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Use of Cannais in Palliative Care
Use of Cannais in Palliative Care
CURRENT
OPINION Use of cannabis and cannabinoids in palliative
care setting
Karthik AR and Sushma Bhatnagar
Purpose of review
Cannabis products have been used for various ailments since ancient times. But their use diminished in the
medical community due to the legal and social concerns of substance abuse. With evolving evidence of
their use in alleviating various symptoms, resurgence of interest in their medicinal use is seen in the past
decade.
Recent findings
Clinical evidence for cannabis products in treating various ailments has been far from robust. Their use is
based on anecdotal and low-quality evidence. This review attempts to revisit the recent medical literature
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pain control. Given the widespread distribution of might be another reason for the negative result in
cannabinoid receptors in the brain and nervous addition to inadequate therapeutic efficacy.
tissue, cannabinoids have been tried for alleviating A Cochrane review by Mucke et al. [9] on effect
pain. There are some anecdotal reports of cannabi- of cannabinoids for adult neuropathic pain included
noids being effective in this subset of ‘difficult to 16 studies with 1750 participants. The cannabinoids
treat’ patients. A case report of a schwannomatosis studied were oromucosal nabiximols, inhaled
patient with severe intractable pain not responding herbal cannabis, nabilone and dronabinol. The can-
to traditional multidrug regimen responded impres- nabinoids were superior to placebo for substantial
sively well to THC/CBD combination [6]. Cannabi- (low-quality evidence) and moderate pain relief
noids have been found to be promising in pediatric (moderate-quality evidence). Hence, the reviewers
palliative care also [3]. concluded that cannabinoids may be used as third
Hauser et al. [7] performed a systematic review or fourth line of treatment for neuropathic pain
and metaanalysis of randomized controlled trials when established conventional therapies fail. A sub-
(RCTs) to assess the efficacy, tolerability, and safety set of patients with neuropathic pain are likely to
of cannabinoids in cancer pain. They included five benefit from long-term cannabinoid therapy. With
double-blind RCTs including 1534 participants with the available evidence, they are not to be used as first
moderate-to-severe cancer-related pain despite opi- line of treatment for neuropathic pain.
oid therapy. These studies did not include pain
arising because of cancer therapy. Out of these
studies, a metaanalysis was done on four studies CHEMOTHERAPY-INDUCED NAUSEA AND
with 1333 patients. The primary outcomes studied VOMITING
were pain relief of 50% or more from baseline, Cannabinoid receptors are widely distributed in the
patient-perceived global improvement, opioid dose emetic reflex pathway of the brain. Few decades ago,
reduction, tolerability, and safety of cannabinoid decreased incidence of vomiting was seen in
medications. The cannabinoids used were oromu- patients receiving chemotherapy who were mari-
cosal nabiximols or THC. This metaanalysis sug- juana smokers. Subsequently, dronabinol and nabi-
gested that nabiximols and THC had no effect on lone were investigated for CINV. Similar to chronic
pain and opioid consumption in cancer patients pain, there were anecdotal reports of excellent anti-
who had inadequate pain control on opioids. They emetic action of cannabinoids in ‘difficult to treat
found a clinically significant increase in neurologi- cases’ of CINV. However, since the advent of 5-HT3
cal side-effects by the said cannabinoids. They found antagonists, interest on cannabinoids as antiemetics
the quality of evidence to be very low for all trials diminished [10]. Yet, cannabinoids have found
because of a high risk of bias, exclusion of hepatic resurging importance in CINV because of their
and renal insufficiency, and all the studies being ancillary effects such as mitigating anorexia which
sponsored by the drug manufacturer. The trials did is not seen with the popular antiemetics. The anti-
not include opioid naı̈ve patients. All the trials used emetic efficacy of cannabinoids differed with the
the oromucosal route of administration of the drug. type of chemotherapy used with the maximum
This route is known for variability in pharmacoki- efficacy demonstrated against methotrexate as
netic parameters compared with the inhalational opposed to doxorubicin or cyclophosphamide
&
route at a similar dose. Hence, this cannot be [11 ]. A Cochrane review of 23 RCTs concluded that
accepted as robust evidence. cannabinoids were superior to placebo and similar
A recent systematic review and metaanalysis to conventional antiemetics in ameliorating CINV
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carried out by Boland et al. [8 ] included six RCTs [12]. Following successful results with a favorable
with 1460 participants for qualitative analysis and side-effect profile, dronabinol and nabilone were
five RCTs with 1442 participants for meta-analysis. approved for treating CINV. Dronabinol and nabi-
This review was an improvisation of the previous lone have been included in the National Compre-
metaanalysis. It had a broader search strategy, hensive Cancer Network1 guidelines for CINV [13].
included unpublished articles, and the reviewers
contacted the original authors of the trials for addi-
tional findings and study design. Hence, the ANOREXIA AND CACHEXIA
reviewers claim a low risk of bias in this review. The endocannabinoid system is known to have an
The primary outcome was absolute change in mean active role in the appetite-satiety system of the body.
pain intensity. The reviewers claim this review to Endocannabinoids have been found to stimulate
provide good evidence that cannabinoids had no appetite through the CB1 receptors. Rimonabant,
role in cancer pain. The studies had a high number a selective CB1 receptor inverse agonist, was found
of patient withdrawals and lost to follow-up. This to possess anorexic effects and was used to treat
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obesity and metabolic syndrome [3,14]. But a few awaited to define this novel role of cannabinoids
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years later it was withdrawn because of increased in cancer [5 ].
