Cannabis and orofacial pain- a systematic review

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Cannabis and Orofacial Pain: A Systematic Review
Sanford Grossman, Huann Tan, Yusuf Gadiwalla
PII: S0266-4356(21)00219-9
DOI: https://doi.org/10.1016/j.bjoms.2021.06.005
Reference: YBJOM 6505
To appear in: British Journal of Oral & Maxillofacial Surgery
Accepted Date: 11 June 2021
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https://doi.org/10.1016/j.bjoms.2021.06.005
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Cannabis & Orofacial Pain: A Systematic Review 1 
 2 
Authors: Sanford Grossman1, Huann Tan2, Yusuf Gadiwalla3 3 
 4 
 5 
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Author Affiliations: 7 
 8 
1. Department of Oral and Maxillofacial Surgery, Torbay Hospital, Newton Road, 9 
Torquay, United Kingdom TQ2 7AA. Torbay and South Devon NHS Foundation Trust. 10 
sanford.grossman@nhs.net 11 
 12 
2. Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London. 13 
huann.tan@kcl.ac.uk 14 
 15 
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3. Department of Oral Surgery, King’s College Hospital, Denmark Hill, London, SE5 9RS. 17 
King's College Hospital NHS Foundation Trust. yusuf.gadiwalla@nhs.net 18 
 19 
 20 
Corresponding author: Yusuf Gadiwalla. Department of Oral Surgery, King’s College 21 
Hospital, Denmark Hill, London, SE5 9RS. King's College Hospital NHS Foundation Trust. 22 
yusuf.gadiwalla@nhs.net 23 
 24 
Abstract 25 
The naturally occurring Cannabis plant has played an established role in pain management 26 
throughout recorded history. However, in recent years, both natural and synthetic cannabis-based 27 
products for medicinal use (CBPMs) have gained increasing worldwide attention due to growing 28 
evidence supporting their use in alleviating chronic inflammatory and neuropathic pain associated 29 
with an array of conditions. In view of these products’ growing popularity in both the medical and 30 
commercial fields, we carried out a systematic review to ascertain the effects of cannabis and its 31 
synthetically derived products on orofacial pain and inflammation. The application of topical dermal 32 
cannabidiol formulation has shown positive findings such as reducing pain and improving muscle 33 
function in patients suffering from myofascial pain. Conversely, two orally administered synthetic 34 
cannabinoid receptor agonists (AZD1940 and GW842166) failed to demonstrate significant analgesic 35 
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effects following surgical third molar removal. There is a paucity of literature pertaining to the 36 
effects of cannabis-based products in the orofacial region; however, there is a wealth of high-quality 37 
evidence supporting their use for treating chronic nociceptive and neuropathic pain conditions in 38 
other areas. Further research is warranted to explore and substantiate the therapeutic role of 39 
CBPMs in the context of orofacial pain and inflammation. As evidence supporting their use expands, 40 
healthcare professionals should pay close attention to outcomes and changes to legislation that may 41 
impact and potentially benefit their patients. 42 
Keywords: Cannabis, cannabinoids, CBD, THC, orofacial pain, inflammation 43 
 44 
1. Introduction 45 
Cannabis is commonly recognised as a naturally occurring plant that is smoked or ingested for 46 
recreational purposes. However, the use of medical cannabis and cannabinoids has risen throughout 47 
the world in recent years, and we are now seeing it being synthetically produced in multiple forms. 48 
Medical use can include the formulation of oils, creams, capsules or sprays containing chemical 49 
compounds (or synthetic versions) found in cannabis thought to have a number of health benefits. 50 
 51 
The list of countries with regulated pathways of medical cannabis and cannabinoid delivery is 52 
extensive and ever-expanding. Over 30 countries permit its use, including the USA, Canada, 53 
Australia, France, Germany, Spain, and since November 2018, the UK.1,2 54 
 55 
Whilst technically legal in the UK, the use and availability of medical cannabis is highly regulated and 56 
restricted. It is currently available in several forms for patients with rare, severe forms of epilepsy, 57 
adults with chemotherapy-induced nausea or vomiting, and patients suffering from refractory 58 
multiple sclerosis (MS)-related spasticity.3 Conversely, in the USA, the majority of states permit the 59 
use of medical cannabis for a much wider range of purposes, including to alleviate chronic 60 
inflammatory and neuropathic pain associated with conditions such as cancer, human 61 
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immunodeficiency virus (HIV), diabetes and spinal cord injury, and to stimulate appetite in patients 62 
with HIV.4 63 
The recreational use of cannabis remains highly contested and prohibited in the majority of 64 
countries. This may be due to potential adverse health and social effects associated with its 65 
consumption.5 Despite this, an increasing number of countries have begun to either legalise (e.g. 66 
Canada, Uruguay) or decriminalise (e.g. Portugal, Belgium, South Africa) its recreational use.6 At 67 
present, 11 states in the USA have legalised recreational cannabis whilst 26 have decriminalised it, 68 
although it remains illegal at the federal level.7 Cannabis for recreational use has been illegal in the 69 
United Kingdom since 1928 and is currently classified as a Class B drug under the Misuse of Drugs 70 
Act 1971.8 71 
 72 
 73 
Cannabis contains over 500 compounds, with over 100 classified as cannabinoids. Two cannabinoids 74 
are of significant medical interest: delta 9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is 75 
the main active component of cannabis, contributing psychoactive and analgesic properties. CBD 76 
also has an impact on pain and exhibits anti-inflammatory properties.9 Medical cannabis can be 77 
administered through many modalities, including oral or rectal capsules, transdermal patches, 78 
oromucosal or dermal sprays and through vaporising or smoking. The mechanism of administration 79 
affects the bioavailability of the cannabinoids and the consequential effect on the patient.4 First-pass 80 
liver metabolism of orally administered cannabinoids reduce the bioavailability of THC. 81 
Intrapulmonary consumption yields a faster onset and higher systemic bioavailability, as does topical 82 
and transdermal use as the first-pass metabolic effect associated with the oral route is avoided.10 83 
 84 
The mechanism of cannabinoids occurs by activation of two predominant receptors, cannabinoid 85 
type- 1 (CB1) and cannabinoid type-2 (CB2).11 There is extensive literature supporting the presence 86 
of cannabinoid (CB) receptors and ligands in both the central and peripheral nervous systems and 87 
