European Journal of Pain - 2018 - Fitzcharles - Medical Cannabis A Forward Vision For The Clinician

REVIEW ARTICLE
Medical cannabis: A forward vision for the clinician

M.A. Fitzcharles1,2, E. Eisenberg3,4
1 Alan Edwards Pain Management Unit, McGill University Health Centre, Montreal, QC, Canada
2 Division of Rheumatology, McGill University Health Centre, Montreal, QC, Canada
3 Pain Research Unit, Institute of Pain Medicine, Rambam Health Care Campus, Haifa, Israel
4 Technion-Institute of Technology, Haifa, Israel
Correspondence Abstract
Mary-Ann Fitzcharles
E-mail: [email protected] Medical cannabis has entered mainstream medicine and is here to stay.
Propelled by public advocacy, the media and mostly anecdote rather
Funding sources than sound scientific study, patients worldwide are exploring marijuana
No funding was received for this work. use for a vast array of medical conditions including management of
chronic pain. Contrary to the usual path of drug approval, medical
Conflicts of interest
cannabis has bypassed traditional evidence-based study and has been
MAF received consulting fees, speaking fees,
and/or honoraria from ABBVIE, Abbott, legalized as a therapeutic product by legislative bodies in various
amgen, Bristol-Myers Squibb Canada, Jans- countries. While there is a wealth of basic science and preclinical studies
sen, Johnson & Johnson, Lilly and Pfizer. EE demonstrating effects of cannabinoids in neurobiological systems,
received research grants from: Mundi- especially those pertaining to pain and inflammation, clinical study
pharma, Rafa Laboratories, Taro Pharmaceu- remains limited. Cannabinoids may hold promise for relief of symptoms
tical Industries, Dexcel Pharma, Pfizer, MSD,
in a vast array of conditions, but with many questions as yet
Novartis, Syqe Medical, St. Jude Medical,
unanswered. Rigorous study is needed to examine the true evidence for
Israel Pain Association, Israel Cancer Associ-
ation, Israel Scientific Foundation, Focused benefits and risks for various conditions and in various patient
Ultrasounds Surgery (FUS) Foundation and populations, the specific molecular effects, ideal methods of
Teva Pharmaceutical Industries. administration, and interaction with other medications and substances.
In the context of prevalent use, there is an urgency to gather pertinent
This article is content of a special issue on clinical information about the therapeutic effects as well as risks. Even
cannabinoids, part of the issue Eur J Pain
with considerable uncertainties, the health care community must adhere
22:03 (2018) of the European Journal of Pain
to the guiding principle of clinical care ‘primum non nocere’ and continue
to provide empathetic patient care while exercising prudence and
Accepted for publication caution. The health care community must strongly advocate for sound
19 December 2017 scientific evidence regarding cannabis as a therapy.
Significance: Legalization of medical cannabis has bypassed usual drug
doi:10.1002/ejp.1185 regulatory procedures in jurisdictions worldwide. Pending sound
evidence for effect in many conditions, physicians must continue to
provide competent empathetic care with attention to harm reduction.
A vision to navigate the current challenges of medical cannabis is
outlined.
States, Canada and Israel. Propelled largely by public

