeness and applicability of evidence were poor. The
usefulness of the available evidence was limited because report-
ing quality was poor by current standards (Moore 2010a). RCTs
of up to six weeks’ duration do not necessarily provide informa-
tion about longer term use, which is important in treatment of a
chronic condition (Moore 2010a). In particular, concern has been
raised about the lack of evidence on potential problems with long
term recreational use of cannabis (such as safety issues, addiction
and misuse) (Hoch 2015;Volkow 2014). A very limited popula-
tion was studied, who may not be representative for people with
fibromyalgia in routine clinical care.
Quality of the evidence
While both the included studies were randomised and double-
blind, neither provided data that met pre-defined criteria for first-
or second-tier analysis (high to moderate quality evidence). Both
studies were small (the largest treatment group consisted of 40
participants). The studies were of short duration (maximum treat-
ment period of four weeks) and one was of cross-over design with-
out separate reporting of first period data. Both studies used com-
pleter analysis. The quality of evidence according to GRADE for
all outcomes of efficacy, tolerability and safety was very low, down-
graded for the reasons given in Risk of bias in included studies.
Potential biases in the review process
The absence of publication bias (unpublished trials showing no
benefit of cannabinoids over placebo) can never be proved. We
carried out a broad search of studies and felt it was unlikely that
significant amounts of relevant data remain unknown to us. The
degree of exaggeration of treatment effects in cross-over trials com-
pared to parallel group designs is a potential source of major bias
(Elbourne 2002).
Agreements and disagreements with other
studies or reviews
The evidence for efficacy of cannabinoids for fibromyalgia symp-
toms in uncontrolled trials and surveys is as inconsistent as the
RCTs reviewed. In one experimental study designed to examine
the effect of orally administered delta 9-THC on electrically in-
duced pain, nine people with fibromyalgia from Germany received
a daily dose of 2.5 to 15 mg of delta 9-THC, with a weekly in-
crease of 2.5 mg, as long as no adverse events were reported. Five
participants withdrew due to adverse events. Daily recorded pain
of the people with fibromyalgia was significantly reduced over a
three-month period (Schley 2006). One case series of 172 partici-
pants reported from Germany included 32 people with fibromyal-
gia. On average, participants received delta 9-THC 7.5 mg over
seven months. Participants were assessed retrospectively in a tele-
phone survey. On average, maximum pain intensity as determined
using an NRS was recorded as 9.3±1.1 prior to delta 9-THC
and 6.1±2.1 thereafter, but without identification of the time
period for assessment for change in pain. Data on HRQoL, dis-
ability, depression and drop-out rates due to adverse events were
not reported separately for people with fibromyalgia. About 25%
of the total sample did not tolerate the treatment (Weber 2009).
In another study, 28 Spanish people with fibromyalgia who were
herbal cannabis users and 28 non-users, without differences in de-
mographics and clinical variables, were compared. After two hours
of cannabis use, there was a statistically significant reduction of
pain and stiffness, enhancement of relaxation and an increase in
somnolence and feeling of well-being (all P values < 0.001). The
mental health component summary score of the 36-item Short
Form (SF-36) was significantly higher in cannabis users than in
non-users. There were no significant differences in the other SF-36
domains, or in the FIQ (Fiz 2011). In one Canadian case series of
a tertiary care pain centre, cannabinoids were being used by 13%
of people with fibromyalgia, of whom 80% used herbal cannabis
(marijuana). Current unstable mental illness, opioid drug-seeking
behaviour and male sex were all associated with herbal cannabis
use. There was a trend for cannabinoid users to be unemployed
and receiving disability payments (Ste-Marie 2012). In one sur-
vey of the US National Pain Foundation, over 1300 people with
fibromyalgia rated marijuana more effective than Food and Drug
Administration (FDA)-approvedduloxetine, milnacipran and pre-
gabalin. The survey showed that only 8% of duloxetine, 10% of
pregabalin and 10% of milnacipran users found the medication
to be “very effective,” while 60% of duloxetine, 61% of prega-
balin and 68% of milnacipran users replied that the medications,
“does not help at all.” In contrast, 62% of marijuana users rated it
very effective. Only 5% said it did not help at all (National Pain
Foundation 2014).
The findings of this review regarding the most frequent adverse
events associated with cannabinoids (drowsiness, dizziness, dry
mouth) were in line with the findings of one systematic review of
cannabinoids in chronic non-cancer pain that included 18 RCTs
with 766 participants (Lynch 2011). One Canadian case series
point to low tolerability and poorer mental health and function-
ality for cannabinoid users with fibromyalgia (Ste-Marie 2012).
A U T H O R S ’ C O N C L U S I O N S
Implications for practice
For people with fibromyalgia
14Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Clinical trial evidence on the use of cannabis products in fi-
bromyalgia was limited to two small studies with short-term du-
ration. No convincing, unbiased evidence suggests that nabilone
is of value in treating people with fibromyalgia. The tolerability
of nabilone was low in people with fibromyalgia. Adverse events
(particularly somnolence, dizziness, vertigo) may limit its clini-
cal usefulness. We found no relevant study with herbal cannabis,
plant-based cannabinoids or other synthetic cannabinoids than
nabilone in fibromyalgia.
For physicians
Herbal, plant-based and synthetic cannabis products are not li-
censed for fibromyalgia in any country. Other than one weak
recommendation from a trial of a pharmacological cannabinoid
preparation in people with fibromyalgia in the setting of impor-
tant sleep disturbance in the Canadian fibromyalgia guidelines
(Fitzcharles 2013), there is no other current guideline recommen-
dation for use of any cannabis preparation in the management of
fibromyalgia.
For policy makers
The use of herbal cannabis at present cannot be considered evi-
dence-based and this should be explained to people requesting this
treatment (in jurisdictions where it is allowed, e.g. Canada and
Israel).
For funders
Randomised controlled trials with cannabis products may be
worth funding, as there are few confirmed effective drug treat-
ments, in order to establish the efficacy and safety of cannabinoids
compared to established treatments in this population.
Implications for research
Design
To establish whether cannabis products can have a place in the
treatment of fibromyalgia would require large (at least 200 par-
ticipants), randomised, double-blind, parallel group or enriched
enrolment randomised withdrawal (EERW) studies, of adequate
duration (greater than 12 weeks), with outcome measures that
are relevant to clinical practice (responder analysis), and analysis
that does use baseline observation carried forward imputation for
withdrawals.
It might be expected that, at best, only a few people with fibromyal-
gia will benefit from long term use of cannabis products, and co-
hort studies in fibromyalgia link cannabis use to negative health-re-
lated measures (Ste-Marie 2012). A further area of research would
be to identify clinical and demographic characteristics that predict
which people are likely to benefit or to be harmed from cannabis
products, in order to target treatment more effectively.
Population
Studies in any continent and the inclusion of people with major
medical diseases and mental disorders are necessary to provide
external validity of the study findings.