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other tissues such as bone and within the immune system.12 Further to this, CB receptor expression 88 
has been observed in dental pulp11 and periodontal tissues13. 89 
 90 
Synthetic cannabinoids are also available in some countries, and these can be broadly categorised 91 
into groups depending on their structural similarities to naturally occurring cannabinoids and their 92 
relationships with cannabinoid receptors.14 Dronabinol and Nabilone are synthetic cannabinoids 93 
produced for medicinal use that mimic the effects of THC and similarly have the potential to provide 94 
therapeutic effects.15Both drugs are licensed for medicinal use in USA, Germany and the 95 
Netherlands;15 however, only Nabilone is available in the UK.14 96 
 97 
The content of THC and CBD in medical cannabis can be as high as 22% and 9%, respectively.9 Many 98 
health stores now sell food supplements containing cannabinoids which are branded for medicinal 99 
use. In the UK, these remain legal as long as the THC content is below 0.2%.16 Products containing 100 
only CBD are not considered cannabis-based products for medicinal use (CBPMs) and are not classed 101 
as controlled drugs.14 102 
 103 
Patients often present to medical and dental professionals with various aetiologies of orofacial pain 104 
that includes acute pain (e.g. pulpitis, apical periodontitis, post-operative surgical pain), chronic pain 105 
conditions (e.g. temporomandibular joint disorders (TMD) including myogenous and arthrogenous 106 
pain), and neuropathic pain (e.g. trigeminal neuralgia, burning mouth syndrome), amongst others. 107 
Considering the rapidly advancing global acceptance of medicinal cannabis which is popularised by 108 
widely available commercial health products, we recognise a need to explore the evidence base 109 
surrounding the therapeutic effects of cannabis-based products in the orofacial region. 110 
 111 
This systematic review aimed to ascertain the established effect of cannabis and its naturally and 112 
synthetically derived products on orofacial pain and inflammation. 113 
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 114 
2. Materials and methods 115 
This systematic review was conducted according to Preferred Reporting Items for Systematic 116 
Reviews and Meta-analysis (PRISMA) guidance.17,18 117 
 118 
Inclusion criteria 119 
Studies investigating the effects of cannabis-based products on acute and chronic orofacial 120 
nociceptive and neuropathic pain and inflammation were included in the review. We considered 121 
randomised controlled trials, systematic reviews and meta-analyses which involved the use of an 122 
experimentally controlled cannabis-based or derived product and a comparative non-cannabis-123 
based control or placebo drug. No language, publication date, or publication status limits were 124 
applied. Participants of any age with pain or inflammation of orofacial manifestation were included. 125 
We considered all forms of cannabis and its derivatives, both natural and synthetic, as interventions 126 
versus placebo. We did not restrict outcome measures. 127 
 128 
Exclusion criteria 129 
No exclusion criteria were applied. 130 
 131 
Literature search 132 
Studies were identified by searching electronic databases. The search was applied to the following 133 
databases: 134 
1. The Cochrane Database of Systematic Reviews (via the Cochrane Library) (searched 06 135 
January 2021); 136 
2. The Cochrane Central Register of Controlled Trials (CENTRAL) (via the Cochrane Library) 137 
(searched 06 January 2021); 138 
3. MEDLINE (via Ovid) (1946 to 06 January 2021); 139 
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4. Embase (via Ovid) (1974 to 06 January 2021). 140 
 141 
The search strategies are detailed in Appendix 1. 142 
 143 
3. Results 144 
Figure 1 outlines the flow of studies into the quantitative synthesis. A total of three trials were 145 
included in the review. The search of the Cochrane Database of Systematic Reviews, CENTRAL, 146 
MEDLINE and Embase yielded 170 results. After deduplication, 146 trials remained. The remaining 147 
trials were screened for eligibility and 143 were discarded due to irrelevance to orofacial pain or 148 
inflammation. The resulting three trials were included in the review.19-21 149 
 150 
A summary of the reviewed studies and analysis of risk of bias is outlined in Tables 1 and 2, 151 
respectively. 152 
 153 
Characteristics of studies 154 
All three included papers were randomised, double-blind, placebo-controlled clinical trials.19-21 They 155 
were parallel control trials with two arms21, three arms19 and four arms20 comparison. Two studies 156 
did not describe how randomisation was accomplished.19,20 Blinding of patients were reported in all 157 
studies, however, one study did not have consistent placebo and trial drug formats19 and another 158 
did not describe the appearance of the drugs20. Only one study described the process of examiner 159 
blinding.21 There were data reporting errors in two studies' text.19,20 160 
 161 
Visual analogue scale (VAS) with a scoring system of 0 to 10019,20 or 0 to 1021 were used to analyse 162 
the efficacy of CBD as an antinociceptive agent. The efficacy of CBD oral administration in an acute 163 
post-operative surgical removal of third molar pain model was further analysed by measuring the 164 
time and proportion of patients needing rescue medicine, subjective patient global evaluation of the 165 
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study drug and fear of pain questionnaires.19,20 The pharmacokinetics (Cmax and tmax) and adverse 166 
events (AEs) were analysed and observed in two studies.19,20 The subjective central nervous system 167 
(CNS) related CBD effects were checked using the visual analogue mood scale (VAMS).19 The 168 
potential use of transdermal CBD ointment as myorelaxant in patients' masseter muscles with TMD 169 
was further measured with electromyographic muscle activity (EMG).21 Meta-analysis was not 170 
performed in this review due to the CBD agents targeting different cannabinoid receptors (specific 171 
CB2 versus CB1/CB2) and variations in administration route (oral solution versus capsule versus 172 
transdermal), dosage, the pain model (acute nociceptive human pain model versus chronic TMD 173 
pain) and outcome assessment time. 174 
 175 
 176 
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CBD with oral route administration 177 
Kalliomäki et al. (2013) and Ostenfeld et al. (2011) performed a parallel comparison between CBD, 178 
non-steroidal anti-inflammatory drugs (NSAIDs), and placebo.19,20 NSAIDs have been the 179 
recommended analgesic medications to relieve acute post-operative oral surgical pain. Both studies 180 
had administered a pre-emptive single dose cannabinoid (AZD1940 800µg19, GW842166 800mg20) 181 
between 1 to 1.5 hours before the procedure. CB1/CB2 receptor agonist AZD1940 and CB2 receptor 182 
