©

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© 2018 EDIZIONI MINERVA MEDICA Minerva Anestesiologica 2018 August;84(8):955-69

Online version at http://www.minervamedica.it DOI: 10.23736/S0375-9393.18.12287-5

REVIEW

The role of cannabinoids in pain control:

the good, the bad, and the ugly
Joseph V. PERGOLIZZI Jr 1, Jo A. LEQUANG 1 *, Robert TAYLOR Jr 1,
Robert B. RAFFA 1, Daniel COLUCCI 2, NEMA Research Group ‡

‡Members are listed at the end of the paper

1NEMA Research, Inc., Naples, FL, USA; 2Department of Bioengineering, Northeastern University, Boston, MA,
USA
*Corresponding author: Jo A. LeQuang, NEMA Research, Inc., 868 106th Ave North, Naples, FL 34108, USA.
E-mail: joann@leqmedical.com

A B STRACT
Cannabinoids appear to possess many potential medical uses, which may extend to pain control. A narrative review of the
literature has found a variety of studies testing botanical and synthetic cannabinoids in different pain syndromes (acute
pain, cancer pain, chronic noncancer pain, fibromyalgia pain, migraine, neuropathic pain, visceral pain, and others). Re-
sults from these studies are mixed; cannabinoids appear to be most effective in controlling neuropathic pain, allodynia,
medication-rebound headache, and chronic noncancer pain, but do not seem to offer any advantage over nonopioid
analgesics for acute pain. Cannabinoids seem to work no better than placebo for visceral pain and conferred only modest
analgesic effect in cancer pain. Cannabinoids do many good things — they appear to be effective in treating certain types
of pain without the issues of tolerance associated with opioids. Negatively, marijuana currently has a very murky legal
status all over the world — laws regulating its use are inconsistent and in flux. Thus, both patients and prescribers may
be unsure about whether or not it is an appropriate form of pain control. Cannabinoid-based analgesia has been linked
to potential memory deficits and cognitive impairment. A great deal more remains to be elucidated about cannabinoids
which may emerge to play an important role in the treatment of neuropathic and possibly other painful conditions. There
remains a great deal more to learn about the role of cannabinoids in pain management.
(Cite this article as: Pergolizzi JV Jr, LeQuang JA, Taylor R Jr, Raffa RB, Colucci D; NEMA Research Group. The role of
cannabinoids in pain control: the good, the bad, and the ugly. Minerva Anestesiol 2018;84:955-69. DOI: 10.23736/S0375-
9393.18.12287-5)
Key words: Cannabinoids - Dronabinol - Medical marijuana - Chronic pain - Analgesia.

C annabinoids are increasingly of interest to

society because of their largely untapped
role in addressing many medical conditions and
their recent legalization (and legitimization) in
many of the societies that had previously banned
them. There over 60 different cannabinoids, of
which Δ9tetrahydrocannabinol (THC) is the best
known; THC is the major psychoactive ingredi-
ent in botanical marijuana or Cannabis sativa.1
Botanical and synthetic cannabinoids have been
evaluated with promising results in the treatment
of numerous conditions, including most promi-
nently nausea and vomiting and epilepsy. Their
potential role in pain control is a subject of great
interest.
The precise analgesic mechanism of action
of THC remains to be fully elucidated. Studies
show a stronger analgesic benefit of cannabi-
noids in animals than in humans.2 Cannabinoids
bind to receptors (to date, cannabinoid [CB] re-
ceptor types 1 and 2 have been identified, but it
is suspected others exist).3 Their physiological

