Cannabis and Cannabinoid Research

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DOI: 10.1089/can.2021.0156 and other resources online.

Clinical Practice Guidelines for Cannabis

and Cannabinoid-Based Medicines in the Management
of Chronic Pain and Co-Occurring Conditions
Alan D. Bell,1 Caroline MacCallum,2 Shari Margolese,3 Zach Walsh,4 Patrick Wright,5 Paul J. Daeninck,6,7
Enrico Mandarino,3,8 Gary Lacasse,5,* Jagpaul Kaur Deol,9 Lauren de Freitas,10 Michelle St. Pierre,4 Lynne Belle-Isle,5
Marilou Gagnon,11 Sian Bevan,12 Tatiana Sanchez,4 Stephanie Arlt,10 Max Monahan-Ellison,13 James O’Hara,14
Michael Boivin,15 and Cecilia Costiniuk16–18,*; and External Review Panel{

Abstract
Background: One in five individuals live with chronic pain globally, which often co-occurs with sleep problems,
anxiety, depression, and substance use disorders. Although these conditions are commonly managed with
cannabinoid-based medicines (CBM), health care providers report lack of information on the risks, benefits,
and appropriate use of CBM for therapeutic purposes.
Aims: We present these clinical practice guidelines to help clinicians and patients navigate appropriate CBM use
in the management of chronic pain and co-occurring conditions.
Materials and Methods: We conducted a systematic review of studies investigating the use of CBM for the
treatment of chronic pain. Articles were dually reviewed in accordance with Preferred Reporting Items for Sys-
tematic Reviews and Meta-Analyses guidelines. Clinical recommendations were developed based on available
evidence from the review. Values and preferences and practical tips have also been provided to support clinical
application. The GRADE system was used to rate the strength of recommendations and quality of evidence.
Results: From our literature search, 70 articles met inclusion criteria and were utilized in guideline development,
including 19 systematic reviews and 51 original research studies. Research typically demonstrates moderate ben-
efit of CBM in chronic pain management. There is also evidence for efficacy of CBM in the management of
comorbidities, including sleep problems, anxiety, appetite suppression, and for managing symptoms in some
chronic conditions associated with pain including HIV, multiple sclerosis, fibromyalgia, and arthritis.

1
Department of Family and Community Medicine, University of Toronto, Toronto, Canada.
2
Faculty of Medicine, Department of Internal Medicine, University of British Columbia, Vancouver, Canada.
3
Canadian HIV Trials Network, University of British Columbia, Vancouver, Canada.
4
Department of Psychology, University of British Columbia, Kelowna, Canada.
5
Canadian AIDS Society, Ottawa, Canada.
6
Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada.
7
CancerCare Manitoba, Winnipeg, Canada.
8
MJardin Group Canada, Toronto, Canada.
9
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
10
Centre for Addiction and Mental Health, Institute for Mental Health Policy Research, Toronto, Canada.
11
Canadian Institute for Substance Use Research, University of Victoria, Victoria, Canada.
12
Arthritis Society, Toronto, Canada.
13
Medical Cannabis Canada, Toronto, Canada.
14
Independent Consultant, Toronto, Canada.
15
CommParm Consulting, Inc., Barrie, Ontario, Canada.
16
Chronic Viral Illness Service/Division of Infectious Diseases, Department of Medicine, McGill University Health Centre, Montreal, Canada.
17
McGill Cannabis Research Centre, McGill University, Montreal, Canada.
18
Research Institute of the McGill University Health Centre, Montreal, Canada.
{
See Acknowledgements.

*Address correspondence to: Gary Lacasse, Canadian AIDS Society, 1554 Carling Avenue, Suite 355, Ottawa ON K1Z 7M4, Canada, E-mail: gary_lacasse@hotmail.com or Cecilia
Costiniuk, MD, MSc, Research Institute of the McGill University Health Centre and Department of Medicine, Division of Infectious Diseases and Chronic Viral Illness Service,
Room EM2.3226, 1001 Boulevard Decarie, Montreal, QC H4A 3J1, Canada; E-mail: cecilia.costiniuk@mcgill.ca

ª Alan D. Bell et al., 2023; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License
[CC-BY] (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.

1
2 BELL ET AL.

Conclusions: All patients considering CBM should be educated on risks and adverse events. Patients and clini-
cians should work collaboratively to identify appropriate dosing, titration, and administration routes for each in-
dividual.
Systematic Review Registration: PROSPERO no. 135886.
Keywords: cannabinoids; cannabinoid-based medicines; cannabis; marijuana; chronic pain; sleep disorders

Introduction bidiol [CBD] vs. THC/CBD products), the reason is

Across the globe, one in five individuals live with that evidence exists for these specific cannabinoids or
chronic pain,1 and estimates of chronic pain prevalence combinations. Note that we cannot extrapolate from
may be 20–25% in some countries and regions.2 Two one cannabinoid to another, nor from a combination
thirds of individuals report it as moderate to severe.3–5 product to one cannabinoid, since the evidence for
Approximately 50% of these individuals have lived doing so does not exist.
with chronic pain for more than 10 years.3 Chronic Practical tips were formulated qualitatively based on
pain often co-occurs with insomnia, anxiety, depression, a discussion of panel members from their cumulative
post-traumatic stress disorder (PTSD), and substance clinical experience, rather than a formal algorithm.
use disorders such as opioid and alcohol use disor-
der.6–12 Chronic pain and these co-occurring conditions Search strategy and study eligibility
are also among the most common conditions for which In May 2019, an electronic search was conducted for
cannabinoid-based medicines (CBM), derived from the peer-reviewed articles (2001–2019), in English, in the
cannabis plant, are used therapeutically.13–16 following electronic databases: Academic Search Com-
Recently, there has been a proliferation of systematic plete, Cochrane Database of Systematic Reviews, Evi-
reviews on CBM and chronic pain and co-occurring dence Based Medicine Reviews, OVID Medline,
conditions. Given new legal regimes globally regarding PsychINFO, PubMed, CINAHL, and Web of Science.
recreational cannabis and CBM derived from the can- The search strategy was as previously described.17
nabis plant, health care providers need to be aware of Studies focusing exclusively on efficacy of synthetic
the potential efficacy and harms. Here, we present Clin- pharmaceutical cannabinoids (such as nabilone or dro-
ical Practice Guidelines for the use of Cannabis and nabinol) were excluded.
CBM in the Management of Chronic Pain and Co- In addition, studies reporting on results of a single
occurring Conditions. These guidelines examine litera- patient (n = 1) were also excluded. As nabiximols con-
ture focused on cannabis and CBM derived from the tain plant-derived cannabinoids, they were included.
cannabis plant rather than synthetic, pharmaceutical- Complete inclusion and exclusion criteria are listed in
grade cannabinoids in an effort to fill an important Supplementary Table S1 in the protocol.17 Study
knowledge gap. types including systematic reviews, meta-analyses, con-
trolled trials, uncontrolled trials, observational studies,
Materials and Methods and cross-sectional designs were included, whereas sys-
Our previously published protocol17 outlined the inclu- tematic reviews and original research articles were
sion/exclusion criteria for studies (PICOS breakdown), summarized separately. Guideline development was
process for data extraction (using Preferred Reporting primarily based on original research given the hetero-
Items for Systematic Reviews and Meta-Analyses geneity of previous systematic reviews.
[PRISMA] conventions) strategy for data synthesis, as-
sessment of evidence and recommendations (GRADE Study screening and selection
system), risk of bias assessment, and procedures for Using the PRISMA conventions,18 a Data Synthesis
data analysis/synthesis. Conclusions relate to availabil- Committee determined study eligibility by reading
ity of evidence, and the evidence available does not sup- identified abstracts. Each abstract was independently
port doing this for every cannabinoid and cannabinoid dually reviewed. Full-text screening occurred in cases
combination. of uncertainty. Disagreements on inclusion were re-
When we report on adverse effects for specific can- solved through a discussion by two reviewers. Full-
nabinoids (i.e., tetrahydrocannabinol [THC] vs. canna- text screening was also independently dually reviewed.
CBM CHRONIC PAIN CPGS 20221025 CCR 3

