Applications of Cannabinoids in Neuropathic Pain: An Updated Review

Abstract

Neuropathic pain is experienced due to injury to the nerves, underlying disease conditions or toxicity induced by chemotherapeutics. Multiple factors can contribute to neuropathic pain such as central nervous system (CNS)-related autoimmune and metabolic disorders, nerve injury, multiple sclerosis and diabetes. Hence, development of pharmacological interventions to reduce the drawbacks of existing chemotherapeutics and counter neuropathic pain is an urgent unmet clinical need. Cannabinoid treatment has been reported to be beneficial for several disease conditions including neuropathic pain. Cannabinoids act by inhibiting the release of neurotransmitters from presynaptic nerve endings, modulating the excitation of postsynaptic neurons, activating descending inhibitory pain pathways, reducing neural inflammation and oxidative stress and also correcting autophagy defects. This review provides insights on the various preclinical and clinical therapeutic applications of cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN) in various diseases and the ongoing clinical trials for the treatment of chronic and acute pain with cannabinoids. Pharmacological and genetic experimental strategies have well demonstrated the potential neuroprotective effects of cannabinoids and also elaborated their mechanism of action for the therapy of neuropathic pain.

I. INTRODUCTION

Cannabis, a drug derived from the flowers and buds of the Cannabis sativa plant is used therapeutically for various diseases for centuries.^1,2 Since 2700 B.C., it is used by the ancient Chinese people for various medical practices such as rheumatic pain, intestinal constipation, disorders of the female reproductive system and malaria.² Cannabinoids are basically C21 terpenophenolic group of compounds present in Cannabis sativa L., which include their analogs and transformation products.³ However, cannabinoids in a broader sense refer to all cannabinoid receptor ligands and its related compounds including endogenous cannabinoid receptor ligands and synthetic cannabinoid analogs.⁴ Based on the source of derivation, these are classified into three types, which include (a) endocannabinoids (eCBs), endogenous animal derivatives of polyunsaturated fatty acids (PUFAs); (b) phytocannabinoids (pCBs), obtained from plants; and (c) synthetic cannabinoids. Majority of the phytocannabinoids are present in female flowers and in most aerial parts of the cannabis plants.⁵ DeltΔ9-tetrahydrocannabinol (Δ9-THC), deltΔ8-tetrahydrocannabinol (Δ8-THC), and cannabinol (CBN) are examples of psychoactive cannabinoids found in cannabis plants. Cannabichromene (CBC), cannabidiol (CBD), and cannabigerol (CBG) are common non-psychoactive pCBs present in cannabis plants.⁶ Many subclasses of cannabinoids have been identified, which includes CBG, the first cannabinoid to be known; cannabigerolic acid (CBGA; carboxylic acid form of CBG), the earliest known biosynthetic cannabinoid produced in cannabis plants; CBC: five CBC type cannabinoids are known mostly with C5 and a few with C3 side chains; CBD: seven CBD-type cannabinoids have been identified containing Cl, C3, C4, or C5 side chains among which C5 is prevalent; Δ9-THC and Δ8-THC types. CBG, a non-psychoactive phytocannabinoid is present in high concentrations in Cannabis sativa. CBGA is the precursor of other essential phytocannabinoids.⁷ CBN and cannabinodiol (CBND) are aromatized derivatives (Fig. 1), which are formed due to air oxidation of THC and CBD, respectively.⁴ THCV, a naturally occurring analog of THC is non-psychoactive, neutral CB1 antagonist and functions as an agonist/antagonist of CB2 receptors depending on its dose. However, THC is psychoactive and acts as a CB1 and CB2 receptor agonist. THCV unlike THC causes hypophagic effects under fasting and non-fasting in mice.⁸ Over 150 unique terpenes and 100 different cannabinoids have been identified from various types of cannabis resins.⁹ Monoterpenes such as myrcene, and sesquiterpenes such as β-caryophyllene, α-humulene, bisabolo, and β-famesene are the common terpenes found in most cannabis strains.¹⁰

FIG. 1:

Chemical structures of some phytocannabinoids and synthetic cannabinoids

A. The Endocannabinoid System

Each of the numerous active cannabinoids identified in Cannabis sativa can modulate the body’s endocannabinoid system (ECS).¹¹ Endocannabinoids are produced naturally in the human body, which act as lipid mediators by binding to cannabinoid receptors. ECS is made up of endogenous ligands, cannabinoid receptors and the enzymes responsible for their synthesis and degradation.^11,12 It plays a vital role in the regulation of numerous cognitive and physiological processes of the CNS such as pain, mood, appetite, stress, and memory.^12–14 ECS also regulate physiological processes in the bone, reproductive system, heart, gastrointestinal tract and many other systems.^15–19 Phytocannabinoids are exogenous ligands for numerous receptors of the ECS.¹⁹ Many cannabinoids which are structurally and functionally analogous to the endocannabinoids have been synthesized.^20–22 CB1 and CB2 are the two main isolated endocannabinoid receptors.²⁰ CB1^21,22 and CB2²² receptors belong to the rhodopsin (Rho) family (class A) of G-protein coupled receptors (GPCRs). CB1 receptors are mainly found on the neural tissue consisting of the enteric nervous system and central and peripheral neurons.²³ CB2 receptors are mostly present in immune tissues such as T and B cells, neutrophils, epithelial cells, macrophages as well as in the CNS.^23,24 Figure 2 shows the distribution of the CB1 and CB2 in the human pain system. Generally, CB1 and CB2 receptors signaling are involved in the regulation of neuromodulatory and immunomodulatory functions respectively. CBG shows low binding affinity for CB1 and CB2 receptors.^25–27 ECS is affected due to the ability of CBG to inhibit anandamide (AEA) uptake.²⁸ In vitro studies demonstrate that CBD shows weak antagonistic effects towards CB1 and CB2 receptors^29,30 despite the findings of several reports showing its lack of affinity for these receptors.³¹

FIG. 2:

Localization of the cannabinoid receptors in the pain perception system of humans. The cannabinoid receptor 1 (CB1) is highly expressed in the peripheral nervous system (PNS) such as the sympathetic nerve terminal and in the brain (CNS). They are also observed in the dorsal root ganglion, dermic nerve endings of the primary sensory neurons. Cannabinoid receptor 2 (CB2) is less abundant in the CNS and PNS as compared to CB1.