Measurement (endpoints)
Responder criteria for pain, global impression of change and
health-related quality of life have been established (Bennett 2009;
Dworkin 2008). Responder criteria for sleep problems and fatigue
have not yet been developed.
Comparison between active treatments
Any comparisons should be made with placebo and other drugs
with known efficacy, such as pregabalin. In addition, studies com-
paring single therapies (e.g. cannabis products) versus combina-
tion therapies (e.g. cannabis products and aerobic exercise) are
necessary.
A C K N O W L E D G E M E N T S
Cochrane Review Group funding acknowledgement: The Na-
tional Institute for Health Research (NIHR) is the largest sin-
gle funder of the Cochrane Pain, Palliative and Supportive Care
Group. Disclaimer: The views and opinions expressed therein are
those of the authors and do not necessarily reflect those of the
NIHR, National Health Service (NHS) or the Department of
Health.
This research for BW has been supported (in part) by the Intra-
mural Research Program of the National Institutes of Health, Na-
tional Center for Complementary and Integrative Health. PK was
supported by the “Ruth und Kurt Bahlsen Stiftung”.
The protocol for this review followed the agreed template for
fibromyalgia, which was developed in collaboration with the
Cochrane Musculoskeletal Group and Cochrane Neuromuscu-
lar Diseases Group. The editorial process was managed by the
Cochrane Pain, Palliative and Supportive Care Group.
15Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
R E F E R E N C E S
References to studies included in this review
Skrabek 2008 {published data only}
Skrabek RQ, Galimova L, Ethans K, Perry D. Nabilone for
the treatment of pain in fibromyalgia. Journal of Pain 2008;
9:164–73.
Ware 2010 {published data only}
Ware MA, Fitzcharles MA, Joseph L, Shir Y. The effects of
nabilone on sleep in fibromyalgia: results of a randomized
controlled trial. Anesthesia & Analgesia 2010;110:604–10.
References to studies excluded from this review
NCT00176163 {published and unpublished data}
NCT00176163. Supporting effect of dronabinol on
behavioral therapy in fibromyalgia and chronic back pain.
clinicaltrials.gov/ct2/show/NCT00176163 (accessed 27
June 2016).
NCT01149018 {published data only}
NCT01149018. Efficacy trial of oral tetrahydrocannabinol
in patients with fibromyalgia. clinicaltrials.gov/ct2/show/
NCT01149018 (accessed 27 June 2016).
Additional references
Arnold 2013
Arnold LM, Fan J, Russell IJ, Yunus MB, Khan MA,
Kushner I, et al. The fibromyalgia family study: a genome-
wide linkage scan study. Arthritis and Rheumatism 2013;65:
1122–8.
AUREF 2012
PaPaS author and referee guidance. papas.cochrane.org/
papas-documents (accessed 22 January 2015).
Balshem 2011
Balshem H, Helfand M, Schunemann HJ, Oxman AD,
Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the
quality of evidence. Journal of Clinical Epidemiology 2011;
64:401–6.
Bennett 2009
Bennett RM, Bushmakin AG, Cappelleri JC, Zlateva
G, Sadosky AB. Minimal clinically important difference
in the Fibromyalgia Impact Questionnaire. Journal of
Rheumatology 2009;36:1304–11.
Bradley 2009
Bradley LA. Pathophysiology of fibromyalgia. American
Journal Medicine 2009;122:S22–30.
Choi 2011
Choi CJ, Knutsen R, Oda K, Fraser GE, Knutsen S. The
association between incident self-reported fibromyalgia and
nonpsychiatric factors: 25-years follow-up of the Adventist
Health Study. Journal Pain 2011;11:994–1003.
Clauw 2014
Clauw D. Fibromyalgia: a clinical review. JAMA 2014;311:
1547–55.
de Vries 2014
de Vries M, van Rijckevorsel DC, Wilder-Smith OH,
van Goor H. Dronabinol and chronic pain: importance
of mechanistic considerations. Expert Opinion on
Pharmacotherapy 2014;15:1525–34.
Dworkin 2008
Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland
CS, Farrar JT, et al. Interpreting the clinical importance
of treatment outcomes in chronic pain clinical trials:
IMMPACT recommendations. Journal of Pain 2008;9(2):
105–21. [DOI: 10.1016/j.jpain.2007.09.005]
Eich 2012
Eich W, Häuser W, Arnold B, Bernardy K, Brückle W,
Eidmann U, et al. Fibromyalgia syndrome: general
principles and coordination of clinical care and patient
education [in German]. Schmerz 2012;26:268–75.
Elbourne 2002
Elbourne DR, Altman DG, Higgins JP, Curtin F,
Worthington HV, Vail A. Meta-analyses involving crossover
trials: methodological issues. International Journal of
Epidemiology 2002;31:140–9.
Fitzcharles 2013
Fitzcharles MA, Ste-Marie PA, Goldenberg DL, Pereira JX,
Abbey S, Choinière M, et al. 2012 Canadian Guidelines for
the diagnosis and management of fibromyalgia syndrome:
executive summary. Pain Research & Management 2013;18:
119–26.
Fitzcharles 2014
Fitzcharles MA, Clauw DJ, Ste-Marie PA, Shir Y. The
dilemma of medical marijuana use by rheumatology
patients. Arthritis Care and Research 2014;66:797–801.
Fiz 2011
Fiz J, Durán M, Capellà D, Carbonell J, Farré M. Cannabis
use in patients with fibromyalgia: effect on symptoms relief
and health-related quality of life. PLoS One 2011;6:e18440.
Forseth 1999
Forseth KO, Husby G, Gran JT, Førre O. Prognostic factors
for the development of fibromyalgia in women with self
reported musculoskeletal pain. Journal of Rheumatology
1999;26:2458–67.
Furukawa 2005
Furukawa TA, Cipriani A, Barbui C, Brambilla P,
Watanabe N. Imputing response rates from means and
standard deviations in meta-analyses. International Clinical
Psychopharmacology 2005;29:49–52.
GRADEpro GDT 2015 [Computer program]
McMaster University. GRADEpro GDT 2015: GRADEpro
Guideline Development Tool. McMaster University, 2015.
Guindon 2009
Guindon J, Hohmann AG. The endocannabinoid system
and pain. CNS & Neurological Disorders Drug Targets 2009;
8:403–21.
16Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Higgins 2011
Higgins JPT, Altman DG, Sterne JAC. Chapter 8: Assessing
risk of bias in included studies. In: Higgins JPT, Green
S (editors). Cochrane Handbook for Systematic Reviews
of Interventions Version 5.1.0 [updated March 2011].
The Cochrane Collaboration, 2011. Available from
www.cochrane-handbook.org.
Hillard 2012
Hillard CJ, Weinlander KM, Stuhr KL. Contributions
of endocannabinoid signaling to psychiatric disorders in
humans: genetic and biochemical evidence. Neuroscience
2012;204:207–29.