Reference lists of included studies were searched for strong if the committee considered the benefit to
potential additions. A PRISMA flowchart outlines this clearly outweigh the risk for most individuals. All
process (Supplementary Appendix SA1). other recommendations were specified as weak, indi-
cating a need to consider individual clinical circum-
Data extraction stances, values, and preferences.
Data were extracted independently using a standard-
ized Data Extraction Form to create evidence tables. Risk-of-bias assessment
For each study, data were extracted related to study Two reviewers (M.S.P. and P.W.) assessed potential
identification (author, year published, number and lo- bias and discrepancies were adjudicated by the Data
cation of centres, funding, journal name), number of Synthesis Committee (C.C., Z.W., S.M.). The National
participants, form of CBM, dose and route, study de- Institutes of Health risk-of-bias assessment tools27 were
sign and setting, inclusion/exclusion criteria, aggregate used to assess study quality. These tools were developed
demographic (age, sex, type of pain, co-occurring con- specifically for different study design types, and there-
ditions) and clinical characteristics (co-morbidities), fore heterogeneity of the designs of included studies
outcome measures, and results. We also identified will not affect ability to assess quality appropriately.
types and frequencies of adverse events. Final evalua- Study bias was graded as either ‘‘good quality’’ (score
tion of study quality (very low, low, moderate or of 3), implying low risk of bias, ‘‘fair quality’’ (score
high) included considerations of limitations, inconsis- of 2) implying some risk of bias, or ‘‘poor quality’’
tencies, indirectness, and imprecision. (score of 1), implying high risk of bias. Assessments
of bias were performed at the overall study level.
Data synthesis
Data were extracted using standard data extraction Results
tools. There is significant variability in cannabis re- We identified 4989 records following the removal of
search due to heterogeneity of sample populations, duplicates (Supplementary Appendix SA1). Following
study types and lengths, and CBM interventions (e.g., abstract review, 4824 records were excluded, resulting
CBM type, dosing, administration route, etc.). Patterns in full-text review of 165 articles. Reasons for exclusion
related to efficacy, safety, and tolerability were explored are presented in Supplementary Appendix SA1. Seventy
through narrative synthesis.19,20 Data were compiled studies were included in the final review, including 19
based on availability of quality evidence. Consistent systematic reviews (Supplementary Appendix SA2)
findings and discrepancies were discussed. Evidence and 51 original research studies (Supplementary Appen-
for CBM in the management of chronic pain and co- dix SA3). To avoid redundancy, systematic reviews were
occurring conditions related to efficacy, tolerability, considered independent of primary literature.
safety, indications, dosing, drug interactions, adverse
events, negative effects, and contraindications. Characteristics of systematic reviews
Details of the 19 included systematic reviews are pre-
Assessment of evidence and recommendations sented in Supplementary Appendix SA2, along with
Clinical recommendations and indications were devel- each review’s quality rating as an assessment of risk
oped and presented in relation to CBM use for chronic of bias. Most reviews were rated as either good, or
pain and comorbidities. The Task Force used the fair, representing low or moderate risk of bias, respec-
GRADE system to rate quality of evidence and strength tively. Included reviews were published between 2007
of recommendations.21–26 Values and preferences and and 2018, with 16 of 19 reviews published in 2015 or
practical tips have also been provided to support clini- more recently. The majority of reviews (12) included
cal application. only randomized controlled trials (RCTs).
Three reviews included only systematic re-
Strength of recommendations views,28,29,30 three contained primary research,31–33
Strength of recommendations was specified as strong and one included other systematic reviews, in addition
or weak based on risk and benefit of CBM in the spe- to primary research.34 People with chronic pain were
cific condition. Patient values and preferences, magni- the most commonly studied population (14). One review
tude of effect, and confidence in the evidence were focused on rheumatic disease-associated pain,35 one in-
considered. A recommendation was deemed to be cluded studies of multiple sclerosis (MS) or comparable
4 BELL ET AL.

