ArticlePDF AvailableLiterature Review

The Effectiveness of Cannabinoids in the Management of Chronic Nonmalignant Neuropathic Pain: A Systematic Review

Authors:
  • HealthPartners, United States, St. Paul

Abstract and Figures

Aims: To carry out a systematic review to assess the effectiveness of cannabis extracts and cannabinoids in the management of chronic nonmalignant neuropathic pain. Methods: Electronic database searches were performed using Medline, PubMed, Embase, all evidence-based medicine reviews, and Web of Science, through communication with the Canadian Consortium for the Investigation of Cannabinoids (CCIC), and by searching printed indices from 1950. Terms used were marijuana, marihuana, cannabis, cannabinoids, nabilone, delta- 9-tetrahydrocannabinol, cannabidiol, ajulemic acid, dronabinol, pain, chronic, disease, and neuropathic. Randomized placebo-controlled trials (RCTs) involving cannabis and cannabinoids for the treatment of chronic nonmalignant pain were selected. Outcomes considered were reduction in pain intensity and adverse events. Results: Of the 24 studies that examined chronic neuropathic pain, 11 studies were excluded. The 13 included studies were rated using the Jadad Scale to measure bias in pain research. Evaluation of these studies suggested that cannabinoids may provide effective analgesia in chronic neuropathic pain conditions that are refractory to other treatments. Conclusion: Cannabis-based medicinal extracts used in different populations of chronic nonmalignant neuropathic pain patients may provide effective analgesia in conditions that are refractory to other treatments. Further high-quality studies are needed to assess the impact of the duration of the treatment as well as the best form of drug delivery.
Content may be subject to copyright.
Journal of Oral & Facial Pain and Headache 7
Aims: To carry out a systematic review to assess the effectiveness of cannabis
extracts and cannabinoids in the management of chronic nonmalignant
neuropathic pain. Methods: Electronic database searches were performed
using Medline, PubMed, Embase, all evidence-based medicine reviews, and
Web of Science, through communication with the Canadian Consortium for the
Investigation of Cannabinoids (CCIC), and by searching printed indices from 1950.
Terms used were marijuana, marihuana, cannabis, cannabinoids, nabilone, delta-
9-tetrahydrocannabinol, cannabidiol, ajulemic acid, dronabinol, pain, chronic,
disease, and neuropathic. Randomized placebo-controlled trials (RCTs) involving
cannabis and cannabinoids for the treatment of chronic nonmalignant pain were
selected. Outcomes considered were reduction in pain intensity and adverse
events. Results: Of the 24 studies that examined chronic neuropathic pain, 11
studies were excluded. The 13 included studies were rated using the Jadad
Scale to measure bias in pain research. Evaluation of these studies suggested
that cannabinoids may provide effective analgesia in chronic neuropathic pain
conditions that are refractory to other treatments. Conclusion: Cannabis-
based medicinal extracts used in different populations of chronic nonmalignant
neuropathic pain patients may provide effective analgesia in conditions that are
refractory to other treatments. Further high-quality studies are needed to assess
the impact of the duration of the treatment as well as the best form of drug
delivery. J Oral Facial Pain Headache 2015;29:714. doi: 10.11607/ofph.1274
Key words: cannabinoids, chronic nonmalignant pain, management,
neuropathic pain, systematic review
The use of cannabinoids in treating various conditions dates back
thousands of years in Eastern traditional medicine1 and was intro-
duced to Europe in the 1800s.2 The medical use of cannabis fell
from favor in the 1930s and 1940s for a number of reasons, including
the development of more predictable medications.1,2 Over the past sev-
eral decades, there has been a renewed interest in the medical use of
cannabis for a variety of conditions, including pain.3,4 Historically, pain
has been viewed as a symptom of more serious medical conditions,
but more recently chronic pain has itself been regarded as a complex
illness.5,6 Existing nonsteroidal anti-inflammatory drugs are frequently
ineffective, while currently available opioid medications have numerous
adverse effects and are not always effective in specific types of chronic
pain.5
The earliest clinical studies that evaluated the antinociceptive prop-
erties of cannabinoids were limited by an inadequate sample size and
an insufficient assortment of cannabinoids available for use.7 Of the nu-
merous cannabinoids that have been identified in the cannabis plant,
cannabidiol (CBD) and delta-9-tetrahydroxycannabinol (THC) and its
synthetic derivatives are the most active in humans.4
Earlier reviews of the medical use of cannabinoids in pain therapy
have been based on small sample sizes,7–9 did not include adequate
differentiation of the origins of pain syndromes,10 ,11 and lacked identifi-
cation of cannabinoid responders.11 They also have failed to adequately
assess the clinical relevance of effects,12 safety profiles,13 adverse
events,11,14 and long-term consequences,13 although they have generally
The Effectiveness of Cannabinoids in the Management of
Chronic Nonmalignant Neuropathic Pain:
A Systematic Review
Darrell G . Boychuk , DDS , MSc
Clinician
TMD Clinic
Health Partners
Minneapolis/St Paul, Minnesota, USA
Greg Goddard, DDS
Professor
School of Dentistry
University of California, San Francisco
San Francisco, California, USA
Giovanni Mauro, MD, DDS
Visiting Professor
Dental Center
University of Parma
Parma, Italy
Maria F. Orellana, DDS, PhD, MSc
Associate Clinical Professor
School of Dentistry
University of California, San Francisco
San Francisco, California, USA
Correspondence to:
Dr Darrell Boychuk
UCSF School of Dentistry
Box 0438
San Francisco, CA 94143, USA
Email: dgboychuk@gmail.com
©2015 by Quintesse nce Publishing Co Inc.
© 2015 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY.
NO PART MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
8 Volume 29, Number 1, 2015
Boychuk et al
considered cannabinoids to be “promising.10–13 The
most recent systematic review15 included clinical trials
of cannabinoids for chronic neuropathic pain, but also
for chronic (non-cancer) pain related to fibromyalgia,
rheumatoid arthritis, and mixed sources. Furthermore,
it included a trial solely comparing a cannabinoid with
an active control group (dihydrocodeine) and no pla-
cebo control group16 and two trials where pain was
not the primary symptom targeted for each subject.17,18
Moreover, additional studies have been published
since this systematic review, including one that utilized
novel delivery methods19 and two that used enriched
enrollment to study only those patients deemed re-
sponsive to cannabinoid extracts.2 0,21
Therefore, the primary objective of the present
systematic review was to determine the effectiveness
of cannabinoids in the management of chronic non-
malignant neuropathic pain. A secondary aim was to
summarize adverse events, as there appears to be a
degree of contention in regard to their severity.
Materials and Methods
The following terms were used to identify high-quality
articles among the published abstracts:
Human clinical trials
Chronic nonmalignant neuropathic pain
Cannabis or cannabinoids as active agent(s)
A computerized search was then conducted us-
ing PubMed (1966 to April 30, 2013), Embase (1988
to April 30, 2013), Web of Science (1945 to April
30, 2013), and all evidence-based medicine reviews
and databases (Cochrane Database of Systematic
Reviews, ASP Journal Club, Database of Abstracts of
Reviews of Effects [DARE], and Cochrane Controlled
Trials Register [CCTR]) (to April 30, 2013) for can-
nabis/cannabinoids and pain. Terms used in this lit-
erature search were combined as follows: (marijuana
OR marihuana OR cannabis OR cannabinoids OR
nabilone OR delta-9-tetrahydrocannabinol OR can-
nabidiol OR ajulemic acid OR dronabinol) AND (pain
OR chronic OR disease OR neuropathic). A flow dia-
gram of the literature search is shown in Fig 1.