B. Applications of Cannabinoids

Figure 3 summarizes the various applications of cannabinoids in medicine. Several studies have shown that cannabinoids have clinical applications in various diseases which are as follows.

FIG. 3:

Therapeutic applications of cannabinoids

1. Inflammatory Bowel Disease and Digestive Disorders

Inflammatory bowel diseases (IBD) are chronic immune-mediated diseases which include ulcerative colitis (UC) and Crohn’s disease (CD).³² Symptoms of IBD include periods of inflammatory flares, quiescence, and relapse, which affects the patient both psychologically and emotionally.³³ The ECS, present throughout the gastrointestinal tract has been shown to play a role in regulating food intake, emesis, gastric secretion, visceral sensation and intestinal inflammation.³⁴ Animal studies have shown that CB1 receptor agonists reduces gastrointestinal propulsion and transit.^35,36 A study by Borrelli et al. has shown the benefits of CBG in the treatment of inflammatory bowel disease using a murine colitis model by the administration of dinitrobenzene sulphonic acid (DNBS) intracolonically. CBG reduced murine colitis, the macrophage production of nitric oxide and ROS production in intestinal epithelial cells.³⁷

2. Cancer and Tumors

Inflammation, apoptosis and antioxidant defensive mechanisms play a pivotal role in progression of various cancers.^38–42 There are several ongoing research into nanodrug delivery systems (NDDSs) such as liposomes to improve the safety and efficacy of chemotherapeutic agents.^42–44 The use of immunotoxins for cancer treatment have also been well explored.^42,45 CBG has been shown to bind to specific targets, which play a role in the prevention of various cancers. It is reported to be effective in xenograft models of colon cancer by acting as a TRPM8 antagonist, increasing the production of reactive oxygen species (ROS) and activating apoptotic pathways.⁴⁶ Cannabinoids administered through inhalation route in combination with nanomaterials have shown good efficacy in lung cancer.⁴⁷ Moreover, intratumoral administration of low doses of cannabinoids can also enhance the effectiveness of chemotherapeutics.^48–50 Combination of cannabinoids and radiotherapy also showed good anti-cancer efficacy in glioma and pancreatic cancer.⁵¹ Common side effects of cytotoxic chemotherapy such as muscle wasting, anorexia, and metabolic dysregulation pose dose-limiting effect on the efficacy of cannabinoids, which affects the quality of life and mortality. Cannabis sativa extracts and analogues of the major phytocannabinoid, Δ9-THC have been used to treat chemotherapy-induced appetite loss and nausea, but psychoactive side effects limit their clinical usage. In a study by Brierley et al., CBG has been shown to stimulate appetite in healthy rats without neuromotor side effects in an acute cachectic phenotype model induced by cisplatin (6 mg/kg i.p.) in male rats.⁵² CBG (120 mg/kg) modestly increased food intake, mainly at 36–60 h, and strongly attenuated cisplatin-induced weight loss from 6.3% to 2.6% at 72 h, demonstrating the potential of CBG for the treatment of chemotherapy-induced cachexia.⁵² An in vitro study by Zhang et al. has demonstrated that CBD inhibits the proliferation and colony formation of human gastric cancer (SGC-7901) cells,⁵³ during which an upregulation in the expression of p53 and ataxia telangiectasia-mutated gene (ATM) as well as a downregulation in the expression of p21 protein are observed after CBD treatment. CBD was shown to increase Bax expression and decrease Bcl-2 expression levels, which eventually results in upregulation of cleaved caspase-3 and 9, finally leading to apoptosis.⁵³ CBD increases intracellular reactive oxygen species levels and causes cell cycle arrest at the G0-G1 phase in gastric cancer cells. CBD has been reported to induce apoptosis through various mechanisms including caspase activation and ROS formation in human glioma (U87 and U373) cells.⁵⁴ The growth of C6 glioma cells was inhibited when co-cultured with CBD and tamoxifen.⁵⁵ Several reports have shown the ability of CBD to inhibit tumor cell proliferation and metastasis by inducing autophagy or apoptosis.^56,57

Non-psychoactive phytocannabinoids (pCBs) derived from Cannabis sativa could be a novel therapeutic option for treatment of cachexia due to their pleiotropic pharmacological activities such as appetite stimulation. A study in rats by Brierley et al. has shown that purified CBG is an appetite stimulant.⁵⁸ The effects of CBG-rich botanical drug substance (BDS), a potent non-psychoactive extract of Cannabis on feeding behavior was investigated and an increase in the total food intake was observed with CBG-BDS treatment group. CBG-BDS was concluded to be a novel appetite stimulant, which may be more potent than purified CBG and is devoid of psychoactive Δ9-tetrahydrocannabinol.⁵⁸

3. Ocular

A study by Colansanti et al. has demonstrated that topical chronic administration of CBN/CBG using osmotic minipumps induced reduction of intraocular pressure (IOP) in cats. However, CBN unlike CBG caused conjunctival erythema and hyperemia.⁵⁹ Different concentrations of CBN and CBG were given as a single drop or chronically using osmotic minipumps for 9 days. A single dose of CBN showed moderate effect on intraocular pressure after a single dose and it caused a more significant reduction in ocular tension during chronic administration. Although CBG had similar effects, the response was greater than CBN. A pilot study by Tomida et al. has assessed the effects of low doses of CBD and Δ−9-THC on intraocular pressure (IOP) when administered through sublingual route. In this study, various concentrations of CBD and Δ−9-THC were given to six patients with ocular hypertension or early primary open angle glaucoma. IOP was temporarily reduced by a single 5 mg sublingual dose of Δ−9-THC. However, 20 mg CBD did not show reduction in IOP, whereas there was a transient increase in IOP when 40 mg CBD was administered sublingually.⁶⁰