1. Introduction advocacy, the media and political agendas, with lim-
Unprecedented in this era of modern medicine is the ited sound scientific study, patients are exploring use
current challenge of cannabis as a treatment for a of cannabis as a treatment strategy and are also self-
vast array of medical conditions. In the last decade, medicating with this substance. Medical cannabis is
cannabis as a therapy has been catapulted into the a current reality and is here to stay. Contrary to
medical arena as a result of legalization for medical usual medical practice whereby a product proceeds
use in various jurisdictions, especially the United through a defined process before acceptance as a
© 2018 European Pain Federation - EFICâ Eur J Pain 22 (2018) 485--491 485
15322149, 2018, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejp.1185 by Cochrane Mexico, Wiley Online Library on [29/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
The way forward for medical cannabis M.A. Fitzcharles, E. Eisenberg
therapy, cannabis has bypassed standard scientific phytocannabinoids, and pharmaceutical preparations
scrutiny and has entered mainstream medicine in that are synthesized (Pertwee, 2006).
countries worldwide (D’Souza and Ranganathan, Phytocannabinoids are found in the annual flow-
2015). It is therefore the responsibility of the medical ering plant belonging to the Cannabaceae family, of
community to hasten to assemble as much informa- which Cannabis is the genus, with various species.
tion regarding benefits and risks of medical cannabis The species, Cannabis sativa has mostly been a com-
in order to counsel patients and provide competent mercial plant providing hemp fibre, whereas Canna-
clinical care. bis indica, originating in the Indian subcontinent,
In this review, we will focus on the cannabinoid was originally cultivated for psychotropic properties.
effects in the management of pain and highlight areas Known for its fibrous qualities for over 10,000 years,
that we believe are relevant to clinical practice. the plant Cannabis sativa remains a valued modern
Knowledge of the state-of-the-art will allow the medi- commercial product in the manufacture of paper,
cal community to move forward in this age of preva- textiles, plastics and biofuels (Tourangeau, 2015;
lent use of medicinal cannabis. More detailed analyses Andre et al., 2016). The medicinal and psychoactive
of specific issues pertaining to medical cannabis are properties of cannabinoids have been recognized for
covered in other papers in this special issue of the thousands of years, with writings beginning in
journal. This article is based on the Ulf Lindblom Spe- ancient China and Egypt attesting to effect in inflam-
cial lecture delivered at the 19th Congress of the Euro- mation and rheumatic pain (Kalant, 2001; Russo,
pean Pain Federation EFIC in Copenhagen in 2017. 2007). Cannabis has been used as an analgesic and
antispasmodic amongst other uses in the Western
world since the mid-1800s, and is currently identi-
2. Cannabinoids and the
fied as one of the 50 fundamental herbs of tradi-
endocannabinoid system
tional Chinese medicine (Kalant, 2001; Aggarwal
The endocannabinoid system is found through the et al., 2009). The psychoactive properties of the
human body and comprises receptors and ligands. plant were recorded by the historian Herodotus in
Although mostly associated with neuronal tissue, 440 BCE when he described the Scythians scattering
both peripheral and central, the system extends to hemp seeds on hot stones in order to inhale the
other tissues including skin, bone, joints and vapours in steam baths.
hematopoietic defence cells (Pertwee, 2006). This From the early 1920s, marijuana, which is the
system functions to restore homeostasis by promo- common colloquial term and derived from the dried
tion of sleep, appetite, stress reduction and modula- leaves and flowers of the hemp plant, was increas-
tion of pain and inflammation and thereby ingly regulated and mostly banned worldwide, espe-
counterbalances the ‘fight and fly’ phenomenon cially following the revised International Opium
(Steiner and Wotjak, 2008). Therefore, harnessing Convention International Convention relating to Danger-
the effects of down-modulation of the stress phe- ous Drugs in 1925 which regulated Indian hemp and
nomenon presents an attractive therapeutic option the preparations derived therefrom (Aggarwal et al.,
for numerous conditions. The understanding of the 2009). Cannabinoid molecules may be categorized
molecular underpinnings of the endocannabinoid into two broad groups, namely active molecules with
system is fairly recent with identification of the or without psychoactive effect, and inactive mole-
cannabinoid receptors, CB1 and CB2 in the late cules. Both Cannabis sativa and Cannabis indica are
1980s, and then subsequent discovery of various currently cultivated to provide delta-9 tetrahydro-
endocannabinoid ligands (Howlett, 2005; Pertwee, cannabinol (D9-THC) and cannabidiol (CBD), the
2015). The endogenous ligands termed endocannabi- two best studied molecules with potential for thera-
noids are derived from arachidonic acid and are pro- peutic effect. Concentrations of these two molecules
duced on demand in response to tissue injury or in various bred strains may, however, vary greatly
following a pre-synaptic neuronal trigger. When depending upon genetic manipulation.