Two researchers determined the eligibility of ar-
ticles and selected them by analyzing the title and
abstracts of each article. All the articles that met
the inclusion criteria based on their abstracts were
selected and collected. Discrepancies between the
two researchers were resolved through evaluation
by a third researcher. Once the actual articles were
obtained, the final selection was independently com-
pleted by two researchers who evaluated each article
and compared their results. The use of an adequate
control group to factor out placebo effect, randomiza-
tion of the sample, and double blinding of the primary
investigator and subjects were considered as inclu-
sion criteria at this stage of the selection process, as
defined within the context of the Jadad scale,22 which
was used to rate the quality of the articles. Any dis-
crepancies were settled through evaluation by a third
researcher. As well, reference lists of the selected
articles were hand-searched for additional relevant
publications that may have been overlooked during
the database searches. In cases where specific data
was necessary for the discussion, and was not spec-
ified in the article, efforts were made to contact the
authors to obtain the required extra information.
Fig 1 Flow diagram of the literature search.
Manual search
0 papers
Electronic search
24 abstracts
Selection criteria on
24 abstracts
Selection criteria on
24 papers
24 papers
22 papers
19 papers
18 papers
17 papers
13 papers remain at final selection
Excluded
2 case reports
Excluded 3 studies
with no
placebo control group
Excluded 1 study
examining
spasticity-related pain in
multiple sclerosis patients
Excluded 1 study
examining heterogeneous
pain symptoms in
34 patients
Excluded 4 studies
that did not consider
pain reduction as an
outcome for entire sample
Potentially
appropriate
to be included
0 papers
Potentially appropriate
to be included
24 papers
© 2015 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY.
NO PART MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
Boychuk et al
Journal of Oral & Facial Pain and Headache 9
Results
Identification of Studies
The search results and the final number of abstracts
selected from the various databases are provided
in Table 1. When comparing the database results, it
was found that Medline, PubMed, Embase, and Web
of Science repeated all of the abstracts. CCTR in-
cluded 6 abstracts and ACP Journal Club contained
1 abstract, all of which were repeated in Medline,
PubMed, Embase, and Web of Science. The authors
did not obtain any further hits from communication
with the Canadian Consortium for the Investigation
of Cannabinoids (CCIC), nor did they obtain any fur-
ther hits from an Internet search of websites for the
International Association for the Use of Cannabis as
Medication (IACM), GW Pharmaceuticals, and the
International Association for Cannabis Research.
After the complete articles of the 24 abstracts initially
selected were read, only 13 fulfilled the initial selec-
tion criteria. Manual searching of the references from
these 13 studies did not reveal any study that had not
appeared in the electronic search.
Eleven of the 24 articles were rejected for the fol-
lowing reasons: One was rejected because it was a
case report that involved only one patient and it dealt
with inflammatory as opposed to neuropathic pain.23
Another was rejected because it was a case report
that included only one subject who underwent mul-
tiple interventions.24 Another was rejected because
it consisted of 34 “n of 1” studies with patients who
were not suffering exclusively from neuropathic pain.25
Rather, the primary pain symptoms were heteroge-
neous in nature and two patients described primary
symptoms that were not painful in nature (tremor and
bladder urgency). Three studies were rejected due
to lack of a placebo control group.16,26,27 Four studies
(that examined the effects of cannabinoids on multi-
ple sclerosis symptoms) were excluded because they
considered pain reduction as an outcome for only a
portion of their samples,17,18,28,29 and one study was
excluded because it examined spasticity-related pain
in multiple sclerosis patients.30 Summaries of the 11
articles that were rejected are displayed in Table 2.
Upon elimination of the aforementioned stud-
ies, 13 remained for inclusion in the systematic
review.19 –21, 31– 40
The cannabinoids administered for neuropathic
pain therapy fall into three groups: whole plant, extract,
and synthetic. The whole plant cannabinoids are de-
livered as smoke or vapor, the extracts are delivered
as an aerosol spray, and the synthetic cannabinoids
are ingested orally. Of the 13 studies analyzed in the
systematic review, 10 examined phytocannabinoids
Table 1 Search Results from Different Databases
Database Search terms Results Selected
Percentage of
total selected
abstracts*
PubMed marijuana OR marihuana OR cannabis OR cannabinoids
OR nabilone OR delta-9-tetrahydrocannabinol OR
cannabidiol OR ajulemic acid OR dronabinol AND pain OR
chronic OR disease OR neuropathic
3,870 13 100
Medline marijuana OR marihuana OR cannabis OR cannabinoids
OR nabilone OR delta-9-tetrahydrocannabinol OR
cannabidiol OR ajulemic acid OR dronabinol) AND pain OR
chronic OR disease OR neuropathic
3,870 13 100
Medline in-process and
other non-indexed citations
marijuana OR marihuana OR cannabis OR cannabinoids
OR nabilone OR delta-9-tetrahydrocannabinol OR
cannabidiol OR ajulemic acid OR dronabinol AND pain OR
chronic OR disease OR neuropathic
43 13 100
Embase marijuana OR marihuana OR cannabis OR cannabinoids
OR nabilone OR delta-9-tetrahydrocannabinol OR
cannabidiol OR ajulemic acid OR dronabinol AND pain OR
chronic OR disease OR neuropathic
1,122 12 100
all EBM reviews (Cochrane
Database of Systematic
Reviews, ASP Journal Club,
DARE, and CCTR)
marijuana OR marihuana OR cannabis OR cannabinoids
OR nabilone OR delta-9-tetrahydrocannabinol OR
cannabidiol OR ajulemic acid OR dronabinol AND pain OR
chronic OR disease OR neuropathic
113 758
Web of Science marijuana OR marihuana OR cannabis OR cannabinoids
OR nabilone OR delta-9-tetrahydrocannabinol OR
cannabidiol OR ajulemic acid OR dronabinol AND pain OR
chronic OR disease OR neuropathic
1,2 01 12 100
* Percentages do not add up to 100% because the same reference could be found in several databases . EBM = evidence-based medicine;
DARE = Database of Abstracts of Reviews of Effects; CCTR = Cochrane Controlled Trials Register.
© 2015 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY.
NO PART MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
10 Volume 29, Number 1, 2015
Boychuk et al
(natural cannabinoids)19,21,31–37,40; 4 of these includ-
ed smoked cannabis31,32,34,35; 5 included cannabis-
based medicinal extracts (CBME) in the form of oro-
mucosal sprays (nabiximols)21,33,36,37,40; and 1 utilized
a novel delivery system involving vaporized canna-
bis.19 The remaining 3 studies included synthetic
cannabinoids, with dronabinol (a synthetic THC),38
nabilone (an analog of dronabinol),20 and CT-3
(1’, 1’Dimethylheptyl-Δ8-tetrahydrocannabinol-11-oic
acid)39 as the active agents. The 13 studies were
published between 2003 and 2013. A total of 771
subjects completed the trials. In terms of quality, the
trials all rated highly on the Jadad scale, with a mean
score of 4.9/5.0.
