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Journal of Pain Research 2018:11 837–842
Journal of Pain Research Dovepress
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REVIEW
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/JPR.S160556
Pharmacotherapeutic considerations for use
of cannabinoids to relieve pain in patients with
malignant diseases
Marija
Darkovska-Serafimovska1
Tijana Serafimovska2
Zorica Arsova-Sarafinovska1
Sasho Stefanoski3
Zlatko Keskovski3
Trajan Balkanov4
1Department of Pharmacology,
Faculty of Medical Sciences, Goce
Delcev University, Stip, Republic of
Macedonia; 2Faculty of Pharmacy, Ss
Cyril and Methodius University of
Skopje, Skopje, Republic of Macedonia;
3NYSK Holdings, Skopje, Republic
of Macedonia; 4Department of
Pharmacology and Toxicology, Faculty
of Medicine, Ss Cyril and Methodius
University of Skopje, Skopje, Republic
of Macedonia
Purpose: The aim of this review was to assess the efficacy of cannabis preparations for
relieving pain in patients with malignant diseases, through a systematic review of randomized
controlled trials (RCTs), which were predominantly double-blind trials that compared cannabis
preparation to a placebo.
Methods: An electronic search of all literature published until June 2017 was made in MED-
LINE/PubMed, Embase, The Cochrane Controlled Trials Register and specific web pages
devoted to cannabis.
Results: Fifteen of the 18 trials demonstrated a significant analgesic effect of cannabinoids as
compared to placebo. The most commonly reported adverse effects were generally well tolerated,
mild to moderate. The main side effects were drowsiness, nausea, vomiting and dry mouth. There
is evidence that cannabinoids are safe and modestly effective in neuropathic pain and also for
relieving pain in patients with malignant diseases. The proportion of “responders” (patients who
at the end of 2 weeks of treatment reported ≥30% reduction in pain intensity on a scale of 0–10,
which is considered to be clinically important) was 43% in comparison with placebo (21%).
Conclusion: The target dose for relieving pain in patients with malignant diseases is most likely
about 10 actuations per day, which is about 27 mg tetrahydrocannabinol (THC) and 25 mg can-
nabidiol (CBD), and the highest approved recommended dose is 12 actuations per day (32 mg
THC/30 mg CBD). Further large studies of cannabinoids in homogeneous populations are required.
Keywords: cancer management, chronic pain, cannabidiol, tetrahydrocannabinol, medical
marihuana, nabiximols, cannabinoid receptors
Introduction
Pain is a disagreeable sensorial and emotional experience that subjects associate with
tissue damage and impairs quality of life.1 Effective therapeutic options for patients
living with different forms of pain are limited. Opioids and anti-inflammatory drugs
as first-line medications for the treatment of pain in patients with malignant diseases
do not always give satisfactory results.
In traditional medicine, cannabis preparations have been used for thousands of
years to treat disease or alleviate symptoms, but their efficacy for specific indications
is not clear. Clinical use of cannabinoid substances is restricted, due to legal and ethical
reasons, as well as limited evidence showing benefits. The medical use of cannabis is
attractive to patients suffering from malignant diseases. However, scientific justifica-
tion or positive experience of the use of cannabis in patients with malignant diseases
has only been found for the following indications: alleviation of sickness, nausea and
Correspondence: Marija Darkovska-
Seramovska
Department of Pharmacology, Faculty
of Medical Sciences, Goce Delcev
University, “Krste Misirkov” 10-A. PO
201, Stip, 2000, Republic of Macedonia
Email marija.darkovska@udg.edu.mk
Journal name: Journal of Pain Research
Article Designation: REVIEW
Year: 2018
Volume: 11
Running head verso: Darkovska-Serafimovska et al
Running head recto: Cannabinoids for relief of pain in patients with malignant diseases
DOI: http://dx.doi.org/10.2147/JPR.S160556
This article was published in the following Dove Press journal:
Journal of Pain Research
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Darkovska-Seramovska et al
vomiting associated with the use of cytotoxic therapy, pain
relief and stimulation of appetite (treatment of cachexia).