ligands bind to the cannabinoid receptors, the neural
pain signals and inflammatory responses are down-
3. Preclinical study informs the clinician
regulated. The two best studied endocannabinoids
are anandamide and 2-arachidonyl-sn-glycerol (2- Preclinical study, the foundation upon which clinical
AG). Other molecules that may similarly bind to the management is built, has shown that cannabinoid
cannabinoid receptors and activate this system are receptor agonists block pain in various models of
those derived from plant extracts termed acute and chronic pain and that inflammation is
486 Eur J Pain 22 (2018) 485--491 © 2018 European Pain Federation - EFICâ
M.A. Fitzcharles, E. Eisenberg The way forward for medical cannabis
attenuated (Johanek et al., 2001; Lim et al., 2003; In striking contrast to the abundance of comment in
Baker and McDougall, 2004; Schuelert and McDou- the public domain concerning the therapeutic effects
gall, 2008; Sanchez Robles et al., 2012). Extensive of cannabinoids in disease, there has been only lim-
study points to antinociceptive activity of both CB1 ited sound clinical study due to the illegal status of
and CB2 receptor agonists, either singly or in combi- cannabinoids in most countries. Fortunately basic
nation, with CB2 activity believed to affect microglial science study pertaining to cannabinoids in health
cells and thereby reduce neuroinflammatory mecha- and disease has been able to progress.
nisms (Cheng and Hitchcock, 2007; Correa et al., In two recent systematic reviews, one examining
2009). The CB2 receptor is believed to be particularly the effects of all cannabinoids for all diseases, and
important in central neuronal pain circuits with ago- the other focussing on cannabinoid use for chronic
nist activity inducing dopamine release in midbrain pain, the evidence for effect is generally poor in
areas that contribute to descending pain control as view of the poor study quality, small numbers of
well as the placebo effect (Shang and Tang, 2017). participants, short study duration, various cannabi-
In animal models of inflammatory arthritis, mim- noid preparations used and a frequent high rate of
icking human rheumatoid arthritis, inflammatory bias (Whiting et al., 2015; Nugent et al., 2017).
effects can be modulated by upregulation of cannabi- With only two of the 28 studies reported by Whit-
noid receptor activity or increased production of ing et al., (2015) assessed as having a low risk of
endocannabinoids, with attenuation of joint destruc- bias, the authors stated that studies generally sug-
tion (Malfait et al., 2000; Schuelert and McDougall, gested improvements in pain measures, but often
2008). Similarly, endocannabinoids and CB1 and failed to reach statistical significance in individual
CB2 receptor proteins are found in human synovial studies. Notably, the odds ratio for the average
tissue from patients with both rheumatoid arthritis number of patients reporting at least a 30% reduc-
and osteoarthritis (Richardson et al., 2008). Ajulemic tion in pain was reported as OR, 1.41(95% CI,
acid, a synthetic THC-11 analogue, has anti-inflam- 0.99–2.00), a value that crosses 1. In the second
matory properties by reducing interleukin-6 and systematic review by Nugent et al., (2017), which
fibroblast metalloproteinase production and promot- focussed on the effects on chronic pain and harms,
ing apoptosis (Bidinger et al., 2003). Recent study the authors report a low strength of evidence for
demonstrating a profibrotic effect of CB1 receptor, effect on neuropathic pain in some patients, but
but a probable anti-fibrotic effect of the CB2 receptor insufficient evidence for effect on pain associated
highlights the complexity of this system, that does with multiple sclerosis, cancer and mixed pain con-
not always function in a unidirectional manner ditions. It is therefore surprising that The National
(Marquart et al., 2010). Academies Committee on the Health Effects of
Beyond effects on the inflammatory pathway, the Marijuana concluded that there is substantive evi-
endocannabinoid system plays a vital role in neu- dence that cannabis is effective for treatment of
ronal development by affecting axon and dendrite chronic pain, especially neuropathic pain in adults
growth and pruning in order to create specific and (National Academies of Sciences E, and Medicine,
secure neuronal circuitry in the adult brain (Njoo 2017). Therefore, the sum of the clinical evidence
et al., 2015). Finally, rat studies have demonstrated to date is confounded by many factors including
that cannabinoid administration alters brain matura- studies with mixed patient populations, use of dif-
tion in the young animal with resulting neuropsy- ferent cannabinoid preparations and in various for-
chiatric consequences in the adult (Renard et al., mulations, and wide ranges in dosing. It is also
2016). Therefore, in summary, the cannabinoid sys- notable that there are only limited studies evaluat-
tem counterbalance inflammatory mechanisms with ing the effects of medical cannabis in any form.
modulation of pain and inflammation holding pro- Although studies generally report improvement in
mise for therapeutic effects, but with impact on symptoms of pain, especially that of a neuropathic
brain development there is a cautionary note regard- quality, the results often do not reach significance,