Main Outcomes
Amongst the studies utilizing whole plant cannabi-
noids, Abrams et al35 found a statistically significant
reduction in pain intensity in the group assigned to
the active drug (3.5% smoked cannabis) when com-
pared with placebo. In fact, daily pain decreased by
34% for active drug over placebo and a greater than
30% reduction was reported in 54% of patients tak-
ing active drug as opposed to 24% taking placebo.
Ellis et al34 found a statistically significant de-
crease in pain as measured by the Descriptor
Differential Scale in patients treated with canna-
bis compared with those treated with placebo.
Participants in this trial were titrated to a target dose
“affording the best achievable pain relief without un-
acceptable adverse effects,” with the THC content
of cannabis utilized ranging from 1% to 8%. The pro-
portion of patients who obtained greater than 30%
pain relief also favored those taking cannabis over
those taking placebo.
Ware et al31 compared cannabis with concentra-
tions of 2.5%, 6%, and 9.4% THC against placebo
and found a statistically significant difference in pain
intensity for those using cannabis with 9.4% THC
content as compared with those taking placebo.
Wilsey et al32 noted a statistically significant de-
crease in both pain intensity and pain unpleasantness
for those subjects taking the active agents (3.5% and
7% smoked cannabis) over those subjects taking
placebo.
Wilsey et al19 utilized a novel delivery system in their
other trial which compared “medium-dose” (3.53%
THC content), “low dose” (1.29% THC content), and
placebo cannabis delivered in vaporized form. They
showed low-dose and medium-dose cannabis to be
equally effective in reducing pain intensity measured
by a visual analog scale (VAS), with results that were
statistically significant when compared with placebo.
Amongst the studies utilizing cannabinoid ex-
tracts, Berman et al40 showed treatment with each
of two active drugs (THC:CBD and THC alone) re-
sulted in a statistically significant reduction in pain
intensity and significant improvement in sleep when
compared to treatment with placebo. The reduc-
tion in pain intensity did not meet the two-point dif-
ference (on an 11-point numerical rating scale) that
was assumed by the authors on an a priori basis to
be clinically significant, in accordance with Farrar et
al.41 Most (80%) of the patients enrolled in this study
continued the open-label extension study utilizing the
THC:CBD combination.
Like Berman et al,40 Rog et al37 also showed a sta-
tistically significant reduction in both mean pain inten-
sity and sleep disturbance when the same THC:CBD
extract was compared with placebo.
Nurmikko et al36 also showed a statistically signif-
icant reduction in mean pain intensity when compar-
ing the same extract with placebo, with more patients
in the active drug group reporting greater than 30%
reduction. In addition, “an open-label extension study
(that included 71% of eligible subjects) showed that
the initial pain relief was maintained without dose es-
calation or toxicity for 52 weeks.”36
In contrast with the three aforementioned studies
that investigated CBME, Selvarajah et al33 found no
Table 2 Studies that Fulfilled Initial Selection Criteria but Were Later Rejected
Authors Reason(s) for rejection
Holdcroft et al23 Case report
Maurer et al24 Case report
Notcutt et al25 Case reports
Clermont-Gnamien et al26 Lack of control group
Attal et al27 Lack of control group
Wade et al17 Pain reduction was not the primary outcome for all subjects and was not measured for the entire sample
Wade et al18 Pain reduction was not the primary outcome for all subjects and was not measured for the entire sample
Zajicek et al28 Pain reduction was not the primary outcome for the study and was not measured for the entire sample
Zajicek et al29 Pain reduction was not the primary outcome for the study and was not measured for the entire sample
Wissel et al30 Pain was spasticity related
Frank et al16 Lack of placebo control
© 2015 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY.
NO PART MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
Boychuk et al
Journal of Oral & Facial Pain and Headache 11
significant difference between subjects treated with
THC:CBD and placebo in terms of reduction in the
two primary outcome measures (mean daily pain
scores and Neuropathic Pain Scale scores).
The most recent of the studies that examined
CBME was that of Langford et al.21 Of the five studies
that utilized cannabinoid extracts,21,33,36,37,40 this study
was unique in that it incorporated an enriched-enroll-
ment randomized-withdrawal design with two phases.
Phase A took place over 14 weeks and was followed
by phase B, which included a 14-week open-label pe-
riod coupled with a 4-week randomized withdrawal
period. The results were equivocal,21 since an interim
analysis showed a significant difference at week 10
of phase A in favor of THC:CBD, but at week 14 (the
end of phase A) there was no statistically significant
difference; the number of responders in the place-
bo group had increased during the final 4 weeks of
phase A, while the number of responders in the active
drug group remained steady. The authors speculated
that the placebo response may have been related to
the flexible dosing design incorporated into this and
two previous studies that had utilized the oral spray.
As a result, those who took placebo administered a
significantly larger number of doses than those who
took THC:CBD, “potentially confounding the compar-
ison between treatment groups.21 “When the groups
were balanced for daily sprays, the THC:CBD group
showed greater separation from placebo.”21 Nurmikko
et al36 and Rog et al37 also noted that the mean number
of daily sprays of CBME was significantly higher in the
placebo groups of their respective studies. In phase B
of the study (randomized withdrawal) by Langford et
al,21 the proportion of subjects “failing treatment” was
significantly lower for those taking the CBME than for
those taking placebo.
In those studies that utilized synthetic cannabi-
noids, Karst et al39 showed significant pain relief when
CT-3 was compared with placebo, and Svendsen et
al38 showed clinically significant improvement in pain
relief reflected in reductions in spontaneous median
pain intensity and radiating pain. Toth et al also noted
those achieving a reduction in pain intensity greater
than 30% and 50% were significantly greater, and
results for sleep interference were significantly better,
in the active drug group as compared to the place-
bo group.20 Fewer symptoms unique to neuropathic
pain sufferers as measured by the Neuropathic Pain
Symptom Inventory were reported by those diag-
nosed with diabetic peripheral neuropathy who were
taking nabilone as compared with those receiving
placebo during the double-blind phase.
Adverse Events
The smoked cannabis studies reported some sim-
ilarities for adverse events. Abrams et al35 reported
smoked cannabis with 3.5% THC to be “well toler-
ated.” Ratings of adverse events were low in both
active drug and placebo groups. Those events most
frequently reported were sedation, anxiety, confusion,
disorientation, and dizziness, and no withdrawals oc-
curred due to adverse events.
Wilsey et al32 also noted there were no withdraw-
als in their trial due to “tolerability issues.” The most
prominent psychoactive effects were sedation, hun-
ger, and confusion. Extensive neuropsychological
testing showed impaired cognition in those subjects
taking 7% THC, while those taking 3.5% THC expe-
rienced impaired learning and memory.
Ellis et al34 reported two subjects withdrew from
their trial due to adverse events. Side effects were
more frequently reported by those taking cannabis
than those taking placebo; they included difficulty
concentrating, fatigue, sleepiness/sedation, increase
sleep duration, decreased salivation, and increased
thirst.