Pain relief is the most commonly cited reason for the medi-
cal use of cannabis.2–5
Mechanism of action of cannabinoids
Cannabinoids bind to cannabinoid receptors and act as ago-
nists. Cannabinoid receptors are cell membrane receptors,
members of the G protein-coupled receptors. They are acti-
vated by three major groups of ligands: endocannabinoids,
plant cannabinoids and synthetic cannabinoids. Four subtypes
of these receptors have been identified. Two have been cloned
(CB1 and CB2 cannabinoid receptors),6,7 while the other two,
WIN and abnormal-cannabidiol (abn-CBD) receptors, have
been characterized pharmacologically.8–11
The analgesic effect of cannabinoids as a result of binding
of cannabinoids to cannabinoid receptors has been confirmed,
and the role of the endocannabinoid system in pain relief
has been verified in various types of pain: somatic, visceral
and neuropathy.12 Classical analgesics, nonsteroidal anti-
inflammatory drugs or opioids, paracetamol and antidepres-
sants (with an analytical effect in some conditions) increase
the activity of the endocannabinoid system.12
The discovery of the endocannabinoid system and the
development of animal models with different forms of pain
have recently demonstrated the synergism between the opi-
ate and cannabinoid systems.12 There is a large amount of
preclinical data in animal models on the analgesic effect
of cannabinoids, predominantly Δ9-tetrahydrocannabinol
(THC), nabilone and dronabinol, or combinations of THC and
cannabidiol (CBD) and some other synthetic cannabinoids;
and analgesic effects in the treatment of cancer-related pain
without serious side effects have been shown.13–15
In humans, pharmacodynamic studies have demonstrated
the effect of cannabinoids on provoked somatic pain (e.g.,
thermal stimulation), capsaicin-induced hyperalgesia, painful
spasms in patients with multiple sclerosis (MS), and neuro-
pathic pain in HIV/AIDS patients.12,26–28,30
Available cannabinoid analgesic agents
Two finished drug products – nabilone (Cesamet) and
dronabinol (Marinol) – have been approved in many coun-
tries for the “prevention/treatment of chemotherapy induced
nausea and vomiting”.15 The only pharmaceutical industry
drug product carrying the cannabinoid therapeutic principle
with regulatory approval (in some countries) for pain relief
in patients with malignant diseases is nabiximols (Sativex
spray). Sativex® (GW Pharmaceuticals, Cambridge, UK)
is an oromucosal cannabis-based spray combining a CB1
partial agonist (THC) with a cannabinoid system modulator
(CBD).16,17 It was approved by Health Canada in June 2005
for prescription for central neuropathic pain in MS, and in
August 2007, it was additionally approved for the treatment of
cancer pain, as an adjuvant analgesic in adults with advanced
malignancy, who, despite the highest tolerated opioid dose,
still feel moderate to severe chronic pain.18
In randomized controlled trials (RCTs), Sativex was
adjunctively added to optimal drug regimens in patients with
intractable symptoms, those often termed “untreatable”. The
recommended maximum is 12 daily doses (32.4 mg THC and
30 mg CBD).12 Data on the analgesic effect of nabiximols in
malignant patients are shown primarily as an illustration of
the effects of different ratios of THC/CBD.