ing neuronal development. but with all studies reporting a considerable rate of
side effects.
In the context of recent overuse of opioids for
4. Evidence for effect in the
the management of chronic pain, an agent that
management of chronic pain
could reduce opioid use is desirable. Although pre-
With this background of the preclinical science, the clinical evidence points to an important opioid-
clinician must turn to evidence for effect in disease. sparing effect for cannabinoids, and clinical studies
showed some clinical benefits, the latter conclusions 5. Evidence for risk
are less reliable in view of poor study quality, espe-
cially inadequate reporting of opioid dose changes Studies of the risks related to medical cannabis use
and mixed findings for analgesic effects (Nielsen in defined patient populations are limited. Extrapola-
et al., 2017). In a recent open-label study of medic- tion of risks from populations of recreational users to
inal cannabis use for patients with chronic pain patients with various diseases is not ideal, but in the
over a 6-month period, patients reported improved absence of study may provide some insight. A
pain severity and interference, but more striking healthy young person using recreational marijuana
was that 44% of those on opioids had discontinued is distinctly different from a person with a chronic
opioid treatments (Haroutounian et al., 2016). Indi- disease seeking medical therapy. Whereas the young
rect evidence for an opioid sparing effect of recreational user has made a personal choice in
cannabinoids is the observation that there has been order to achieve a psychoactive effect, a patient is
a reduction in prescription drugs for which cannabis seeking relief of a symptom that is persistent, has
could be an alternative, including opioids, in states likely not sufficiently responded to other treatments
in the United States (US) that had implemented and is impacting quality of life. In a single study that
medical marijuana legislation (Bradford and Brad- was designed to evaluate side effects of smoked her-
ford, 2016). Furthermore, any treatment focused bal cannabis in patients with chronic pain over a
towards relief of suffering should in addition to study duration of 1 year, the rate of serious adverse
symptom relief be associated with benefits to events did not differ between those using or not
health-related quality of life (HRQoL). Here again, using cannabis (Ware et al., 2015). With over half of
results have been disappointing. In a systematic each group treated with opioids, serious adverse
review of 20 studies, of which 11 were randomized events were reported to be over 20 events/100
controlled trials, there were small improvements in patient-years for both groups, representing a consid-
HRQoL for some patients with pain, multiple sclero- erable high number of events (Ware et al., 2015).
sis and inflammatory bowel disease, with reduced Harms associated with cannabis use for chronic pain
effects in some patients with human immunodefi- have been reported in a recent systematic review
ciency disease, leading the authors to conclude that (Nugent et al., 2017). Nugent and colleagues
the evidence for effect of cannabinoids and HRQoL reported an increased risk of short-term adverse
are inconclusive (Goldenberg et al., 2017). effects of dizziness and tiredness, as well as an
In contrast to the limited number of high-quality increased risk of motor vehicle accidents, psychosis
randomized clinical trials of cannabinoids in dis- and short-term effects on cognition, but insufficient
ease, observational studies report patient satisfac- evidence for other harms (Nugent et al., 2017).
tion with cannabinoid treatments. In a study of The National Academies Committee on Health
almost 1000 persons, two-thirds of whom had Effects of Marijuana has highlighted the increased
chronic pain, accessing medical cannabis from can- risks of motor vehicle accidents, increased risk of
nabis dispensaries in the north-eastern United cannabis overdose injuries in children, but unclear
States, cannabis was reported to be 70% effective evidence for all-cause mortality or occupational
for pain relief (Piper et al., 2017). In a review of injury associated with marijuana (National Acade-
cannabis use amongst patients receiving opioid mies of Sciences E, and Medicine, 2017). This report
therapy for persistent pain, Reisfeld and colleagues further confirms the impaired performance in cogni-
reported concomitant cannabis use to range from 6 tive domains of learning, memory and attention
to 39%, but with statistically significant associa- related to recent cannabis use within the previous
tions with present and future aberrant opioid- 24 h, as well as some suggestion that these impair-
related behaviours (Reisfield et al., 2009). There- ments may persist in persons who have used canna-
fore in summary, there is currently limited infor- bis previously, but stopped smoking cannabis. In
mation available from reliable randomized addition there is mounting evidence that cannabis
controlled trials examining the therapeutic effects use during adolescence has a negative impact on
of cannabis for chronic pain, although there is educational attainment and lifetime achievement in
increasing report of considerable subjective effect. employment, income, and social relationships and
It is, however, evident that the current body of roles (Meier et al., 2012). Mental health disorders