Vol. 84 - No. 8 Minerva Anestesiologica 955

 ©
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to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
PERGOLIZZI CANNABINOIDS IN PAIN CONTROL
ligands (endocannabinoids) have been implicat-
ed in numerous physiological pathways. Indeed,
the endogenous cannabinoid system — which
includes enzymes and proteins that regulate con-
centrations of cannabinoids — have been consid-
ered a relevant and exciting research target for
analgesia.
The known CB-1 and CB-2 receptors are
G-protein coupled receptors embedded in cell
membranes. The ligand (endocannabinoid)
binds at the receptor site and triggers second-
messenger enzymatic activity, mainly producing
adenylate cyclase inhibition, voltage-gated cal-
cium-channel blocking, and activates mitogen-
responsive protein kinase and protein channels.2
These endocannabinoid ligands are derivatives
of arachidonic acid and are part of the eico-
sanoid-signaling network.2 More abundant than
µ-opioid-receptors, CB-1 receptors are present
in the peripheral sensory nerve endings up to the
brain and in many parts of the brain itself (hy-
pothalamus, hippocampus, cerebellum, and oth-
ers). Because there is only low expression of CB
receptors in the brainstem compared to µ-opioid-
receptors, cannabinoids — unlike opioids — are
not associated with respiratory depression.2 It is
known that CB-1 receptors are expressed in parts
of the brain associated with nociception and they
receive nociceptive inputs from the primary af-
ferent neurons. Preclinical evidence suggests
CB-2 receptors also play a role in nociceptive
perception.2 CB-2 receptors are found in the gas-
trointestinal tract and appear to inhibit adenylyl
cyclase; they may play a role in immune system
modulation and may mediate analgesia to the pe-
riphery.
THC may interfere with the affective aspects
of pain, that is, the perception of pain signals.4
The frontal-limbic distribution of CB receptors
suggests that cannabinoids preferentially tar-
get the affective aspects of pain. In a functional
magnetic resonance imaging (fMRI) study, THC
reduced the unpleasantness associated with cap-
saicin-induced pain but did not lessen the inten-
sity of the pain itself.5
The aim of our review was to describe the
clinical implications in the ongoing work sur-
rounding the use of cannabinoids for pain treat-
ment—the good, the bad, and the ugly.
956 Minerva Anestesiologica August 2018
Literature search
The PubMed, Embase, and Cochrane databases
were searched on May 17, 2017 with the key-
word “cannabinoid + pain” and the search lim-
ited to clinical studies and comparative studies
published from 1988 to present. A total of 348
potential results were returned. Of those 348 ar-
ticles, 94 were deemed on-topic. After eliminat-
ing articles that were not in English, those that
did not describe clinical trials, duplicates from
the multiple searches, and articles about obscure
conditions (Mediterranean fever), 38 articles
remained (one of them described two studies).
Articles were grouped by painful syndrome.
The authors excluded references that discussed
the role of cannabinoids in multiple sclerosis
although some of those studies addressed pain
or spasticity-related pain. These were excluded
because the pain endpoint in these studies was
usually secondary, if included at all, and the pain
associated with MS involves spasticity, which
is a better topic for more specific review. Some
of our references, in particular for background
statistics, come from websites maintained by
the Centers for Disease Control and Prevention
and the World Health Organization. In some
instances, the bibliographies of the selected ar-
ticles were reviewed. Our goal was to summarize
what is known to date about cannabinoids in the
treatment of painful conditions. This is a narra-
tive rather than a systematic review.
The clinical studies evaluating analgesic ef-
fects of cannabinoids could be organized by
categories: allodynia, cancer pain, chronic non-
cancer pain (such as musculoskeletal pain syn-
dromes), dental pain, experimental pain, fibro-
myalgia, headache, neuropathy, postoperative
pain, and visceral pain. The agents used in these
studies varied ranging from botanical marijuana,
synthetic products, semisynthetic products, and
others. A short description of these substances
precedes the clinical trial results.
Types of cannabinoids
This paper includes studies about the role of can-
nabinoids and pain and includes botanical and
synthetic cannabinoids.
 ©
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cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
CANNABINOIDS IN PAIN CONTROL PERGOLIZZI
Botanical cannabinoids
Botanical cannabis or marijuana (Cannabis sati-
va) is provided to organizations conducting clini-
cal trials by the National Institute on Drug Abuse
(NIDA).6, 7 Its relative strength is described as
its percentage of THC, ranging from about 1%
(low) to 12.4% (high).8 Botanical marijuana can
vary in strength depending on the strain of the
plant and even the particular crop. For studies us-
ing botanical marijuana, the placebo is typically
created from the whole plant following extrac-
tion of cannabinoids. Botanical cannabis may
be smoked as a cigarette, vaporized, or ingested
(typically added to a food or beverage).
Synthetic cannabinoids
For the purposes of this narrative review, we did
not distinguish among botanical versus synthetic
cannabinoids nor among the various synthetic
versions. Some of the products that were evalu-
ated in the studies described herein appear be-
low. A few of the studies cited in our research
relied on oils or extracts of THC that were not
definitively described.
Dronabinol (Marinol®, Unimed Pharmaceuticals,
Inc., Marietta, GA, USA)
Dronabinol is (6aR-trans)-6a,7,8,10a-tetra-
hydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]
pyran-1-ol, a synthetic Δ9-tetrahydrocannabinol
(THC).9 This same substance occurs naturally
in botanical marijuana. The analgesic actions of
THC are thought to result principally from its
high affinity binding (K1=10 nM) and partial
agonist activity at CB1.
Nabilone (Cesamet™, Valeant Pharmaceuticals
International, Costa Mesa, CA, USA)
Nabilone is a synthetic cannabinoid,(±)-trans-3-
(1,1-dimethylheptyl)-6,61,7,8,10,10a-hexahydro-
1-hydroxy-6-6-dimethyl-9H-dibenzol). It is avail-
able as an oral capsule of 1 mg.10 It is a racemic mix-
ture consisting of (S,S)-(+)- and (R,R)-(-)-isomers.
Nabiximol (oromucosal cannabindiol, Sativex®,
GW Pharmaceuticals, Wiltshire, UK)
Nabiximol combines THC plus other cannabi-
noids, including cannabidiol (CBD) along with
Vol. 84 - No. 8 Minerva Anestesiologica 957
others. The product is formulated to be deliv-
ered as an oral spray absorbed in the buccal cav-
ity, either under the tongue or inside the cheek.
Available dosages are 10, 20, 30, and 50 mL.11
Sativex is not currently approved in the USA, but
is available in Mexico and in many European na-
tions.
THC tablet (Namisol®, Echo Pharmaceuticals,
Leiden, The Netherlands)
Namisol® is a tablet containing ≥98% botanical
THC delivered as an oral tablet. In this formula-
tion, it may offer optimized pharmacokinetic and
pharmacodynamic effects over botanical mari-
juana.12
Ajulemic acid (Corbus Pharmaceuticals, Norwood,
MA, USA)
Ajulemic acid (AJA, sometimes called CT3) is a
synthetic form of THC based on the modification
of a non-psychoactive THC metabolite to create
1,1-dimethylheptyl-Δ8-THC-11-oic acid.13
Others
AZD 1940, a novel peripherally acting cannabi-
noid CB-1 receptor agonist, entered Phase I de-
velopment in late 2007, but developmental work
was discontinued in 2009.14
Painful conditions
Cannabinoids have been evaluated in a variety of
different painful conditions with mixed and even
confusing results (Table I). In addition to anal-
gesia, cannabinoids may help reduce anxiety,15
restore healthful sleep,16 and enhance mood,17 all
of which may contribute to better pain control.
Allodynia
A THC/CBD endocannabinoid system modula-
tor was evaluated in a five-week, randomized,
double-blind, placebo-controlled, parallel-design
study.18 Patients were on a stable analgesic regi-
men upon enrollment into the study which they
continued. Patients were randomized to THC/
CBD or placebo and allowed to self-titrate their
medication. Patients in the THC/CBD group had
significantly greater reductions in pain intensity
 ©
or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access COPYRIGHT 2018 EDIZIONI MINERVA MEDICA
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This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically

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PERGOLIZZI CANNABINOIDS IN PAIN CONTROL