neuropathic pain,36 one included systematic reviews that toms. Whiting et al reported significant improvement
analyzed cannabinoids for pain, spasticity, or nausea and in anxiety with cannabinoids over placebo; however,
vomiting,29 and two included people using medical can- in studies where anxiety was studied as a secondary
nabinoids regardless of indication.32,37 outcome, they found no significant difference. Martin-
Most reviews explored both pharmaceutical syn- Sanchez et al analyzed mood disturbances only within
thetic and plant-based cannabinoids (15/19). Three re- the context of adverse events but found euphoria to be
views focused exclusively on plant-based cannabis and a common occurrence with a number needed to harm
plant-derived cannabinoid extracts.34,38,39 Park and (NNH) of 8, and dysphoria to be less common with an
Wu focused exclusively on non-synthetic cannabis, as NNH of 29.
their review solely included people using medical can- Finally, in a review focused on people living with
nabis. Reviews that focused exclusively on pharmaceu- chronic neuropathic pain, Mucke et al reported canna-
tical synthetic cannabinoids were excluded. binoids to be more efficacious than placebo for treating
In terms of efficacy for chronic pain reduction, most psychological distress.
reviews (14/19) reported that cannabinoids provided
analgesia in at least some contexts. Nugent et al Evidence summaries and clinical guideline
found non-synthetic cannabinoids beneficial for neu- recommendations
ropathic pain, but they found insufficient evidence in 1. CBM use for people with chronic pain
other types of pain. In addition, Stockings et al reported Forty-seven studies relevant to pain management were
nabiximols to be effective for MS-related pain; how- reviewed, including 22 RCT,46–67 11 pre-post studies or
ever, generally there was insufficient evidence for can- uncontrolled trials,68–78 11 cross-sectional or observa-
nabinoids to be used as a pain treatment. Five reviews tional cohort studies,79–89 and 3 case series.90–92 Most
found inadequate evidence to support cannabinoids as studies (38/47) reported at least moderate benefits of
an effective pain treatment.28,29–31,35 CBM for chronic pain,46–48,50,51,54,55,57,59–70,73–80,82–84,
86–92
Of the eight reviews that obtained a ‘‘good’’ quality seven were inconclusive or found insufficient
rating, representing the lowest risk of bias, seven evidence,49,53,56,58,71,72,85 and two reported mixed
found cannabinoids to be beneficial for pain relief. results.52,81
However, in some instances, the analgesic effect of can- Associated improvements in secondary outcomes,
nabinoids was described as ‘‘moderate’’40 or ‘‘small.’’41 including QoL, functionality, and mood, have also
Most reviews analyzed prevalence of adverse events been observed with the use of medical cannabis in ad-
associated with cannabinoids. Although common, ad- dition to reductions in pain severity, intensity, and in-
verse events were typically mild to moderate in severi- terference. For details of the individual studies, see
ty.34,39–42 Adverse events were similar between reviews Appendix A in Supplementary Data.
and included drowsiness, dizziness, and dry mouth.
Aviram and Samuelly-Leichtag suggested that adverse Recommendations. 1. We recommend the use of
events could not entirely be attributed to cannabinoids CBM as monotherapy, replacement, or adjunct treat-
as ‘‘the participating patients in the included trials had ment, in people living with chronic pain, for the man-
pre-existing diagnoses and in many of the trials, they agement of chronic pain including central and/or
used concomitant medications.’’43 peripheral neuropathic pain to improve pain outcomes.
A few reviews included analysis of pain comorbid- Strong Recommendation, Moderate-Quality Evidence
ities. Of the reviews that studied sleep and sleep prob- 2. We recommend the use of CBM as monotherapy,
lems within the context of chronic pain, analyses fairly replacement or adjunct treatment, in people living with
consistently supported that cannabinoids provided at chronic pain, for mobility in those not achieving ade-
least partial benefit.32,33,35,37,40–42,44,45 Findings were quate response to other modalities.
more heterogenous regarding the efficacy of cannabi- Weak Recommendation, Low-Quality Evidence
noids for mood disorders and related issues. Four re-
views reported that cannabinoids improved anxiety in Values and preferences. The recommendations place
pain populations.35,37,41,44 high value on the improvement in chronic pain, func-
Stockings et al did not find any significant difference tionality, and secondary outcomes, including time to
between cannabinoid and comparator groups in overall sleep, quality of sleep, anxiety, and depression, in
emotional functioning or depressive or anxiety symp- those living with chronic pain and using CBM
CBM CHRONIC PAIN CPGS 20221025 CCR 5

compared with placebo. The recommendations also ciated with CBM use. For details of the individual stud-
outweigh the risks of non-serious adverse events with ies, see Appendix B in Supplementary Data.
CBM (dizziness, disturbance in attention, somnolence,
dry mouth, nausea, diarrhea) as compared with adverse Recommendations. 1. We recommend the use of
events from standard analgesia (opioids and serotonin- CBM for the management of muscular and neuro-
norepinephrine reuptake inhibitors [SNRIs] or opioids pathic pain in people living with HIV who are not
monotherapy), including constipation, loss of appetite, achieving adequate response, or those experiencing ad-
unclear mentation, reduced affect, hemorrhoids, and verse effects to other treatment modalities.
substance use disorder. Strong Recommendation, Moderate-Quality Evidence
2. We recommend CBM use for the management of
Practical tip. A wide variety of formulations and routes HIV-related symptoms, including nausea, anxiety, de-
including smoking, vaping, oral capsule, oral oil, and pression, lack of appetite, and weight loss in people liv-
oromucosal sprays showed benefits in chronic pain, ing with HIV. CBM use is for symptom management
mood disorders, mobility, and sleep. Adverse events only and should not replace the use of antiretroviral
due to combustion, and exposure to second-hand therapies.
smoke, make smoked CBM less favorable. The inhala- Strong Recommendation, Low-Quality Evidence
tion route of CBM is restricted to the vaporization of
Values and preferences. The recommendations place
dried flower over combustion for the management of
high value on the benefit of neuropathic and muscular
breakthrough pain due to rapid onset and shorter dura-
pain relief in people with HIV over the risks of adverse
tion of action.
events of a mainly non-serious nature such as dizziness,
Oral products, as a route of administration may be
disturbance in attention, balance disorder, somnolence,
preferred for the longer duration of action (6–8 h)
dry mouth, nausea, diarrhea, fatigue, or confused state
compared with inhaled cannabis, particularly in the
and those of a more serious nature such as pulmonary
evening (due to somnolence). This will allow for
and cardiovascular effects of inhaled substances.
greater symptom control in patients who experience
chronic persistent daily symptoms and/or disease. Practical tip. A wide variation is seen in the dose and
Oral oil and capsule formulations can be easier to administration routes of cannabinoids used to optimize
dose accurately (mg) and provide consistent and repro- the treatment effect and adverse event ratio. A slow
ducible dosing. dose titration, initiated with CBD-predominant canna-
binoids, should be used to individualize treatment
Practical tip. The strongest evidence for reduction of (Fig. 2).
chronic pain symptoms is for THC formulations, not
CBD. The majority of adverse events are associated Practical tip. Although benefit was observed in HIV
with THC. Adverse Events due to CBM are mild and nerve and muscle pain mostly with smoked formula-
may be better tolerated than other centrally acting pre- tions, oils and capsules have been shown to have the
scription medications. Patients report that adverse ef- strongest evidence in MS. Oils and capsules provide
fects generally subside within 48 h or when the the greatest consistency for dosage and titration and
titration phase is stopped. The best way to reduce the are not associated with potential adverse events asso-
potential adverse effects with THC is with safe, low- ciated with inhalation of CBM.
dose initiation and titration (Fig. 2). In addition, a
CBD dominant product can be used in combination 3. CBM use for people living with multiple
with THC to attenuate side effects. The initiation of sclerosis and chronic pain
CBD during daytime with the addition of THC at bed- Twelve studies examined CBM for pain in people with
time can also further mitigate these effects. MS, including nine RCTs,50,52,53,55,58,65,66,67,77 two open-
label studies,77,78 and one cross-sectional study.82 Seven
2. CBM use for people with HIV and chronic pain studies involved nabiximols,49,52,53,55,58,77,78 three in-
Three studies examined CBM to treat pain in people volved extracts delivered through capsule,65–67 and
with HIV, including two RCTs46,51 and one cross- two involved whole plant cannabis.50,82 Study length
sectional study.88 All three studies reported significant ranged from 3 days to 2 years. Most studies (9/12)
improvements in HIV-related pain management asso- reported improvements in pain associated with CBM
6 BELL ET AL.