agonist GW842166 failed to show a potent improvement in acute post-operative dental pain. The 183 
difference in post-intervention group pain scores at post-dose 8 hours between AZD1940 (800mg) 184 
and placebo was a mere 1-unit difference (p = 0.48).19 Despite a post-intervention difference of -8.12 185 
(90%CI -20.87, 4.62) between GW842166 800mg and placebo at 10 hours post-dose, there was no 186 
statistically significant pain reduction seen in CBD patients.20 Hence, AZD1940 and GW842166 did 187 
not demonstrate statistical effectiveness in reducing the VAS pain score compared to placebo. 188 
Patients in the naproxen 500mg group had a significant reduction in their VAS score (p<0.0001) with 189 
a post-intervention difference of 234mmh.19 Similar results seen in a combination of pre-operative 190 
ibuprofen 800mg and a four-hour post-dose 400mg showed an approximate fourfold higher (90%CI -191 
44.16, -19.43) difference of post-intervention pain scores relative to placebo.20 192 
Corresponding to post-operative pain, Kalliomäki et al. (2013) performed additional analysis on pain 193 
during jaw movement and reported a similar result with no statistically significant difference 194 
between AZD1940 and placebo (p=0.56), but a significant difference between naproxen and placebo 195 
(p<0.0001).19 196 
Using a 4-point categorical verbal rating scale (VRS) (0-3 with less is better), GW842166 800mg 197 
reported a small improvement (post-intervention VRS difference -0.31, 95%CI-0.68,0.07) in pain 198 
rating in comparison to ibuprofen (post-intervention VRS difference -0.92, 95%CI -1.28,-0.56)199 
relative to placebo.20 200 
AZD1940 did not achieve a statistically significant difference compared to placebo in the time to first 201 
rescue drug administration (p=0.06), but a significant difference noted between naproxen and 202 
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placebo (p<0.0001).19 23 of the 26 GW842166 800mg patients requested rescue medication with a 203 
mean time of 4.83 hours (95%CI 0.71, 1.26) which was relatively not significant compared with 204 
placebo (p=0.702).20 However, ibuprofen reported a significant difference in the first dose of rescue 205 
medication (median time 11.47 hours; 95%CI 0.63,093; p=0.005). 206 
The proportion of AZD1940 patients needing rescue medication was 61% whereas in the placebo 207 
group it was 73%, with no statistically significant difference (p=0.08).19 At four hours post-operative, 208 
approximately 50% of AZD1940 and placebo patients took their first rescue medication, but less than 209 
20% in the naproxen group required it. A patient's likelihood to request rescue drug in GW842166 210 
was 0.95 compared to ibuprofen 0.77 relative to placebo.20 211 
There was no significant difference between pre-operative GW842166 800mg and placebo patient 212 
reported global evaluation scores at post-dose 10 hours (median difference 0.0; 95%CI 0.0,1.0; 213 
p=0.217) but a significant difference at 24 hours (median difference 1.0; 95%CI 0.0,1.0; p=0.019).20 214 
Ibuprofen showed a statistically significant improvement at both 10 hours and 24 hours (p<0.0001). 215 
The significant pain relief effects of ibuprofen compared to single-dose CBD should be interpreted 216 
with caution due to the administration of ibuprofen 400mg four hours post-operatively. 217 
AZD1940 demonstrated a significant elevation of VAMS scores compared to placebo with ‘high’ and 218 
‘sedated’ effects over seven- and nine- hours post-dose, respectively.19 The ‘high’ and ‘sedated’ CNS 219 
effects peaked at 75 minutes and two hours respectively. There was no distinction dissimilarity 220 
between AZD1940 and placebo in other VAMS scores such as ‘stimulated’, ‘anxious’, and ‘down’. 221 
The mean maximum plasma concentration (Cmax) for GW842166 800mg was 0.714µg/mL20 and 222 
9.3nmol/L for AZD194019. The median time to achieve Cmax was similar for GW842166 800mg and 223 
AZD1940; three hours. The mean concentration over post-dose eight hours for AZD1940 was 236 224 
nmol.h/L19 and over 10 hours GW842166 800mg was 4.56 µg.h/mL20. There was no strong evidence 225 
to establish a relationship with higher GW842166 concentrations with lower VAS scores. 226 
Mild to moderate AEs were reported across all active treatment and placebo groups of the included 227 
studies. The AE occurrence (%) reported by Ostenfeld et al. (2011) is approximately similar across 228 
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the three active treatment groups (GW842166 800mg, 100mg, ibuprofen) and placebo; 18 (67%), 21 229 
(71%), n=22 (71%), n=19 (61%).20 230 
Common AEs seen in respective AZD194019 and GW84216620 800mg usage (percentage of patients 231 
with AEs) were such as: headache (13%, 15%), nausea (26%, 11%) and syncope (5%, 7%). Other AEs 232 
reported in GW842166 800mg were pyrexia (11%), diarrhoea (4%), odynophagia (4%) and vomiting 233 
(4%). 234 
Apart from a numerical reduction in the mean plasma levels of testosterone, LH and TSH, the 235 
patients administered AZD1940 had general standard clinical chemistry and haematology results.19 236 
There were no clinically relevant differences in ECG or body temperature between patients 237 
administered AZD1940 and placebo. AZD1940 had hemodynamic effects with a reduction in mean 238 
standing systolic and diastolic blood pressure (BP) and a corresponding mean pulse increase. The 239 
most remarkable difference between AZD1940 and placebo in mean standing (for 2 min) blood 240 
pressure (BP) was recorded at four hours post-dose, with mean standing systolic/diastolic BP change 241 
from baseline after AZD1940 administration −12.5/−10.5 mmHg and placebo 3.4/2.1 mmHg, and 242 
mean standing pulse rate change of 20.3 bpm and placebo 3.4 bpm 243 
There were no severe adverse events reported for GW842166 800mg,20 but one patient in AZD1940 244 
had four severe syncope episodes and another patient had a severe headache.19 AZD1940 has 245 
reported a high 80% of patients with postural dizziness. There was no exclusion of participants from 246 
both trials due to the adverse events. 247 
 248 
Transdermal CBD formulation 249 
Transdermal CBD ointment (CBD 2.0g) and placebo showed a statistically significant change of 250 
means from baseline (MD) on day 14 (CBD: MD -3.93, p <0.00001; Placebo: MD -0.50, p=0.011).21 251 
However, a larger difference was noted with the used of CBD ointments than placebo. There was a 252 
significant change from baseline mean EMG scores at day 14 for bilateral masseter muscle in 253 
patients treated with CBD ointments (MD: 0.03, p<0.0001). CBD ointment application demonstrated 254 
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an impressive reduction in the masseter muscle EMG activity and pain intensity during resting 255 
position, reducing myofascial arthralgia. 256 
There were no adverse events noted with the use of transdermal CBD formulation.21 257 