Table I.—An overview of the studies discussed in the following sections. Note that the darker the box in the “snap-
shot” column, the greater degree of pain relief.
Number of related Product(s) included
Condition studies included in Results Snapshot
in this section
review (patients)
Allodynia 1 (N.=125) Oromucosal spray The spray significantly reduced pain and Reduced pain
improved allodynia compared to placebo
Cancer pain 4 (N.=539) Oromucosal spray (3 Mixed results; no benefit over placebo in head Modest benefits
studies), nabilone (1 and neck cancer patients, modest results in
study) end-of-life patients as add-on analgesia with
opioids
Chronic noncancer 4 (N.=288) Botanical (1), liquid All studies resulted in significant Reduced pain
pain THC (1), dronabinol improvements in pain
(1), nabilone (1)
Dental pain 1 (N.=123) Novel CB-2 receptor GW-842166 did not significantly reduce pain No, ibuprofen
agonist GW-842166 versus placebo, although ibuprofen (two works better
doses of 400 mg each) did
Experimental pain 5 (N.=95) Nabilone (2), cannabis In most studies, cannabinoids offered no No or very
extract, botanical, analgesic benefit over placebo; a modest limited effect
oral THC (1 study analgesic effect was found with 4% THC
each) botanical marijuana but not with 2% of 8%
THC botanical marijuana
Fibromyalgia 2 (N.=69) Nabilone (2) One study showed a significant decrease in Mixed results
pain, the other did not
Headache 1 (N.=26) Nabilone Nabilone was more effective than ibuprofen Reduced
for reducing medication-overuse headache pain versus
pain and helped reduce dependence on ibuprofen
medication
Neuropathy 18 (N.=1,706) Botanical (8), Cannabinoids relieve pain significantly better Reduced
oromucosal (4), than placebo but not as well as codeine and pain versus
nabilone (3), AJA not superior to diphenhydramine placebo
(2), dronabinol (1)
Postoperative pain 2 (N.=81) Nabilone (1) and oral Cannabinoids did not reduce pain No effect
THC (1) significantly more than placebo
Visceral pain 2 (N.=89) Oral THC (2) Cannabinoids did not reduce pain No effect
significantly more than placebo

scores than placebo patients along with improve-
ments in the Neuropathic Pain Scale, the Sleep
NRS, and dynamic allodynia and punctate allo-
dynia scores.18
Cancer pain
Nabilone was evaluated in a randomized, dou-
ble-blind, placebo-controlled study for managing
symptoms associated with head and neck cancer
and was not better than placebo.19 In a two-week
open-label study of cancer pain patients at end
of life who had inadequate opioid analgesia,
pain severity scores and “worst pain” domains
decreased significantly with the THC oromuco-
sal spray; in addition, insomnia and fatigue im-
proved significantly over baseline.20
In a study of nabiximol in cancer patients
on opioid therapy with poorly controlled pain,
patients were randomized to graded doses of
nabiximol (1-4, 6-10, or 11-16 sprays per day) or
placebo and treated over five weeks (N.=263).21
The proportion of patients in each group who
achieved a 30% reduction in pain intensity was
similar among all groups but in a secondary con-
tinuous responder analysis of average daily pain
versus baseline, nabiximol patients had signifi-
cantly better pain control (P=0.035), particularly
in the low-dose (P=0.008) and medium-dose
(P=0.039) groups.21 This suggests a potential
“ceiling effect” of cannabinoid analgesia.
In a two-week, double-blind, randomized, pla-
cebo-controlled, parallel-group study of terminal
cancer patients with moderate to severe cancer
pain (previously taking strong opioids) patients
were assigned to receive oromucosal cannabi-
noid (THC/CBD), oromucosal THC extract, or
placebo; patients were followed at seven to 10

