From Volume 50, Issue 6, June 2023 | Pages 512-515
Chronic neuropathic orofacial pain is an extremely debilitating disorder that poses a burden to patients as well as the economy. Although a common condition, the management and treatment for those affected remains limited. Cannabidiol is a safe, non-psychoactive compound derived from the
Chronic pain can be defined as persistent pain after an inflammatory response to an acute cause has stopped.1 The prevalence of chronic pain among the UK population is high, with a meta-analysis estimating that chronic pain affects between 33.3% and 50% of the UK population, of whom 10.4% and 14.3% report ‘moderate’ or ‘severely’ disabling limitations associated with chronic pain.2 Furthermore, chronic pain is an economic burden, costing the UK economy £10 billion yearly.3
Chronic orofacial pain makes up 20–25% of chronic pain conditions.4,5 Chronic orofacial pain can be felt along the sensory nerve supply of the trigeminal system, affecting regions of the face, mouth and anterior scalp. Chronic pain falls into two classes: pain that is derived from nerves (neuropathic pain); and persistent inflammatory pain. Hapak and colleagues divide neuropathic pain into neurovascular (eg chronic migraine headaches and cluster headaches), neurological (eg primary and secondary neuropathies) and idiopathic origin (eg burning mouth syndrome).6
The majority of neurovascular-type pain presents as headache conditions, with migraines being the most common primary headache disorder.7 Migraines present as severe, unilateral or bilateral pulsating throbbing pain, that worsens with exertion and improves with rest. Migraine is highly debilitating, and when occurring for more than 15 days is termed chronic migraine. The prevalence of chronic migraines is higher in the female population (17–22%) than in males (6–10%).7,8
Neurological pain can be categorized into primary and secondary neuropathies. Primary neuropathies are characterized by unilateral episodes of short, sharp paroxysmal pain spreading across branches of the trigeminal nerve (trigeminal neuralgia) or glossopharyngeal nerve (glossopharyngeal neuralgia). Secondary neuropathic pain includes aetiologies such as those induced by chemotherapy and post-traumatic neuropathies. Post-traumatic neuropathies, where injury to the trigeminal nerves occurs most frequently in the inferior alveolar nerve and lingual nerve owing to third molar surgery, implant placement, and delivery of local anaesthesia.9 Provoking factors associated with primary and secondary neuropathies include pain that is stimulated by non-noxious stimuli, termed allodynia. When elicited from mechanical stimulation, such as talking, eating and brushing teeth, this is termed mechanical allodynia. Mechanical allodynia can be caused by low thresholds of A-beta fibres or nociceptors (pain), with thermal allodynia related to hyperexcitability of A-delta fibres (cold). Other provoking factors include mechanical hyperalgesia, where abnormal nociceptive inputs result in increased pain with painful stimulation. Allodynia is one of many complications that can result from traumatic neuropathy, which results in social disability and reduced quality of life.10 Some medications, used in chemotherapy for cancer patients, are associated with iatrogenic peripheral sensory neuropathies, presenting as signs of chronic neuropathic orofacial pain, including allodynia and hyperalgesia.
Idiopathic pain can vary from intermittent or constant spontaneous pain, produced by noxious stimuli associated with provoking factors, such as allodynia, or dysaesthetic pain that can be burning in nature.11 Burning mouth syndrome (BMS), otherwise known as stomatodynia, is defined as a burning sensation or dysaesthesia, where no medical or dental cause can be found in an otherwise intact and normal oral mucosa.12 The management of this condition is difficult owing to the absence of research into the underlying aetiology. The highest level of evidence for treatment can be seen with cognitive behavioural therapy, with some evidence for gabapentin and tricyclic antidepressants.13
The primary treatment of chronic neuropathic orofacial pain is pharmacological management. The National Institute for Health and Care Excellence (NICE) recommends initial treatment with antidepressants (amitriptyline or duloxetine), and anticonvulsants (gabapentin or pregabalin). Trigeminal neuralgia is treated with carbamazepine.14 Many of these medications are costly, with a review finding the total cost of gabapentin and pregabalin to the NHS was £237.9M in 2013.15 Furthermore, there is evidence of unwanted drug interactions and adverse reactions. Carbamazepine has been reported to interact with medication regularly seen in dental practices, such as anticoagulants (eg DOACS), antibiotics (eg clarithromycin, erythromycin) and antifungals (eg fluconazole, miconazole) restricting its use for some patients.16 A systematic review found that 65% of patients on carbamazepine experienced adverse events, such as dizziness and drowsiness.17 There has been a sharp increase in the prescription of amitriptyline, with it now being used more commonly to treat pain than depression.18 Although amitriptyline is used for the treatment of neuropathic pain, a systematic review has found that there is a lack of supportive unbiased evidence for its beneficial effect, with few studies meeting the most recent research standards.19
There is also a lack of data that warrants surgical treatment for patients with chronic neuropathic orofacial pain. Techniques, such as microvascular decompression for the treatment of trigeminal neuralgia, risk long-term complications such as facial paraesthesia after surgery.20 Early diagnosis of trauma-related neuropathy is key for optimal neurological recovery; however, there is a lack of evidence for reparative surgery, making it evident that new choices for intervention should be sought.12
Chronic neuropathic orofacial pain is a highly debilitating condition that is associated with a poor quality of life. Treatment of these conditions is difficult, with some medication associated with potential adverse outcomes, or lack of evidence to support reparative surgery in practice. A novel medication that is safe and cost-effective for the treatment of chronic neuropathic orofacial pain should be considered for these patients.