Hoch 2015
Hoch E, Bonnet U, Thomasisus R, Ganzer F, Havemann-
Reinecke U, Preuss UW. Risks associated with the non-
medical use of cannabis. Deutsches Arzteblatt International
2015;112:271–8.
Häuser 2011
Häuser W, Kosseva M, Üceyler N, Klose P, Sommer C.
Emotional, physical, and sexual abuse in fibromyalgia
syndrome: a systematic review with meta-analysis. Arthritis
Care and Research 2011;63:808–20.
Häuser 2013a
Häuser W, Galek A, Erbslöh-Möller B, Köllner V, Kühn-
Becker H, Langhorst J, et al. Posttraumatic stress disorder in
fibromyalgia syndrome: prevalence, temporal relationship
between posttraumatic stress and fibromyalgia symptoms,
and impact on clinical outcome. Pain 2013;154:1216–23.
Häuser 2013b
Häuser W, Urrútia G, Tort S, Uçeyler N, Walitt B.
Serotonin and noradrenaline reuptake inhibitors
(SNRIs) for fibromyalgia syndrome. Cochrane Database
of Systematic Reviews 2013, Issue 1. [DOI: 10.1002/
14651858.CD010292]
Häuser 2014a
Häuser W, Henningsen P. Fibromyalgia syndrome - a
somatoform disorder?. European Journal Pain 2014;18:
1052–9.
Häuser 2014b
Häuser W, Walitt B, Fitzcharles MA, Sommer C. Review
of pharmacological therapies in fibromyalgia syndrome.
Arthritis Research & Therapy 2014;16:201.
Jadad 1996
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds
DJ, Gavaghan DJ, et al. Assessing the quality of reports of
randomized clinical trials: is blinding necessary?. Controlled
Clinical Trials 1996;17(1):1–12. [DOI: doi.org/10.1016/
0197-2456(95)00134-4]
Kalant 2001
Kalant H. Medicinal use of cannabis: history and current
status. Pain Research & Management 2001;6:80–91.
Kalso 2013
Kalso E, Aldington DJ, Moore RA. Drugs for neuropathic
pain. BMJ 2013;347:f7339. [DOI: 10.1136/bmj.f7339]
L’Abbé 1987
L’Abbé KA, Detsky AS, O’Rourke K. Meta-analysis in
clinical research. Annals of Internal Medicine 1987;107:
224–33.
Lange 2010
Lange M, Petermann F. Influence of depression on
fibromyalgia: a systematic review [in German]. Schmerz
2010;24:326–33.
Lee 2012
Lee YH, Choi SJ, Ji JD, Song GG. Candidate gene studies
of fibromyalgia: a systematic review and meta-analysis.
Rheumatology International 2012;32:417–26.
Lee 2013
Lee MC, Ploner M, Wiech K, Bingel U, Wanigasekera
V, Brooks J, et al. Amygdala activity contributes to the
dissociative effect of cannabis on pain perception. Pain
2013;154:124–34.
Long 2009
Long JZ, Nomura DK, Vann RE, Walentiny DM, Booker L,
Jin X, et al. Dual blockade of FAAH and MAGL identifies
behavioral processes regulated by endocannabinoid crosstalk
in vivo. Proceedings of the National Academy of Science of the
United States of America 2009;106:20270–5.
Lunn 2014
Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating
painful neuropathy, chronic pain or fibromyalgia. Cochrane
Database of Systematic Reviews 2014, Issue 1. [DOI:
10.1002/14651858.CD007115.pub3]
Lynch 2011
Lynch ME, Campbell F. Cannabinoids for treatment of
chronic non-cancer pain: a systematic review of randomized
trials. British Journal of Clinical Pharmacology 2011;72:
735–44.
McQuay 1998
McQuay H, Moore R. An Evidence-based Resource for Pain
Relief. Oxford: Oxford University Press, 1998.
Moore 1998
Moore RA, Gavaghan D, Tramèr MR, Collins SL, McQuay
HJ. Size is everything - large amounts of information are
needed to overcome random effects in estimating direction
and magnitude of treatment effects. Pain 1998;78(3):
209–16. [DOI: 10.1016/S0304-3959(98)00140-7]
Moore 2009
Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ.
Pregabalin for acute and chronic pain in adults. Cochrane
Database of Systematic Reviews 2009, Issue 3. [DOI:
10.1002/14651858.CD007076.pub2]
Moore 2010a
Moore RA, Eccleston C, Derry S, Wiffen P, Bell RF, Straube
S, et al. “Evidence” in chronic pain - establishing best
practice in the reporting of systematic reviews. Pain 2010;
150(3):386–9. [DOI: 10.1016/j.pain.2010.05.011]
Moore 2010b
Moore RA, Straube S, Paine J, Phillips CJ, Derry S, McQuay
HJ. Fibromyalgia: moderate and substantial pain intensity
17Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
reduction predicts improvement in other outcomes and
substantial quality of life gain. Pain 2010;149(2):360–4.
[DOI: 10.1016/j.pain.2010.02.039]
Moore 2010c
Moore RA, Smugar SS, Wang H, Peloso PM, Gammaitoni
A. Numbers-needed-to-treat analyses - do timing, dropouts,
and outcome matter? Pooled analysis of two randomized,
placebo-controlled chronic low back pain trials. Pain 2010;
151(3):592–7. [DOI: 10.1016/j.pain.2010.07.013]
Moore 2010d
Moore RA, Moore OA, Derry S, Peloso PM, Gammaitoni
AR, Wang H. Responder analysis for pain relief and
numbers needed to treat in a meta-analysis of etoricoxib
osteoarthritis trials: bridging a gap between clinical trials
and clinical practice. Annals of the Rheumatic Diseases 2010;
69(2):374–9. [DOI: 10.1136/ard.2009.107805]
Moore 2011a
Moore RA, Wiffen PJ, Derry S, McQuay HJ. Gabapentin
for chronic neuropathic pain and fibromyalgia in adults.
Cochrane Database of Systematic Reviews 2011, Issue 3.
[DOI: 10.1002/14651858.CD007938.pub2]
Moore 2011b
Moore RA, Straube S, Paine J, Derry S, McQuay HJ.
Minimum efficacy criteria for comparisons between
treatments using individual patient meta-analysis of acute
pain trials: examples of etoricoxib, paracetamol, ibuprofen,
and ibuprofen/paracetamol combinations after third molar
extraction. Pain 2011;152(5):982–9. [DOI: 10.1016/
j.pain.2010.11.030]
Moore 2011c
Moore RA, Mhuircheartaigh RJ, Derry S, McQuay
HJ. Mean analgesic consumption is inappropriate
for testing analgesic efficacy in post-operative pain:
analysis and alternative suggestion. European Journal of
Anaesthesiology 2011;28(6):427–32. [DOI: 10.1097/
EJA.0b013e328343c569]
Moore 2012a
Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ.