958 Minerva Anestesiologica August 2018

 ©
or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access COPYRIGHT 2018 EDIZIONI MINERVA MEDICA
cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
CANNABINOIDS IN PAIN CONTROL PERGOLIZZI
days and then at the end of the study (14 to 20
days).22 The pump device was set up to deliver
100 µL per pump activation, resulting in a dose
of 2.7 mg THC and 2.5 mg CBD for the TCH/
CBD group or 2.7 mg THC for the THC group.
Patients could self-titrate their dose with a maxi-
mum of eight pumps permitted in any three-hour
period or 48 actuations in any 24-hour period.
Pain was significantly reduced versus placebo
for the THC/CBD group, but not for the THC-
alone group (P=0.024 and P=0.204, respective-
ly). About twice as many patients in the THC/
CBD group (43%) had reduced pain by at least
30% compared to the THC group (23%) and
placebo (21%). No significant differences were
observed with respect to the use of rescue medi-
cation.22
Chronic noncancer pain
The COMPASS trial was designed to evaluate
the safety of botanical marijuana in the treatment
of chronic noncancer pain syndromes.23 A stan-
dardized botanical product (12.5% THC) was
dispensed to chronic nonmalignant pain patients
(N.=215) and controls (N.=216) over a year with
primary endpoints related to safety. Median daily
dose in the cannabis group was 2.5 g/day; pa-
tients could smoke, vaporize, or take cannabis
orally. The rate of serious adverse events was
similar between groups, but marijuana users had
a significantly higher rate of non-serious adverse
events (incidence rate ratio 1.73, 95% confi-
dence interval [CI], range 1.41 to 2.13). In this
study, cannabis patients exhibited a significant
reduction in average pain intensity over one year
(change 0.92, 95% CI, range 0.62 to 1.23) ver-
sus control patients (change 0.18, 95% CI, range
-0.13 to 0.49).23
Thirteen chronic noncancer pain patients ad-
ministeredoral THC completed a questionnaire.24
Patients were asked to self-report the effect size
of several domains: total pain, ability to carry
out everyday activities, social activities, dealing
with pain, analgesic use, quality of sleep, quality
of mood, and appetite. Each domain was scored
on a scale of 0 to 10 and the total reported score
was the sum of all eight domains. A maximum
score of 80 was possible; a maximum score of
32 or more was considered “adequate” response.
Vol. 84 - No. 8 Minerva Anestesiologica 959
Adequate response to treatment was reported by
5/13 patients (38%) taking THC of which 6/13
(46%) reported adverse events.24
In a study of 30 patients on opioid therapy to
manage chronic noncancer pain, patients were
randomized to either 10 or 20 mg of dronabinol
or placebo over the course of three eight-hour
visits.25 The study was designed as a randomized,
single-dose, double-blind, placebo-controlled,
crossover trial. Dronabinol patients had signifi-
cantly decreased pain intensity and increased pa-
tient satisfaction compared to placebo patients;
there was no difference in analgesic response
between the dronabinol 10 and 20 mg groups.25
A randomized, controlled trial of 30 patients
with chronic nonmalignant pain was designed as
a double-blind pilot study divided into a 14-week
cross over period (two four-week medication
phases plus washout periods); this study was then
followed by a 16-week observational course dur-
ing which patients could select Drug A or Drug
B.26 Patients were administered nabilone (1 mg
tablets with the option of taking a maximum of
4 per day) or placebo. Nabilone significantly de-
creased pain compared to placebo and more than
four times as many patients opted to continue the
study with nabilone instead of placebo (≥85% of
patients). Patients in this study had a variety of
chronic pain syndromes including back pain and
headache.26
Dental pain
Acute pain associated with third-molar extrac-
tion was evaluated in a randomized, placebo-
controlled study of a novel CB-2 receptor ago-
nist (GW-842166) at doses of 100 or 800 mg
versus ibuprofen 400 mg and placebo.27 Patients
received the drug about an hour before dental
surgery; ibuprofen patients were administered
a second dose of 400 mg ibuprofen about four
hours later. Ibuprofen was significantly more ef-
fective than placebo for relieving pain, and of-
fered better duration of analgesia, proportion of
patients requiring rescue medication, and time
elapsed to the need for rescue medication. When
rescue medication was requested, there was no
evidence that the coadministration of rescue an-
algesic plus GW-842166 offered any beneficial
additive effect.
 ©
or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access COPYRIGHT 2018 EDIZIONI MINERVA MEDICA
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This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
PERGOLIZZI CANNABINOIDS IN PAIN CONTROL
Experimental pain
A randomized, double-blind, placebo-controlled,
crossover study in 30 healthy men involved sin-
gle doses of nabilone (1, 2, and 3 mg) and visual
analog scale (VAS) measurement of pain intensi-
ty after intradermal injections of capsaicin in the
forearm.28 Capsaicin cream was applied topically
to the calf to induce experimental hyperalgesia.
Pain and hyperalgesia were measured at baseline
and then two to three-and-a-half hours after dos-
ing. CNS effects were evaluated at baseline and
24 hours after dosing based on a VAS mood scale
that described feelings of being “stimulated,”
“anxious,” “sedated” or “down.” In this study of
experimentally induced pain, nabilone did not
significantly reduce primary pain or secondary
(hyperalgesic) pain, although dose-dependent
CNS effects occurred from about 90 minutes to
six hours after dosing. No analgesic or antihy-
peralgesic effects were observed with nabilone
in this population.28
In a double-blind, crossover study of 18
healthy women, pain was induced by creating
a circular sunburn region on one upper leg and
patients were randomized to receive cannabis
extract in an oral capsule or placebo.29 Heat and
electrical pain thresholds were determined at the
erythema, the area of secondary hyperalgesia,
and the contralateral leg. Intradermal capsaicin
was used to evoke pain and flare. No analgesic
or antihyperalgesic activity was observed with
cannabis over placebo.29 In a double-blind, pla-
cebo-controlled, crossover study single doses of
nabilone (0.5 and 1 mg) conferred no analgesic
benefit in a study of experimental heat pain.30
Intriguingly, this study found nabilone produced
better results in women and was associated with
an antihyperalgesic effect that was not evident
for men.30
In a randomized, double-blind, placebo-con-
trolled, crossover study of 15 healthy volunteers,
low-dose (2% THC), medium-dose (4% THC),
and high-dose (8% THC) marijuana was smoked
and intradermal capsaicin was used to create
cutaneous hyperalgesia; 5 and 45 minutes after
smoking the marijuana, patients were injected
in the forearm with capsaicin.31 Control patients
were given placebo cigarettes. At 45 minutes af-
960 Minerva Anestesiologica August 2018
ter smoking, there was a significant decrease in
capsaicin-induced pain with the medium dose,
no change with the low dose, and a concomitant
significant increase in capsaicin-induced pain
with the high dose. This study suggests that not
only is there a ceiling effect for analgesia, but
that there may be a therapeutic window for dos-
ing smoked marijuana for effective pain relief.31
In a study of experimental pain, neither oral