use, including both studies involving whole plant can- Both the RCT and published abstract demonstrated
nabis and all three involving extracts delivered through improvement in pain in patients with an arthritic con-
capsules. dition. For details of the individual studies, see Appen-
The majority of studies were limited by small num- dix D in Supplementary Data.
bers of participants, short duration of treatment, and
some crossover and blinding deficiencies. For details Recommendation. 1. We recommend the use of
of the individual studies, see Appendix C in Supple- CBM, as adjunct treatment, for the management of
mentary Data. chronic pain in people living with arthritic conditions
in those not achieving adequate response to other mo-
Recommendations. 1. We recommend the use of dalities.
CBM, as adjunct treatment, for pain management in Strong Recommendation, Low-Quality Evidence
people with MS not achieving adequate response to
Values and preferences. The recommendation places
other modalities.
high value on the benefit of improvement in pain, sleep,
Strong Recommendation, Moderate-Quality Evidence
and other co-morbid conditions over the risks of ad-
2. We recommend the use of CBM, as adjunct treat-
verse events of a mainly non-serious nature such as diz-
ment, for the management of muscle spasm in people
ziness, disturbance in attention, balance disorder,
living with MS in those not achieving adequate re-
somnolence, dry mouth, nausea, diarrhea, fatigue, or
sponse to other modalities.
confused state.
Strong Recommendation, Moderate-Quality Evidence
3. We recommend the use of CBM, as adjunct treat- Practical tip. Best evidence of benefit is in participants
ment, for the management of sleep disorder in people with rheumatoid arthritis for improvement in pain,
living with MS in those not achieving adequate re- sleep, other co-morbid conditions, and markers of in-
sponse to other modalities. flammation. A balanced THC/CBD oromucosal prod-
Strong Recommendation, Low-Quality Evidence uct titrated to *15 mg of each component may be
tried. If an oral formulation is used, a slow titration
Values and preferences. The recommendations place of THC as shown in Figure 2 should be employed.
high value on the benefit of pain, spasticity, and sleep
disturbance relief seen in people with MS over the Practical tip. As dizziness and falls have been identi-
risks of adverse events, of a mainly non-serious nature, fied as potential adverse events associated with CBM
including dizziness, disturbance in attention, balance use, a clear understanding of risks should be achieved
disorder, somnolence, dry mouth, nausea, diarrhea, fa- before CBM initiation, especially for populations with
tigue, or confused state. an increased risk of bone loss/osteoporosis. Consider a
lower THC starting dose, slower titration period, and
Practical tip. A wide dose variation of cannabinoids consistent monitoring.
was used in studies involving MS patients. Total daily
THC oral dose of 10–15 mg, as a divided dose twice Practical tip. A single abstract publication has sugges-
daily, was most commonly used. A slow dose titration ted benefit from topical CBD 125 mg bid for localized
should be used to individualize treatment (Fig. 2). pain management of knee osteoarthritis. This format
can be applied to the affected joints as a cream, oil,
Practical tip. Although benefit was observed in pain, or spray. This approach can be expected to be associ-
spasticity, and sleep with oral oil, capsule, smoked and ated with a very low risk of any adverse events. More
oromucosal formulations, the strongest evidence is for research is needed regarding the efficacy and safety of
the use of oils and capsules. These formulations also topical CBM.
provide the greatest consistency for dosage and titration
and are not associated with potential adverse events as- 5. CBM use for people living with fibromyalgia
sociated with inhalation of CBM. and chronic pain
There was a total of six studies that included partici-
4. CBM use for people living with an arthritic pants with fibromyalgia and pain. Four of these studies
condition experiencing chronic pain included people with fibromyalgia as part of the study
One RCT,48 one pre-post survey,70 and one published participants but the authors did not produce a separate
abstract93 have been identified in the literature search. analysis for pain management in fibromyalgia and
CBM CHRONIC PAIN CPGS 20221025 CCR 7

therefore these studies are not heavily considered in graine.70,88,94,95 One study was a conference abstract
this section.72,76,91,92 Each of these studies found im- and included as gray literature.94 Of these four studies,
provements in pain across their wider study sample. two utilized pre/post designs,70,94 and two were cross-
In an open-label study, two thirds of study participants sectional.88,95 Each study reported at least some im-
living with fibromyalgia responded well to sublingual provement from cannabis in participants experiencing
THC treatment.72 For details of the individual studies, headaches. For details of the individual studies, see
see Appendix E in Supplementary Data. Appendix F in Supplementary Data.

Recommendation. 1. We recommend the use of Recommendation. 1. We recommend the use of

CBM, as adjunct treatment, for management of back CBM, as an adjunct treatment, for the management
pain, fibromyalgia pain, or other chronic pain in people of chronic migraine or chronic headache, in those
with fibromyalgia who are not achieving an adequate not achieving adequate response to other modalities.
response to standard analgesics. Weak Recommendation, Low-Quality evidence
Strong Recommendation, Low-Quality Evidence
Values and preferences. The recommendations place
Values and preferences. This recommendation places high value on the benefit of migraine and headache
high value on the improvement in back pain, chronic relief over the risk of adverse events, which are mainly
pain, fibromyalgia pain, and improvement in function, non-serious in nature and include somnolence and
quality of life (QOL), and secondary outcomes, includ- dizziness.
ing anxiety, among patients living with fibromyalgia
from CBM use, over the low risk of non-serious adverse Practical tip. Some people also experience headache
events (reddening of the eyes, increased appetite, and due to cannabis, therefore it will be important to assess
sore throat) as compared with adverse events with stan- the individual treatment response. Dosage form will be
dard analgesics (constipation, loss of appetite, lack of important to consider if CBM is used for prophylaxis
mental clarity, reduced affect, and hemorrhoids). versus treatment of migraine or headache, given differ-
ent timing of onset.
Practical tip. Fibromyalgia is a heterogeneous complex
pain syndrome, which frequently occurs with other Practical tip. To limit exposure to adverse events, in-
pain syndromes and symptom clusters. This needs to dividuals should start low, go slow, and follow a struc-
be considered when extrapolating this study informa- tured initiation and titration plan (Fig. 2). Patients and
tion to other patients living with fibromyalgia. physicians should work collaboratively to identify ap-
propriate administration route(s) that meet the needs
Practical tip. In clinical practice, SNRI are used off-label
of the individual.
as a multimodal treatment for symptoms such as insom-
nia, depression, and anxiety in patients suffering from
7. CBM use for people living with chronic pain
fibromyalgia; likewise, CBM can treat these symptom
and nausea
clusters.
Five studies analyzed participant perceptions of can-
Practical tip. All patients using CBM should be edu- nabis as a potential treatment for nausea as a comor-
cated on proper vaporization (to avoid harms of com- bidity of pain.79,85,88,91,92 Each study involved whole
bustion/smoking) and/or cannabis oil/capsule dosing plant cannabis in inhaled or oral formats, with pa-
and titration regimens. To limit adverse effects while tients reporting moderate relief. Although these five
still achieving pain outcomes, THC dosing should be studies found improvements in nausea with cannabis
started low and titrated slowly to an individual re- use, other studies found nausea to be an adverse event
sponse. For elderly and frail patients, consider a lower associated with cannabis use among some partici-
THC starting dose, slower titration period, and consis- pants.46–50,54,57–59,71,72,74,77,78
tent monitoring. These studies were limited by study design (case se-
ries or cross-sectional surveys), small numbers of pa-
6. CBM use for people experiencing chronic tients, unknown duration or dosing of cannabis, and
headache and migraine the possibility of selection and recall bias. It is also un-
Four included studies specifically measured associa- clear which cannabis formulation or route of adminis-
tions between CBM and chronic headache or mi- tration is optimal (smoked vs. oral, THC vs. CBD vs.
8 BELL ET AL.