suicidal ideation in its users. Anorexia and cachexia
are associated with many chronic illnesses includ-
ing cancer and AIDS. Treatment of anorexia OTHER EFFECTS AND OVERALL
strongly influences patient satisfaction [15]. Loss WELLBEING
of appetite in cancer is multifactorial – patient- Nabiximols are approved for treatment of spasticity
&
related, tumor-related, and therapy-related. because of multiple sclerosis [5 ]. A small retrospec-
Patient-related factors include early satiety, depres- tive case series of five patients reported improve-
sion, anxiety, and fatigue. Tumor-related factors are ment of symptomatic paraneoplastic night sweats
because of inflammatory cytokines, mechanical with dronabinol [16]. Apart from addressing indi-
bowel obstruction, malabsorption, and direct vidual symptoms in patients with chronic debilitat-
tumor invasion leading to impaired gut function. ing illnesses, cannabinoids have been found to gain
Cancer treatment may lead to anorexia because of overall patient satisfaction scores and global wellbe-
mucositis, radiation enteritis, dry mouth, nausea, ing. With a low-quality evidence cannabinoids were
vomiting, diarrhea, or constipation [15]. Dronabi- superior to placebo for overall improvement, sleep
nol (THC) is approved for use in AIDS-related problems and psychological distress in patients with
anorexia and was widely used when effective anti- neuropathic pain [9]. A retrospective observation of
retroviral therapy was still evolving. Evidence for 332 cancer patients in the United States noted that
cannabinoids in cancer anorexia and cachexia is of many patients with higher overall symptom scores
low quality. Cancer cachexia is complicated by had a positive urine drug test for THC than those
increased tumor cell turnover rate which is not patients with lower symptom scores [17]. This
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present in AIDS [11 ]. Progestins and corticosteroids denoted that patients were exposed to cannabinoids
are the most commonly used orexigenic agents in from medical and nonmedical sources and were
cancer cachexia. Dronabinol has been found to be aware of the emerging use of cannabis products
inferior to megestrol acetate for appetite improve- for symptom control. However, a metaanalysis by
ment and weight gain in cancer patients [15]. How- Mucke et al. [18] concluded that cannabinoids did
ever, other cannabinoid agents and cannabis not have a positive impact on health related QOL in
extract as a whole should be rigorously tested under patients with cancer or AIDS.
controlled conditions before arriving on a final
decision as to the usefulness of this class of drugs
on a most distressing symptom. PATHWAY FOR FURTHER RESEARCH
Cannabis medications have suffered the complica-
tions of the recreational use of cannabis. The sub-
ANTITUMOR EFFECTS stance abuse potential and the gray market
The emerging interest in using cannabinoids for economics have forced governments worldwide to
cancer treatment is to cure cancer itself. Cannabi- enforce strict laws restricting the availability of can-
noids have shown antitumor effects in various cell nabinoids. There have also been irregularities in the
culture and animal studies. The ability of cannabi- taxonomy of cannabis products [19]. The cannabis
noids to modulate tumor growth in various in-vitro plant has over 1000 different strains and houses over
cancer cell lines appears to be dependent on the cell 100 different phytocannabinoids. Even though THC
type and drug dose. The endocannabinoid system is and CBD constitute the major substances and have
closely associated with the immune system. Canna- been widely studied, the variations in clinical effects
binoids can cause apoptosis, tumor cell cycle arrest seen across various reports and studies may be
&
and inhibit angiogenesis in tumor cells [2 ]. These because of the interaction of the varying amounts
actions are mediated by CB1 and CB2 receptors and of these less known phytocannabinoids. Measures
there seems to be a cannabinoid receptor-indepen- such as weight % and volume % have been used in
dent pathway as well. Cannabinoids are also postu- denoting the potency of THC in dried products and
lated to act through the transient receptor potential oils respectively. Breeding practices of the cannabis
vanniloid receptor 1 (TRPV1) receptor. There have plant have changed over the years such that the
been anecdotal clinical reports of tumor regression dried plant had 3% THC three decades ago and now
with cannabinoids in acute lymphoblastic leukemia has 15–30% THC [3]. As cannabis products are
and pilocytic astrocytoma. An unconventional legally restricted in many countries, researchers
route of intratumor injection of THC found depend on pharmaceutical preparations of varying
improvement in recurrent glioblastoma multi- composition for clinical trials. Hence, the pharma-
forme. High-quality evidence in humans is still codynamic effects observed are bound to vary
among studies. Also, the effects of cannabis vary agents in mitigating some distressing symptoms of
depending on whether the patient is naı̈ve to can- palliative patients. Their use must be studied under
nabis or has had previous recreational exposure. rigorous research conditions to unveil their fullest
Apart from the varying composition of cannabis potential. This kind of high-quality evidence is
products, the field is complicated by the various urgently required. Until such robust clinical evidence
routes available for cannabis administration. Can- is available, the use of cannabinoids must be guarded
nabinoids can be administered orally, oromuco- and reserved for specific instances.
sally, as inhaled vapors and as a smoked product
&
[5 ]. Each of these routes has varying pharmacoki- Acknowledgements
netic profiles. Most of the existing studies on can- None.
nabinoids have studied their use later in the disease
course after multiple treatment options have failed Financial support and sponsorship
rather than in early disease [20]. This might be a
None.
factor responsible for negative results. Pharmacoge-
nomic studies have identified heterogeneity of sin-
Conflicts of interest
gle-nucleotide polymorphisms in cannabinoid
pharmacokinetics among individuals and may be There are no conflicts of interest.
responsible for varying responses across studies [21].
Research on cannabis products must take into con-
REFERENCES AND RECOMMENDED
sideration these effects for the results to be valid
READING
and reproducible. Papers of particular interest, published within the annual period of review, have
Cannabis research is majorly funded by drug been highlighted as:
& of special interest
manufacturing companies and hence there always && of outstanding interest
0952-7907 Copyright ß 2020 Wolters Kluwer Health, Inc. All rights reserved. www.co-anesthesiology.com 845
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