THC 20 mg nor oral THC combined with mor-
phine (20/30 mg, respectively) showed signifi-
cant analgesic effect for pressure and heat testing
but THC plus morphine showed a slight analge-
sic effect for experimental electrical pain.32
Fibromyalgia
A double-blind, placebo-controlled trial of fibro-
myalgia patients (N.=40) randomized patients
into two groups: nabilone versus placebo.33
Nabilone patients started with 0.5 mg orally at
bedtime and were titrated up to 1 mg twice daily
over four weeks. The nabilone patients showed a
significant decrease in VAS pain scores and anxi-
ety pain scores at four weeks (VAS for pain was
-2.04, P<0.02) over baseline; no significant im-
provements occurred in the placebo group. Sig-
nificantly more side effects occurred in the nabi-
lone group at two and four weeks versus placebo
(P<0.02 and P<0.05, respectively).33
Pain was a secondary endpoint in a double-
blind, active-control, equivalency crossover
study designed to compare nabilone (0.5 to 1.0
mg before bedtime) to amitriptyline (10 to 20
mg before bedtime) in 29 fibromyalgia patients
suffering chronic insomnia.34 Sleep parameters
improved in both groups with nabilone emerging
superior to amitriptyline for insomnia. While this
is an important finding and may relate indirectly
to pain symptomology, neither agent was effec-
tive specifically in relieving pain.34
In a Cochrane review of drugs for fibromyal-
gia pain, two studies of cannabinoids were iden-
tified (N.=72) but deemed to be at moderate risk
of bias and presenting equivocal results.35
Headache
Medication-overuse headache or rebound head-
aches occur in chronic headache patients (par-
 ©
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cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
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CANNABINOIDS IN PAIN CONTROL PERGOLIZZI
ticularly but not exclusively in migraineurs) and
resist conventional treatments. In a randomized,
double-blind, active-controlled, crossover study
comparing nabilone 0.5 mg/day to ibuprofen 400
mg/day over eight weeks followed by a one-week
washout and crossover, 26 medication-overuse
headache patients found nabilone more effec-
tive than ibuprofen in reducing pain intensity
(P<0.05), daily analgesic consumption (P<0.05)
as well as better quality of life.36 Furthermore,
nabilone significantly reduced patients’ depen-
dence on their problematic medication (-41%,
P<0.01).36
Neuropathy
Neuropathic pain involves aberrant signaling
and is considered maladaptive;37 it can be chal-
lenging to control pharmacologically.38 Neu-
ropathy may be primary or secondary to another
condition, such as diabetes mellitus type 2. Many
chronic painful conditions, such as chronic low
back pain, have a neuropathic component.
In a randomized, double-blind, placebo-con-
trolled, crossover study, 39 patients with central
or peripheral neuropathic pain were randomized
into three groups for consumption of vapor-
ized botanical marijuana: medium-dose (3.53%
THC marijuana), low dose (1.29% THC), or
placebo marijuana.39 Patients took four to eight
puffs and were monitored over five hours. Pain
was assessed using a 100-mm VAS, the Patient
Global Impression of Change (PGIC) to as-
sess pain relief, and the Neuropathic Pain Scale
(NPS), an eleven-point VAS scale with pain de-
scriptors relevant to neuropathy. When present,
allodynia was measured using a 100-mm VAS.
Patients were monitored for adverse events and
asked about subjective perceptions of psycho-
active drug properties. Patients in the medium-
dose (61%) and low-dose (57%) groups reported
a 30% reduction in pain intensity versus base-
line, compared to 26% in the placebo group. The
difference between active groups and placebo
achieved statistical significance (P=0.0069 for
placebo vs. low-dose and P=0.0023 for placebo
vs. medium-dose) but there was not statistically
significant difference between the low-dose and
medium-dose cannabinoid groups. The number-
needed-to-treat (NNT) to achieve a 30% pain
Vol. 84 - No. 8 Minerva Anestesiologica 961
reduction was 3.2 for placebo vs. low-dose and
2.9 for placebo versus medium-dose, but was
25 for medium-dose vs. low-dose. Pain relief
as measured on the PGIC showed active-group
patients achieving greater pain relief at all time
points (over five hours) compared to placebo.
Side effects were minimal and no patient with-
drew from the study.
In a study of 96 adult neuropathic pain pa-
tients, patients were randomized to maximum
doses of either dihydrocodeine 240 mg or nabi-
lone 2 mg. At 14 weeks, dihydrocodeine offered
greater pain control than nabilone and had fewer
side effects.40
A randomized, double-blind, placebo-con-
trolled crossover study of 16 patients with pain-
ful diabetic neuropathy treated with four single-
dose session of either placebo or cannabis (1%,
4%, and 7% THC groups) found significant
dose-dependent differences in spontaneous pain
scores between doses (the difference between
high-dose versus low-dose cannabis and the dif-
ference between high-dose versus medium-dose
cannabis were both P<0.001).41
Add-on nabilone was evaluated in a single-
center, randomized, double-blind, placebo-con-
trolled, flexible-dose (1 to 4 mg/day) study in pa-
tients with diabetic peripheral neuropathic pain
who had inadequate pain control with conven-
tional medications.42 Nabilone significantly re-
duced pain versus placebo over four weeks at an
average dose of 2.9±1.1 mg/day.42 Nabilone was
also evaluated in peripheral neuropathy patients
in a six-month open-label study.43 The pharmaco-
logical regimens of patients were assessed; those
who had not taken pain medication either served
as the control group (some patients rejected pain
relievers) or received gabapentin or nabilone as
monotherapy. For patients on drug therapy for
pain, the therapy was documented and patients
were offered gabapentin or nabilone as add-on
therapy. The decision about whether to add gaba-
pentin or nabilone to the existing pharmacologi-
cal regimen was made by the patient and physi-
cian together. Dosing was flexible. Patients were
monitored at baseline, one-week later by phone
interview, then at three- and six-month intervals
at in-clinic visits. For monotherapy patients, pa-
tients treated with either gabapentin or nabilone
 ©
or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access COPYRIGHT 2018 EDIZIONI MINERVA MEDICA
cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
PERGOLIZZI CANNABINOIDS IN PAIN CONTROL
showed significant improvement in VAS pain
scores at three and six months over baseline and
also had significant improvements at six months
versus three months. In the adjuvant group, gaba-
pentin significant improved VAS scores after six
months but not at three months; nabilone patients
showed significant improvement at three and six
months and six months versus three months.43
In a study of seven adults with neuropathic
pain secondary to spinal cord injury, patients
were administered either dronabinol or diphen-
hydramine in a randomized, double-blind, cross-
over, controlled group study.44 Diphenhydramine
was chosen for the control group because it does
not have analgesic properties but it mimics some
of the possible adverse events associated with
dronabinol. Rescue medication (oxycodone/
acetaminophen 5/325 mg, up to eight tablets in
24 hours) was available to both groups. Pain re-
lief was not significantly different between the
dronabinol and diphenhydramine groups; side
effects in both groups were similar (dry mouth,
constipation, fatigue, drowsiness).44