Amitriptyline for neuropathic pain and fibromyalgia in
adults. Cochrane Database of Systematic Reviews 2012, Issue
12. [DOI: 10.1002/14651858.CD008242.pub2]
Moore 2012b
Moore RA, Straube S, Eccleston C, Derry S, Aldington D,
Wiffen P, et al. Estimate at your peril: imputation methods
for patient withdrawal can bias efficacy outcomes in chronic
pain trials using responder analyses. Pain 2012;153(2):
265–8. [DOI: 10.1016/j.pain.2011.10.004]
Moore 2013a
Moore RA, Straube S, Aldington D. Pain measures and
cut-offs - ’no worse than mild pain’ as a simple, universal
outcome. Anaesthesia 2013;68(4):400–12. [DOI: 10.1111/
anae.12148]
Moore 2013b
Moore A, Derry S, Eccleston C, Kalso E. Expect analgesic
failure; pursue analgesic success. BMJ 2013;346:f2690.
[DOI: 10.1136/bmj.f2690]
Moore 2014a
Moore RA, Cai N, Skljarevski V, Tölle TR. Duloxetine
use in chronic painful conditions - individual patient data
responder analysis. European Journal of Pain 2014;18(1):
67–75. [DOI: 10.1002/j.1532-2149.2013.00341.x]
Moore 2014b
Moore RA, Derry S, Taylor RS, Straube S, Phillips CJ. The
costs and consequences of adequately managed chronic non-
cancer pain and chronic neuropathic pain. Pain Practice
2014;14(1):79–94.
Mork 2010
Mork PJ, Vasseljen O, Nilsen TI. Association between
physical exercise, body mass index, and risk of fibromyalgia:
longitudinal data from the Norwegian Nord-Trøndelag
Health Study. Arthritis Care and Research 2010;62:611–7.
Mork 2012
Mork PG, Nilsen TI. Sleep problems and risk of
fibromyalgia: longitudinal data on an adult female
population in Norway. Arthritis and Rheumatism 2012;64:
281–4.
National Pain Foundation 2014
National Pain Foundation. Marijuana rated
most effective for treating fibromyalgia, 2014.
www.thenationalpainfoundation.org/pain-news.php
(accessed 1 April 2015).
Norman 2001
Norman GR, Sridhar FG, Guyatt GH, Walter SD.
Relation of distribution- and anchor-based approaches in
interpretation of changes in health-related quality of life.
Medical Care 2001;39:1039–47.
O’Brien 2010
O’Brien EM, Staud RM, Hassinger AD, McCulloch RC,
Craggs JG, Atchison JW, et al. Patient-centered perspective
on treatment outcomes in chronic pain. Pain Medicine 2010;
11(1):6–15. [DOI: 10.1111/j.1526-4637.2009.00685.x]
Oaklander 2013
Oaklander AL, Herzog ZD, Downs HM, Klein MM.
Objective evidence that small-fiber polyneuropathy
underlies some illnesses currently labeled as fibromyalgia.
Pain 2013;154:2310–6.
Owens 2015
Owens B. Drug development: the treasure chest. Nature
2015;525:S6–8.
Pacher 2006
Pacher P, Bátkai S, Kunos G. The endocannabinoid system
as an emerging target of pharmacotherapy. Pharmacological
Reviews 2006;58:389–462.
Queiroz 2013
Queiroz LP. Worldwide epidemiology of fibromyalgia.
Current Pain and Headache Reports 2013;17(8):356. [DOI:
10.1007/s11916-013-0356-5]
18Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
RevMan 2014 [Computer program]
The Nordic Cochrane Centre, The Cochrane Collaboration.
Review Manager (RevMan). Version 5.3. Copenhagen:
The Nordic Cochrane Centre, The Cochrane Collaboration,
2014.
Russo 2008
Russo EB. Clinical endocannabinoid deficiency (CECD):
can this concept explain therapeutic benefits of cannabis in
migraine, fibromyalgia, irritable bowel syndrome and other
treatment-resistant conditions?. Neuro Endocrinology Letters
2008;29:192–200.
Schaefert 2015
Schaefert R, Welsch P, Klose P, Sommer C, Petzke F, Häuser
W. Opioids in chronic osteoarthritis pain. A systematic
review and meta-analysis of efficacy, tolerability and safety
in randomized placebo-controlled studies of at least 4 weeks
duration [in German]. Schmerz 2015;29:47–59.
Schley 2006
Schley M, Legler A, Skopp G, Schmelz M, Konrad
C, Rukwied R. Delta-9-THC based monotherapy in
fibromyalgia patients on experimentally induced pain, axon
reflex flare, and pain relief. Current Medical Research and
Opinion 2006;27:1269–76.
Sommer 2012
Sommer C, Häuser W, Burgmer M, Engelhardt R, Gerhold
K, Petzke F, et al. Etiology and pathophysiology of
fibromyalgia syndrome [in German]. Schmerz 2012;26:
259–67.
Ste-Marie 2012
Ste-Marie PA, Fitzcharles MA, Gamsa A, Ware MA,
Shir Y. Association of herbal cannabis use with negative
psychosocial parameters in patients with fibromyalgia.
Arthritis Care & Research (Hoboken) 2012;64:1202–8.
Straube 2010
Straube S, Derry S, Moore RA, Paine J, McQuay HJ.
Pregabalin in fibromyalgia - responder analysis from
individual patient data. BMC Musculoskeletal Disorders
2010;11:150. [DOI: 10.1186/1471-2474-11-150]
Sultan 2008
Sultan A, Gaskell H, Derry S, Moore RA. Duloxetine
for painful diabetic neuropathy and fibromyalgia pain:
systematic review of randomised trials. BMC Neurology
2008;8:29. [DOI: 10.1186/1471-2377-8-29]
van Houdenhove 2004
Van Houdenhove B, Egle UT. Fibromyalgia: a stress
disorder? Piecing the biopsychosocial puzzle together.
Psychotherapy and Psychosomatics 2004;73:267–75.
Volkow 2014
Volkow ND, Compton WM, Weiss SR. Adverse health
effects of marijuana use. New England Journal of Medicine
2014;371:879.
Weber 2009
Weber J, Schley M, Casutt M, Gerber H, Schuepfer
G, Rukwied R, et al. Tetrahydrocannabinol (Delta 9-
THC) treatment in chronic central neuropathic pain and
fibromyalgia patients: results of a multicenter survey.
Anesthesiology Research and Practice 2009;2009:pii: 827290.
Wiffen 2013
Wiffen PJ, Derry S, Moore RA, Aldington D, Cole P, Rice
ASC, et al. Antiepileptic drugs for neuropathic pain and
fibromyalgia - an overview of Cochrane reviews. Cochrane
Database of Systematic Reviews 2013, Issue 11. [DOI:
10.1002/14651858.CD010567.pub2]
Wolfe 1990
Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier
C, Goldenberg DL, et al. The American College of
Rheumatology 1990 Criteria for the Classification
of Fibromyalgia. Report of the Multicenter Criteria
Committee. Arthritis and Rheumatism 1990;33:160–72.