 258 
4. Discussion 259 
The study by Nitecka-Buchta et al. (2019) was the first of its kind and whilst demonstrating that the 260 
CBD formulation reduced sEMG activity and pain intensity in the masseter muscles in the patients 261 
involved in the trial, the sample size and follow-up period are limited and further high-quality 262 
research is needed in this field.19 263 
The studies by Kalliomäki et al. (2013) and Ostenfeld et al. (2011) ultimately showed no statistically 264 
significant post-operative pain improvement following mandibular third molar surgery in 265 
comparison to ibuprofen. 266 
CBDs are often used in chronic pain and inflammatory conditions due to a higher concentration of its 267 
pain signalling sites in the central nervous system (CB1 receptors) and immune system (CB2). 268 
Simultaneously, NSAIDs peripheral action predominates its central antinociceptive mechanism and 269 
may have a better impact in acute post-surgical pain. 270 
 271 
Given the limited evidence assessing the effects of cannabis-based products on orofacial pain and 272 
inflammation, the authors believed a discussion on the wider use of these products in the medical 273 
field would be of interest to the readers. 274 
 275 
Medical cannabis has played an established role in pain management throughout recorded history. 276 
The exact extent of medical cannabis is not completely understood. Its earliest recorded use was 277 
3500 years ago in what is now Romania.22 Early evidence suggests that cannabis may have been 278 
used for pain relief around 400 AD.23 Cannabis was first listed as a medicinal product in the United 279 
States Pharmacopoeia in 1850.22 280 
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Chronic Pain 281 
Beyond the orofacial region, there is a vast sum of research drawing various conclusions on the 282 
impact of cannabis and its natural- and synthetic-based medicinal products on chronic pain of 283 
multiple aetiologies. Many authors have found evidence to support these products’ use as 284 
reasonable treatment options in providing pain relief to those suffering either entirely from chronic 285 
neuropathic pain,9,24,25,26,27,28 non-cancer, nociceptive pain,29,30 or both.31,4,32,33,34,35 Across the 286 
aforementioned studies, mixed aetiologies of non-cancer, nociceptive pain were included, including 287 
pain associated with diabetic peripheral neuropathy, fibromyalgia, MS-related spasticity, HIV-288 
associated sensory neuropathy, and rheumatoid arthritis, amongst others. In contrast to this wealth 289 
of support, the findings of one meta-analysis suggest that the evidence base to supportthe effective 290 
use of cannabinoids in alleviating chronic non-cancer pain is limited and that cannabinoids are 291 
unlikely to function as effective analgesics for this group.36 292 
 293 
Furthermore, Kosiba et al. (2019) examined patient-reported reasons for medicinal cannabis use and 294 
found that amongst 6665 participants from over 30 countries, 67% reported using it for analgesia.37 295 
Although the above studies span beyond the scope of this review, it is plausible that their findings 296 
could apply to the treatment of chronic musculoskeletal, neurovascular and neuropathic orofacial 297 
pain. 298 
 299 
Arthralgia and Myalgia 300 
A randomised, double-blind, placebo-controlled trial, exploring the effect of Sativex® (GW 301 
Pharmaceuticals, UK), a plant-based cannabinoid medicine, on 58 patients with rheumatoid arthritis, 302 
found a statistically significant reduction in pain intensity at rest and on movement and a 303 
consequentially improved associated quality of sleep.38 The impact of this product on joint 304 
inflammatory pain is promising and may have clinical application to other joint disorders including 305 
TMD. 306 
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Skrabek et al. (2008) carried out a randomised, double-blind, placebo-controlled trial investigating 307 
the benefit of Nabilone on pain reduction and quality of life improvement in 40 patients with 308 
fibromyalgia.39 The Nabilone group reported a significant decrease in pain intensity, anxiety and the 309 
impact fibromyalgia had on their lives. This finding in relation to fibromyalgia may similarly apply to 310 
TMD, since despite being clinically distinct conditions, both are chronic pain disorders characterised 311 
by a combination of myalgia and arthralgia. 312 
 313 
Headache disorders 314 
There is limited evidence from robust clinical trials to support the use of cannabis for headache 315 
disorders. 316 
 317 
Pini et al. (2012) carried out a small double-blind, placebo-controlled trial of 26 patients that 318 
investigated the use of Nabilone in treating refractory medication overuse headache (MOH), a 319 
frequent complication of migraine. The authors found that Nabilone significantly reduced pain 320 
intensity, decreased analgesic intake, and improved quality of life.40 321 
Further to this, in 2016, Rhyne et al. carried out a retrospective review of 121 adult patients 322 
suffering from migraine who were treated with medical cannabis. They found migraine frequency 323 
reduced from 10.4 to 4.6 episodes per month (P < 0.0001).41 324 
 325 
The remaining body of evidence pertaining to the use of cannabis and its natural and synthetic 326 
derivatives in the field of headache disorders is mostly anecdotal and preliminary, consisting largely 327 
of case series and reports. These studies report that cannabis may improve pain from 328 
migraines.42,43,44 There are also cases that suggest cannabis may reduce pain intensity in chronic 329 
headaches,45 refractory cluster headaches,46 and headaches resulting from pseudotumour cerebri.47 330 
 331 
 332 
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Psychiatric disorders 333 
Although not directly relevant to oral and maxillofacial surgery, many facial pain patients may suffer 334 
from psychiatric disorders concurrently. There is evidence to suggest that CBPMs may have 335 
therapeutic potential in treating a number of psychiatric conditions including social anxiety disorder, 336 
psychosis, post-traumatic stress disorder (PTSD) and substance addiction.48 However, it should be 337 
noted that evidence is limited in this field and further research is needed before the benefit of 338 
CBPMs in this context can be substantiated.48,49 339 
 340 
Other Head and Neck findings 341 
Of further interest are several papers that were identified during the initial search strategy that did 342 
not directly answer the research question but provide valuable commentary on cannabis-based 343 
products and synthetic cannabinoids for medicinal use in the head and neck. 344 
In 1977, Raft el al. explored the effect of intravenous THC as premedication for dental extractions.50 345 
They found that THC did not exert true analgesic effects for either experimental or surgical pain. 346 