Ware et al31 found “no serious or unexpected
adverse events” amongst those patients taking can-
nabis. Headache, dry eyes, burning sensation, diz-
ziness, numbness, and cough were most frequently
reported in the highest dose group (9.4% THC).
Reports of “feeling high and euphoria” were very rare.
Wilsey et al19 found subjects who took either of
the active drugs to be more sedated, confused, nau-
seated, and hungry than those who took placebo.
The side effects were dose-dependent. As in their
earlier study,32 neuropsychological testing revealed
the “greatest dose effects” were “on memory and
learning, where effect sizes were in the small to me-
dium range and unlikely to have significant impact on
daily functioning.”
Of the five studies that utilized the cannabinoid
extracts,21,33,36,37,40 the most frequently encountered
adverse effects were dizziness/vertigo, tiredness/
somnolence/fatigue, dry mouth, and dysgeusia. An
increased incidence of mouth ulcers, dysgeusia, and
sore throat was associated with the use of the oro-
mucosal spray, a cannabinoid extract combined with
ethanol.21,37,40 Rog et al37 reported “cognitive side ef-
fects were limited to long-term memory storage” and
Nurmikko et al36 found no variation in “objective mea-
surement of psychomotor performance” between the
active drug and placebo groups.
Adverse effects of dizziness, tiredness, headache,
and myalgia were most frequently encountered in the
subjects who received dronabinol.38 In those who re-
ceived nabilone for treatment of diabetic peripheral
neuropathy, confusion was the most serious among a
number of adverse effects, which were generally “mild
to moderate in intensity” and which also included “diz-
ziness, dry mouth, drowsiness, impaired memory, leth-
argy, euphoria, headache, and increased appetite.20
© 2015 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY.
NO PART MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
12 Volume 29, Number 1, 2015
Boychuk et al
Finally, in subjects who received the synthetic canna-
binoid CT-3, tiredness and dry mouth were reported
as the most frequent adverse effects, but no major
physical adverse effects were observed.39
Duration of the Treatment
The duration of the treatment of the selected studies
ranged from less than 1 week to 6 weeks or more.
This variability did not appear to have affected the pri-
mary outcome of the studies.
Number Needed to Treat (NNT)
Nine out of 13 studies clearly stated a NNT ranging
from 2 to 4, with no differences among type of can-
nabinoids. A simple calculation of the reciprocal of
results difference between active treatment and pla-
cebo allowed the authors to assess that the sample
size was adequate for all the remaining four papers,
except for that of Selvarajah et al.33
Discussion
The quasi-totality of the high-quality studies included
in the present systematic review suggests that can-
nabinoids provide significant pain reduction in both
the short term and longer term, without significant
side effects, but must be balanced with the equivocal
results of one very large study21 and with a number of
negative unpublished trials (http://www.clinicaltrials.
gov/ct2/results?term=cannabis+neuropathic+pain).
In the only published study33 with negative re-
sults, it was noted that depression (as measured
by the depression subscale of the Hospital Anxiety
and Depression Scale) was a major confounder.
However, there were other significant limitations ap-
parent in its design. It was stated by the authors that
“there was a significant main effect of depression on
total pain score (TPS), suggesting that in both treat-
ment arms, patients who were depressed were more
likely to respond to intervention.”33 TPS was defined
by the authors as the “average score of all three
pain modalities,” which are described as “superfi-
cial, deep, and muscular pain.33 However, none of
these three pain modalities was specifically defined
by the authors, the association between each of the
three modalities and diabetic peripheral neuropathy
was not explained, and nowhere in the article was
TPS supported as a valid measure for painful dia-
betic peripheral neuropathy. Although subjects were
screened for depression, it was not specified if
they were screened for other psychiatric disorders,
nor was it specified, in the case of those subjects
who were considered depressed, if the depression
was associated with their underlying condition. The
authors did not provide a summary of the specific
classes/names of concomitant medications taken
by subjects who participated in the study. Instead,
they simply indicated: “Patients continued preex-
isting neuropathic pain treatment during the study”
and “those with persistent pain, despite an adequate
trial of tricyclic antidepressants, were recruited.”33 In
addition, the study was a parallel group design that
included a total of only 29 subjects randomized to
two arms, and there was no indication of the NNT
and no evidence provided to support the adequacy
of the study sample size.33
A more recent systematic review and meta-anal-
ysis14 that examined cannabis treatment for chronic
pain concluded, “currently available evidence indi-
cates that treatment of chronic pain based on can-
nabinoids compounds would entail more risk than
benefit, including the risk of the appearance of events
in which the pain—if it is of low intensity—might even
come to pose a secondary problem in the subject.”
In contrast, the present systematic review found very
few risks related to the use of cannabinoid com-
pounds in the treatment of chronic neuropathic pain.
The vast majority of adverse events listed were con-
sidered minor in nature. As well, open-label exten-
sions up to 2 years in duration failed to reveal any
evidence of longer-term side effects.
Many of the cannabinoid studies evaluated in the
present systematic review indicated that the medica-
tions traditionally used to treat chronic pain (such as
opioids and anti-epileptic drugs) are of limited ther-
apeutic value in managing chronic neuropathic pain
and also have adverse effects. Most of these stud-
ies added cannabinoids to a stable regimen of pa-
tients’ current medications. Many of these patients
reported intractable pain of higher intensity. Hence,
cannabinoids should be considered at least an ef-
fective adjunct if not an alternative therapy for the
treatment of chronic neuropathic pain. But of note
in this regard was the observation in one study37 that
the meta-analysis upon which Farrar et al41 based the
suggestion that a 30% reduction in pain was clini-
cally significant “did not include patients with central
neuropathic pain, in which relatively small decreases
in pain intensity are often highly valued by patients.
A limitation of the present systematic review was
the variability in duration of the studies evaluated.
Although the authors did not find any evidence for
an effect of treatment duration, probably due to the
chronic nature of neuropathic pain conditions evalu-
ated, this variability may play a potential role in the re-
sults of the studies and must be taken into account in
evaluating these results. The systematic review also
did not address the differences in efficacy or adverse
effects among the different types of cannabinoids
and the methods of their administration. In addition,
although it covered several chronic nonmalignant
© 2015 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY.
NO PART MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
Boychuk et al
Journal of Oral & Facial Pain and Headache 13
neuropathic pain conditions, a consistent feature
was the significant improvement of pain across the
studies.
Newer delivery methods for cannabinoids are
much safer than smoking. Oromucosal spray systems
provide more consistent blood levels and thereby
allow titration to effective levels of analgesia while
minimizing adverse effects. The oromucosal delivery
systems also provide a level of abuse protection by
limiting the number of daily applications.
Other benefits of cannabinoids appear to include
improvement in sleep quality, appetite, nausea, and
anxiety. Recently developed synthetic cannabinoids,
such as CT-3, await further testing in order to deter-
mine their effectiveness in various chronic pain situ-
ations and to compare their side effect profiles with
traditional synthetic cannabinoids, such as dronabi-
nol and nabilone, as well as along with newer canna-
binoid extracts.
Conclusions
This systematic review suggests that cannabinoids
may provide effective analgesia in chronic neuro-
pathic pain conditions that are refractory to other
treatments. Further high-quality studies are urgently
needed to assess the impact of the duration of the
treatment as well as the best form of drug delivery.