4. Obesity and Metabolic Disorders

Fellous et al. explored the potential therapeutic effects of Cannabis sativa plant (or phytocannabinoids) derived non-euphoric compounds including tetrahydrocannabivarin (THCV), CBD, CBG, cannabidiolic acid (CBDA) and CBGA on the growth of endogenous BM-MSCs and the alterations on cellular differentiation into mature adipocytes.⁶¹ In vitro and in vivo experiments revealed that 5 μM of CBD, CBDA, CBGA and THCV increase the viability of BM-MSCs. CBG and CBD either alone or in combination stimulate BM-MSCs to mature into adipocytes via distinct molecular mechanisms. Phytocannabinoids further prevented the palmitate-induced insulin signaling impairment in adipocytes differentiated from BM-MSCs. Phytocannabinoids were suggested as a potential novel pharmacological tool to regain control of the functionality of adipose tissue in metabolic disorders such as type 2 diabetes mellitus (T2DM) and lipodystrophy.⁶¹

5. Skin Disorders

All the classes of cannabinoids interact with the skin cannabinoid receptors and regulate the pathways, which affect the homeostasis and metabolism of skin appendages and cutaneous cells.⁶² Due to the ability of phytocannabinoids to inhibit keratinocytes proliferation and modulate even the associated inflammatory components, phytocannabinoids serve as a potential treatment for psoriasis.⁶³ A patent was filed in 2019 on topical CBD and CBG treatment for psoriasis. CBD and CBG have been shown to be effective in trail subjects in a dose-dependent manner by inhibiting inflammatory cytokines and angiogenic growth factors.⁶⁴ A study in mice has shown that topical administration of phytocannabinoids effectively alleviate 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced erythema.⁶⁵ Several in vitro and in vivo experiments have reported that phytocannabinoids inhibit sebocytes proliferation and decrease pro-inflammatory cytokines expression and sebum production. A decrease in erythema and sebum production without side effects were confirmed in a human trial which involved topical application of phytocannabinoids for 12 weeks.^66–68 On the contrary, CBG and cannabigerovarin (CBGV) increased sebum production in human sebocytel (SZ95) cells.^28,69

6. Neurological Disorders and Neurodegenerative Diseases

CBD functions as an anti-inflammatory and neuroprotective agent in neurodegenerative disorders. A study by Rajan et al. has demonstrated that CBD reversed alterations of various genes associated with oxidative stress, mitochondrial dysfunction and pathology of amyotrophic lateral sclerosis (AML) using an in vitro model system of human gingiva-derived mesenchymal stromal cells (hGMSCs).⁷⁰ Double-blind, randomized cross-over design revealed that CBD was neither effective nor toxic at a dose of 700 mg/kg in neuroleptic-free patients diagnosed with Huntington’s disease (HD).⁷¹ A study by Zuardi et al. has demonstrated that CBD decreased stereotypy induced by dopaminergic agonists but did not induce catalepsy, an extrapyramidal side effect of antipsychotics such as haloperidol.⁷² CBD at higher doses of greater than 120 mg/kg increased prolactin levels, a side effect observed similar to clozapine treatment, indicating that CBD acts as atypical antipsychotic agent. CBD decreases hyperlocomotion and prepulse inhibition (PPI) impairment induced by amphetamine, glutamate NMDA receptor non-competitive antagonists such as ketamine and MK801 in rats and mice.^73–76 CBD independent of NGF has showed neurorestorative potential in MPP+ model of Parkinson’s disease.⁷⁷ CBD shows reduced affinity towards endocannabinoid receptors but higher towards Transient Receptor Potential Vanilloid receptor type 1 (TRPV1). TRPV1, a non-selective channel in its active form facilitates glutamate release and Ca²⁺ permeability, which cause neuronal excitability in epilepsy. Anti-epileptic action of CBD involves desensitization of TRPV1channels and normalization of intracellular Ca²⁺ levels.⁷⁸ CBD also shows high affinity towards serotonin receptors such as 5-HT_1A and 5-HT_2A, which differ in their characteristics and functions. 5HT₁ receptors activated in the hippocampus increase neurotransmission whereas 5-HT_1A receptor activation in raphe nuclei leads to serotonergic neurons inhibition.⁷⁹ Δ9-THC and CBD are used therapeutically for central nervous system (CNS) diseases such as epilepsy, anxiety, depression and schizophrenic psychosis because of their neurological actions and lipophilic nature. However, Δ9-THC and CBD differ in their penetrability and disposition in the brain. The positive effects of cannabinoids on cognitive function could be due to their protective effect on blood brain barrier (BBB), cerebrovascular structure and function. CBD will not be converted to THC by the biosynthetic enzymes or pathways present in the human body. However, CBD rapidly gets cyclized to THC in acidic pH conditions of stomach, which suggests that oral administration of CBD can cause some side effects due to its conversion to THC. This study also suggests the need to explore other routes of administration such as transdermal-based for delivery of CBD in order to reduce the formation of psychoactive cannabinoids.⁸⁰ THC causes psychomotor and cognitive impairments, increased heart rate and dry mouth. However, these effects were not observed when CBD is administered orally at high doses to healthy individuals orally.^81,82 In another study, oral CBD (1 mg/kg body weight) administered together with THC (0.5 mg/kg body weight) to health volunteers minimized THC-induced anxiety. This shows that of CBD blocks THC-induced anxiety.⁸³ Oral CBD (600 mg) pretreatment significantly reduced anxiety, cognitive impairment, and discomfort in patients with generalized social anxiety disorder.⁸⁴ A double-blind study conducted at the University of Cologne revealed that CBD administered orally at a dose of 800 mg daily for 2–4 weeks showed efficacy in 42 patients with schizophrenia or schizophreniform disorder but side effects such as extrapyramidal symptoms, increased prolactin levels, and weight gain were observed.⁸⁵ CBD enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia by increasing serum anandamide levels, which suggests that anandamide deactivation inhibition may be responsible for the antipsychotic effects of CBD in the treatment of schizophrenia.⁸⁵