In 2014, McDonaugh et al. investigated the potential role of cannabinoids in treating symptoms of 347 
neuropathic orofacial pain (NOP) including trigeminal neuralgia, persistent idiopathic facial pain, 348 
burning mouth syndrome and postherpetic neuralgia.51 Considering the established role of the 349 
endocannabinoid system in analgesia and evidence of cannabinoid activity in the pathophysiological 350 
mechanisms involved in NOP disorders, the authors conclude that cannabinoids have a therapeutic 351 
effect on these conditions. 352 
In a survey of 112 patients with multiple sclerosis-associated trigeminal neuralgia, 70% found that 353 
cannabis provided relief from their symptoms.52 Of further interest is a case report of a patient with 354 
MS-related limb spasticity who suffered from trigeminal neuralgia. The patient received Nabiximols, 355 
the cannabinoid compound used in Sativex®, to treat their spasticity and experienced a marked 356 
improvement of their trigeminal neuralgia.53 357 
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Chelliah et al. (2018) reported a series of three cases where patients suffering from epidermolysis 358 
bullosa applied CBD oil topically and experienced amelioration of pain, reduction in blistering and 359 
rapid wound healing.54 360 
 361 
Adverse effects 362 
In contrast to the mounting support for the use of cannabis-based medicinal products, there is some 363 
limited evidence reporting potential drawbacks associated with their use. Eight patients were 364 
observed with multiple sclerosis who self-administered Sativex® oromucosal spray, containing both 365 
THC and CBD in alcohol, for analgesic purposes. All patients reported a burning sensation following 366 
use of the spray and half exhibited visible white patches on the floor of the mouth, although the 367 
lesions resolved spontaneously and were considered likely to be the result of chemical trauma or 368 
burn. There is also a possibility that the lesions were the result of the high alcohol concentration 369 
rather than the cannabis-derived components.55 There has also been a case report suggesting a link 370 
between vaping cannabis and oromucosal ulceration.56 371 
 372 
There is evidence to suggest a link between the repeated consumption of natural and synthetic 373 
cannabinoids and psychological and physical adverse effects, such as psychotic states, affective 374 
disorders, cognitive impairments, cardiovascular and gastrointestinal symptoms, amongst others.57 375 
There are concerns that certain CBPMs may be counterproductive in treating psychiatric disorders 376 
due to the propsychotic and anxiogenic properties of THC.48 377 
 378 
According to the International Standard Randomised Controlled Trial Number (ISRCTN) registry58 and 379 
ClinicalTrials.gov,59 new studies exploring the therapeutic potential of cannabis and its derivatives 380 
are underway across the world, including within the UK. In the UK, the CBD market has an estimated 381 
worth of approximately £300 million per year (larger than the total Vitamin D (£145M) and Vitamin 382 
C (£119M) markets combined). The market is expanding rapidly and predicted to reach a value of 383 
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almost £1 billion by 2025. This is equal to the value of the entire UK herbal supplement market in 384 
2016.60 Scientific findings may further stimulate pharmaceutical investment in cannabis-based 385 
products for medical use. We are likely to see further investment in the applicability of these 386 
products to treating inflammation and pain.60 387 
 388 
In 2019, a US survey was published exploring the attitudes, beliefs andknowledge of 62 primary care 389 
providers in relation to medical cannabis. The majority of providers believed that medical cannabis 390 
was a legitimate medical therapy and over one third believed that it should be offered to patients as 391 
a therapeutic option. Over three quarters of providers wanted to learn more about medical 392 
cannabis.61 Whilst there is no comparative survey involving UK-based healthcare professionals, it 393 
could be postulated that UK practitioners would share a similar interest in learning more about the 394 
role of medical cannabis and its applicability to modern healthcare. 395 
 396 
5. Conclusions 397 
To the authors knowledge, this is the first systematic review of the effect of the medicinal use of 398 
cannabis-based products for orofacial pain and inflammation. The use of cannabis-based products in 399 
healthcare remains controversial and in its infancy. There appears to be a societal social stigma 400 
associated with the use of cannabis and its derivatives for medical use, although this viewpoint may 401 
be slowly evolving. There is a wealth of high-quality evidence supporting the use of cannabis-based 402 
products for treating chronic nociceptive and neuropathic pain; however, the evidence pertaining 403 
specifically to orofacial manifestations is extremely limited. Further research is warranted to 404 
investigate the efficacy of these products and their applicability to this field. However, as the body of 405 
evidence supporting its use continues to grow, medical and dental professionals should pay close 406 
attention to these outcomes and any changes to legislation as there potentially could be great 407 
benefits to patients. 408 
 409 
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Conflict of Interest 410 
No conflicts of interest 411 
 412 
Ethics statement/confirmation of patient permission 413 
Ethics approval not required. Patient permission/consent not required 414 
 415 
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58. ISRCTN Registry [Internet]. Isrctn.com. 2020 [cited 27 June 2020]. Available from: 561 
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https://clinicaltrials.gov/ 564 
60. Gibbs B, Yates A, Liebling J, O'Sullivan S. CBD in the UK [Internet]. 2019 [cited 24 April 2020]. 565 
Available from: https://irp-566 
cdn.multiscreensite.com/51b75a3b/files/uploaded/Report%20%7C%20CBD%20in%20the%2567 
0UK%20-%20Exec%20Summary.pdf 568 
61. Philpot L, Ebbert J, Hurt R. A survey of the attitudes, beliefs and knowledge about medical 569 
cannabis among primary care providers. BMC Family Practice. 2019;20(1). 570 
 571 
Figures and Tables 572 
Figure 1: Flow chart of articles included in the review 573 
Table 1: Summary of reviewed studies 574 
Table 2: Risk of bias analysis 575 
 576 
 577 
 578 
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https://clinicaltrials.gov/
https://irp-cdn.multiscreensite.com/51b75a3b/files/uploaded/Report%20%7C%20CBD%20in%20the%20UK%20-%20Exec%20Summary.pdf
https://irp-cdn.multiscreensite.com/51b75a3b/files/uploaded/Report%20%7C%20CBD%20in%20the%20UK%20-%20Exec%20Summary.pdf
https://irp-cdn.multiscreensite.com/51b75a3b/files/uploaded/Report%20%7C%20CBD%20in%20the%20UK%20-%20Exec%20Summary.pdf24 
 