evidence would not be sufficiently robust to be associated with cannabis use are prevalent. Aside
accepted by regulatory authorities as an approved from acute psychotic episodes related to the
treatment for any condition. increased concentrations of THC in the street
product, there is evidence for decreased motivation results for effects on air-flow, both immediate and
as well as an association of psychotic-like experi- long-term as well as the development of chronic
ences and schizophrenia related to cannabis use, obstructive airways disease have however been
especially when initiated at a younger age (Volkow reported, with limitations of studies similar to those
et al., 2016; Bourque et al., 2017). for the cancer studies (Joshi et al., 2014).
The association or development of substance use
and/or abuse is a concern for patients using cannabis
6. The current reality
for medical reasons. Frequent cannabis use is associ-
ated with cannabis dependence, especially when ini- There is a common perception that cannabis is a
tiated at a younger age, and is likely to increase risk harmless pleasure for recreational use and that
of developing substance dependence for other prod- access should not be restricted or illegal. It is also
ucts (van der Pol et al., 2015). In an animal model well known that once a substance has achieved legal
of alcohol preferring rats, stimulation of the CB1 status, there is increased widespread use as has been
receptor promoted alcohol intake, supporting the seen for alcohol and tobacco. There is also a com-
hypothesis that the cannabinoid system has modula- mon perception that medical cannabis is an excellent
tory effects on neural circuitry involved in alcohol treatment for a variety of conditions including pain,
drinking behaviour (Colombo et al., 2002). In a mental health disorders especially anxiety, sleep dis-
recent study, in the United States, a quarter of orders amongst others (Sznitman and Bretteville-
chronic pain patients using medical cannabis were Jensen, 2015). This perception, however, is typically
identified as high-risk alcohol drinkers (Davis et al., supported by either weak evidence or no evidence at
2018). Furthermore, the National Academies Com- all. Unfortunately, the risks related to cannabis in
mittee has concluded that there is moderate evi- general have been whitewashed by the media with
dence for the development of substance dependence increased focus on the purported benefits of both
and/or abuse disorder in the setting of cannabis use, recreational and medicinal cannabis. It can be
highlighting the need for vigilance in this regard by understood that once regulatory authorities have
the treating physician (National Academies of approved a product, the population anticipates that
Sciences E, and Medicine, 2017). due diligence regarding risks has been addressed. In
Another area of contention that requires study jurisdictions where medical cannabis is legal, there is
and clarification is whether smoking cannabis is also a notion of smudging of the fine line between
alone a risk factor for lung cancer. Study to date has recreational and medicinal use. It is also known that
been fraught by confounders such as concomitant many persons currently using medical cannabis had
cigarette smoking, self-report of cannabis use, vari- previously used the product recreationally (Pacula
able smoking techniques, and unclear and small et al., 2016).
numbers for chronic or heavy cannabis use.
Although the National Academies of Sciences has
7. Lessons learned
concluded that there is no statistical association
between cannabis smoking and incidence of lung When jurisdictions are considering legalizing canna-
cancer, this assessment was based on information bis for medical purposes, they could do well to look
from a single systematic review and an epidemiologi- to the experience of others in order to protect both
cal review, with considerable limitations identified patients and society. In the first instance, it is para-
for both reviews (Huang et al., 2015; Zhang et al., mount that medical and recreational use remains
2015; National Academies of Sciences E, and Medi- entirely distinct (Cairns and Kelly, 2017). This has
cine, 2017). Similar limitations of study design have reasons that extend from reducing the risks for
been noted in the systematic review of Martinasek patients, maintaining the therapeutic relationship,
et al., (2016) that reported an increased risk ratio of providing incentive for further study, as well as
lung cancer and cannabis use of between 2 to 4. The addressing issues of reimbursement and education
longest duration epidemiological study to date for both patients and the health care community.
reported a 2.12 risk of lung cancer with heavy can- Treatment with medical cannabis must not be
nabis use, for almost 50,000 Swedish military viewed as a self-administered and unregulated ther-
recruits followed over 40 years (Callaghan et al., apy, but should rather adhere to the basic principles
2013). It is intuitive that lung function should be of good medical care. The pitfalls that have been
affected by inhalation of a combustible substance observed to date include the use of excessive quan-
that is composed of many chemicals. Discordant tities of cannabis by some persons, diversion of
medically accessed product, and indiscriminate and 9. Summary