7. Cardiovascular

The cardiovascular effects of both synthetic and endogenous cannabinoids have been well demonstrated in numerous studies.^86–89 The key component of cannabis, Δ9-THC causes tachycardia in humans. Phytocannabinoids induce cardiovascular effects, which vary from one species to another. Cardiovascular effects observed with Δ9-THC are different in animals when compared to humans.^90,91 Δ9-THC causes tachycardia in humans, and conscious monkeys,⁹² whereas bradycardia in other animal models.^93–95 The main CYP of cardiomyocytes, CYP2J2, metabolizes AEA into cardioprotective epoxides (EET-EAs). Arnold et al. assessed the CYP2J2 metabolism kinetics with AEA, Δ9-THC, Δ8-THC, CBN, CBD, CBG, and CBC.⁶ Phytocannabinoids are observed to be highly catalyzed by CYP2J2 when compared to AEA. Moreover, these phytocannabinoids strongly inhibit the metabolism of AEA by CYP2J2 of which Δ9-THC has shown the strongest inhibition.⁶ A study by Hao et al. has revealed the cardioprotective potential of CBD in doxorubicin-induced cardiotoxicity model.⁹⁶ Doxorubicin (DOX), a common broad-spectrum chemotherapeutic drug is limited by its dose-dependent cardiotoxicity, which may cause irreversible cardiomyopathy or heart failure.⁹⁷ DOX induces cardiotoxicity by oxidative stress,^98,99 nitrosative and nitrative stress,^100,101 dysfunction/toxicity of the mitochondria,^97,102–104 activation of proteins associated with apoptosis and necrosis,¹⁰⁵ as well as metabolic and lipid signaling pathway dysregulation.^106–108 There was significant improvement in DOX-induced cardiac dysfunction, cell death and oxidative/nitrative stress after CBD treatment. CBD promoted biogenesis and cardiac mitochondrial function, which were impaired by DOX.⁹⁶

8. Arthritis and Pain

Oral, parental and topical administration of nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, diclofenac, ibuprofen, and naproxen are used as a current treatment for various types of arthritis (rheumatoid arthritis, septic arthritis, juvenile idiopathic arthritis).¹⁰⁹ Arthritis requires continuous administration of drugs to sustain the quality of life in patient and the major problem encountered is the side effects of these drugs. Novel strategies and targets are being researched as alternate treatment options to relieve the pain caused by arthritis.¹¹⁰ CBD has been successfully delivered for treatment of inflammation in different species via transdermal route.^111–113 Despite its hydrophobicity and poor oral bioavailability, CBD has been shown to reduce inflammation and pain without side effects. A study by Hammell et al. demonstrates the efficacy of transdermal delivery of CBD in rats in reducing inflammation and pain in a Freund’s adjuvant-induced monoarthritic knee joint model.¹¹⁴ CBD gels ranging from 0.6 to 62.3 mg/day showed reduction in joint swelling, infiltration of immune cells as well as synovial membrane thickening in a dose-dependent manner. A dose dependent decrease in pro-inflammatory markers were observed in the spinal cord and dorsal root ganglia.¹¹⁴ Pain possesses somatosensory, motivational, cognitive, and affective properties,¹¹⁵ and is an experience that engages various parts of the brain and constitute different neurochemical mechanisms.¹¹⁶ Currently, the use of scaffolds as a drug delivery matrix have been successful in various fields of tissue engineering such as bone formation, periodontal regeneration, cartilage development, for artificial corneas, in tendon repair and ligaments as well as in tumors. They are also used in joint pain inflammation, osteochondrogenesis, and wound dressings.¹¹⁷ Cannabinoids including THC, CBD and synthetic cannabinoids have been reported in rodents to promote eCB action in decreasing pain, inflammation, depression, and anxiety similar to the effects of direct CB1 agonists.^118–123

B. What is Peripheral Neuropathy?

Peripheral neuropathy (PN) involves damage to multiple parts of the peripheral nerve extending from the cell body (i.e., the dorsal root ganglion or anterior horn cell) to the cell projection itself, with its myelin outer coating and axonal projection.¹²⁴ Factors responsible for the development of PN include diabetes mellitus, shingles, exposure to toxins such as lead and chemotherapies, vitamin B12 deficiency, alcoholism, autoimmune disorders such as rheumatoid arthritis, Lyme disease, syphilis, HIV, etc.¹²⁵ It can affect motor, sensory or autonomic fibers depending on the underlying cause.¹²⁵

II. CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY (CIPN)

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious unwanted side effect associated with the therapeutic usage of some chemotherapeutic agents in cancer patients.¹²⁶ Substances that can damage the peripheral sensory and motor neurons and cause CIPN are categorized into six groups: (a) platinum based antineoplastic drugs (oxaliplatin and cisplatin); (b) immunomodulatory drugs such as thalidomide; (c) vinca alkaloids (vincristine and vinblastine); (d) epothilones (ixabepilone); (e) proteasome inhibitors (bortezomid); and (f) the taxanes (paclitaxel and docetaxel).¹²⁷ Therapeutic usage of these drugs induce anti-cancer effects and peripheral neuropathy through different mechanisms, which include mitochondrial dysfunction, oxidative stress, microtubule disruption, neuroinflammation, and ion channel dysregulation.¹²⁸ These drugs cause peripheral sensory symptoms such as paresthesia, dysesthesia, pain, numbness, tingling, and sensitivity to touch and temperature and motor symptoms such as weakness, gait and balance disturbances.¹²⁹ CIPN is a common clinical problem that affects about 30–40% of patients receiving neurotoxic chemotherapy and leads to a significant increase in the annual healthcare costs.¹³⁰ Patients receiving chemotherapy have common side effects of which CIPN is not an exception. CIPN is characterized by symptoms such as nerve pain in the upper and lower extremities, loss of sensory and motor nerves. A systematic review on the assessment of the incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy revealed that the prevalence rate of CIPN is 68.1% and 60.0% during the first and third month after chemotherapy.¹³¹