Appendix 1. Detailed Search Strategies for Each Database 579 
 580 
The Cochrane Database of Systematic Reviews and CENTRAL (via the Cochrane Library) 581 
 582 
1. (cannabi*):ti,ab,kw OR (endocannabinoid*):ti,ab,kw OR (tetrahydrocannabinol):ti,ab,kw OR 583 
(marijuana):ti,ab,kw 584 
2. (pain):ti,ab,kw OR (inflammat*):ti,ab,kw OR (neuralgia):ti,ab,kw OR (neuropath*):ti,ab,kw 585 
OR (analgesi*):ti,ab,kw 586 
3. (dental):ti,ab,kw OR (tooth):ti,ab,kw OR (teeth):ti,ab,kw OR (mouth):ti,ab,kw OR 587 
(oral):ti,ab,kw 588 
4. (facial):ti,ab,kw OR (orofacial):ti,ab,kw OR (maxillofacial):ti,ab,kw OR 589 
(temporomandibular):ti,ab,kw OR (trigeminal):ti,ab,kw 590 
5. (randomised controlled trial):pt OR (systematic review):pt OR (meta-analysis):pt 591 
6. #3 OR #4 592 
7. #1 AND #2 AND #6 593 
8. #7 AND #5 594 
 595 
MEDLINE and Embase (via Ovid) 596 
 597 
1. cannabi*.ab. or cannabi*.ti. or cannabi*.kw. 598 
2. endocannabinoid*.ab. or endocannabinoid*.ti. or endocannabinoid*.kw. 599 
3. tetrahydrocannabinol.ab. or tetrahydrocannabinol.ti. 600 
4. delta-9-tetrahydrocannabinol.ab. or delta-9-tetrahydrocannabinol.ti. or delta-9-601 
tetrahydrocannabinol.kw. 602 
5. marijuana.ab. or marijuana.ti. or marijuana.kw. 603 
6. 1 or 2 or 3 or 4 or 5 604 
7. pain.ab. or pain.ti. or pain.kw. 605 
8. inflammat*.ab. or inflammat*.ti. or inflammat*.kw. 606 
9. neuralgia.ab. or neuralgia.ti. or neuralgia.kw. 607 
10. neuropath*.ab. or neuropath*.ti. or neuropath*.kw. 608 
11. analgesi*.ab. or analgesi*.ti. or analgesi*.kw. 609 
12. 7 or 8 or 9 or 10 or 11 610 
13. dental.ab. or dental.ti. or dental.kw. 611 
14. tooth.ab. or tooth.ti. or tooth.kw. 612 
15. teeth.ab. or teeth.ti. or teeth.kw. 613 
16. mouth.ab. or mouth.ti. or mouth.kw. 614 
17. oral.ab. or oral.ti. or oral.kw. 615 
18. facial.ab. or facial.ti. or facial.kw. 616 
19. orofacial.ab. or orofacial.ti. or orofacial.kw. 617 
20. maxillofacial.ab. or maxillofacial.ti. or maxillofacial.kw. 618 
21. temporomandibular.ab. or temporomandibular.ti. 619 
22. trigeminal.ab. or trigeminal.ti. or trigeminal.kw. 620 
23. 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 621 
24. 6 and 12 and 23 622 
25. limit 24 to (meta analysis or systematic review or randomized controlled) 623 
 624 
 625 
 626 
 627 
 628 
 629 
Literature search 
Databases: The Cochrane Database of Systematic 
Reviews, CENTRAL, MEDLINE, Embase 
Search results combined (n = 170) 
Records after duplicates removed (n = 146) 
Articles screened for eligibility on basis of title and 
abstract 
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Figure 1: Flow chart of articles included in the review. 630 
Table 1: Summary of reviewed studies. 631 
 632 
Table 2: Risk of bias analysis 633 
 634 
Study 
ID 
Random 
sequenc
e 
generati
on 
 