Acknowledgments
The authors report no conflicts of interest related to this study.
References
1. Guy GW, Whittle BA, Robson P. The Medicinal Uses of
Cannabis and Cannabinoids. Chicago: Pharmaceutical Press,
2004.
2. Kalant H. Medicinal use of cannabis: Histor y and current sta-
tus. Pain Res Manag 2001;6:80–91.
3. Tramer MR, Carroll D, Campbell FA, Reynolds DJ, Moore RA ,
McQuay HJ. Cannabinoids for control of chemotherapy in-
duced nausea and vomiting: Quantitative systematic review.
BMJ 2 001; 323 :16–21.
4. Grotenhermen F. Pharmacology of cannabinoids. Neuro
Endocrinol Lett 2004;25:14–23.
5. Pollack A. The search for the killer painkiller. The New York
Times, February 15, 2005;Sect F:1.
6. Ware MA, Gamsa A, Persson J, Fitzcharles MA. Cannabis for
chronic pain: Case series and implications for clinicians. Pain
Res Manag 2002;7:95–99.
7. Campbell FA, Tramer MR, Carroll D, Reynolds DJ, Moore RA ,
McQuay HJ. Are cannabinoids an effective and safe treatment
option in the management of pain? A qualitative systematic re-
view. BMJ 2001;323:13–16.
8. Harstall C. Use of Cannabis or Cannabinoids for Non-
malignant Chronic Pain. Edmonton, Alberta: Alberta Heritage
Foundation for Medical Research, Health Technology
Assessment. TechNote 42, February 2004.
9. Bagshaw SM, Hagen NA. Medical efficacy of cannabinoids
and marijuana: A comprehensive review of the literature. J Palliat
Ca r e 2 0 02;1 8:111–1 22 .
10. Iskedjian M, Bereza B, Gordon A , Piwko C, Einarson TR. Meta-
analysis of cannabis based treatments for neuropathic and mul-
tiple sclerosis-related pain. Curr Med Res Opin 2007;23:17–24.
11. Solaro C, Messmer Uccelli M. Pharmacological management
of pain in patients with multiple sclerosis. Drugs 2010;70:
1245–125 4.
12. Martin Fontelles MI, Goicoechea Garcia C. Role of canna-
binoids in the management of neuropathic pain. CNS Drugs
2008;22:645–653.
13. Rahn EJ, Hohmann AG. Cannabinoids as pharmacothera-
pies for neuropathic pain: From the bench to the bedside.
Neurotherapeutics 2009;6:713–737.
14. M artin-Sanchez E, Furukawa TA, Taylor J, M artin JL. Sys tematic
review and meta-analysis of cannabis treatment for chronic
pain. Pain Med 2009;10:1353–1368.
15. Lynch ME, Campbell F. Cannabinoids for treatment of chronic
non-cancer pain: A systematic review of randomized trials. Br J
Clin Pharmacol 2011;72:735–744.
16. Frank B, Serpell MG, Hughes J, Matthews JNS, Kapur D.
Comparison of analgesic effects and patient tolerability of
nabilone and dihydrocodeine for chronic neuropathic pain:
Randomised, crossover, double blind study. BMJ 2008;336:
199 –2 01.
17. Wade DT, Robson P, House H, Makela P, Aram J. A preliminary
controlled study to determine whether whole-plant cannabis
extracts can improve intractable neurogenic symptoms. Clin
Rehabil 2003;17:21–29.
18. Wade DT, Makela P, Robson P, House H, Bateman C. Do
cannabis-based medicinal extracts have general or specific
effects on symptoms in multiple sclerosis? A double-blind,
randomized, placebo-controlled study on 160 patients. Mult
Scler 2004;10:434 –441.
19. Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe
H. Low-dose vaporized cannabis significantly improves neuro-
pathic pain. J Pain 2013;14:136–148.
20. Toth C, Mawani S, Brady S, et al. An enriched-enrolment,
randomized withdrawal, flexible-dose, double-blind, place-
bo-controlled, parallel assignment efficacy study of nabilone
as adjuvant in the treatment of diabetic peripheral neuropathic
pain. Pain 2012;153:2073–2082.
21. Langford RM, Mares J, Novotna A, et al. A double-blind, ran-
domized, placebo-controlled, parallel-group study of THC/
CBD oromucosal spray in combination with the existing treat-
ment regimen, in the relief of central neuropathic pain in pa-
tients with multiple sclerosis. J Neurol 2013;260:984–997.
22. Jadad AR, Moore RA , Carroll D, et al. Assessing the quality
of reports of randomized clinical trials: Is blinding necessary?
Control Clin Trials 1996;17:1–12.
23. Holdcroft A, Smith M, Jacklin A, et al. Pain relief with oral can-
nabinoids in familial Mediterranean fever. Anaesthesia 1997;
52:483–486.
24. Maurer M, Henn V, Dittrich A , Hofmann A. Delta-9-
tetrahydrocannabinol shows antispastic and analgesic effects
in a single case double-blind trial. Eur Arch Psychiatr y Clin
Neurosci 1990;240:1–4.
25. Notcutt W, Price M, Miller R, et al. Initial experiences with me-
dicinal extracts of cannabis for chronic pain: Results from 34
‘N of 1’ studies. Anaesthesia 2004;59:440–452.
© 2015 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY.
NO PART MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
14 Volume 29, Number 1, 2015
Boychuk et al
26. Clermont- Gnamien S, Atla ni S, Attal N, Le M ercier F, Guirimand
F, Brasseur L . The therapeutic use of D9-tetrahydrocannabinol
(dronabinol) in refractory neuropathic pain. Presse Med 2002;
31:184 0 –184 5.
27. Attal N, Brasseur L, Guirimand D, Clermond-Gnamien S,
Atlami S, Bouhassira D. Are oral cannabinoids safe and effec-
tive in refractory neuropathic pain? Eur J Pain 2004;8:173–177.
28. Zajicek JP, Sanders HP, Wright DE, et al. Cannabinoids in
multiple sclerosis (CAMS) study: Safety and efficacy data for
12 months follow up. J Neurol Neurosurg Psychiatry 2005;76:
1664–1669.
29. Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment
of spasticity and other symptoms related to multiple sclerosis
(CAMS study): Multicentre randomised placebo-controlled
trial. Lancet 2003;362:1517–1526.
30. Wissel J, Haydn T, Müller J, et al. Low dose treatment with the
synthetic cannabinoid Nabilone significantly reduces spastici-
ty-related pain: A double-blind placebo-controlled cross-over
trial. J Neurol 2006;253:1337–1341.
31. Ware MA, Wang T, Shapiro S, et al. Smoked cannabis or
chronic neuropathic pain: A randomized controlled trial. CMA J
2010;182;E694–E701.
32. Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, place-
bo-controlled, crossover trial of cannabis cigarettes in neuro-
pathic pain. J Pain 2008;9:506–521.
33. Selvarajah D, Gandhi R, Emery CJ, Tesfaye S. Randomized
placebo-controlled double-blind clinical trial of canna-
bis-based medicinal product (Sativex) in painful diabetic neu-
ropathy: Depression is a major confounding factor. Diabetes
Care 2010;33:128–130.