Botanical cannabis to be taken three times
a day through a pipe (25 mg) was evaluated in
adults with chronic neuropathic pain secondary
to surgery or trauma.45 In this randomized con-
trolled trial (N.=21), patients were randomized to
receive one of three potencies of cannabis 2.5%,
6%, and 9.4% or placebo (0 THC). At the high-
est potency, average daily pain intensities on VAS
were significantly lower than placebo (0% THC),
but lesser potencies did not confer on patients a
statistically significant improvement. Further-
more, the group receiving 9.4% THC cannabis
reported significantly better sleep and improved
ability to fall asleep versus the control group, but
there were no differences among groups for mood
or quality of life.45 In a randomized, double-blind,
placebo-controlled crossover study of 38 patients
with central and peripheral neuropathy, patients
were randomized to get high-dose (7%) or low-
dose (3.5%) botanical marijuana cigarettes or pla-
cebo.46 No difference was observed in pain im-
provement between high-dose and low-dose mar-
ijuana and both offered significantly better pain
control than placebo (P=0.016). This study also
evaluated “pain unpleasantness” or the patient’s
emotional response to pain; pain was more toler-
962 Minerva Anestesiologica August 2018
able at higher cumulative doses of cannabis than
placebo (P<0.01).46 The time at which results of
the marijuana smokers and the placebo patients
separated was about 120 minutes after smoking.
In a controlled, crossover study, 21 patients
with chronic neuropathic pain for longer than
six months were randomized to two seven-day
courses of treatment: two daily doses of a syn-
thetic cannabinoid analog (1’,1’dimethylheptyl-
Δ8-tetrahydrocannabinol-11-olic acid;CT-3) for a
total of 40 mg per day or placebo.47 Pain inten-
sity on VAS was significantly lower for CT-3 pa-
tients compared to placebo patients three hours
after intake of the drug (P=0.02) but the effect
diminished at eight hours. CT-3 patients also re-
ported more adverse events than placebo patients
(P=0.02), the most frequent of which were dry
mouth and fatigue.47
Neuropathic pain secondary to HIV can be
challenging to treat. In a double-blind, placebo-
controlled crossover trial, 127 HIV patients with
neuropathic pain were randomized to placebo
groups or botanical cannabis (potency ranged
from 1% and 8% THC) four times daily for five
consecutive days in two-week treatment phases
separated by a two-week washout.48 Patients who
entered the study on pharmacological regimens
for pain control could continue with them and add
on cannabis. Both cannabis groups had greater
degrees of pain relief than placebo (P=0.016) and
46% of the cannabis groups achieved at least 30%
pain reduction compared to 18% in the placebo
group.48 In a prospective, randomized, placebo-
controlled study, 50 HIV patients with painful
neuropathy were assigned to smoke marijuana
(3.56% THC) or placebo cigarettes three times a
day for a course of five days.49 Smoked cannabis
significantly reduced daily pain versus placebo,
34% vs. 17%, respectively (P=0.03). More than
half of the cannabis patients (52%) achieved at
least a 30% reduction in pain compared to about
a quarter of the placebo group (24%), P=0.04.
The first marijuana cigarette reduced chronic
pain by a median of 72% compared to 15% with
the placebo cigarette (P=0.04). In addition, can-
nabis was able to reduce experimentally provoke
hyperalgesia but did not relieve pain in an experi-
ment using a noxious heat stimulus.49 In a survey
of HIV-positive individuals (N.=523), 27% said
 ©
or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access COPYRIGHT 2018 EDIZIONI MINERVA MEDICA
cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
CANNABINOIDS IN PAIN CONTROL PERGOLIZZI
they used cannabis (whether or not prescribed) to
manage symptoms, including nerve pain (90%),
paresthesia (85%), and muscle pain (94%) as well
as other symptoms such as loss of appetite (97%)
and nausea (93%).50 Of those who used marijua-
na to manage these symptoms, 47% reported a
deterioration of memory function. Men were sig-
nificantly more likely than women to report us-
ing marijuana to manage symptoms (P<0.01). Of
the cannabis users, 71% smoked marijuana as the
sole route of administration, 20% only ingested it
in food, and the balance used both routes. Most
of those who used cannabis reported using it dai-
ly (55%) and 24% of users reported smoking four
or more times per day. In the HIV patients in this
survey who reported having pain (45%), 94%
said cannabis offered symptomatic pain relief.50
Neuropathic pain associated with brachial
plexus root avulsion was studied in 48 patients
(baseline pain score 4/11) who were random-
ized in a double-blind, placebo-controlled, three-
period crossover study.51 All patients were on a
pharmacological analgesic regimen but had in-
adequate pain control. Patients entered a baseline
period (two weeks), followed by three two-week
treatment periods during which they received
one of three oromucosal spray preparations: an
oromucosal formulation of whole plant extract
with about a one-to-one ratio of THC to CBD;
a whole plant extract of Cannabis sativa (GW-
2000-02), containing primarily THC; or placebo.
The primary endpoint, pain intensity reduction,
was significantly lower than baseline overall, but
failed to drop by two points as the study’s hy-
pothesis predicted.51
Oromucosal THC spray was evaluated in an
open-label follow-on study over 38 weeks in 234
patients with neuropathic pain.52 As measured
on a numeric rating scale, pain intensity scores
decreased over baseline and the proportion of
patients who achieved at least a 30% reduction
in pain increased over time up to about nine
months; at least half of them achieved a 30% im-
provement at all points in time.52 The spray was
also evaluated in 303 patients with treatment-re-
sistant peripheral neuropathic pain with allodyn-
ia with significantly more THC spray patients
achieving at least 30% pain relief than placebo
patients (P=0.034).53
Vol. 84 - No. 8 Minerva Anestesiologica 963
In a study of a thermal-metered dose inhaler
for botanical cannabis (N.=8) for treating neu-
ropathic pain, a 45% reduction in pain intensity
was reported about 20 minutes after inhalation
(P=0.001) but pain returned to baseline levels in
about 90 minutes.54
A pilot study in 16 patients with chemothera-
py-induced peripheral neuropathy (CIPN) evalu-
ated an oral mucosal THC spray versus placebo
in a randomized design.55 Pain reduction on a
numeric rating scale was similar between groups
with a number-needed-to-treat (NNT) for pain
relief of five. The average decrease in pain inten-
sity for placebo patients was 0.6 but in respond-
ers (5/11 were deemed responders), the decrease
averaged 2.6.55
Ajulemic acid (AJA), a synthetic form of can-
nabinoid, was evaluated in a double-blind, cross-
over clinical trial in chronic neuropathic pain
patients.56 Patients were randomized into AJA
(40 mg for the first four days and then 80 mg for
the next three days) or placebo groups. At seven
days, AJA did not offer significant relief of me-
chanical hypersensitivity pain, but the VAS score
showed significant pain reduction with AJA ver-
sus placebo (P=0.021) and the NNT to obtain
30% improvement in pain relief were 2.14 and
5.29 for AJA 40 mg and AJA 80 mg, respective-
ly. NNT to obtain a 50% improvement were 9.00
(AJA 40 mg) and 10.0 (AJA 80 mg).56
Postoperative pain
Nabilone was evaluated in a double-blind, place-