Allocation 
concealme
nt 
Blinding of 
participant
s and 
personnel 
Blinding 
of 
outcome 
assessm
ent 
Incompl
ete 
outcome 
data 
Selecti
ve 
reporti
ng 
Other 
bias 
Kalliom
äki et 
al., 
201319 
Low risk Unclear 
risk. 
No 
description 
on how 
randomisat
ion is 
performed 
Unclear 
risk. 
Differences 
in the drug 
administrat
ion 
methods 
between 
CBD and 
naproxen 
 
Low risk Low risk. 
No 
withdra
wal or 
loss of 
follow-
up 
Low 
risk 
Unclear 
risk. 
Incorrec
t data in 
text on 
AZD194
0 
sample 
size 
Ostenfe
ld et al., 
201120 
Low risk Unclear 
risk. 
No 
description 
on how 
randomisat
ion is 
performed 
Low risk Low risk Low risk. 
2 
patients 
with 
GW8421
66 
800mg 
were 
withdra
wn with 
reason 
stated 
and 
were 
excluded 
from 
statistica
l analysis 
 
Low 
risk 
Unclear 
risk. 
Incorrec
t data in 
table 4 
(median 
differen
ce) of 
the 
article 
Nitecka
-Buchta 
et al., 
201921 
Low risk Low risk Low risk Low risk Low risk Low 
risk 
Low risk Jo
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Study ID Treatment/ 
Regimen 
Number of patients Age 
(year) 
Assessment 
method 
Outcome findings Adverse events (AEs) Result summary 
 Total Treatmen
t 
Control 
Kalliomäki 
et al., 
201319 
1. AZD1940 
800µg oral 
solution & 
naproxen 
placebo 
capsule. 
2. AZD1940 
placebo oral 
solution & 
naproxen 
placebo 
capsule. 
3. Naproxen 
500mg capsule 
(for assay 
sensitivity) & 
AZD1940 
placebo oral 
solution. 
All study drugs 
were 
administered 
1.5 hours 
before the 
surgery 
151 AZD1940 
n=61; 
naproxen 
n=31 
n=59 20.7 1. Visual 
analogue 
scale (VAS) 
(0 to 8 
hours) of 
post-
operative 
pain 
There was no statistically 
significant difference in the 
VAS (0–8 h) between patients 
administered AZD1940 and 
placebo (p = 0.48). 
There was a steep increase in 
pain score between 0 to 4 h 
(approximately 40mmh unit 
changes) before reaching a 
plateau stage. 
No serious AEs reported in 
AZD1940 and placebo 
postural dizziness (80%, 32%), 
nausea (26%, 14%), 
hypotension (21%, 5%) and 
headache (13%, 5%). Syncope 
was reported in AZD1940 
(n=3) and placebo (n=2). Most 
AE were of mild and 
moderate intensity. One 
patient in the AZD1940 group 
had four episodes of severe 
syncope and another patient 
had a severe headache. 
AZD1940 in general has 
normal clinical chemistry and 
haematology results. There 
were no clinically relevant 
differences in ECG or body 
temperature between 
AZD1940 and placebo. 
AZD1940 had hemodynamic 
effects with a reduction in 
mean standing systolic and 
diastolic blood pressure (BP) 
and a corresponding mean 
pulse increase. 
Single dose of The 
CB1/CB2 receptor 
agonist AZD1940 did 
not significantly 
improve post-
operative dental pain 
at doses exerting 
subjective cannabinoid 
effects. The two most 
common AEs, postural 
dizziness and nausea, 
were observed more 
frequently in AZD1940 
than placebo group. 
 