34. Ellis R J, Toperoff W, Vaida F, et al. Smoked medicinal cannabis
for neuropathic pain in HIV: A randomized, crossover clinical
trial. Neuropsychopharmacology 2008;34:672–680.
35. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-
associated sensory neuropathy: A randomized placebo-con-
trolled trial. Neurology 2007;68:515–521.
36. Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ,
Haines D. Sativex successfully treats neuropathic pain char-
acterised by allodynia: A randomised, double-blind, place-
bo-controlled clinical trial. Pain 2007;133:210–220.
37. Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, con-
trolled trial of cannabis-based medicine in central pain in multi-
ple sclerosis. Neurology 2005;65:812–819.
38. Svendsen KB, Jensen TS, Bach FW. Does the cannabi-
noid dronabinol reduce central pain in multiple sclerosis?
Randomised double blind placebo controlled crossover trial.
BMJ 2004;329:253–257.
39. Karst M, Salim K, Burstein S, Conrad I, Hoy L, Schneider U.
Analgesic effect of the synthetic cannabinoid CT-3 on chronic
neuropathic pain: A randomized controlled trial. JAMA 2003;
29 0 :1757–1762 .
40. Berman JS, Symonds C, Birch R. Efficacy of two cannabis
based medicinal extracts for relief of central neuropathic pain
from brachial plexus avulsion: Results of a randomised con-
trolled trial. Pain 2004;112:299–306.
41. Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM.
Clinical importance of changes in chronic pain intensity mea-
sured on an 11-point numerical pain rating scale. Pain 2001;94:
149 –15 8 .
© 2015 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY.
NO PART MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
... Furthermore, the pulmonary problems associated with smoking would be a serious drawback for long-term use in illnesses that are chronically painful, including musculoskeletal problems. [115][116][117][118][119][120][121][122][123][124] Relief of muscle spasticity Numerous claims have been made concerning the effectiveness of cannabis in treating muscle spasms, especially in MS, although the majority of these claims are based on unproven subjective experiences rather than rigorous scientific research. [125][126][127] To evaluate the activity of cannabis against MS-induced spasticity, a well-designed pragmatic randomized controlled trial with a high internal validity was carried out. ...
... Given legalization efforts across the United States, increasing numbers of individuals are exploring MC, which has been demonstrated to be an effective adjunctive treatment for a variety of clinical indications. [16][17][18][19] Current estimates indicate more than 5.5 million MC patients are registered in the United States, 20 with chronic pain, anxiety, and sleep disturbances among the most commonly reported indications for use. 21,22 Previous research has underscored the importance of differentiating between medical and recreational cannabis use. ...
... The ECS helps maintain physiological, emotional, and cognitive homeostasis, is a biological system that consists of endocannabinoids (neurotransmitters) and cannabinoid receptors (CB1 and CB2) expressed throughout the CNS (including the limbic system), and peripheral nervous system. 14,15 The CB1 receptors control neurotransmitter release to avoid excessive neuronal activity. It leads to diminish anxiety, calming, reducing pain, and inflammation. ...
Full-text available
Preprint
Introduction: Temporomandibular disorders (TMD) and orofacial pain present therapeutic challenges. Interest in the use of CBD-based medications has outpaced the knowledge of its efficacy and safety in treating TMD. The objective of this review was to evaluate the effectiveness of CBD-based medications in individuals with TMD. Materials and Methods: The PubMed, Embase, Scopus databases were examined. The search was filtered to include only papers published from 2007 to 2022. The main question was asked: Can CBD/Cannabis play an important role in the therapy of orofacial pain and TMD? Results: After applying the inclusion and exclusion criteria and analyzing the abstracts, 31 articles were finally selected. Conclusions: CBD should be taken into consideration in the therapy of masticatory muscles in patients with TMD and orofacial pain. Further research is needed for CBD administration.
... In recreational users of cannabis, coughing fits, anxiety and paranoia were the most common adverse reactions [28]. In the clinical trial setting, oral, gastrointestinal, or sublingual administered cannabis, was associated with nausea, fatigue, vertigo/hallucinations, diarrhea, constipation, and dry mouth [29][30][31][32][33]. In our study, the administration of a nanoparticle water soluble cannabis-based medicine resulted in mild drowsiness, fatigue, and nausea. ...
Full-text available
Article
This pilot study aimed to assess the safety, tolerability, pharmacokinetics and exploratory analgesic effect of a novel water-soluble oro-buccal nanoparticle spray of a cannabis-based medicine (MDCNS-01) in patients with advanced incurable malignancy with unrelieved pain from opioid analgesic. The study was a non-blinded single arm 2 stage study. Stage I was a single escalating dose (n = 5) [2.5 mg Δ9-THC and 2.5 mg CBD) versus a 3-fold escalated dose. Stage II was an up-titrated dose in patients with advanced cancers and intractable pain (n = 25). During Stage I with an increased cannabis-based medicine dose, maximum observed plasma concentrations of cannabinoids were dose dependant. The water-soluble formulation in the current study resulted in a higher median (min, max) systemic exposure of Δ9-THC than CBD (AUC from 2.5 mg each of Δ9-THC and CBD, was 1.71 ng mL.h −1 (1.1, 6.6) and 0.65 ng mL.h −1 (0.49, 4.1), respectively). During stage II a subgroup of patients diagnosed with breast and prostate cancers with bone metastases, had the highest mean pain score improvement from baseline of 40% (unadjusted) and 33% (adjusted for rescue medication use). For all patients the most reported adverse events were mild or moderate drowsiness affecting 11 (44%) and 4 (6%) patients, respectively, and nausea and vomiting that affected 18 (72%) patients. The water-soluble cannabis-based medicine provided acceptable bioavailability for Δ9-THC/CBD, appeared safe and tolerable in advanced incurable cancers with uncontrolled pain with preliminary evidence of analgesic efficacy.
... The wide array of effects and multiple clinical applications of CBD explains the increasing interest of the scientific community in this substance-there are currently more than 170 ongoing clinical trials investigating this cannabinoid, its therapeutic potential and interactions. In fact, this alkaloid compound has garnered attention for its anti-inflammatory, anti-oxidant [8], analgesic [9], and anticonvulsant [10] effects. ...
Full-text available
Article
Background and objective: Cannabidiol, one of the main components of the Cannabis sativa plant, is a non-psychotropic cannabinoid that has recently drawn the attention of researchers and clinicians for its potential therapeutic applications. In this systematic review, we aim to describe the possible effects of cannabidiol in appetite and body weight. Methods: Both authors independently ran a thorough search in both PubMed and Cochrane databases up to 31 July, 2022 and included every peer-reviewed, original randomized controlled clinical trial that reported data on either of the said outcomes. Risk of assessment bias was performed with Cochrane's risk of bias tool and results were summarized in tables. Results: A total of 11 trials were included in this review. Of these, the majority reported on cannabidiol reducing appetite and/or body weight whilst some have found no significant changes and one trial described an increase in appetite. Conclusions: This systematic review suggests that cannabidiol has an anorexigenic effect, correlated with a decrease in body weight. However, most of the studies included in the present review raised some concerns in terms of risk of bias. We believe further research is needed in order to clarify potential mechanisms involved in the effect of cannabidiol on feeding/appetite.