THC/CBD products) for nausea. For details of the in- withdrawal from studies and point to the potential ben-
dividual studies, see Appendix G in Supplementary efits for patients with chronic pain states.
Data.
Practical tip. Many studies used CBM in the form of
Recommendation. 1. We recommend considering the standardized-dose CE (nabiximols and others), which
use of CBM to reduce nausea in people living with allowed for easier titration and effective dose-finding.
chronic pain as monotherapy or adjunct treatment The presence of products, including CBD, may reduce
for those not achieving adequate response to other the incidence of psychiatric or euphoric effects. Oral
treatment modalities. formulations may also be considered and are not asso-
Weak Recommendation, Low-Quality Evidence ciated with potential adverse events associated with in-
halation of CBM.
Values and preferences. This recommendation does not
refer to the use of CBM in cancer-related pain or emeto- Practical tip. Sleep disturbances in patients with MS
genic therapy, and places high value on the benefit of showed the most improvement with CBM used for
CBM for nausea relief, over the risk of adverse events, pain and/or spasticity. This is a group who should
which are mainly non-serious in nature. be routinely assessed for the suitability of treatment
with CBM.
Practical tip. All published data on nausea benefit in
chronic pain have come from survey or cross-sectional Practical tip. To limit exposure to adverse events, in-
studies. As such, no practical tips on cannabis type, dividuals should start low, go slow, and follow a struc-
mode of administration, or concentration of THC or tured initiation and titration plan (Fig. 2).
CBD can be made.
9. CBM use for people living with chronic pain
8. CBM use for people with sleep problems experiencing appetite loss
and symptoms of sleep deprivation experiencing Seven studies assessed CBM use on appetite in partici-
chronic pain pants experiencing chronic pain, including two
Sleep issues are often a target symptom for cannabis RCTs,59,63 two cross-sectional studies,79,88 two case se-
use and 25 of the studies assessed impacts of CBMs ries,91,92 and one pre-post study.70 The RCT assessed
on sleep, including 16 RCTs,47–49,52–55,57–60,65–67,74,75 did not demonstrate a significant difference between
four cross-sectional survey studies,79,80,82,87 three pre- CBM and placebo. The two case series and one cross-
post style studies,70,73,85 and two case series studies.91,92 sectional study reported some improvement in appe-
Of these studies, 10 included consumption of whole tite, whereas another case series did not find significant
plant cannabis by participants,60,70,73,79,80,82,85,87,91,92 benefit. For details of the individual studies, see Appen-
12 involved cannabis extracts (CEs) consumed by oro- dix I in Supplementary Data.
mucosal spray,47–49,52–55,57–59,74,75 and 3 involved par-
ticipants treated with cannabis extract capsules.65–67 Recommendation. 1. We recommend the use of
Almost all studies found benefit for sleep in some or THC-dominant cannabis for people with problematic
most participants. For details of the individual studies, loss of appetite in association with chronic pain, over
see Appendix H in Supplementary Data. no treatment.
Strong Recommendation, Low-Quality evidence
Recommendation. 1. We recommend the use of CBM
as monotherapy, replacement or adjunct treatment, to Values and preferences. The recommendation places
improve sleep and symptoms of sleep deprivation in high value on the benefit of improved appetite, and pre-
people living with chronic pain not responsive to, or in- sumably nutrition, over the risks of adverse events of a
tolerant of, other modalities or pharmacologic treat- mainly non-serious nature such as dizziness, distur-
ment. bance in attention, balance disorder, somnolence, dry
Strong Recommendation, Moderate-Quality Evidence mouth, nausea, diarrhea, fatigue, or confused state.
Values and preferences. The recommendations place Practical tip. All published data on appetite improve-
high value on the benefit of CBM for disturbances in ment in chronic pain have been associated with the use
sleep and poor sleep quality. Adverse events such as of THC dominant products. A single RCT failed to dem-
somnolence, drowsiness, and sleepiness rarely caused onstrate benefit from CBD; however, this cannabinoid
CBM CHRONIC PAIN CPGS 20221025 CCR 9

may provide other benefits, including a reduction in and capsules provide the greatest consistency for dosage
pain and anxiety. and titration, are not associated with potential adverse
events associated with inhalation of CBM, and may
Practical tip. One cross-sectional study noted an in- also offer advantages in the context of sleep disturbance
creased risk of problematic cannabinoid use in patients and nightmares that are prominent among some indi-
using CBM for appetite improvement. All patients viduals with PTSD.
using CBM should be monitored for cannabis use dis-
order. The Cannabis Use Identification Test- Revised 11. CBM use for people living with chronic pain
may be used for this purpose. To limit exposure to ad- experiencing anxiety
verse events, individuals should follow a structured ini- Eight studies within this review examined the treatment
tiation and titration plan (Fig. 2). Patients and of anxiety with CBM in people living with chronic
physicians should work collaboratively to identify ap- pain.55,61,70,76,96–99 Although these studies utilized a va-
propriate administration route(s) that meet individual riety of CBM approaches, most evidence—including the
needs. relatively higher quality studies—reported anxiolytic ef-
fects of cannabis. For details of the individual studies,
10. CBM use for people with chronic pain see Appendix K in Supplementary Data.
experiencing PTSD
Two studies included analysis of cannabis as a treat- Recommendation. 1. We recommend the use of CBM
ment for PTSD symptoms.70,79 One study evaluating as adjunct therapy to improve symptoms of anxiety in
cannabis in patients with PTSD as the primary condi- people living with chronic pain not responsive to, or in-
tion rated the mean helpfulness of CBM in the moder- tolerant of, non-pharmacologic treatment.
ately helpful range79 Among the larger sample Strong Recommendation, Moderate-Quality Evidence
(n = 186), higher levels of traumatic intrusions were as-
sociated with higher perceived helpfulness of canna- Values and preferences. The recommendations place
bis.79 The second study found that the numbers of high value on the benefit of CBM for anxiety symptoms
participants with PTSD reporting severe pain at base- over the risks of adverse events of a mainly non-serious
line dropped from 56% at baseline to 11% at 4 months nature such as dry mouth, disturbance in attention and
of CBM use. Improvements were also reported in abil- memory, as well as the potential for acute transient in-
ity to cope with pain and overall QOL, mood, sleep, creases in anxiety and panic.
and concentration.70 For details of the individual stud- Practical tip. The only RCT to compare doses of herbal
ies, see Appendix J in Supplementary Data. cannabis suggested that chemovars (strains) with 9%
THC—which would be generally considered a moder-
Recommendation. 1. We recommend the use of CBM ate to low strength herbal cannabis—are more effective
to improve PTSD symptoms in people living with than herbal cannabis with low to very low levels of
chronic pain not responsive to, or intolerant of, non- THC, regardless of CBD content. To limit exposure to
pharmacologic treatment. adverse events, individuals should follow a structured
Weak Recommendation, Low-Quality Evidence initiation and titration plan (Fig. 2).
Values and preferences. The recommendations place Practical tip. Other modes of administration might also
high value on the benefit of CBM for pain, intrusion be advantageous; specifically, orally ingested CBMs
symptoms, sleep disturbance, and improved mood provide the greatest consistency for dosage and titra-
and QOL seen in people living with PTSD over the tion, are not associated with potential adverse events
risks of adverse events of a mainly non-serious nature associated with inhalation of CBM, and may also
such as dry mouth, disturbance in attention and mem- offer advantages in the context of sleep disturbance
ory, as well as the potential for the development of non- that may be prominent among some individuals with
medical use. problematic anxiety.
Practical tip. The single study that reported dose sugg- Practical tip. It is well recognized that THC has the
ested that 1–1.5 g/day of herbal cannabis was typical. potential to trigger acute transient increases in anxiety
However, other modes of administration were not dis- and panic. Individuals should be warned of this adverse
cussed but might nonetheless be advantageous; oils effect and closely followed for it.
10 BELL ET AL.