Wolfe 2010
Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz
RS, Mease P, et al. The American College of Rheumatology
preliminary diagnostic criteria for fibromyalgia and
measurement of symptom severity. Arthritis Care and
Research 2010;62:600–10. [DOI: 10.1002/acr.20140]
Wolfe 2011
Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL,
Häuser W, Katz RS, et al. Fibromyalgia criteria and
severity scales for clinical and epidemiological studies: a
modification of the ACR Preliminary Diagnostic Criteria for
Fibromyalgia. Journal of Rheumatology 2011;38:1113–22.
Wolfe 2013
Wolfe F, Brähler E, Hinz A, Häuser W. Fibromyalgia
prevalence, somatic symptom reporting, and the
dimensionality of polysymptomatic distress: results from a
survey of the general population. Arthritis Care and Research
2013;645(5):777–85. [DOI: 10.1002/acr.21931]
Wolfe 2014
Wolfe F, Walitt BT, Häuser W. What is fibromyalgia, how is
it diagnosed and what does it really mean?. Arthritis Care
and Research 2014;66:969–71. [DOI: 10.1002/acr.22207]
Yunus 2008
Yunus MB. Central sensitivity syndromes: a new paradigm
and group nosology for fibromyalgia and overlapping
conditions, and the related issue of disease versus illness.
Seminars in Arthritis and Rheumatism 2008;37:339–52.
Üçeyler 2011
Üçeyler N, Häuser W, Sommer C. Systematic review with
meta-analysis: cytokines in fibromyalgia syndrome. BMC
Musculoskeletal Disorders 2011;28:245.
Üçeyler 2013a
Üçeyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider
S, Schmid A, et al. Small fibre pathology in patients with
fibromyalgia syndrome. Brain 2013;136:e247.
Üçeyler 2013b
Üçeyler N, Sommer C, Walitt B, Häuser W. Anticonvulsants
for fibromyalgia. Cochrane Database of Systematic Reviews
2013, Issue 10. [DOI: 10.1002/14651858.CD010782]
Indicates the major publication for the study
19Cannabinoids for fibromyalgia (Review)
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C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Skrabek 2008
Methods Study setting: single centre study, Outpatient Musculoskeletal Rehabilitation clinic,
Canada
Study design: parallel
Duration therapy: 4 weeks
Follow-up: 4 weeks
Participants 40 (93% women, race not reported, mean age 49 years)
Interventions Active drug: nabilone 0.5 mg to 1 mg/day twice a day at bedtime: 20 participants
Placebo: 20 participants
Rescue or allowed medication: no details reported. Participants were asked to continue
any current medication including breakthrough medications, but not to begin any new
therapy
Outcomes Pain: daily diary mean pain VAS 0-10
Fatigue: FIQ subscale VAS 0-100
Sleep: Not assessed
Depression: FIQ subscale VAS 0-100
Anxiety: FIQ subscale VAS 0-100
Disability: FIQ subscale VAS 0-100 *
Health-related quality of life: FIQ total score (0-100)
Participant-perceived improvement: not assessed
AEs: recorded at each visit. No details of assessment reported
*Outcome not reported
Notes Oxford Quality Score: R1, DB2, W1, Total 4/5
Funding sources and any declaration of interest of primary investigators: supported
by Valeant Canada and an HSC Medical Stuff Council Fellowship Fund. No declaration
of interest of primary investigators included
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk No details reported
Allocation concealment (selection bias) Low risk Pharmacy controlled
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Study medication was identical in appear-
ance to placebo
20Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Skrabek 2008 (Continued)
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Outcomes assessed by the participants who
were blinded to the intervention
Incomplete outcome data (attrition bias)
All outcomes
High risk No ITT analysis
Selective reporting (reporting bias) High risk Outcome disability not reported and not
provided on request
Group similarity at baseline Unclear risk No significant differences in demographic
and clinical characteristics of the study
groups
Sample size bias High risk < 50 participants per study arm
Ware 2010
Methods Study setting: single centre study, pain clinic, Canada
Study design: cross-over
Duration therapy: 2 weeks each with 2 weeks’ washout between the 2 periods
Follow-up: none
Participants 32 (81% women, race not reported, mean age 50 years)
Interventions Active drug: nabilone 0.5 or 1 mg/day orally flexible: 29 participants
Active comparator: amitriptyline oral flexible 10 or 20 mg/day: 29 participants
Rescue or allowed medication: no details reported
Outcomes Pain: McGill Pain Questionnaire total score (1-78)
Fatigue: FIQ subscale VAS 0-100 *
Sleep: Insomnia Severity Index (0-25) and Leeds Sleep Evaluation Questionnaire
Depression: FIQ subscale VAS 0-100 *
Anxiety: FIQ subscale VAS 0-100 *
Disability: FIQ subscale VAS 0-100 *
Health-related quality of life: FIQ total score (0-100)
Participant-perceived improvement: not assessed
AEs: recorded at each visit. No details of assessment reported
*Outcome not reported and not provided on request
Notes Oxford Quality Score: R2, DB1, W1, Total 4/5
Funding sources and any declaration of interest of primary investigators: supported
by a grant of Valeant (Canada) and McGill University Health Center. Declaration of
interest of primary investigators included
Risk of bias
21Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Ware 2010 (Continued)
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Randomly assigned block sizes by a com-
puter program
Allocation concealment (selection bias) Low risk Schedule retained by the study pharmacists
only
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Sealed opaque capsules containing study
drugs identical in appearance for both arms
(personal communication)
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Outcomes assessed by the participants who
were blinded to the intervention
Incomplete outcome data (attrition bias)
All outcomes
High risk No ITT analysis
Selective reporting (reporting bias) High risk No data for the FIQ subscales anxiety, dis-
ability, fatigue and depression provided
Group similarity at baseline Low risk Cross-over design
Sample size bias High risk < 50 participants per study arm
AE: adverse event; DB: double blind; FIQ: Fibromyalgia Impact Questionnaire; ITT: intention-to-treat; R: randomisation; VAS: visual
analogue scale; W: withdrawal.
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
NCT00176163 After contacting trial author: study data were prepared for publication; study design with 4 groups (behavioural
therapy + dronabinol, behavioural therapy + placebo, behavioural therapy alone, standard medical therapy) did
not meet inclusion criteria
NCT01149018 After contacting trial author: study was not conducted due to organisational reasons
22Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
D A T A A N D A N A L Y S E S
This review has no analyses.