inappropriate use for conditions that do not justify
such treatments. Finally, unethical medical practice In summary, medicinal herbal cannabis use is preva-
involves the provision of prescriptions for medical lent and is a reality. Only with information obtained
cannabis by some physicians who either do not through valid and reliable clinical study can the
have a full knowledge of a patient, do not assume therapeutic potential of cannabinoids in general and
clinical responsibility for the patient, or perhaps medical cannabis in particular be assessed. In the
provide prescriptions for persons who are not valid current absence of a body of reliable information,
patients. the health care community must endeavour to
inform patients as best as possible, but should not
accede to anecdote in this 21st century. Cannabi-
8. The way forward noids in some form may hold outstanding promise
There are currently more questions and uncertain- for use in a range of conditions, but we cannot be
ties concerning medical cannabis than answers, and beguiled by only advocacy. Clinicians are obligated
the clinician may offer a wish list to the researchers to provide the best competent clinical care by adher-
for further study. Amongst the many uncertainties ing to the principles of evidence-based medicine
are the following: are the clinical effects related to combined with clinical wisdom. At this time, the
a single or combination of molecules; do molecules health care community must speak with a rational,
other than THC and CBD have potential for thera- empathetic and sound scientific voice in order to
peutic benefit; do specific molecules have effect on effectively counsel patients. For this reason, it will be
specific symptoms or conditions; what is the effect important to proceed rapidly with meticulous clinical
of other drug interactions with cannabis; will study to allow the science to inform fundamental
adverse effects outweigh the positive effects; and issues that arise in the clinic, but with the time-hon-
will tolerance develop and require progressively oured medical ethic of ‘do no harm’ to patients and
higher doses to achieve clinical effects?. There is society.
also a need to understand dosing and methods of
administration (inhalation, ingestion, transmucosal References
or transdermal) of various cannabinoid products.
Aggarwal, S.K., Carter, G.T., Sullivan, M.D., ZumBrunnen, C., Morrill,
Beyond administration of cannabinoid products, R., Mayer, J.D. (2009). Medicinal use of cannabis in the United
manipulation of the endocannabinoid system should States: Historical perspectives, current trends, and future directions.
be further explored. J Opioid Manag 5, 153–168.
Andre, C.M., Hausman, J.F., Guerriero, G. (2016). Cannabis sativa: The
Importantly, the true effect of cannabinoids in plant of the thousand and one molecules. Front Plant Sci 7, 19.
many conditions requires objective measurement. Baker, C.L., McDougall, J.J. (2004). The cannabinomimetic
With regard to the management of chronic pain con- arachidonyl-2-chloroethylamide (ACEA) acts on capsaicin-sensitive
TRPV1 receptors but not cannabinoid receptors in rat joints. Br J
ditions, medical cannabis should not be seen as a Pharmacol 142, 1361–1367.
replacement for opioid treatment, especially in coun- Bidinger, B., Torres, R., Rossetti, R.G., Brown, L., Beltre, R. et al.
tries where overuse of opioids has been prevalent (2003). Ajulemic acid, a nonpsychoactive cannabinoid acid, induces
apoptosis in human T lymphocytes. Clin Immunol 108, 95–102.
over the past few years. Studies of longer duration Bourque, J., Afzali, M.H., O’Leary-Barrett, M., Conrod, P. (2017).
and with defined illnesses are required, including Cannabis use and psychotic-like experiences trajectories during early
attention to specific patient populations, such as the adolescence: The coevolution and potential mediators. J Child Psychol
Psychiatry 58, 1360–1369.
young, the elderly, pregnant and lactating women Bradford, A.C., Bradford, W.D. (2016). Medical Marijuana laws reduce
and those with other medical comorbidities. There is prescription medication use in medicare part D. Health Aff (Millwood)
also a need to rethink and be innovative in our 35, 1230–1236.
Cairns, E.A., Kelly, M.E.M. (2017). Why support a separate medical