There are varying severities of the side effects of anticancer therapies, and some can persist over several years. A review by Stone and DeAngelis demonstrated that more than 20 chemotherapy treatments and radiotherapies may lead to syndromes, which affect the central and peripheral nervous system (PNS) irrespective of the primary disease.¹³² PNS complications have been observed with at least 21 distinct chemotherapy agents including cisplatin, carboplatin and oxaliplatin.¹³² Pain relates to the interruption of sensory function due to large myelinated sensory fibers damage. In CIPN, there is a general damage of PNS which affects motor and autonomic functions. PNS damage can be caused by oxidative stress, calcium homeostasis alterations, axon degeneration and membrane remodeling which results from neuroinflammation and activation of apoptotic pathways.¹³³ Several studies have shown the effect of platinum-based chemotherapy in causing CIPN. A study by Kelly et al. showed that high concentrations of cisplatin (10–50 μM), oxaliplatin or carboplatin (100–500 μM) in rat sensory neurons cause increased cell death and apoptosis,¹³⁴ which is mostly due to reactive oxygen species production and 8-oxoguanine DNA damage accumulation.¹³⁴ The bodies of sensory neurons located in DRG are the known targets of Pt based compounds.¹³⁵ Pt-based compounds lead to morphological changes, usually observed in the nucleoli, whose form is affected by decreased production of ribosomal RNA. The formation of DNA-Pt adducts hinders transcription thereby leading to apoptosis especially in large neuronal cells, which are generally dependent on active transcription and translation.¹³⁶ A review by Zajaczkowska et al. reveals that altered excitability of peripheral neurons is caused by Pt induced ion channels deregulation and compromised mitochondrial DNA transcription.¹³⁷ Activation of microglia and astrocytes during the initial stages of neuroinflammation was observed and this study corroborates with similar observations by Colvin et al., which shows the role of cytokines in neuronal toxicity. Generally, the mechanisms which are involved for anticancer effect of various chemotherapeutics are also responsible for the neurotoxic effect they cause.¹³⁷ The combined effect of procarbazine, CCNU and vincristine (PCV) is utilized as an adjuvant therapy in cerebral glioma recurrence. A study by Postma et al. has showed that out of 26 patients with recurrent gliomas treated with PCV, four of them developed central neurotoxic side effects including focal neurological deficit, cognitive disturbances, slow EEG background activity as well as hematological and hepatic toxicity.¹³⁸ After months of chemotherapy discontinuation, prolonged myelosuppression and neurological deficits are observed in three of these four patients. The central neurotoxic effects were hypothesized to be resulting from the intensive PCV although all four patients have previously been treated with radiotherapy and anticonvulsants.¹³⁸ Breast cancer patients treated with paclitaxel who developed neuropathy showed differential expression in several pathways involved in mitochondrial dysfunction such as oxidative stress¹³⁹ in a study by Kober et al.¹⁴⁰ Bioenergetic deficits in peripheral nerves have also been observed in CIPN.¹⁴¹ A study by Flatters and Benner revealed that rats treated with paclitaxel had swollen vacuolated mitochondria that is usual of about 3 months of pain-like behaviors.¹⁴² Several animal studies have shown that chemotherapy increases oxidative stress.^143,144

III. MECHANISM OF CIPN INDUCTION BY VINCA ALKALOIDS

Vincristine is an antimitotic drug utilized for the treatment of numerous tumors and hematologic malignancies such as breast cancer, leukemia and non-Hodgkin’s lymphomas. Microtubules are essential for nerve axons function in vesicle mediated transport and interference of these by vincristine causes axonopathy, which manifests gradually.¹⁴⁵ Vincristine as a chemotherapy is essential for the treatment of pediatric malignancies including medulloblastomas and neuroblastomas. Vincristine works by binding to β-tubulin leading to the inhibition of microtubule formation, which subsequently stops cell division and interrupts cancer cell growth.¹⁴⁶ A dose-dependent peripheral neuropathy involving sensory, autonomic and motoric interruptions are observed in most of the patients during vincristine treatment.^147–150 Vincristine-induced motor neuropathy is characterized by foot drop, cramps and abnormalities in gait.¹⁵¹ Loss of sensory discrimination, tingling and numbness are sensory symptoms of vincristine-induced neuropathic pain.¹⁵² Vincristine deregulates and modifies neuronal mitochondria structurally, which leads to activation of apoptotic pathway, neuronal excitability and glial cells dysfunction.¹⁴⁶

Vincristine induced autonomic dysfunctions are characterized by symptoms such as constipation, urinary retention, orthostatic hypotension and paralytic ileus.^153,154 Although vincristine has poor blood-brain barrier penetration,¹⁵⁵ numerous reports show that vincristine treatment cause cranial nerve palsies and CNS toxicity.^156–158

IV. DIABETIC PERIPHERAL NEUROPATHY (DPN)

Diabetic peripheral neuropathy refers to diabetes mellitus induced neuropathic conditions, which vary from one another.¹⁵⁹ It is also commonly termed as distal symmetric poly neuropathy or diabetic sensorimotor neuropathy. It mainly damages the nerves present in the arms and legs. More than 80% of the people with clinical diabetic neuropathy are known to be suffering from this form of neuropathies.¹⁶⁰ DPN is defined as the presence of symptoms and/or signs in the peripheral nerves, predominantly affecting the lower extremities in the absence of other causes of neuropathy.¹⁶¹ Clinical symptoms of DPN include tingling, burning and painful sensation, sharp pin prick sensations and muscle cramps, sensitivity to touch, loss of balance and in coordination, numbness or loss of sensitivity to thermal and mechanical stimuli and insensitivity to trauma, which leads to foot ulcerations and amputations.¹⁶² DPN, a multifactorial disorder which arises due to hyperglycemia and/or insulin deficiency, is characterized by symptoms and/or signs in the peripheral nerves, which predominantly affects the lower extremities in the absence of other factors contributing neuropathy.¹⁶³ These interrelated defects lead to a progressive unmyelinated and myelinated peripheral nerve fiber loss or damage. The pathophysiology of DPN is associated with multiple factors which makes it challenging to identify targeted therapeutic regimen for this condition. Reports have shown that metabolic excess mediated damage to the endothelial cells of blood vessels supplying blood flow initiates the pathological events in the neurons and glial cells.¹⁶⁴ Conversely, metabolic excess inside the dorsal root ganglions or sciatic nerves activates many alternative metabolic pathways such as the polyol pathway, hexosamine pathway, protein kinase C pathway, AGE’s formation, etc., thereby leading to redox imbalance which initiates apoptotic pathways to kill these cells.¹⁶⁵ Accumulating literature extensively explains the involvement of autophagic deficiency, mitochondrial dysfunction, disabled mitochondrial biogenesis, inflammation, oxidative stress, endoplasmic stress, etc., in the progression of DPN.¹⁶⁵ Oxidative stress has been reported recently to play key factor in advancement of DPN.^163,166,167 Oxidative stress is promoted by hyperglycemia by both non-enzymatic and enzymatic mechanisms such as non-enzymatic protein glycation and glucose reduction to sorbitol by nicotinamide dinucleotide-linked enzyme aldose reductase (AR).^163,166 Sorbitol accumulation in the body results in the reduction of taurine, which is an endogenous antioxidant,¹⁶⁸ and osmolytes, thus leading to oxidative stress.^163,166,169