A P P E N D I C E S
Appendix 1. Methodological considerations for chronic pain
There have been several recent changes in how efficacy of conventional and unconventional treatments is assessed in chronic painful
conditions. The outcomes are now better defined, particularly with new criteria for what constitutes moderate or substantial benefit
(Dworkin 2008); older trials may only report participants with “any improvement”. Newer trials tend to be larger, avoiding problems
from the random play of chance. Newer trials also tend to be longer, up to 12 weeks, and longer trials provide a more rigorous and
valid assessment of efficacy in chronic conditions. New standards have evolved for assessing efficacy in neuropathic pain, and we are
now applying stricter criteria for inclusion of trials and assessment of outcomes, and are more aware of problems that may affect our
overall assessment. To summarise some of the recent insights that must be considered in this new review.
1. Pain results tend to have a U-shaped distribution rather than a bell-shaped distribution. This is true in acute pain (Moore
2011b;Moore 2011c), back pain (Moore 2010c), arthritis (Moore 2010d), and fibromyalgia (Straube 2010); in all cases, mean results
usually describe the experience of almost no-one in the trial. Data expressed as means are potentially misleading, unless they can be
proven to be suitable.
2. As a consequence, we have to depend on dichotomous results (the person either has or does not have the outcome) usually from
pain changes or patient global assessments. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials
(IMMPACT) group has helped with their definitions of minimal, moderate and substantial improvement (Dworkin 2008). In
arthritis, trials shorter than 12 weeks, and especially those shorter than eight weeks, overestimate the effect of treatment (Moore
2010d); the effect is particularly strong for less effective analgesics, and this may also be relevant in neuropathic-type pain.
3. The proportion of participants with at least moderate benefit can be small, even with an effective medicine, falling from 60%
with an effective medicine in arthritis, to 30% in fibromyalgia (Moore 2009;Moore 2010d;Moore 2013b;Moore 2014a;Sultan
2008). One Cochrane review of pregabalin in neuropathic pain and fibromyalgia demonstrated different response rates for different
types of chronic pain (higher in diabetic neuropathy and postherpetic neuralgia and lower in central pain and fibromyalgia) (Moore
2009). This indicates that different neuropathic pain conditions should be treated separately from one another, and that pooling
should not be done unless there are good grounds for doing so.
4. Individual participant analyses indicate that people who get good pain relief (moderate or better) have major benefits in many
other outcomes, affecting quality of life in a significant way (Moore 2010b;Moore 2014b).
5. Imputation methods such as last observation carried forward (LOCF), used when participants withdraw from clinical trials, can
overstate drug efficacy especially when adverse event withdrawals with drug are greater than those with placebo (Moore 2012b).
Appendix 2. CENTRAL search strategy
1. MeSH descriptor: [Cannabis] this term only (263)
2. MeSH descriptor: [Cannabinoids] explode all trees (506)
3. (cannabis OR hemp OR marijuana OR ganka OR hashish OR marihuana OR bhang OR cannibinoid OR cannabinoids OR marinol
OR dronabinol OR nabilone OR cesamet OR dexanabinol OR sativex OR tetrahydrocannabinol): ti,ab,kw (Word variations were
searched) (1884)
4. OR/ 1-3 (1888)
5. (fibromyalgia):ti,ab,kw or (fibromyalgi$):ti,ab,kw or (fibrositis):ti,ab,kw or (fms):ti,ab,kw (1463)
6. MeSH descriptor: [Fibromyalgia] explode all trees (673)
7. OR/ 5-6 (1463)
8. (animal):ti,ab,kw (17838)
9. (human):ti,ab,kw (653277)
10. 9 not 8 (637801)
23Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
11. 4 and 7 and 10 in Trials (3)
Appendix 3. MEDLINE (via Ovid) search strategy
#1. (“cannabis”[MeSH Terms] OR “cannabis”[Tiab]) OR (“cannabis”[MeSH Terms] OR “cannabis”[Tiab] OR “hemp”[Tiab])
OR (“cannabis”[MeSH Terms] OR “cannabis”[Tiab] OR “marijuana”[Tiab]) OR (“Ganka”[Journal] OR “ganka”[Tiab]) OR
(“cannabis”[MeSH Terms] OR “cannabis”[Tiab] OR “hashish”[Tiab]) OR (“cannabis”[MeSH Terms] OR “cannabis”[Tiab] OR
“marihuana”[Tiab]) OR (“cannabis”[MeSH Terms] OR “cannabis”[Tiab] OR “bhang”[Tiab]) OR (“cannabinoids”[MeSH Terms]
OR “cannabinoids”[Tiab]) OR (“cannabinoids”[MeSH Terms] OR “cannabinoids”[Tiab] OR “cannabinoid”[Tiab]) OR (“dronabi-
nol”[MeSH Terms] OR “dronabinol”[Tiab] OR “marinol”[Tiab]) OR (“dronabinol”[MeSH Terms] OR “dronabinol”[Tiab]) OR
(“nabilone”[Supplementary Concept] OR “nabilone”[Tiab]) OR (“nabilone”[Supplementary Concept] OR “nabilone”[Tiab] OR “ce-
samet”[Tiab]) OR (“HU 211”[Supplementary Concept] OR “HU 211”[Tiab] OR “dexanabinol”[Tiab]) OR (“tetrahydrocannabinol-
cannabidiol combination”[Supplementary Concept] OR “tetrahydrocannabinol-cannabidiol combination”[Tiab] OR “sativex”[Tiab])
OR (“dronabinol”[MeSH Terms] OR “dronabinol”[Tiab] OR “tetrahydrocannabinol”[Tiab]) (34605)
#2. “fibromyalgia”[MeSH Terms] OR “fibromyalgia”[All Fields] OR “fibrositis”[All Fields] OR FMS[all] (13986)
#3. randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR drug therapy[sh] OR
randomly[tiab] OR trial[tiab] OR groups[tiab] (3589205)
#4. animals[mh] NOT humans[mh] (4011177)
#5.#3 NOT #4 (3091881)
#6. #1 AND #2 AND #5 (20)
Appendix 4. EMBASE (via Ovid) search strategy
1. (TITLE-ABS-KEY(cannabis) OR TITLE-ABS-KEY(hemp) OR TITLE-ABS-KEY(marijuana) OR TITLE-ABS-KEY(ganja) OR
TITLE-ABS-KEY(hashish) OR TITLE-ABS-KEY(marihuana) OR TITLE-ABS-KEY(bhang) OR TITLE-ABS-KEY(cannibinoid)
OR TITLE-ABS-KEY(cannabinoids) OR TITLE-ABS-KEY(marinol) OR TITLE-ABS-KEY(dronabinol) OR TITLE-ABS-
KEY(nabilone) OR TITLE-ABS-KEY(cesamet) OR TITLE-ABS-KEY(dexanabinol) OR TITLE-ABS-KEY(sativex) OR TITLE-ABS-
KEY(tetrahydrocannabinol)) AND DOCTYPE(ar OR re) (48947)
2. (TITLE-ABS-KEY(fibromyalgia) OR TITLE-ABS-KEY(fibrositis) OR TITLE-ABS-KEY(fms)) AND DOCTYPE (ar OR re)
(19146)
3. (TITLE-ABS-KEY ( “randomized controlled trial” ) OR TITLE-ABS-KEY ( “controlled trial” ) OR TITLE-ABS-KEY ( placebo )
OR TITLE-ABS-KEY ( “single blind” ) OR TITLE-ABS-KEY ( “double blind” ) ) AND DOCTYPE ( ar OR re ) (648952)
4. #1 AND #2 AND #3 (47)