methods of assembling data to direct clinical care. access framework for cannabis? CMAJ 189, E927–E928.
Perhaps this is a setting in which the traditional ran- Callaghan, R.C., Allebeck, P., Sidorchuk, A. (2013). Marijuana use and
domized controlled trial will be less applicable, with risk of lung cancer: A 40-year cohort study. Cancer Causes Control 24,
1811–1820.
a need to look to large-scale, longitudinal cohort Cheng, Y., Hitchcock, S.A. (2007). Targeting cannabinoid agonists for
observational studies to answer clinical questions. inflammatory and neuropathic pain. Expert Opin Investig Drugs 16,
And finally, there must be a clear distinction 951–965.
Colombo, G., Serra, S., Brunetti, G., Gomez, R., Melis, S. et al. (2002).
between recreational use of cannabis and that for Stimulation of voluntary ethanol intake by cannabinoid receptor
medical purposes, both by regulatory authorities and agonists in ethanol-preferring sP rats. Psychopharmacology 159, 181–
the health care community. 187.
Correa, F., Docagne, F., Mestre, L., Clemente, D., Hernangomez, M., Nugent, S.M., Morasco, B.J., O’Neil, M.E., Freeman, M., Low, A. et al.
Loria, F., Guaza, C. (2009). A role for CB2 receptors in anandamide (2017). The effects of cannabis among adults with chronic pain and
signalling pathways involved in the regulation of IL-12 and IL-23 in an overview of general harms: A systematic review. Ann Intern Med
microglial cells. Biochem Pharmacol 77, 86–100. 167, 319–331.
Davis, A.K., Walton, M.A., Bohnert, K.M., Bourque, C., Ilgen, M.A. Pacula, R.L., Jacobson, M., Maksabedian, E.J. (2016). In the weeds: A
(2018). Factors associated with alcohol consumption among medical baseline view of cannabis use among legalizing states and their
cannabis patients with chronic pain. Addict Behav 77, 166–171. neighbours. Addiction 111, 973–980.
D’Souza, D.C., Ranganathan, M. (2015). Medical Marijuana: Is the cart Pertwee, R.G. (2006). Cannabinoid pharmacology: The first 66 years. Br
before the horse? JAMA 313, 2431–2432. J Pharmacol 147(Suppl 1), S163–S171.
Goldenberg, M., Reid, M.W., IsHak, W.W., Danovitch, I. (2017). The Pertwee, R.G. (2015). Endocannabinoids and their pharmacological
impact of cannabis and cannabinoids for medical conditions on actions. Handb Exp Pharmacol 231, 1–37.
health-related quality of life: A systematic review and meta-analysis. Piper, B.J., Beals, M.L., Abess, A.T., Nichols, S.D., Martin, M.W., Cobb,
Drug Alcohol Depend 174, 80–90. C.M., DeKeuster, R.M. (2017). Chronic pain patients’ perspectives of
Haroutounian, S., Ratz, Y., Ginosar, Y., Furmanov, K., Saifi, F., Meidan, medical cannabis. Pain 158, 1373–1379.
R., Davidson, E. (2016). The effect of medicinal cannabis on pain and van der Pol, P., Liebregts, N., de Graaf, R., Korf, D.J., van den Brink,
quality-of-life outcomes in chronic pain: A prospective open-label W., van Laar, M. (2015). Three-year course of cannabis dependence
study. Clin J Pain 32, 1036–1043. and prediction of persistence. Eur Addict Res 21, 279–290.
Howlett, A.C. (2005). A short guide to the nomenclature of seven- Reisfield, G.M., Wasan, A.D., Jamison, R.N. (2009). The prevalence and
transmembrane spanning receptors for lipid mediators. Life Sci 77, significance of cannabis use in patients prescribed chronic opioid
1522–1530. therapy: A review of the extant literature. Pain Med 10, 1434–1441.
Huang, Y.H., Zhang, Z.F., Tashkin, D.P., Feng, B., Straif, K., Hashibe, Renard, J., Rushlow, W.J., Laviolette, S.R. (2016). What can rats tell us
M. (2015). An epidemiologic review of marijuana and cancer: An about adolescent cannabis exposure? Insights from preclinical
update. Cancer Epidemiol Biomarkers Prev 24, 15–31. research. Can J Psychiatry 61, 328–334.
Johanek, L.M., Heitmiller, D.R., Turner, M., Nader, N., Hodges, J., Richardson, D., Pearson, R.G., Kurian, N., Latif, M.L., Garle, M.J. et al.
Simone, D.A. (2001). Cannabinoids attenuate capsaicin-evoked (2008). Characterisation of the cannabinoid receptor system in
hyperalgesia through spinal and peripheral mechanisms. Pain 93, synovial tissue and fluid in patients with osteoarthritis and
303–315. rheumatoid arthritis. Arthritis Res Ther 10, R43.
Joshi, M., Joshi, A., Bartter, T. (2014). Marijuana and lung diseases. Russo, E.B. (2007). History of cannabis and its preparations in saga,