Approved ongoing clinical trials
An investigational new drug (IND) application to study
Sativex in advanced clinical trials in the USA was approved
by the FDA in January 2006 in patients with intractable
cancer pain.15
Recently, the European Medicine Agency (EMEA)
approved two double-blind, placebo-controlled safety and
efficacy studies of Sativex as adjunctive therapy to opiates:
the first one in pediatric patients from 8 to less than 18
years of age with cancer-related pain and the second one
in pediatric patients from birth to less than 8 years of age
with cancer-related pain (decision number P/0298/2014, PIP
number EMEA-000181-PIP02-13). The completion date of
the pediatric investigation plan is by July 2026.19
On February 17, 2016, orphan designation (EU/3/16/1621)
was granted by the European Commission to GW Pharma-
ceuticals, for THC and CBD from extracts of Cannabis sativa
for the treatment of glioma.20
Methods
An electronic search of all literature published until June 2017
was made in MEDLINE/PubMed, Embase, The Cochrane
Controlled Trials Register and specific web pages devoted to
cannabis. A systematic review of literature identified RCTs,
evaluating the efficacy of cannabinoids in various chronic
pain conditions that are not related to malignant diseases
(including MS and HIV/AIDS neuropathies), compared with
placebo and sometimes other active treatments.21–38 They
demonstrated an analgesic effect of dronabinol, nabilone
and natural THC and CBD in comparison with smoking
marijuana. A detailed overview of preclinical and clinical
data on the analgesic efficacy of cannabinoids is found in the
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839
Cannabinoids for relief of pain in patients with malignant diseases
document Health Canada2 and Ethnopharmacology.39 Only
three RTCs evaluated the efficacy of cannabinoids compard
to placebo in various pain conditions that are related to
malignant diseases.40-42 The studies selected were double-
blind RTCs with a crossover or parallel design.
Selection criteria
A systematic review of literature using the keywords canna-
binoids, pain, malignant diseases, THC and RCTs identified
198 reports, of which 73 were potentially relevant RCTs,
based on title and abstract screening. Seven of them had
no relevant information obtained as full-text studies, five
reports were duplicates (they contained data that had previ-
ously been published), 60 were in other clinical examinations
(chemotherapy-induced nausea and vomiting, spasticity due
to MS, sleep disorders and HIV/AIDS) and ten compared
efficacy of cannabis for the treatment of chronic pain. Only
three RCTs evaluated the efficacy of cannabinoids in pain
conditions that are related to malignant diseases compared
with synthetic THC and placebo (Figure 1).40–42
Review of relevant research
In the intervention group, subjects were required to
have received cannabis preparation, which at minimum
contained the cannabinoids THC and CBD, applied by
oral administration. Synthetic derivates of THC, such as
dronabinol, nabilone or benzopyranoperidine, were likewise
included. In the control group, subjects were required to have
received a placebo treatment.40–42
The measure of efficacy chosen was the variable “inten-
sity of pain” as scored by numeric analog scales. Patients at
the end of 2 weeks of treatment reported ≥30% reduction in
pain intensity on a scale of 0–10, which was considered as
clinically important.
Double-blind, 2-week, multicenter RCT,
placebo-controlled study
Respondents to the double-blind, 2-week, multicenter RCT,
placebo-controlled study40 were adult patients with malignant
diseases in terminal stage, who for at least a week used high
(the most tolerated) doses of strong opiates, and despite this
showed an intensity of pain ≥4 on a scale of 0–10.
For the treatment, patients were randomized into three
groups. The first group received Sativex oral spray (nabixi-
mols, 2.7 mg THC, 2.5 mg CBD per actuation) (n=60), the
second group received THC as oral spray (2.7 mg THC per
actuation) (n=58) and the third group received placebo spray
(n=59). During the first week, the dose was titrated in patients
based on tolerability and analgesia. The maximum permis-
sible dose was 8 actuations in 3 hours (in intervals of at least
15 minutes between two doses) or at most 48 actuations for
24 hours (130 mg THC and 120 mg CBD).
The proportion of “responders” (patients who at the end
of 2 weeks of treatment reported ≥ 30% reduction in pain
intensity on a scale of 0–10, which is considered to be clini-
cally important) in the Sativex group was 43% (statistically
significantly compared with placebo; an improvement of
–1.37 vs –0.69); in the THC group 23% (non-significant
change compared with placebo; an improvement of –1.01
vs –0.69) and in the placebo group 21%.