12. CBM use for people living with chronic pain 13. Adjunctive CBM use for people living
experiencing depression with chronic pain experiencing unsatisfactory
Findings for depressive symptom outcomes appeared analgesia from opioid treatment
to be contingent on the types of CBMs used, with Four studies specifically addressed the efficacy of com-
herbal cannabis appearing to be more effective than ex- bined opioid analgesics with cannabis therapy for
tracts. An RCT of smoked cannabis found that it im- chronic pain. One study evaluated the addition of va-
proved depressive symptoms significantly with a porized cannabis to patients taking sustained-release
medium-sized effect over placebo.60 Three cross- opioids for a variety of chronic pain conditions.68
sectional studies also report antidepressant effects of These studies demonstrated a reduction in pain with
CBM.82,97,98 Studies involving the use of cannabis ex- the addition of CBM to their opioid regimen. Several
tracts are generally less positive regarding the benefits additional studies found improvements in chronic
of CBM for treating depression in people with chronic pain associated with CBM use within samples that in-
pain. In contrast to these positive results, three RCTs cluded participants concurrently using opioids to treat
found no significant difference between nabiximols pain.52,54,60,100,101 For details of the individual studies,
and placebo in depression scores.53,55,58 For details of see Appendix M in Supplementary Data.
the individual studies, see Appendix L in Supplemen-
tary Data. Recommendation. 1. We recommend the use of
CBM, as adjunctive treatment to opioids, for the man-
Recommendation. 1. We recommend the use of CBM agement of chronic pain in those experiencing unsatis-
as adjunct therapy to improve symptoms of depression factory analgesia from opioid treatment.
in people living with chronic pain experiencing unsat- Strong Recommendation, Moderate-Quality Evidence
isfactory results from standard treatment.
Weak Recommendation, Moderate-Quality Evidence Values and preferences. The recommendations place
high value on the improvement in chronic pain, fibro-
Values and preferences. The recommendations place myalgia pain, functionality, spasms, and secondary out-
high value on the benefit of CBM for depressive symp- comes of depression and anxiety, in those with chronic
toms over the risks of adverse events of a mainly non- pain using CBM adjunctly over the low risk of non se-
serious nature such as dry mouth, disorientation, and rious adverse events (fatigue, sedation, impairment in
disturbance in attention and memory. The CBM concentration, reduced salivation) as compared with
should not take the place of other anti-depressant treat- adverse events with standard opioid analgesic therapy
ments, including pharmacological and non- (constipation, loss of appetite, feeling of reduced mental
pharmacological treatments, such as psychotherapeutic acuity and flat affect, hemorrhoids, dependency, respi-
intervention. ratory depression).

Practical tip. The only RCT to compare doses of herbal Practical tip. Evidence included in this review found
cannabis suggested that chemovars with 9% THC— efficacy of inhaled CBM as adjunct treatment for
which would be generally considered a moderate to chronic pain. Inhalation as an administration route is
low strength herbal cannabis—are more effective advantageous for managing break-through pain due
than herbal cannabis with low to very low levels of to rapid onset and shorter duration of action. Other
THC. To limit exposure to adverse events, individuals routes of administration, including oils and capsules,
should follow a structured initiation and titration plan may be preferred due to dosage consistency and lack
(Fig. 2). of adverse events associated with inhalation, though
further research with these routes is needed. Pain man-
Practical tip. Other modes of administration might also agement can be individualized above baseline and can
be advantageous; specifically, orally ingested CBMs be managed on demand and titrated to desired effect.
provide the greatest consistency for dosage and titra-
tion, are not associated with potential adverse events Practical tip. Cannabis is rarely used as a first-line agent.
associated with inhalation of CBM, and may also It is important to assess and document the response to
offer advantages in the context of sleep disturbance currently approved medications. This includes medi-
that may be prominent among some individuals with cation name, dose, duration, response, and tolerabil-
depression. ity. Some physicians will use cannabis in conditions
CBM CHRONIC PAIN CPGS 20221025 CCR 11