Curr Opin Pulm Med 20, 173–179. science, and sobriquet. Chem Biodivers 4, 1614–1648.
Kalant, H. (2001). Medicinal use of cannabis: History and current Sanchez Robles, E.M., Bagues Arias, A., Martin Fontelles, M.I. (2012).
status. Pain Res Manage 6, 80–91. Cannabinoids and muscular pain. Effectiveness of the local
Lim, G., Sung, B., Ji, R.R., Mao, J. (2003). Upregulation of spinal administration in rat. Eur J Pain 16, 1116–1127.
cannabinoid-1-receptors following nerve injury enhances the effects Schuelert, N., McDougall, J.J. (2008). Cannabinoid-mediated
of Win 55,212-2 on neuropathic pain behaviors in rats. Pain 105, antinociception is enhanced in rat osteoarthritic knees. Arthritis
275–283. Rheum 58, 145–153.
Malfait, A.M., Gallily, R., Sumariwalla, P.F., Malik, A.S., Andreakos, E., Shang, Y., Tang, Y. (2017). The central cannabinoid receptor type-2
Mechoulam, R., Feldmann, M. (2000). The nonpsychoactive cannabis (CB2) and chronic pain. Int J Neurosci 127, 812–823.
constituent cannabidiol is an oral anti-arthritic therapeutic in murine Steiner, M.A., Wotjak, C.T. (2008). Role of the endocannabinoid
collagen-induced arthritis. Proc Natl Acad Sci USA 97, 9561–9566. system in regulation of the hypothalamic-pituitary-adrenocortical
Marquart, S., Zerr, P., Akhmetshina, A., Palumbo, K., Reich, N. et al. axis. Prog Brain Res 170, 397–432.
(2010). Inactivation of the cannabinoid receptor CB1 prevents Sznitman, S.R., Bretteville-Jensen, A.L. (2015). Public opinion and
leukocyte infiltration and experimental fibrosis. Arthritis Rheum 62, medical cannabis policies: Examining the role of underlying beliefs
3467–3476. and national medical cannabis policies. Harm Reduct J 12, 46.
Martinasek, M.P., McGrogan, J.B., Maysonet, A. (2016). a systematic Tourangeau, W. (2015). Re-defining environmental harms: Green
review of the respiratory effects of inhalational Marijuana. Respir Care criminology and the state of Canada’s hemp industry. Can J Criminol
61, 1543–1551. Crim Justice 57, 528–554.
Meier, M.H., Caspi, A., Ambler, A., Harrington, H., Houts, R. et al. Volkow, N.D., Swanson, J.M., Evins, A.E., DeLisi, L.E., Meier, M.H.
(2012). Persistent cannabis users show neuropsychological decline et al. (2016). Effects of cannabis use on human behavior, including
from childhood to midlife. Proc Natl Acad Sci USA 109, E2657–E2664. cognition, motivation, and psychosis: A review. JAMA Psychiatry 73,
National Academies of Sciences E, and Medicine. (2017). The Health 292–297.
Effects f Cannabis and Cannabinoids: The Current State of Evidence and Ware, M.A., Wang, T., Shapiro, S., Collet, J.P. (2015). Cannabis for the
Recommendations for Research (Washington, D.C.: The National management of pain: Assessment of safety study (COMPASS). J Pain
Academies Press). 16, 1233–1242.
Nielsen, S., Sabioni, P., Trigo, J.M., Ware, M.A., Betz-Stablein, B.D. Whiting, P.F., Wolff, R.F., Deshpande, S., Di Nisio, M., Duffy, S. et al.
et al. (2017). Opioid-sparing effect of cannabinoids: A systematic (2015). Cannabinoids for medical use: A systematic review and meta-
review and meta-analysis. Neuropsychopharmacology 42, 1752–1765. analysis. JAMA 313, 2456–2473.
Njoo, C., Agarwal, N., Lutz, B., Kuner, R. (2015). The cannabinoid Zhang, L.R., Morgenstern, H., Greenland, S., Chang, S.C., Lazarus, P.
receptor CB1 interacts with the WAVE1 complex and plays a role in et al. (2015). Cannabis smoking and lung cancer risk: Pooled analysis
actin dynamics and structural plasticity in neurons. PLoS Biol 13, in the international lung cancer consortium. Int J Cancer 136, 894–903.
e1002286.

European Journal of Pain - 2018 - Fitzcharles - Medical Cannabis A Forward Vision For The Clinician

Uploaded by

Copyright:

Available Formats

European Journal of Pain - 2018 - Fitzcharles - Medical Cannabis A Forward Vision For The Clinician

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

European Journal of Pain - 2018 - Fitzcharles - Medical Cannabis A Forward Vision For The Clinician

Uploaded by

Copyright:

Available Formats

REVIEW ARTICLE

Medical cannabis: A forward vision for the clinician

States, Canada and Israel. Propelled largely by public

medically accessed product, and indiscriminate and 9. Summary

You might also like