Regarding side effects, in the Sativex group, 10/60
patients dropped out of treatment because of the side effects;
in the second group where THC was orally administrated as
spray, 7/58 patients dropped out of treatment because of the
side effects and in the placebo group, 3/59 patients dropped
out of treatment because of the side effects. The main side
effects were drowsiness, nausea, vomiting and dry mouth.
Extension of the main double-blind,
2-week, multicenter RCT, placebo-
controlled study
In 2013, an extension of the main study was opened.28 A total
of 39 patients with chronic pain due to malignant disease,
198 Title and abstracts screened
125 Excluded reports
73 Full reports assessed
70 Excluded reports:
28 Chemotherapy-induced nausea
and vomiting
14 Spasticity due to multiple sclerosis
10 Chronic pain
7 No relevant information
5 Duplicates
4 HIV/AIDS
2 Sleep disorders
3 RCTs included – evaluating the
efficacy of cannabinoids in pain
conditions that are related to
malignant diseases
Figure 1 Flow of studies through the review process.
Abbreviation: RCTs, randomized controlled trials.
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Darkovska-Seramovska et al
who had been treated with opioids in a previous study but
with an inadequate analgesic response, were involved in a
new extended open, randomized, controlled, multicenter
study for 2 weeks in which patients continued treatment with
Sativex.41 Doses remained unchanged. Of the 39 patients, 15
were treated for less than 2 weeks; others gradually withdrew
from treatment during 1 year due to side effects (23/39), loss
of efficacy (3/39) and a number of other reasons.
The study showed that the long-term use of THC/CBD
spray is generally well tolerated without any loss of effect
for pain relief because of long-term use. Moreover, patients
who continued to use spray did not seek to increase the dose
of spray or other medications for pain relief, suggesting
that the adjuvant use of cannabinoids in cancer-related pain
could be useful.
Multicenter, double-blind, placebo-
controlled RCT, three different doses of
Sativex
Respondents to this multicenter, double-blind, placebo-
controlled RCT, with three different doses of Sativex,42 were
adult patients with malignant diseases in terminal stage, who
for at least a week used high (the most tolerated) doses of
strong opiates, and despite this showed an intensity of pain
≥4 on a scale of 0–10.
For treatment, patients were randomized to receive three
different doses of Sativex: group 1 received 4 actuations per
day (10.8 mg THC, 10 mg CBD) (n=91), group 2 received
10 actuations per day (27 mg THC, 25 mg CBD) (n=88)
and group 3 received 16 actuations per day (43 mg THC, 40
mg CBD) (n=90). A group receiving THC as oral spray and
placebo spray (n=90) was also included. During the first 7
days, the dose was gradually increased (from 1 to 4, 10 or
16) and then adjusted for the next 2 weeks. From the 21st to
the 35th day, there was a 14-day evaluation period.
Patients who at the end of 2 weeks of treatment reported
≥30% reduction in pain intensity on a scale of 0–10 were
considered clinically important.
The results showed that with increasing doses, several
patients dropped out of treatment because of side effects:
3/91 placebo, 5/91 lowest dose, 6/88 medium dose and 20/90
highest dose. Overall, the share of those with ≥30% reduction
in pain did not differ for Sativex vs placebo. However, in an
analysis that evaluated the average daily pain score during 14
days, the lowest and midpoint doses were better than placebo.
There is no RTC for relief of pain in malignant diseases
that evaluates “smoking marijuana” or some other herbal prep-
aration consisting of natural THC and CBD, except Sativex.