V. APPLICATION OF CBD, CBN, AND CBG IN NEUROPATHIC PAIN

Pain is classified into two main types: chronic and acute, as shown in Fig. 4. Cannabinoids are one of the potential candidates for the therapy of neuropathic, inflammatory, and cancer associated pain.^170–172 These cannabinoids have been studied for different neuropathy conditions in animals such as DPN, CIPN, chronic construction traumatic injury (CCI), trigeminal neuralgia, etc. A study by Lazic et al. revealed that CBD was highly effective with minimal side effects when compared to cannabis and Δ9-THC, the efficacies of which are hindered due to side effects.¹⁷³ THC and CBD reduce CCI induced mechanical allodynia in a dose dependent manner. However, side effects are less with CBD when compared to THC. Moreover, co-administration of low doses of THC and CBD significantly reduced allodynia in a biphasic dose-dependent manner with minimal side effects in an animal model of neuropathic pain.¹⁷³ Another study by Ward et al. shows the protective action of CBD in combating paclitaxel (PAC) induced neuropathic pain partly through mediation by the 5-HT_1A receptor system.¹⁷⁴ The combination of CBD and PAC chemotherapy was suggested because of its minimal side effects as well as its ability to attenuate CIPN.¹⁷⁴ Recently, CBD was recruited in phase 2 clinical trials for studying its pain-relieving effects against DPN (NCT04679545). This study intends to evaluate the impact of CBD on neuropathic pain, anxiety, and sleep quality compared to a placebo control. University of Copenhagen registered in clinicaltrials.gov to study the effects of CBD in attenuating oxaliplatin or paclitaxel induced neuropathy in a phase 2 clinical trials (NCT04582591). Meta-analysis of 16 studies with 1750 participants showed that cannabis-based medicines (oral mucosal spray of TCH + CBD, nabilone and dronabinol) may increase the number of people achieving 50% or greater pain relief compared with placebo.¹⁷⁵ In another systematic review and meta-analysis of randomized controlled trials articulated cannabis-based medicines might be effective for chronic pain treatment, based on limited evidence, primarily for neuropathic pain (NP) patients.¹⁷⁶ Figure 5 summarizes possible pathways by which cannabinoids attenuates neuropathic pain and other disease conditions.

FIG. 4:

Types of pain. Neuropathic pain is sub-type of chronic pain and could be central/peripheral. Peripheral neuropathic pain includes diabetic neuropathy, CIPN and HIV related neuropathic pain.

FIG. 5:

Plausible mechanism of action of cannabinoids in protecting peripheral neurons against various disease conditions. Cannabinoids have been found to activate TRPV1 ion channels, GPR55 and 5HT1A receptors including CB1 and CB2 receptors. By activation of these receptors or by regulating the downstream AMPK, Nrf2, NF-κB and BDNF cell signalling pathways, Cannabinoids improved neurogenesis, increased autophagosomes formation, increased mitochondrial biogenesis and improved mitochondrial function and enhanced antioxidant response with decreasing inflammation in different conditions of neuropathy. AMPK, adenosine monophosphate-activated protein kinase; Atg, anti-thymocyte globulin; BDNF, brain-derived neurotrophic factor; FIP200, FAK family kinase-interacting protein of 200 kDa; GSH, Glutathione; HO1, heme oxygenase 1; mTOR, mechanistic target of rapamycin; SIRT1, silent mating type information regulation 2 homolog 1; NRF, nuclear respiratory factor; Nrf2, nuclear factor erythroid 2 (NFE2)-related factor 2; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PGC-lα, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; TFAM, mitochondrial transcription factor; Ulk1, unc-51 like autophagy activating kinase; VPS34, vacuolar protein sorting 34.

A. US Food and Drug Administration (FDA)-Approved Products and Clinical Trials

Two synthetic cannabis-related drug products, Dronabinol and Nabilone containing Δ9-THC are approved by the FDA for the treatment of anorexia associated with weight loss in AIDS patients and chemotherapy-induced nausea and vomiting. Another FDA approved product is CBD, a cannabis-derived compound¹⁷⁷ for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in children who are 2 years and above.¹⁷⁸ Lennox-Gastaut syndrome, a disease characterized by multiple types of seizures is usually first diagnosed in children between 3 to 5 years and usually persists into adulthood. Various anti-epileptic drugs are used as first-line treatment and CBD is used as an adjuvant therapy.¹⁷⁹ CBD stands as the only FDA approved treatment for the patients with Dravet syndrome.¹⁸⁰ Epidiolex, a pure CBD oral solution manufactured by GW pharmaceuticals received approval from the FDA when it significantly decreased the frequency of seizures in cases of treatment-resistant epilepsy from several trials.^181–183 CBD has been explored for potential therapeutic use in cancers, chronic pain, neurodegenerative diseases such as Alzheimer and Parkinson disease, inflammatory and psychiatric diseases.^184,185 However none of these trials (as shown in Tables 1 and 2) have been approved by the FDA for the treatment of neurodegenerative disease, chronic pain, cancers and psychiatric diseases with CBD oil.^186,187

TABLE 1:

Clinical trials of cannabinoids in neuropathic pain

Study Title	ID and year (estimated )	Status	Condition	Intervention	Phase
Cannabinoids and an Anti-inflammatory Diet for the Treatment of Neuropathic Pain After Spinal Cord Injury	NCT04057456 2020–2022	Not yet Recruiting	Spinal Cord Injuries Neuropathic Pain	Drug: TCH/CBD Capsules Other: Anti-inflammatory diet	Phase 2188
Cannabinoids Effects on the Pain Modulation System	NCT02560545 2015–2019	Unknown	Neuropathic Pain	Drug: Cannabis oil	N/A189
Effect of Cannabinoids on Spasticity and Neuropathic Pain in Spinal Cord Injured Persons	NCT01222468 2012–2015	Completed	Muscle Spasticity as a Result of Spinal Cord Injury	Drug: Nabilone 0.5 mg Drug: Placebo	Phase 2190
Nabilone for the Treatment of Phantom Limb Pain	NCT00699634 2009–2011	Completed	Phantom Limb Pain Neuropathic Pain	Drug: Nabilone	N/A191
Sativex for Treatment of Chemotherapy Induced Neuropathic Pain	NCT00872144 2009–2014	Completed	Neuropathic Pain	Drug: Sativex	Phase 3192
Efficacy Study of Nabilone in the Treatment of Diabetic Peripheral Neuropathic Pain	NCT01035281 2008–2011		Diabetic Neuropathies	Drug: Nabilone, flexible dosing	Phase 3193
Effect of Cannabis and Endocannabinoids on HIV Neuropathic Pain	NCT03099005 2018–2020	Recruiting	Cannabis HIV Neuropathy Pain Syndrome	Drug: Cannabis	Phase 2194
An Observational Post-Marketing Safety Registry of Sativex®	NCT02073474 2011–2015	Completed	Multiple Sclerosis Diabetes Cancer Neuropathic Pain	Drug: Sativex	N/A195
Efficacy and Safety of the Pain Relieving Effect of Dronabinol in Central Neuropathic Pain Related to Multiple Sclerosis	NCT00959218 2007–2010	Completed	Central Neuropathic Pain in Multiple Sclerosis	Drug: Dronabinol Drug: Placebo	N/A196
Trial of Dronabinol and Vaporized Cannabis in Neuropathic Low Back Pain	NCT02460692 2016–2020	Recruiting	Cannabis Low-Back Pain Neuropathic Pain	Drug: Placebos Drug: Dronabinol Drug: Vaporized Cannabis 3.7% THC/5.6% CBD	N/A197
Effect of Delta-9-Tetrahydrocannabinol on the Prevention of Chronic Pain in Patients with Acute CRPS (ETIC-Study)	NCT00377468 2006–2008	Unknown	Complex Regionl Pain Syndromes CRPS	Drug: Delta9-Tetrahydrocannabinol	Phase 2198

TABLE 2:

Clinical trials of cannabinoids in chronic and acute pain

Study title	ID and year (estimated )	Status	Condition	Intervention	Phase
Study to Evaluate the Efficacy of Dronabinol (Marinol) as Add-On Therapy for Patients on Opioids for Chronic Pain	NCT00153192 2001–2006	Completed	Chronic Pain	Drug: Marinol (dronabinol)	Phase 2 and Phase 3199
Vaporized Cannabis for Chronic Pain Associated with Sickle Cell Disease (Cannabis-SCD)	NCT01771731 2014–2017	Completed	Sickle Cell Disease (Chronic Pain)	Drug: Cannabis	Phase 1 and Phase 2200
A Study to Compare Sublingual Cannabis Based Medicine Extracts with Placebo to Treat Brachial Plexus Injury Pain	NCT01606189 2001–2002	Completed	Pain	Drug: Immediate-release Oral Morphine Sulfate Tablets Other: Thermal and Pressure Nociceptive Sensitivity Drug: GW-1000–02(Sativex) Drug: GW-2000–02(THC (25 mg/ml) Drug: Placebo	Phase 3201
Pain Research: Innovative Strategies with Marijuana (PRISM)	NCT03522324 2018–2022	Recruiting	Chronic Pain Chronic Low Back Pain Cannabis Use	Drug: Cannabis Edible	N/A202
Opioid and Cannabinoid Pharmacokinetic Interactions	NCT00308555 2006–2009	Completed	Pain	Drug: Cannabis	Phase l203
Safety and Efficacy of Medical Cannabis Oil in the Treatment of Patients with Chronic Pain	NCT03337503 Jan 2018-Dec 2018	Unknown	Chronic Pain	Drug: THC and CDB in a 1 to 1 ratio Drug: Experimental: THC and CBD in a 1 to 2 ratio Drug: High CBD with trace THC oil Other: Placebo	Phase 4204
Efficacy of Ultra-Micronized Palmitoylethanolamide (Um-PEA) in Geriatric Patients with Chronic Pain	NCT02699281 2015–2016	Completed	Chronic Pain	Drug: Ultramicronized palmitoylethanolamide Drug: Placebo	Phase 4205
Treatment of Chronic Pain with Cannabidiol (CBD) and Delta-9-tetrahydrocannabinol (THC)	NCT03215940 2018–2020	Recruiting	Chronic Pain	Drug: Dronabinol	Early Phase 2 206
Dronabinol Opioid Sparing Evaluation (DOSE) Trial	NCT03766269 2018–2019	Recruiting	Chronic Pain	Drug: Dronabinol	Phase 2207
Effect of Delta-9-Tetrahydrocannabinol on the Prevention of Chronic Pain in Patients with Acute CRPS (ETIC-Study)	NCT00377468 2006–2008	Unknown	Complex Regional Pain Syndromes (CRPS)	Drug: Delta9-Tetrahydrocannabinol	Phase 2198
Namisol®) in Patients with Persistent Postsurgical Abdominal Pain	NCT01562483 2012–2014	Completed	Postsurgical Pain Abdominal Pain Chronic Pain	Drug: Tetrahydrocannabinol Drug: Placebo	Phase 2208
Δ9-THC (Namisol®) m Chronic Pancreatitis Patients Suffering From Persistent Abdominal Pain	NCT01551511 2012–2014	Completed	Pancreatitis, Chronic Abdominal Pain Chronic Pain	Drug: Tetrahydrocannabinol Drug: Placebo	Phase 2209
Outcomes Mandate National Integration With Cannabis as Medicine (OMNI-Can)	NCT03944447 2018–2025		Chronic Pain Chronic Pain Syndrome Chronic Pain Due to Injury Chronic Pain Due to Trauma Fibromyalgia Seizures Hepatitis C Cancer	Drug: Cannabis, Medical	Phase 2210
Use of the Cannabinoid Nabilone for the Promotion of Sleep in Chronic, Non-Malignant Pain Patients	NCT00384410 2005	Unknown	Pain	Drug: Nabilone	Phase 2211
Cannabis Oil for Chronic Non-Cancer Pain Treatment	NCT03635593 2019–2022	Not yet recruiting	Chronic Non-cancer Pain	Drug: CBD Drug: CBD+THC Other: Placebo	Phase 2212
Efficacy Study of Δ9-THC to Treat Chronic Abdominal Pain (Delta-pain)	NCT01318369 2011–2013	Completed	Cannabinoids Tetrahydrocannabinol Chronic Pancreatitis Abdominal Pain	Drug: Namisol Drug: Diazepam	Phase 2213
Supporting Effect of Dronabinol on Behavioral Therapy in Fibromyalgia and Chronic Back Pain	NCT00176163 2005–2009	Completed	Behavioral: Operant behavioral treatment; Drug: THC	Fibromyalgia Back Pain	Phase 2214
Palmitoylethanolamide for Post-operative Pain Prevention (PEA for CPSP)	NCT01491191 2012–2013	Unknown	Dietary Supplement: Palmitoylethanolamide Dietary Supplement: Placebo	Chronic Post-operative Pain	N/A215
Nabilone Versus Amitriptyline in Improving Quality of Sleep in Patients With Fibromyalgia	NCT00381199 2006–2007	Completed	Drug: Amitriptyline Hydrochloride Drug: Nabilone	Fibromyalgia Sleep Initiation and Maintenance Disorders	N/A216
Efficacy of Palmitoylethanolamide-polydatin, Combination on Chronic Pelvic Pain in Patients With Endometriosis	NCT02372903 2013–2015	Completed	Drug: Administration of micronized Palmitoylethanolamide (PEA)-Transpolydatin	Endometriosis Chronic Pelvic Pain	N/A217
Nabilone Use For Acute Pain in Inflammatory Bowel Disease Patients	NCT03422861 2020–2021	Not yet recruiting	Drug: Nabilone Drug: Placebos	Inflammatory Bowel Diseases	N/A218
Evaluation of Dronabinol For Acute Pain Following Traumatic Injury	NCT03928015 2019–2021	Enrolling by invitation	Drug: Adjunctive dronabinol Drug: Systemic analgesics	Traumatic Injury Pain, Acute	Phase 2219
Cannabidiol, Morphine, Pain (CMP)	NCT04030442 2019–2021	Recruiting	CBD Chronic Pain	Drug: Immediate release oral morphine sulfate tablets Other: Thermal and Pressure nociceptive sensitivity	Phase 1220