Appendix 5. Inclusion and exclusion criteria of the studies
Study Inclusion criteria Exclusion criteria
Skrabek 2008 Participant met American College of
Rheumatology (1990) criteria for the classification of
fibromyalgia
Aged 18-70 years
Any gender
participant did not received benefit from a tricyclic
antidepressant, muscle relaxant, paracetamol
(acetaminophen) or non-steroidal anti-inflammatory
drugs for management of their pain
No previous use of oral cannabinoids for pain
Participant’s pain was better explained by a
diagnosis other than fibromyalgia
Abnormalities on routine baseline blood work
including electrolytes, urea and creatinine, a complete
blood count and liver function tests (aspartate
transaminase, alanine aminotransferase, gamma
glutamyl transpeptidase, alkaline phosphatase and
lactate dehydrogenase). Normal tests taken within 3
months prior to the study were accepted if there was no
24Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
management history of acute illness since the time the blood was
drawn
Heart disease (cannabinoids can reduce heart rate
and blood pressure). People with heart disease were
excluded based on a history of angina, myocardial
infarction or congestive heart failure and clinical
examination
Schizophrenia or other psychotic disorder
Severe liver dysfunction (participants excluded if
there was an elevation of any of the baseline liver
enzymes)
History of untreated non-psychotic emotional
disorders
Cognitive impairment
Major illness in another body area
Pregnancy
Nursing mothers
Aged < 18 years old
History of drug dependency
Known sensitivity to marijuana or other
cannabinoid agents
Ware 2010 Aged 18 years
diagnosis according to the American College of
Rheumatology classification criteria
Experiencing self reported disturbed sleep
Negative urine screen for cannabinoids
Women of childbearing potential agreed to use
adequate contraception during study and for 3 months
after study
Ability to attend research centre every second week
for approximately 7-9 weeks and be able to be contacted
by telephone during the study period
Stable drug regimen for 1 month prior to
randomisation
Normal liver (aspartate transaminase < 3 x normal)
and renal function (serum creatinine < 133 µmol/L)
Haematocrit > 38%
Negative serum beta subunit of human chorionic
gonadotropin
Proficient in English or French
Willing and able to give written informed consent
Ability to follow study protocol (cognitive and
situational)
People currently using cannabis or cannabinoid or
tricyclic antidepressants and who are unable to undergo
a 2-week washout period before entering the study
Pain due to cancer
Unstable cardiac disease such as cardiac
arrhythmias, cardiac failure, ischaemic heart disease or
hypertension (or a combination) on clinical history and
examination
History of psychotic disorder or schizophrenia
Known hypersensitivity to cannabinoids,
amitriptyline or related tricyclic antidepressants
Currently taking or unable to stop taking
monoamine oxidase inhibitors (a 2-week washout
period is necessary for people taking monoamine
oxidase inhibitors)
History of seizures/epilepsy
Diagnosis of glaucoma
Urinary retention
Pregnancy or breast-feeding, or both
Participation in other clinical trial in the 30 days
prior to randomisation
Recent manic episode (within the past year)
Current suicidal ideation or history of suicide
attempts
25Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 6. Summary of efficacy in single studies
Study Treatment Efficacy outcomes at the end of treatment
Skrabek 2008 Nabilone 1 mg bid orally vs. placebo
Titration from 0.5 mg to 1 mg bid from week 1 to 4
50% pain reduction: not reported and not provided on
request
PGIC: not assessed
Pain: nabilone mean 4.8 (SD 2.2), placebo mean 5.7 (SD
1.8) * (P value = 0.02)***
Sleep: not assessed
Fatigue: no significant difference **
Depression: no significant difference **
Anxiety: nabilone mean 4.3 (SD 1.8); placebo mean 4.9
(SD 2.2) * (P value < 0.01)***
Health-related quality of life: mean 54 (SD 22.3); placebo
mean 64 (SD 13.4) *; (P value < 0.01)***
Ware 2010 Nabilone 0.5 or 1 mg vs. amitriptyline 10 or 20 mg at
bedtime each
Titration in each of 2 periods of 2 weeks,
with 2 weeks’ washout between the 2 treatment periods
50% pain reduction: not reported and not provided on
request
PGIC: not assessed
Mean pain intensity: no significant difference **
Sleep: nabilone: mean 9 (SD 10.8); amitriptyline mean
13 (SD 10.8) *
Fatigue: not reported
Depression: not reported
Anxiety: not reported
Health-related quality of life: no significant difference **
bid: twice daily; PGIC: Patient Global Impression of Change; SD: standard deviation; vs.: versus.
* Data extracted from figures. Data not provided on request.
** No means and SDs reported. Data not provided on request.
*** P values as reported by authors.
There were no significant differences between nabilone and placebo groups after the 4-week wash-out period (Skrabek 2008).
Appendix 7. Summary of tolerability and safety in single studies
Study Adverse events (cannabinoid vs.
control)
Withdrawal due to adverse events
(nabilone vs. comparator)
Serious adverse events
(nabilone vs. comparator)
Skrabek 2008 Nabilone vs. placebo:
Drowsiness 47% vs. 6%
Dry mouth 33% vs. 6%
Vertigo 27% vs. 0%
Ataxia 20% vs. 6%
Confusion 13% vs. 6%
Decreased concentration 13% vs. 6%
15% vs. 0% 0% vs. 0%
26Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
Ware 2010 Nabilone vs. amitriptyline:
Dizziness 32% vs. 13%
Headache 13% vs. 19%
Nausea 29% vs. 3%
Dry mouth 23% vs. 10%
Drowsiness 23% vs. 3%
Constipation 19% vs. 3%
Insomnia 10% vs. 0%
3% vs. 0% 0% vs. 0%
vs: versus.
W H A T ’ S N E W
Last assessed as up-to-date: 26 April 2016.
Date Event Description
19 July 2016 Review declared as stable See Published notes.
C O N T R I B U T I O N S O F A U T H O R S
MAF and WH drafted the protocol.
PK and WH developed and ran the search strategy.
The PaPaS information specialist provided support.
PK and WH selected which studies to include.
MAF and WH extracted data from studies.
WH entered data into Review Manager 5, carried out the analysis, drafted the final review and will be responsible for updates.
All review authors interpreted the analysis.
D E C L A R A T I O N S O F I N T E R E S T
BW: none known; BW is a pain physician who treats people with fibromyalgia.
PK: none known.