Discussion
The natural and synthetic agonists of the cannabinoid recep-
tors have shown positive therapeutic results in the treatment
of various pathological conditions, including pain as an
inevitable symptom of tissue damage. The antinociceptive
and anti-hyperalgesic effect of cannabinoids at the peripheral
and central levels has been demonstrated and confirmed in
various models of acute and chronic pain.43,44
The adverse effects (AEs) of cannabinoids on the cen-
tral nervous system (CNS) are associated with abnormal
psychomotor behavior, short-term memory impairment and
intoxication.45
This review is prepared according to recommendations for
systematic reviews.46,47
A systemic literature review identified
more RCTs evaluating the efficacy of cannabinoids/cannabis
in pain conditions, but only three double-blind controlled
RTCs comparing the effectiveness of cannabinoids with
synthetic THC and placebo in a variety of painful conditions
that are associated with malignant disease.
In the first double-blind, 2-week multicenter RCT, pla-
cebo-controlled study,40 the proportion of responders in the
Sativex group was 43%, in the THC group was 23% and in
the placebo group was 21%. Extension of the main double-
blind, 2-week, multicenter RCT, placebo-controlled study41
in 2013 showed that long-term use of THC/CBD spray is
generally well tolerated without any loss of effect for pain
relief because of long-term use. A multicenter double-blind,
placebo-controlled RCT, in which three different doses
of Sativex were used,42 showed that with increasing doses
of THC/CBD, several patients dropped out of treatment
because of side effects and those with ≥30% reduction in
pain did not differ for Sativex vs placebo.
Thus, in two high-quality studies, the primary outcome
of one can be regarded as positive and the other negative;
however, both can be considered as evidence of the effective-
ness of Sativex in specific painful conditions.
The inefficacy of the THC oral spray in one study, and
variable results with relatively high doses of dronabinol,
indicate that THC alone may not be sufficient for a good
analgesic effect. This means that THC should be combined
with CBD in order to achieve desire results.
Medicines that contain active ingredients that act as ago-
nists of cannabinoid receptors are a promising therapeutic
approach for treatment of various types of pain: neuropathic,
inflammatory and oncological. This primarily refers to prepa-
rations containing exactly known similar amounts of THC
and CBD, intended for the treatment of patients who do not
respond to conventional therapy.11,41,42
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Cannabinoids for relief of pain in patients with malignant diseases
In the studies of Sativex in patients with malignant dis-
eases and pain despite opioid therapy, the target dose is most
likely about 10 actuations per day (the average number of
actuations in one RCT was 9; in the second, the “successful”
dose was 6–10 actuations per day), which is about 27 mg THC
and 25 mg CBD, and the highest approved recommended dose
is 12 actuations per day (32 mg THC/30 mg CBD). The dose
is introduced gradually, from 1 to 4–6 actuations during the
day, for 5–7 days.12,37
Conclusion
There is evidence, although limited, to support the use of can-
nabis pharmacotherapy in the treatment of different forms of
pain in patients. If a patient with chronic pain and their health-
care provider work together through first- and second-line
treatment modalities without success, a trial of cannabis or
a cannabinoid may be a reasonable next step. With increased
use of medical cannabis as pharmacotherapy for pain comes
a need for comprehensive risk–benefit discussions that take
into account the significant possible AEs of cannabis.
Numerous randomized clinical trials have demonstrated
the safety and efficacy of Sativex in central and peripheral
neuropathic pain, rheumatoid arthritis and cancer pain. Com-
mon AEs included dizziness, dry mouth, nausea, fatigue,
somnolence, euphoria and vomiting.
The recommended daily dose for the treatment of pain
is a maximum of 32.4 mg THC and 30 mg CBD. Data on
the analgesic effect of nabiximols in patients with malignant
diseases are shown primarily as an illustration of the effects
of different ratios of the THC/CBD combination. The degree
to which cannabinoid analgesics will be adopted in adjunc-
tive pain management practices remains to be determined.
Further large studies of cannabinoids in homogeneous
populations are required.
Author contributions
All authors contributed toward data analysis, drafting and
critically revising the paper and agreed to be accountable
for all aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.
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