bo-controlled, parallel-group study in which 41
patients were randomized to receive nabilone 1
mg, nabilone 2 mg, ketoprofen 50 mg, or pla-
cebo every 8 hours for the first 24 hours after sur-
gery (mostly gynecologic and orthopedic opera-
tions).57 All patients had access to patient-con-
trolled analgesia (PCA) morphine. Pain scores
at rest and pain on movement were significantly
higher in the nabilone 2 mg group than the other
groups.57 In a double-blind, placebo-controlled,
single-dose study, 40 women undergoing elec-
tive abdominal hysterectomy were randomized
to receive either oral THC 5 mg or placebo on
day 2 after surgery (following patient-controlled
analgesia on day 1).58 In this study, THC did
not offer any analgesic benefit over placebo, al-
 ©
or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access COPYRIGHT 2018 EDIZIONI MINERVA MEDICA
cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
PERGOLIZZI CANNABINOIDS IN PAIN CONTROL
though THC patients reported they were more
aware of their surroundings (40% vs. 5%, respec-
tively, P=0.04).58
Visceral pain
In a randomized, single-dose, double-blinded,
placebo-controlled, two-way crossover study in
24 patients with acute pancreatitis, a single dose of
8 mg THC or active placebo (5 or 10 mg of diaze-
pam) was well tolerated but did not reduce pain.59
In a placebo-controlled study, 65 patients with
chronic abdominal pain (secondary to chronic
pancreatitis or chronic postabdominal-surgery
pain) were randomized to receive THC (3 mg
three times a day for five days, then 5 mg three
times a day for five days, followed by a main-
tenance dose of 8 mg three times a day up until
days 50-52) or placebo while maintaining their
current pharmacological regimens, including
other analgesics.60 Oral THC was well absorbed
and tolerated but at days 50-52 of the study, THC
did not relieve pain better than placebo. The dif-
ference between VAS scores at the start and cul-
mination of the study decreased by a mean value
of 1.6 and 1.9 points, for the THC and placebo
patients (not significant).60
Cannabinoids combined with opioids
In many of the studies reviewed above, cannabi-
noids were sometimes used as add-on therapy to
a stable analgesic regimen which may have in-
volved opioid therapy. Cannabinoids and opioids
both offer antinociception by acting along sepa-
rate but related pathways. Receptors for these
two classes of drugs rely on similar intracellular
signaling mechanisms and lead to a decrease in
cyclic adenosine monophosphate production due
to G-protein activation.61, 62 Cannabinoids may
increase the release of endogenous opioids.63
Evidence for synergistic pain-relieving benefits
have been confirmed in a study of 24 chronic
pain patients taking sustained-release morphine
or oxycodone and supplemented with vaporized
cannabis over a five-day study.64 The cannabi-
noids did not alter the pharmacokinetic behav-
ior of the opioids and pain was significantly de-
creased by an average of 27% with the addition
of vaporized cannabis over opioid monotherapy.
964 Minerva Anestesiologica August 2018
In a study of 100 radical prostatectomy pa-
tients with regional lymphadenectomy treated
with mu-opioid agonist piritramide, neither an
additive nor a synergistic analgesic benefit could
be observed with the addition of dronabinol 5 mg
on the first and second day following surgery.65 In
a double-blind, four-treatment, crossover study
of experimental pain in 13 healthy volunteers,
patients were randomized to one of four groups:
THC plus morphine, THC plus placebo, placebo
plus morphine, and placebo plus placebo.66 THC
was provided in the form of Marinol 5 mg; mor-
phine was administered as a 0.2 mg/kg IV bolus.
Placebo was available in pill form or as a saline
IV bolus. At the doses used in this study, neither
agent as monotherapy had a significant analgesic
effect versus placebo, but a synergistic analgesic
effect between THC and morphine was noted.66
Discussion
Cannabinoids are likely to play an increasingly
greater role in modern medicine, which may in-
clude pain control. However, cannabinoids pres-
ent to clinicians not only mixed results in terms
of analgesia but aspects that may be described as
the good, the bad, and the ugly.
The good
Marijuana appears to reduce pain intensity in
many (but not all) painful conditions. This is par-
ticularly evident in the treatment of neuropathic
pain syndromes which are very challenging to
manage using conventional pharmacological
treatments. Furthermore, evidence suggests a
possible ceiling effect for pain control, such that
low-dose THC treatments may be quite effective
in this neuropathic population.39
Tolerance with prolonged exposure does not
appear to be an issue with cannabinoids. No ap-
parent increase in tolerance occurred in a long-
term, neuropathic pain patient study using an
oromucosal spray.52 In a study of terminal cancer
patients who failed to achieve adequate analgesia
with opioid therapy, self-titration of THC spray
reduced pain significantly, and did not result in
patients trying to increase their dose of THC
or in seeking other pain-relieving agents.20 In a
study of MS patients with chronic central neuro-
 ©
or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access COPYRIGHT 2018 EDIZIONI MINERVA MEDICA
cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
CANNABINOIDS IN PAIN CONTROL PERGOLIZZI
pathic pain, long-term use of oromucosal THC/
CBD was associated with significant pain relief
and no tolerance over two years.67
Adverse events were reported in these studies
(most of which were short term), but these events
were typically mild to moderate and well toler-
ated by the patients.
Medical marijuana may bring with it the ad-
ditional benefit of lowering prescription opioid
overdose mortality. Based on data from 1999 to
2010, United States laws allowing for the medi-
cal use of marijuana can be associated with sig-
nificantly lower opioid overdose mortality rates
by state.68 This statistical effect persisted even
when opioid overdose deaths due to heroin were
included.68 Potential reasons for this association
have been proposed. Pain patients, even those
with indications for opioids, may prefer to use
marijuana. People in pain without healthcare
system access or financial resources may find
marijuana a safer, easier, and more cost-effective
way to self-medicate their pain compared to buy-
ing opioids from the street market. Finally, the
use of marijuana may reduce pain to the point
that patients with legitimate opioid prescriptions
may not need to take opioids as often. Moreover,
it has been speculated that marijuana may be
helpful in managing opioid withdrawal symp-
toms and the transition away from opioids.69, 70
In theory at least, this means that some opioid
abusers may be able to self-manage their own
rehabilitation without resorting to official treat-
ment centers (which are not always accessible to
them and can be expensive). There also may be
recreational polydrug abusers who opportunis-
tically take a variety of drugs, from opioids to
marijuana, and the availability of high-potency
marijuana offers users a vastly cheaper, less dan-
gerous, more legal, and comparably durable high
compared to opioids. This area warrants further
study.
The bad
In studies in which patients smoked botani-
cal marijuana, many reported that they felt its
well-known psychoactive effects, which not all
patients reported as pleasant.39 In a randomized,
single-dose clinical trial, chronic noncancer pain