MAF is a rheumatologist and pain physician who treats people with fibromyalgia. She is the head of the steering committee of the
Canadian guideline on fibromyalgia. She has received:
1. Consulting fees from AMGEN (one each in 2013, 2015, two in 2014) and Bristol-Myers Squibb Canada (one in 2014);
2. Speaking/education fees from Janssen (one in 2014), Johnson & Johnson (one each in 2013, 2014), UCB Canada (one in
2015), Valeant (two in 2013), Pfizer (one in 2013) and Lilly (two in 2013, three in 2014);
27Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
3. In clinic training for ABBVIE staff (one each in 2014, 2015);
4. AD Board honoraria from Janssen (one in 2014), Pfizer (one in 2013), Purdue (one in 2013), Johnson & Johnson (one in 2014).
TP: none known; TP is a specialist pain physician and manages people with fibromyalgia.
WH is a specialist in general internal medicine, psychosomatic medicine and pain medicine, who treats people with fibromyalgia. He
is a member of the medical board of the German Fibromyalgia Association. He is the head of the steering committee of the German
guideline on fibromyalgia and a member of the steering committee of the European League Against Rheumatism (EULAR) update
recommendations on the management of fibromyalgia. He received speaking fees for one educational lecture each from MSD Sharpe
& Dohme (2014) and Grünenthal (2015) on pain management.
S O U R C E S O F S U P P O R T
Internal sources
No sources of support supplied
External sources
Ruth und Kurt Bahlsen Stiftung, Germany.
Petra Klose was supported by the Ruth und Kurt Bahlsen Stiftung.
National Center for Complementary and Integrative Health, USA.
Brian Walitt has been supported (in part) by the Intramural Research Program of the National Institutes of Health, National Center
for Complementary and Integrative Health.
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
We added selective outcome reporting (reporting bias) and group similarity at baseline (selection bias) in the risk of bias assessment.
We defined criteria for assessing the reported methodology quality of the trials and for downgrading the quality of evidence.
N O T E S
A new search within two years is not likely to identify any potentially relevant studies likely to change the conclusions. Therefore,
this review has now been stabilised following discussion with the authors and editors. The review will be assessed for updating in four
years. We will update the review before this date if new evidence likely to change the conclusions is published, or if standards change
substantially which necessitate major revisions.
28Cannabinoids for fibromyalgia (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
... In this regard, recent evidence brought to light the use of cannabinoids as an alternative treatment for FM [8,9]. Although the evidence supporting cannabis use in chronic pain conditions is abundant and well established, clinical applicability and safety have not been properly reported in FM [10,11]. For instance, cannabis use is associated with some significant risks, e.g., addiction and psychiatric, cognitive, and developmental impairments [11]. ...
... As previously mentioned, THC, the main psychoactive constituent of cannabis, activates CB1 and CB2 receptors, consequently inducing central and peripheral neuronal activity, and is responsible for the analgesic and psychomimetic effects of cannabis [27]. As much as THC has great clinical effects, a study has shown that, unfortunately, most patients who used THC (2.5-15 mg daily for three months) as therapeutic form gave up early due to THC side effects, but those who completed it had marked reductions in visual analog scales (VAS) of subjective pain [10]. The broad-spectrum cannabis oil studied here has low levels of THC and higher levels of CBD [13], the main non-intoxicating constituent of cannabis [27]. ...
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... Para estimar os efeitos dos três princípios ativos citados, foram realizados ensaio clínicos e estudos observacionais comparando ora com um grupo placebo e ora com a amitriptilina(LAWSON, 2016;FITZCHARLES et al., 2016;TSANG;GIUDICE, 2016;WALITT et al., 2016;LATORRACA et al., 2018;ROCCO;RADA, 2018;BERGER et al., 2020;TZADOK;ABLIN, 2020; MAYORGA-ANAYA et al., 2021).De acordo com pesquisa feita a partir da análise de ensaios clínicos e de revisões sistemáticas, houve um rápido favorecimento no uso de nabilona e dronabinol para melhorar principalmente o sono e a dor, enquanto no uso do tetrahidrocanabinol apresentou resposta positiva apenas sobre o quadro álgico (SILVA; REMTULA; GONÇALVES, 2021). Ademais, quando direcionado para o estudo principalmente da nabilona, poucos eventos adversos foram avaliar o dronabinol versus amitriptilina para fibromialgia, foi visto que esse tipo de canabinóide promoveu resultados superiores sobre a melhora da qualidade de vida dos usuários reduzindo, por exemplo, a dor destas pessoas (LAWSON, 2016). ...
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... Similar to migraine, fibromyalgia is associated with hyperalgesia, a lowered pain threshold associated with central endocannabinoid hypofunction in the spinal cord. According to Russo et al., the approved drugs for fibromyalgia, duloxetine, milnacipran (serotonin and adrenergic inhibitors, respectively), and pregabalin (an anticonvulsant used to treat neuropathic pain) showed little efficacy in treating fibromyalgia compared to Cannabis [106][107][108]. ...
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Existe un gran espectro de enfermedades reumáticas, cada una con orígenes y desarrollos diferentes. El enfoque reumatológico, clasifica las distintas afecciones en una serie de grandes grupos. Así se enmarcan como trastornos neurovasculares, enfermedades metabólicas, neoplasias, reumatismo de los tejidos blandos, enfermedades del tejido conjuntivo, artropatías inflamatorias o artropatías degenerativas, en este libro abordamos las situaciones complejas en la práctica clínica para así brindar pautas de un abordaje integral de las principales presentaciones de estas patologías.
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There are intriguing theories regarding the biology of fibromyalgia. Whilst several researchers assume it is a psychogenic, others believe that fibromyalgia is a disease of neurological sensitization (an overactive alarm system). Fibromyalgia is a clinical entity that present with a mix of the symptoms including chronic widespread pain and other non-pain linked symptoms, such as poor sleep, fatigue and cognitive disturbances. Furthermore, fibromyalgia exhibits substantial variation not only between various patients, but also in the same patient during the disease course. Identifying a common language and classification to diagnose and treat fibromyalgia represent another challenge, as patients may seek care from different disciplines (such as rheumatology, general practice, neurology, psychology, or psychiatry and in some cases orthopedic surgery) with unique perspectives and terminologies. Furthermore, in concordance with other medically unexplained pain syndromes, fibromyalgia may be classified in several ways (such as functional somatic syndrome, chronic widespread pain syndrome, persistent somatoform pain disorder, somatic symptom disorder, affective spectrum condition, and central sensitivity syndrome). This chapter will discuss the debate of fibromyalgia as a bitterly controversial condition, the science of pain and where fibromyalgia fits in. It will then discuss fibromyalgia as a pain processing problem, different sources of pain in fibromyalgia patients and the wind-up theory. The chapter will expand to discuss Fibromyalgia associated comorbidities, fibromyalgia pain in the clinical setting, fibromyalgianess, neuroimaging, as well as pain pathways and the pharmacotherapy of Fibromyalgia.
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