... The long-term sequelae of these complications are not well studied, and as a result, may lead to increased disability and increased economic strain on healthcare systems [8]. Furthermore, previous literature indicates marijuana, specifically cannabidiol, may be useful for pain management [4,9], however, studies also revealed that the co-use of marijuana with opioids (also commonly used in treating pain) or alcohol has been shown to worsen overall health outcomes when compared to using opioids alone [10,11]. This is important to note since previous medical literature found a correlation in patients using marijuana with concomitant opioid use compared to non-opioid users [12,13]. ...
Article
Introduction: There are health implications with the statewide legalization of recreational marijuana that are still not fully understood and require further examination. This study evaluates the prevalence of marijuana use in patients being treated for a variety of conditions and whether correlations exist between marijuana use, mental health conditions, and concomitant use of psychotropic medications. Methods: Data were collected from an electronic medical record (EMR) as part of a retrospective chart audit. A total of 500 charts were reviewed during a six-month timeframe from December 1, 2018 to May 31, 2019 with the start date approximating the timing of when marijuana became recreationally legalized in the State of Michigan. Results: This study demonstrated a point prevalence of 15.8% since 79 of the 500 charts reviewed had marijuana use documented. Additionally, marijuana users were more likely to have a history of cocaine use, schizophrenia, antipsychotic use, and tobacco use. Conclusion: Trends identified in this study provide a comparison point for the local prevalence of marijuana use immediately post state-wide legalization, with a projected increasing trend due to the removal of legal barriers.
... Reasons for this are varied and complex, including considerable medicolegal and bureaucratic hurdles (9). But also there is concern by the medical profession that the randomized control trial (RCT) evidence base for medical cannabis in relation to pain is limited: ranging from weakly positive (10)(11)(12)(13) to inconclusive or negative (14)(15)(16)(17). ...
Full-text available
Article
Background Prescribed cannabinoids are now legal in the UK and increasingly being used for a variety of conditions, with one of the most frequent conditions being chronic pain. This paper describes the characteristics of individuals seeking prescribed cannabinoids for the treatment of chronic pain in Project Twenty 21, a UK based real world data registry of prescribed cannabis patients.Method By 1st November 2021 data were available for 1,782 people who had sought treatment with medical cannabis as part of Project Twenty 21. The most common diagnosis among this cohort was chronic pain with 949 (53.5%) of the cohort reporting a primary condition related to chronic pain. Medical and self-report data on the characteristics of these patients, their health status and type/s of cannabinoid/s prescribed are summarized in this report.ResultsOf the 949 people reporting chronic pain as a primary condition 54.7% were male and their average age was 42.0 years (range = 18–84). Patients reported a low quality of life and high levels of comorbidity: people reported an average of 4.6 comorbid conditions with the most common comorbid conditions including anxiety, depression, insomnia and stress. A range of cannabinoid products were prescribed with the most common products being classified as high THC flower (48.5%). The majority of patients also reported using at least one other prescribed medication (68.7%).Conclusions Consistent with findings in other national and international databases, chronic pain was the most common primary condition in this real world study of prescribed cannabinoids. There was considerable variation in the types of chronic pain, comorbid pathology and in the characteristics of products being prescribed to treat these conditions. Together, this evidence supports the utility of real world evidence, as opposed to clinical trial approaches to studying the potential benefits of prescribed cannabinoids in treating chronic pain.
Article
Vasculogenesis (the process of differentiation of angioblasts toward endothelial cells and de novo formation of crude vascular networks) and angiogenesis (the process of harmonized sprouting and dispersal of new capillaries from previously existing ones) are two fundamentally complementary processes, obligatory for maintaining physiological functioning of vascular system. In clinical practice, however, the later one is of more importance as it guarantees correct embryonic nourishment, accelerates wound healing processes, prevents uncontrolled cell growth and tumorigenesis, contributes in supplying nutritional demand following occlusion of coronary vessels and is in direct relation with development of diabetic retinopathy. Hence, discovery of novel molecules capable of modulating angiogenic events are of great clinical importance. Recent studies have demonstrated multiple angio-regulatory activities for endocannabinoid system modulators and endocannabinoid-like molecules, as well as their metabolizing enzymes. Hence, in present article, we reviewed the regulatory roles of these molecules on angiogenesis and described molecular mechanisms underlying them.
Article
Introduction: : Refractory neuropathic pain (ReNP), and its definition, is widely disputed amongst clinicians due in part to unclear categorical diagnosing guidelines, overall time duration of neuropathic pain, and the exhaustiveness of treatment options. Usually ReNP is defined as chronic, intractable, and unresponsive neuropathic pain that have otherwise been untreatable. Areas covered: : In this narrative review, we discuss and summarize the effectiveness of prospective ReNP research conducted over the past 10 years. This research looks at pharmacological and interventional therapies in clinical trial settings. The pharmacological therapies discussed include the use of adjuvant treatments to improve the safety and efficacy of conventional approaches. Different modalities of administration, such as injection therapy and intrathecal drug delivery systems, provide targeted drug delivery. Interventional therapies such as neuromodulation, pulse radiofrequency, and nerve lesioning are more invasive, however, they are increasingly utilized in the field, as reflected in ongoing clinical trials. Expert opinion: : Based on the current data from RCTs and systematic reviews, it is clear that single drug therapy cannot be effective and has significant limitations. Transitioning to interventional modalities that showed more promising results sooner rather than later may be even more cost-efficient than attempting different conservative treatments with a high failure rate.
Article
Introduction: : To investigate whether published systematic reviews of randomized controlled trials provide sufficient clarity to inform prescribing of cannabinoid products aimed for medicinal use, we examined their features and findings in two well-researched areas: chronic cancer/noncancer pain and multiple sclerosis (MS)-related symptoms. Areas covered: : Structured searches from January 2011 to 2 February 2021 identified 31 systematic reviews (with/without meta-analyses) that met the inclusion criteria. Support for the efficacy of cannabinoids was minimal in cancer pain, and somewhat stronger in noncancer (especially neuropathic) pain and MS spasticity. All systematic reviews and most meta-analyses grouped cannabinoid products together without appropriate consideration of their differential attributes (active constituent(s), concentration/strength, dosage forms, administration route), dosing regimens or treatment durations. Patient populations and efficacy outcome measures were inhomogeneous, particularly for studies in noncancer pain and MS. Separate results for specific cannabinoid formulations were rarely provided. Expert opinion: : The therapeutic effect of cannabinoids, as already demonstrated for some products, is not reflected clearly in the current range of systematic reviews and meta-analyses in chronic pain and MS. To truly inform evidence-based practice, future publications should aim to present results by individual product from well-conducted clinical trials using appropriate and homogeneous outcome measures in well-defined patient populations.