patients on opioid therapy were assigned to 10
Vol. 84 - No. 8 Minerva Anestesiologica 965
mg or 20 mg dronabinol group or a placebo and
compared to participants smoking botanical
marijuana with THC levels of 1.99% and 3.51%.
This study found dronabinol had similar psycho-
active effects on patients as smoking a marijuana
cigarette.71 Thus, new formulations of cannabi-
noids may still be associated with psychoactive
properties.
The use of marijuana may also be associated
with cognitive impairment, difficulty in learning,
and memory deficits. In a study of neuropathic
pain, patients reported some of these effects but
found them transient and tolerable in light of the
analgesic benefits.39 It has been speculated that
frequent users develop tolerance to cognitive ef-
fects,72 but further study is needed. In a survey
of HIV-positive individuals who used marijuana
to control neuropathic pain (N.=523), about half
(47%) reported impaired memory.50
Emerging evidence has implicated cannabis
with psychosis and psychotic disorders, includ-
ing but not limited to schizophrenia.73 Early, ex-
cessive exposure to cannabis has been linked to
development of a psychotic disorder in a dose-
dependent fashion.74 However, this is not to say
that cannabis causes psychosis. In individuals
with pre-existing schizophrenia, cannabinoids
may transiently worsen symptoms, precipitate
relapse, or have other negative consequences.75-77
It goes beyond the scope of this review to dis-
cuss the potential role of marijuana in impaired
driving and traffic accidents. However, there is
possible that the more widespread acceptance of
medical and recreational marijuana may result in
more cases of driving under the influence and as-
sociated morbidity and mortality.
The ugly
The laws regarding the medical and recreation-
al marijuana use are in flux, and these changes
make it unclear what role cannabinoids can play
— or will play — in the treatment of pain. In
the U.S., for example, marijuana is illegal at the
federal level but some states have chosen to “le-
galize” its use and the federal government — at
least so far — has declined to prosecute. Thus, in
the U.S., marijuana is technically not legal, but
is widely used and is often described as legal.78
A similar situation exists in India. In Germany,
 ©
or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access COPYRIGHT 2018 EDIZIONI MINERVA MEDICA
cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
PERGOLIZZI CANNABINOIDS IN PAIN CONTROL
marijuana is largely legal but heavily regulated;
in neighboring France, marijuana is mostly il-
legal. In Spain, marijuana may be consumed
legally in private but not in public and Span-
ish citizens may grow marijuana for their own
consumption providing the plants are not visible
from a public place. In Sweden and Switzerland,
marijuana is illegal, even for medical purposes.
In Colombia, up to 20 plants are permitted for
individual consumption but marijuana can only
be legally consumed for medical or scientific
purposes. Marijuana is unrestrictedly legal in
Uruguay78 and North Korea.79 Some nations
have no penalties for marijuana use but attach
penalties to its possession. These notations are
not intended to be exhaustive but to underscore
the fact that it may at times be difficult for clini-
cians and their patients to know what is legal and
what is not legal.
Since the legal status of marijuana in many
parts of the world is evolving, inconsistent, and
sometimes difficult to understand, some pain pa-
tients may eschew marijuana in favor of other
analgesics because they do not want to violate
any laws, even unwittingly. Other patients may
reject marijuana as a dangerous drug, due to their
own incomplete understanding of its emerging
role in analgesia. Clinicians may harbor some
of the same prejudices against marijuana as their
patients.
In many communities, even appropriate can-
didates may find medical marijuana difficult to
obtain, either because of prevailing laws, their
own confusion about those regulations, and pos-
sibly even a reticence to initiate the discussion
about marijuana with their healthcare provid-
ers. Resourceful pain patients willing and able
to buy street marijuana may already be using it
as a sort of natural “home remedy.” Anecdotal
reports suggest that many patients obtain mari-
juana on their own to help manage pain or other
pain-related symptoms in order to sleep better,
cope with stress, and manage anxiety.
Conclusions
Cannabinoids play an increasingly important
role in clinical care and in patient’s self-medi-
cation, particularly in the treatment of various
966 Minerva Anestesiologica August 2018
pain syndromes. Medical marijuana offers some
positive benefits in pain treatment, particularly
for neuropathic pain. It appears to be ineffective
in treating acute pain. However, its murky legal
status in some regions and its potential for psy-
choactive effects may limit its utility, although
the lack of psychoactive effects of cannabindiol
might distinguish this compound.
Key messages
•  Marijuana appears to have a variety of
medicinal uses, but results from studies ex-
ploring pain control with cannabinoids are
mixed. Cannabinoids appear to be effective
in treating neuropathic pain, allodynia, med-
ication-rebound headache, and certain types
of chronic noncancer pain, but they are less
or not effective in treating acute pain.
•  Clinicians should be aware that some
studies evaluate botanical cannabinoids
(which may be smoked, vaporized, or ingest-
ed with food) while others study synthetic
cannabinoids. Among the synthetic canna-
binoids are dronabinol, nabilone, nabiximol,
THC tablets, and ajulemic acid. Thus, it is
often difficult to compare studies as they may
use different forms of “cannabis.”
•  A few studies have evaluated the use of
cannabinoids as add-on therapy to combine
with opioids. Cannabinoids and opioids use
separate but related pathways and they may
have an opioid-sparing effect. In the United
States, early data suggest that where medi-
cal marijuana is permitted for pain control,
opioid mortality decreases, even when heroin
overdoses are included.
•  Prolonged exposure to cannabinoids for
pain control does not appear to be associated
with tolerance. However, long-term use has
been associated with cognitive deficits, learn-
ing difficulties, and memory problems.
•  The laws regarding medical marijuana
are currently in a state of flux and many po-
tential patients may be unable to obtain pre-
scriptions. Anecdotal reports suggest that
some patients obtain their own marijuana
(possibly illegally) and self-medicate.
 ©
or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access COPYRIGHT 2018 EDIZIONI MINERVA MEDICA
cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
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CANNABINOIDS IN PAIN CONTROL PERGOLIZZI
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Conflicts of interest.—Robert B. Raffa was an Adboard consultant for medical marijuana dispensary.
Group name.—Jo A. LEQUANG, Joseph V. PERGOLIZZI Jr, Robert B. RAFFA, Robert TAYLOR Jr already listed in the authors’
byline also form the NEMA Research Group.
Comment in: Coluzzi F. Cannabinoids in chronic pain management: a skein to be untangled. Minerva Anestesiol 2018;84:893-5. DOI:
10.23736/S0375-9393.18.12701-5.
Article first published online: January 16, 2018. - Manuscript accepted: January 10, 2018. - Manuscript revised: November 15,
2017. - Manuscript received: July 5, 2017.

Vol. 84 - No. 8 Minerva Anestesiologica 969