Cannabidiol (CBD) belongs to a group of chemicals, named cannabinoids, derived from the Cannabis sativa plant. Cannabinoids can be classified as endocannabinoids (produced naturally in the body), phytocannabinoids (found in Cannabis sativa), and synthetic cannabinoids (manufactured artificially). Research into the role of CBD has revealed that it plays an important role in the management of chronic pain.21,22 CBD, unlike cannabinoid Δ9-tetrahydrocannabinol (THC), is a non-psychoactive component of the cannabis plant.
The toxicity of CBD has been reviewed and has been found to be low in humans.23 Research undertaken by the World Health Organization found CBD maintains a good safety profile, with no reports of abuse or dependence demonstrated.24 However, guidance from NICE showed gaps in its safety profile when used in the treatment of chronic pain in children and mothers who are pregnant or breastfeeding. CBD is therefore not advised in these groups, especially if taking other medication.25 CBD is metabolized in the liver and excreted through the kidneys, therefore patients with renal or hepatic impairment may have reduced clearance. Dose titration for patients with hepatic or renal failure is advised.26 CBD may interact, and cause an increased risk of bleeding, with antiplatelet/anticoagulant medication (eg warfarin), CBD may also increase the concentration of clobazam, phenytoin and ketoconazole, alone, and with traces of THC.27
CBD regulation worldwide is complex and everchanging; however, with its ever-growing acceptance, many countries around the world have begun to modify their national controls to accommodate CBD as a medical product.24 In the UK, CBD in its pure form (Epidyolex, GW Pharmaceuticals, Cambridge, UK) is not controlled under the Misuse of Drug Acts, and is only controlled if it contains more than 0.2% THC.28 Across Europe and the US, the limit of THC varies considerably, with countries such as Switzerland allowing a limit of 1%, the Netherlands 0.05%, and the US has a limit of 0.3%.29–31 Although most countries in Europe have similar THC limits to the UK (0.2%), the varying restriction and limits of THC across the world may cause difficulties in setting up standardized concentrations for research trials, and be problematic when producing and selling CBD across the globe.
CBD is available as a medical product and retailed as a supplement. As a medical product, CBD is sold in its pure form as Epidyolex, administered as an oral liquid. In the UK, Epidyolex has been licensed as a medication, along with clobazam, for the treatment of seizures associated with Lennox–Gastaut syndrome and Dravet syndrome.32
As an unregulated supplement, CBD is sold as an oil, gel, sweet and drink. To be sold in the UK, these products require authorization to be safe for humans and the environment, and to have a legal level of THC less than 0.2%.33 Currently approved supplements contain CBD concentrations that vary from 1% to 15%, and dosages range between 10 and 3000 mg.34 The UK Food Standards Agency is in agreement with NICE in advising that CBD supplements are not to be taken by pregnant/breastfeeding women, or those taking other medication.25,33
Data from the Department of Health and Social Care found the average price of cannabis-based products for medical use per mg of CBD was £0.30/mg.35 The NICE guidance found estimates of the cost-effectiveness of CBD to be uncertain in the treatment of Lennox–Gastaut and Dravet syndrome; however, CBD was still considered an appropriate NHS resource for the treatment of these epileptic disorders.25
CBD supplements have rapidly entered the UK market, with many high street shops now specializing in CBD products for its recreational use as a vapour, injected into other foods as ‘edibles’, and incorporated into beauty products.36 The recreational use of CBD supplements is thought to bring many health benefits to the body, with users predominantly consuming the product for the management of chronic pain.37 A YouGov poll found 71% of consumers use the product for pain relief, and 38% for anxiety and depression.38 The proposed health benefits are not currently recognized by NICE, who have emphasized that CBD should currently not be used as an alternative to prescribed medication.25
A summary of the arguments for and against CBD as licenced medication for the potential treatment of chronic neuropathic pain is seen in Table 1.