where other treatment options have failed or are not experiencing opioid-related adverse events, or display
tolerated. risk factors for opioid-related harm.
Strong Recommendation, Low-Quality Evidence
Practical tip. Concomitant analgesics can be tapered
Values and preferences. The recommendations place
or discontinued once a stable CBM dose is established.
high value on the reduction in the reliance on opioids
This may lead to a reduction in polypharmacy, side ef-
with secondary outcomes improvements, including
fects, drug interactions, as well as an improvement in
sleep, anxiety, and mood, in those living with chronic
adherence and cost saving.
pain and using CBM as adjunct/concurrent to opioids
over the low risk of non-serious adverse events (dry
Practical tip. As there was no change in plasma opioid
mouth, dizziness, increased appetite, sedation, concen-
levels after exposure to cannabis, improved analgesic
tration difficulties) as compared with adverse events
response in patients using cannabis and opioids is
with opioids/standard of care (constipation, loss of ap-
likely due to synergy or additive effect. More research
petite, feeling of reduced mental acuity and flat affect,
is required especially regarding whether cannabis
hemorrhoids, dependency, respiratory depression).
should be considered as a treatment option before opi-
oid initiation based on the lower risk of adverse effects Practical tip. There is a physiologic rationale for co-
versus opioids. administration of cannabis and opioids, which pre-
vents opioid-tolerance and the need for dose
Practical tip. Long-term pain control was observed th- escalation. In addition, cannabis can treat the symp-
rough a reduction in pain scores. Tolerance to adverse toms of opioid withdrawal, reduce or replace opioids.
effects occurs within 48 h of a THC dose increase; how- Thus, cannabis is safer than opioids and makes opioid
ever, tolerance to benefits did not develop over time. consumption safer. More research is required in this
Starting at a low dose and gradually titrating to the low- area.
est effective dose without adverse effects is suggested
(Fig. 2). Practical tip. Clinicians should re-evaluate any patient
on > 50 mg morphine equivalent dose (MED) as their
14. CBM use and opioid sparing for people using risk of fatal overdose is doubled compared to 20 mg
opioids as treatment for chronic pain MED; the risk increases 10-fold with > 90 mg MED.
Opioid sparing, or the reduction of opioid use, result- Both the United States and Canadian opioid guidelines
ing from the use of CBM for pain management was advise clinicians to carefully reassess risk-benefit ratio
the primary outcome in one study86 and a secondary when > 50 mg MED and to avoid > 90 mg MED as
outcome in six studies.69,73,81,84,87,91 there is low evidence for improvements in pain, but a
Three studies found positive associations between significant increase in the risk of harm.
medical cannabis use and opioid sparing.69,73,102 Two Practical tip. Individuals should keep a daily log, in-
other studies reported that the majority of participants cluding dosing and monitoring for efficacy, effects on
reduced their routine pain medications by 60–70%; mood and function, and possible side effects. This will
however, the extent to which opioid medications encourage individuals to slowly titrate cannabis to
were specifically reduced was unclear.87,99 For details symptom control, while minimizing adverse events.
of the individual studies, see Appendix N in Supple- Once individuals using medical cannabis are stabilized,
mentary Data. generally they do not require dose escalation over time.
Recommendations. 1. We recommend the use of Practical tip. Health care providers are encouraged to
CBM as adjunct treatment among people using implement standardized self-administered question-
moderate/high doses of opioids ( > 50 morphine naires such as Patient Health Questionnaire-9, General
equivalent) for the management of chronic pain Anxiety Disorder-7, or Brief Pain Inventory starting
and/or to increase opioid sparing. with the initial intake, and to continue in all subsequent
Strong Recommendation, Moderate-Quality Evidence follow ups to reassess risk benefit.
2. We recommend the use of CBM as adjunct treat- A Suggested Approach for Adjunct Cannabinoid
ment for chronic pain among people using any dose of Use for Opioid Sparing. Adapted from Sihota et al103
opioids who are not reaching chronic pain goals, are is shown in Figure 1.
12 BELL ET AL.

FIG. 1. Suggested approach for adjunct cannabinoid use for opioid sparing. Adapted from Sihota et al.103

Additional Practical Considerations clinically are likely to be required for clinical inhibitory
Drug interactions effect.106
Both THC and CBD are predominantly metabolized, This, however, may be of concern when cannabi-
by the liver, through the action of the cytochrome noids are co-administered with drugs having a narrow
P450 system.104,105 A paucity of clinical studies are therapeutic window and also metabolized by these en-
available regarding the effect of cannabinoids on this zymes, such as direct acting oral anticoagulants metab-
enzyme system, but in vitro studies suggest that THC olized through CYP3A4107,108 and clopidogrel requiring
inhibits CYP3A4, CYP3A5, CYP2C9, and CYP2C19, conversion to its active metabolite by CYP2C19.109 Sig-
whereas CBD inhibits CYP2C19, CYP3A4, and nificantly elevated levels of the antiepileptic clobazam
CYP3A5. Due to the weak inhibitory effect of these and its metabolite, n-desmethylclobazam, have been
cannabinoids, higher concentrations than those seen observed when co-administered with very high doses
CBM CHRONIC PAIN CPGS 20221025 CCR 13

of CBD, likely due to co-metabolism through CYP2C19 tion to minimize these effects.116 The CBD can be asso-
and CYP3A4.110 ciated with transaminitis, which is typically dose-
Preclinical studies have reported that cannabinoids related and more common at very high doses
may also bind membrane transporters including breast (800 mg/day). Transaminitis typically improves by
cancer resistance protein111 and P-gp,112,113 which can, lowering the dose of CBD. Patients using CBD regu-
theoretically, impact the effect of other medications. larly should undergo periodic monitoring of liver en-
A comprehensive overview of the pharmacokinetic inter- zymes and should avoid excessive alcohol use.127,128
actions of cannabinoids has been reported by Alsherbiny
and Li114 Pharmacodynamic interactions also need to be Additional safety concerns
considered with CBM, particularly THC, administration. The CBM use is typically not recommended for chil-
Additive effects can occur when cannabinoids are com- dren and youth.129 In addition, parents and those living
bined with sympathomimetics (e.g., tachycardia, hyper- with children should use caution to avoid exposure to
tension), central nervous system depressants such as second-hand smoke. People living with chronic pain
alcohol and opioids (e.g., drowsiness, ataxia), and anti- and prescribing clinicians should always have a clear
cholinergics (e.g., tachycardia, confusion).115 understanding of risks and adverse events before
CBM initiation, including legal ramifications such as
Adverse effects the inability to drive after THC consumption. It is rec-
< A concern from patients and clinicians are the ad- ommended that CBM use follow a structured initiation
verse effects associated with cannabis use. The process and have clinical supervision throughout.
adverse effects that are the most commonly associ-
ated with cannabis are related to THC-dose and Dosing
the route of administration.116 The THC-related Two publications and one poster addressing dosing of
adverse effects include dizziness, cognitive impair- CBM have been identified.130–132 All are concordant
ment, dry mouth, tachycardia, anxiety, drowsi- with the concept of low starting dose to be titrated
ness, and fatigue.116 There is evidence to suggest slowly to achieve optimal target symptom improve-
a positive association between cannabis use and ment with minimal off-target effects, including eupho-
development of psychosis, in people susceptible ria. The optimal therapeutic dose is the dose that
to psychotic disorders.117–119 Although no defini- allows the patient to reach treatment goals, including
tive causal effects have been established, there are pain and symptom reduction and improvement in
case reports of stroke, acute coronary syndrome, function, with minimal or no side effects. Patients do
and cardiac arrhythmias associated with use of not need to feel ‘‘high’’ or impaired to have symptom
cannabis.120,121 Maternal exposure to cannabis improvement.
can adversely affect conception and/or mainte- Bhaskar et al propose three dosing regimens based
nance of pregnancy.122–124 Significant decline in on the clinical situation (Fig. 2): a routine protocol ap-
sperm count, concentration, and motility, as propriate for most patients, a rapid protocol for those
well as an increase in abnormal sperm morphol- with severe pain, terminal illness or those already tak-
ogy have been reported. ing higher dose CBM and a conservative protocol for
Smoking cannabis is associated with respiratory ad- those with frailty, severe comorbidities, and polyphar-
verse effects such as cough, an increase in phlegm, macy. PRN dosing and micro-dosing may also be ac-
and bronchitis.116 Long-term use is associated with ceptable for breakthrough symptom management.
risk of cannabis use disorder, hyperemesis syndrome,
as well as withdrawal symptoms including insomnia, Authorization
anxiety, depression, and tremulousness.125,126 Wide variation in legal status of medical and recrea-
Adverse effects can be mitigated when initiating tional cannabis exists globally. Clinicians authorizing
CBM through low-dose initiation, slow titration and or prescribing CBM should understand and comply
avoiding smoked cannabis.116 In people experiencing with local laws and other regulations regarding its
adverse effects, clinicians can consider adjustment in use. Individuals with conditions where CBM may be
the strain (chemovar) with higher CBD and lower useful are urged to consult and be guided by regulated
THC, reduce the dose, or alter the route of administra- heath care professionals familiar with its use.
14 BELL ET AL.