Full-text available
Article
Objective: To test the effectiveness and long term safety of cannabinoids in multiple sclerosis (MS), in a follow up to the main Cannabinoids in Multiple Sclerosis (CAMS) study. Methods: In total, 630 patients with stable MS with muscle spasticity from 33 UK centres were randomised to receive oral D9-tetrahydrocannabinol (D9-THC), cannabis extract, or placebo in the main 15 week CAMS study. The primary outcome was change in the Ashworth spasticity scale. Secondary outcomes were the Rivermead Mobility Index, timed 10 metre walk, UK Neurological Disability Score, postal Barthel Index, General Health Questionnaire-30, and a series of nine category rating scales. Following the main study, patients were invited to continue medication, double blinded, for up to12 months in the follow up study reported here. Results: Intention to treat analysis of data from the 80% of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months (D9-THC mean reduction 1?82 (n=154, 95% confidence interval (CI) 0.53 to 3.12), cannabis extract 0.10 (n=172, 95% CI 20.99 to 1.19), placebo 20.23 (n=176, 95% CI 21.41 to 0.94); p=0.04 unadjusted for ambulatory status and centre, p=0.01 adjusted). There was suggestive evidence for treatment effects of D9-THC on some aspects of disability. There were no major safety concerns. Overall, patients felt that these drugs were helpful in treating their disease. Conclusions: These data provide limited evidence for a longer term treatment effect of cannabinoids. A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS.
Full-text available
Article
1. The History of Cannabis As a Medicine: Ethan Russo 2. Growth and Morphology of Medicinal Cannabis: David Potter 3. The Breeding of Cannabis Cultivars for Pharmaceutical End-uses: Etienne De Meijer 5. Preclinical Pharmacology: Rik Musty 6. Receptors and Pharmacodynamics Natural and Synthtic Cannabinoids and Endocannabinoids: Roger Pertwee 7. Pharmacokinetics of Cannabinoids: Gabrielle Hawksworth : 8. Clinical Studies of Cannabis-based Medicine: Philip Robson, Geoffrey Guy 9. Cannabis in the Treatment of Neuropathic Pain: Willy Nottcutt 10. Forensic Control of Cannabis: Alex Allan 11. International Control of Cannabis Changing Attitudes: Alice Mead 4. The Evolution of Cannabis and Its Coevolution with the Human Cannabinoid Receptor: John Mcpartland 12. Developing a New Cannabis Based Medicine: Brian Whittle, Geoffrey Guy
Article
Despite all the advances of modern medicine, the main drugs used to fight pain today are essentially the same as those used in ancient times. Hippocrates wrote about the pain-soothing effects of willow bark and leaves as early as 400 B.C. Opium was cultivated long before that. Aspirin and morphine, based on the active ingredients in these traditional remedies, were isolated in the 1800's and helped form the foundation of the modern pharmaceutical industry. But scientists are now trying to find new ways of fighting pain. The effort has been given new impetus by the recent withdrawal of Vioxx and the questions surrounding the safety of similar pills like Celebrex and Bextra. Those concerns come on top of the problems of abuse of narcotic painkillers like OxyContin. "There's a huge void, and no one is filling it," said Remi Barbier, chief executive of Pain Therapeutics, a company in South San Francisco, Calif. But Dr. Barbier's company and dozens of others are trying. And some new treatments may come from things in nature that soothe or sting, like marijuana, hot chili peppers, nicotine and deadly toxins of snails and fish. While the withdrawal of Vioxx leaves more room for newcomers, it also makes their challenge harder. Not only have opioids and aspirin been hard to beat, but the Food and Drug Administration is now expected to demand more evidence that drugs are safe before approving them. But what scientists have going for them now is a more detailed, though still not complete, understanding of the molecular mechanisms by which pain is perceived. The goal is to create drugs that block specific parts of the mechanism while avoiding the side effects that have plagued opioids and anti-inflammatory drugs like aspirin. Tens of millions of Americans suffer from chronic pain, according to various surveys, and millions more suffer acute pain from an illness or injury each year. Specialists say pain has received inadequate attention and treatment. "Pain has historically been viewed as a symptom of other things that are more important," said Dr. Russell Portenoy, chairman of pain management and palliative care at Beth Israel Medical Center in New York. But now, he said, there is a growing realization that "chronic pain is itself an illness, and it's a complex illness." Normal pain -from touching a hot stove, for example -is a beneficial warning system. After an injury nerves can become extra sensitive to pain. A warm shower can be painful on a sunburned back. That, too, is protective, said Dr. Clifford J. Woolf, a professor of anesthesia research at Harvard and Massachusetts General Hospital. The sensitivity forces a person to protect an injured area so it can heal.
Article
The objective was to investigate the effectiveness of cannabis-based medicines for treatment of chronic pain associated with brachial plexus root avulsion. This condition is an excellent human model of central neuropathic pain as it represents an unusually homogenous group in terms of anatomical location of injury, pain descriptions and patient demographics. Forty-eight patients with at least one avulsed root and baseline pain score of four or more on an 11-point ordinate scale participated in a randomised, double-blind, placebo-controlled, three period crossover study. All patients had intractable symptoms regardless of current analgesic therapy. Patients entered a baseline period of 2 weeks, followed by three, 2-week treatment periods during each of which they received one of three oromucosal spray preparations. These were placebo and two whole plant extracts of Cannabis sativa L.: GW-1000-02 (Sativex w ), containing D 9 tetrahydrocannabinol (THC):cannabidiol (CBD) in an approximate 1:1 ratio and GW-2000-02, containing primarily THC. The primary outcome measure was the mean pain severity score during the last 7 days of treatment. Secondary outcome measures included pain related quality of life assessments. The primary outcome measure failed to fall by the two points defined in our hypothesis. However, both this measure and measures of sleep showed statistically significant improvements. The study medications were generally well tolerated with the majority of adverse events, including intoxication type reactions, being mild to moderate in severity and resolving spontaneously. Studies of longer duration in neuropathic pain are required to confirm a clinically relevant, improvement in the treatment of this condition. q 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Article
Unlabelled: We conducted a double-blind, placebo-controlled, crossover study evaluating the analgesic efficacy of vaporized cannabis in subjects, the majority of whom were experiencing neuropathic pain despite traditional treatment. Thirty-nine patients with central and peripheral neuropathic pain underwent a standardized procedure for inhaling medium-dose (3.53%), low-dose (1.29%), or placebo cannabis with the primary outcome being visual analog scale pain intensity. Psychoactive side effects and neuropsychological performance were also evaluated. Mixed-effects regression models demonstrated an analgesic response to vaporized cannabis. There was no significant difference between the 2 active dose groups' results (P > .7). The number needed to treat (NNT) to achieve 30% pain reduction was 3.2 for placebo versus low-dose, 2.9 for placebo versus medium-dose, and 25 for medium- versus low-dose. As these NNTs are comparable to those of traditional neuropathic pain medications, cannabis has analgesic efficacy with the low dose being as effective a pain reliever as the medium dose. Psychoactive effects were minimal and well tolerated, and neuropsychological effects were of limited duration and readily reversible within 1 to 2 hours. Vaporized cannabis, even at low doses, may present an effective option for patients with treatment-resistant neuropathic pain. Perspective: The analgesia obtained from a low dose of delta-9-tetrahydrocannabinol (1.29%) in patients, most of whom were experiencing neuropathic pain despite conventional treatments, is a clinically significant outcome. In general, the effect sizes on cognitive testing were consistent with this minimal dose. As a result, one might not anticipate a significant impact on daily functioning.