 2. VAS (0 to 
8 hours) on 
pain at jaw 
movement 
There was no statistically 
significant difference between 
AZD1940 and placebo for the 
VAS of jaw movement (0–8 h) 
(p = 0.56) 
 
 3. Time and 
proportion 
of patients 
to the first 
rescue 
medicines 
There was no statistical 
difference between placebo 
and AZD1940 in the time 
(p=0.06) and 
proportion of patients 
requesting first rescue 
medication (p=0.08) 
 
 4. Visual 
analogue 
mood 
scales 
(VAMS) 
AZD1940 reported 
significantly higher VAMS 
scores compared with 
placebo at all time points up 
to 7 h post-dose for “high” 
and up to 9 h post-dose for 
“sedated”. VAMS scores were 
maximal at 75 min for “high” 
and at 2 h for “sedated”. 
There were no distinct 
difference in the VAMS scores 
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(“stimulated”, “anxious” and 
“down”) between AZD1940 
and placebo. 
 5. 
Pharmacoki
netics (Cmax 
and tmax) 
The average Cmax for AZD1940 
was 9.3 nmol/L (range 6.7 to 
13.7 nmol/L). The median tmax 
was 2.9 h (range 1.2 to 8.8 h). 
Due to the short sampling 
time of in relation to the t1/2, 
there was a large AUC 236 h 
nmol/L, (range 96 to 865) and 
t 1/2 16.8 h (range 6.2 to 54.0) 
 
 
Ostenfeld 
et al., 
201120 
1. GW842166 
800 mg pre-
operative and 
placebo post-
operative. 
2. GW842166 
100 mg pre-
operative and 
placebo post-
operative. 
3. Ibuprofen 
800 mg pre-
operative and 
ibuprofen 400 
mg post-
operative. 
4. Placebo pre-
operative and 
placebo post-
operative. 
Study drugs 
were 
administered 
1h pre-
operative 
121 Efficacy: 
GW84216
6 (100mg) 
n=34 
GW84216
6 (800mg) 
n=26 
Ibuprofen 
(800mg) 
n=31 
2. Safety 
analysis: 
GW84216
6 (100mg) 
n=34 
GW84216
6 (800mg) 
n=27 
Ibuprofen 
(800mg) 
n=31 
3. PK 
analysis:GW84216
6 (100mg) 
n=34 
GW84216
6 (800mg) 
n=27 
 
Efficacy: 
n=31 
Safety 
analysis: 
n=31 
GW8
4216
6 
(100
mg): 
25.6 
GW8
4216
6 
(800
mg): 
24.9 
Ibupr
ofen 
(800
mg): 
26.6 
Place
bo: 
26.5 
1. VAS (0 to 
10h) of 
post-
operative 
pain 
intensity 
There was no statistically 
significant improvement in 
both 100mg and 800mg 
compared to placebo 
The most common AE was 
headache in all groups (15% 
to 39%) followed by nausea, 
pyrexia, and syncope in the 
GW842166 800mg group; 
nausea and 
pharyngolaryngeal pain in the 
GW842166100 mg group. 
Single doses of 
GW842166 (100 and 
800 mg) failed to 
demonstrate 
meaningful analgesia 
in the acute dental 
pain. 
There was no 
remarkable 
relationship between 
higher mean 
GW842166 
concentrations and 
lower VAS scores. 
 2. Virtual 
numerical 
scale (VRS) 
There was no difference 
between GW842166 100mg 
and placebo, with a lower 
mean score (-0.31) for 
GW842166 800mg. 
 
 3. Time to 
first dose of 
rescue 
medication 
 
There was no statistically 
significant in the time and 
likelihood of receiving both 
GW842166 100mg (p=0.848) 
and 800mg (p=0.702) in 
relative to placebo 
 
 4. Patient 
global 
There was no stastically 
significant difference in the 
 
Jo
ur
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l P
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of
28 
 
evaluation 
by time 
subjective patient evalution of 
treatment efficacy for both 
GW 842166100mg (p=0.549) 
and 800mg (p=0.217) in 
relative to placebo 
 5. Fear of 
pain 
questionnai
res (FAQ) 
There was a positive 
relationship between the total 
fear of pain score with the 
mean VAS scores 
 
 6. 
Pharmacoki
netics (Cmax 
and tmax) 
The Cmax GW842166 100mg 
was 0.285µg/ml and 
0.714µg/ml for 800mg. The 
median tmax for 100mg was 
3.5h and 3.0h for 800mg. 
 
 
Nitecka 
Buchta et 
al., 201921 
CBD 
Formulation 
• Oleum CBD 
2.0 g 
• Aqua 
purificata 3.0 g 
• Ung. 
Cholesterol 5.0 
g 
Control 
Formulation 
• Aqua 
purificata 3.0 g 
• Ung. 
Cholesterol 5.0 
g 
Administration: 
topical 
ointment 
applied and 
rubbed gently 
over the skin 
surface 
(4x4cm) of 
bilateral 
masseter 
muscle. 
Apply twice a 
day for 14 days 
60 30 30 CBD: 
23.2 
Contr
ol: 
22.6 
1. VAS 
(changes of 
mean day 
14 from 
baseline 
day 0) 
Statistically significant 
difference was noted in the 
change of VAS from baseline 
for both CBD (p<0.0001) and 
control (p=0.011) 
There was no adverse report 
observed in the study 
The application of CBD 
formulation over 
masseter muscle 
reduced the masseter 
muscles activities and 
improved the 
myofascial pain 
condition. 
 2. EMG of 
masseter 
muscles 
(changes of 
mean day 
14 from 
baseline 
day 0) 
There was significant 
difference in the EMG of 
bilateral masseter muscles 
(p<0.0001) compared to 
control group 
 
Jo
ur
na
l P
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-p
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of