FIG. 2. Example of oral CBM Dosing and Titration Protocols. Reproduced with permission of Bhaskar
et al.133 CBM, cannabinoid-based medicines.

Strengths and limitations There exist several challenges within CBM and
These guidelines fill an important gap in the literature chronic pain research. With respect to some co-
by providing guidance for clinicians and patients dur- occurring conditions, there still exist relatively few con-
ing a period of cannabis regulation changes. They in- trolled trials. The data related to co-morbid conditions
clude a thorough systematic review with rigorous were typically not the primary focus of included studies
study selection and methods for data extraction, quality and, subsequently, may be underpowered. The lack of
assessment, and data synthesis. Although CBMs may comparative studies where the safety and efficacy of
be used for other purposes, these guidelines present CBM is compared with typical pain treatments is also
recommendations for people living with chronic pain problematic. In addition, challenges commonly exist
and for co-occurring conditions within the context of with unmasking in placebo-controlled trials, represent-
chronic pain and may not be transferable. ing potential risk of bias, especially as pain and many
From the perspectives of people with lived experi- comorbidities are measured with Visual Analog Scale
ence, differences between sativa-predominant and or other subjective measures.
indica-predominant chemovars of cannabis are impor-
tant. For example, anecdotally, THC-dominant sativa Acknowledgment
tends to be stimulating and impede sleep, can augment The authors thank Nancy Chow, Dr. Rob Sealey, and
anxiety and increase heart rate. However, the science Dr. Lynda Balneaves for serving as external reviewers
behind the differences between sativa-predominant for these guidelines.
and indica-predominant chemovars is not well defined
and the published research is undeveloped in this area. Patient and Public Involvement
For these reasons, they were not included in the search Chronic pain and CBM patients were included on the
results that are the foundation of the article. guidelines task force and were involved at every stage
CBM CHRONIC PAIN CPGS 20221025 CCR 15

of development, including project inception, data P.J.D. is a member of the Medical Advisory Board
synthesis, guideline development, and manuscript for Shoppers Drug Mart, a consultant for Reformulary
preparation. Group, a member of the Speakers Bureau for Medical
Cannabis Education for Shoppers Drug Mart and Spec-
Authors’ Contributions trum Therapeutics, and participates in clinical trials for
P.W. and L.B.-I. drafted the protocol. The Data Synthe- CancerCare Manitoba as per contract requirements.
sis Committee (C.C., Z.W., S.M.) led and facilitated the M.G. is the president and co-founder of the Harm
systematic review and were consulted on guideline de- Reduction Nurses Association. She was a board mem-
velopment. T.S. and S.A. conducted the literature ber of The Canadian HIV/AIDS Legal Network. She
search. M.S.P. and P.W. performed data extraction has received an honorarium payment from Merck for
and data interpretation. A.D.B., C.M., C.C., E.M., a presentation on HIV medication side-effects. C.M.
Z.W., P.J.D., L.F., and P.J.D. drafted guideline sections is the Medical Director of Greenleaf Medical Clinic
and recommendations. All authors provided revisions and Translational Life Sciences. She is on the Board
to guidelines. P.W. and C.C. prepared the manuscript. of Directors for the Green Organic Dutchman. She is
All authors conceived and designed the review, and an advisor to Andira, and previously Emerald Health
they read and approved the final manuscript. PW Therapeutics, Vitality Biopharma, Shoppers Drug
and CC are the guarantors of the review. Mart, True Leaf, Resolve Digital Health, Doja, and
Compass Cannabis Clinics. She teaches medical canna-
Author Disclosure Statement bis to medical residents and pharmacy students at the
T.S., S.A., L.B.-I., M.S.P., S.B., M.M.E., L.F., J.K.D., and University of British Columbia. She has provided med-
J.O. do not have any conflicts of interest. P.W. and ical consultation and/or received support for industry-
G.L.’s employer, the Canadian AIDS Society, has re- sponsored continuing medical education from: Cano-
ceived a grant from Canopy Growth Corporation to py/Spectrum, Tilray, Strainprint, Scientus Pharma,
support the development of the clinical practice guide- Aurora, MedReleaf & MD Briefcase.
lines. Z.W. is an advisory board member of Multidisci- E.M. is the co-owner of a start-up company (‘‘Can-
plinary Association for Psychedelic Studies—Canada. nabiscotti, Inc.’’) that will be applying for a cannabis
He has received research support from DOJA and Til- processing license, and is employed by MJardin Can-
ray licensed producers of cannabis and is a former ada. C.C. has received cannabinoids from Tilray, Inc.,
Director of Clinical Research for Indigenous Bloom for use in a clinical trial but has not received any
cannabis company. S.M. is the co-owner of a start-up grant support nor honoraria from the company. She
company (‘‘Cannabiscotti, Inc.’’) that will be applying has received research funding from Merck and Gilead,
for a cannabis processing license. She holds shares in speaker honorarium from Gilead, and consultant fees
Canopy Growth Corporation, Emblem Corp, and Aph- from Viiv Healthcare. She has received funding to at-
ria, Inc. She has received honorarium for research pro- tend conferences from Gilead and Viiv Healthcare.
jects funded by Canopy Growth Corporation and
Tilray. A.D.B. has received funding for consulting, Funding Information
speaking, and/or research from the following commer- This work was supported by the Canadian Institutes for
cial organizations: Amgen, Bristol Myers Squibb, Jans- Health Research, grant no.: 402773; Arthritis Society of
sen, AstraZeneca, Novartis, Pfizer, Bayer, Lilly, Canada, grant no.: NA; Canopy Growth Corporation,
Boehringer Ingelheim, HLS Therapeutics, Spectrum grant no.: NA. Neither the funders nor authors’ affili-
Therapeutics, Sanofi, Bausch Health, Akcea, and ated institutions played any role in the development
Eisai. He holds shares in a wide variety of pharmaceu- of the guidelines.
tical companies and cannabis licensed producers. He
has contributed, pro bono, to publications, position Supplementary Material
statements, and/or clinical practice guidelines from Supplementary Data
the following non-commercial organizations: Throm- Supplementary Table S1
bosis Canada, Hypertension Canada, Heart and Stroke Supplementary Appendix SA1
Foundation, Canadian Cardiovascular Society, and the Supplementary Appendix SA2
Canadian Aids Society. Supplementary Appendix SA3
16 BELL ET AL.

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