| Pros | Cons |
|---|---|
| Some evidence shows CBD can reduce chronic pain |
Evidence is limited, and there is a shortage of long-term research to back proposed benefits |
The endocannabinoid system is complex, and regulates various functions within the body, including, but not limited to, learning and memory, anxiety, addiction, cardiovascular system, and modulation of pain. CBD binds receptors within and outside the endocannabinoid system to produce pain-modulation effects, regulating receptors within the central nervous system and immune system. CBD exhibits potent anti-neuropathic and anti-nociceptive activity by targeting certain transient receptor potential (TRP) channels, such as TRPV1 and TRPA1.21,39 TRPV1 channels have been shown to modulate thermal pain within the periodontal tissue and dental pulp.40 CBD also shows anti-inflammatory and anti-nociceptive activity via activation of serotonin 1a receptor (5-HT1a).41
CBD may play a role as a therapeutic medication in the treatment of chronic neuropathic orofacial pain, with several studies have already been published.21,42,43
In neurovascular pain conditions, such as chronic migraines and cluster headaches, a prospective trial investigating the use of CBD, in conjunction with THC, against both these conditions was undertaken.44 The trial used Bedrolite (Bedrocan, Netherlands), which contains <0.4%THC and 9% CBD, in combination with Bedrocan (Bedrocan, Netherlands) containing 19% THC. Researchers found that 200 mg (Bedrolite and Bedrocan) reduced the intensity of chronic migraine pain by 55%, but not significantly when compared with amitriptyline. However, a 400-mg dose significantly decreased pain intensity in patients with cluster headaches by 43.5%. The limitations of this study lie with the use of Bedrolite, which is not legal in the UK due to its THC content being more than 0.2%. Furthermore, the mechanism by which this therapeutic action was induced was unknown. Further investigation should compare pure CBD, without high concentrations of THC, with amitriptyline, to establish the efficacy for the treatment of chronic migraines and cluster headaches.
A pre-clinical study explored CBD treatment of secondary neuropathic neurological pain induced by chemotherapeutic agents. The effects of CBD were assessed in mice that had been administered paclitaxel, a medication used to treat several types of cancer, which can cause iatrogenic mechanical and thermal allodynia. CBD, when delivered via an intraperitoneal route (5 or 10 mg/kg) was found to prevent the development of allodynia in these mice.42 The proposed mechanism was through 5-HT1a receptor modulation, to which CBD binds producing anti-neuropathic effects. Furthermore, Costa et al found that CBD reversed thermal and hyperalgesia in rat models of chronic neuropathic pain, predominantly via its agonistic action on TRPV1.21 CBD may, therefore, prove to be a novel medication that is able to reverse the iatrogenic damage of chemotherapeutic agents for cancer patients.
A pre-clinical study observing rat models of post-traumatic neuropathy, found CBD reduced mechanical allodynia during a 7-day administration with 10 mg/kg/day through activation of TRPV1 channels.43 It is interesting to find that 5-HT1a, a key modulator of pain, was not involved in the anti-allodynic effects of CBD, but rather anxiolytic. CBD may therefore play role in the prevention of trauma-induced allodynia; however, more data are required to assess its significance, and research should focus on iatrogenic trigeminal nerve injury.
The role of CBD in the treatment of idiopathic facial pain has not been researched. A pilot study observing patients with BMS treated orally with oil derived from Cannabis sativa, found the substance was well tolerated and caused significant remission of oral symptoms.45 However, the CBD oil used contained 8% CBD and THC levels of 6.3%, which are too high to be legal within the UK. By using such high doses of THC in the experiment, the effectiveness of CBD alone in the treatment of BMS is questioned. Future research should ideally compare CBD as a pure substance to establish efficacy for treatment. Although the proposed mechanism has not been investigated, TRPV1 is a critical mediator of thermal hyperalgesia and has been linked to increasing levels of pain in patients with BMS.46 Borsani and co-workers explored the expression of cannabinoid receptors in patients with BMS, and found significant expression of the ion channel receptor TRPV1.47 TRPV1 agonistic activation by capsaicin, a chemical derived from chillis, was shown to desensitize sensory nerve endings, producing a reduced pain perception.48 As CBD binds to TRPV1, it may act like capsaicin and act as a desensitizing agent, but this hypothesis will require investigation.
The management of chronic neuropathic pain continues to be a challenge. Current treatments are costly and associated with adverse reactions, therefore, the therapeutic potential of CBD should be investigated in high-quality clinical trials. With the growing popularity of CBD in society, and encouraging evidence on its therapeutic effects in alleviating chronic neuropathic pain, CBD may be a potentially improving treatment choice for these patients. Future research must improve on the homogeneity of CBD use, as many studies have used CBD in conjunction with varying levels of THC higher than legally allowed in the UK. It is the authors' opinion that researchers should investigate CBD in its purest form for the treatment of chronic neuropathic orofacial pain, using a standardized medical product, such as Epidyolex.