VI. PHARMACOKINETICS OF CANNABINOIDS

The route of administration of cannabinoids has considerable effects on their pharmacokinetics, bioactivity, bioavailability, and effectiveness. Cannabinoids cannot be administered intravenously due to their poor water solubility. In cancer therapy, oral administration of cannabinoids may not be the most effective route due to partial degradation by the acidic environment present in stomach.²²¹ A study by Deiana et al. has assessed the pharmacokinetic profiles of CBD, cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV), and CBG after an acute single-dose intraperitoneal and oral administration in mice and rats.²²² A marble burying test was used to assess the pharmacodynamic-pharmacokinetic relationship of CBD when administered at a dose of 120 mg/kg through oral and intraperitoneal route in mice. Phytocannabinoids dispersed in solutol and administered orally have easily penetrated the blood-brain barrier when compared to cremophor based phytocannabinoids. However, cremophor-based phytocannabinoids administered intraperitoneally showed higher plasma and brain concentrations. CBD and CBDV show higher brain concentrations when administered orally. However, THCV and CBG were more effective when administered through intraperitoneal route.²²² CBD administered orally has shown low bioavailability due to its first-pass metabolism in both dogs and humans.^223,224 The pharmacokinetics of CBD were assessed in healthy dogs in a study by Bartner et al., when administered in the form of oral microencapsulated oil beads, oral CBD-infused oil or CBD-infused transdermal cream.²²⁵ This study demonstrates that oral CBD-infused oil showed good pharmacokinetic profile.^223,225

Oral or intranasal administration of CBD have shown poor bioavailability. CBD has been shown in several studies in rodents to possess antidepressant-like effects,^226–229 but bioavailability is a major challenge in the use of CBD in clinical trials despite its significant effects in suppressing depression.^222,230 The administration of medical cannabis to patients is usually via inhalation,^231,232 spraying,²³³ or oral in the form of oil,²³⁴ capsules,²³⁵ and cookies.²³⁶ Oral administration of CBD or via inhalation has poor bioavailability. Xu et al. explored the pharmacokinetics and the efficacy of CBD administration over a long period via oral and intravenous routes for treating chronic mild stress (CMS).²³⁷

VIII. FUTURE DIRECTIONS

Although cannabinoids have great therapeutic potential in neuropathic pain, there is a need to scale up its production. The production of cannabinoids is limited to the cannabis plant, which may lead to insufficient supply of quality cannabinoids for therapeutic uses. Cannabis plant as a sole source of cannabinoids faces several challenges including climatic, disease and pest control, land/agricultural space, legal issues because of abuse of plant, low quantities of minor phytocannabinoids and chemical procedures for cannabinoid isolation. A solution to this problem could be the use of biotechnological approaches such as microbes and yeast biosynthesis. This will enhance the production of cannabinoids for therapeutic use as well as increase the accessibility of rare cannabinoids for clinical use and drug testing. Biotechnological approaches could lead to the discovery and production of novel cannabinoids, which are more effective or could be used in targeted therapy. Microbial synthesis of cannabinoids can be employed to increase the yield of cannabinoids which are produced in low quantities in the cannabis plant. The selection of the microbes for the synthesis/production of cannabinoids requires certain considerations to be taken into account, such as genetic factors, genetic engineering procedures or biological tools and the pathways for the synthesis of these compounds.