Abstract
Pain is a debilitating phenomenon that dramatically impairs the quality of life of patients. Many chronic conditions, including cancer, are associated with chronic pain. Despite pharmacological efforts that have been conducted, many patients suffering from cancer pain remain without treatment. To date, opioids are considered the preferred therapeutic choice for cancer-related pain management. Unfortunately, opioid treatment causes side effects and inefficiently relieves patients from pain, therefore alternative therapies have been considered, including Cannabis Sativa and cannabinoids. Accumulating evidence has highlighted that an increasing number of patients are choosing to use cannabis and cannabinoids for the management of their soothing and non-palliative cancer pain and other cancer-related symptoms. However, their clinical application must be supported by convincing and reproducible clinical trials. In this review, we provide an update on cannabinoid use for cancer pain management. Moreover, we tried to turn a light on the potential use of cannabis as a possible therapeutic option for cancer-related pain relief.
Pain is a highly unpleasant physical suffering caused by injury or illness. More than 70% of cancer patients suffer from pain, which dramatically impairs their quality of life (QoL) (1). Chronic cancer pain should be treated by a multimodal approach including both non-pharmacological and pharmacological therapies (2). Unfortunately, the opioid treatment causes side effects and inefficiently relieves patients from pain and increases the risk of addiction, thus opioid-based pain management is strictly monitored. Opioids are considered the preferred therapeutic choice for managing moderate and severe cancer pain (3, 4). Although significant efforts have been made to elaborate recommendations and guidelines (4), pain relief in patients with cancer treated with conventional therapies, is very limited. Recently, alternative therapies for cancer pain treatment, including cannabis-based medicines, have been examined. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the most studied compounds derived from the Cannabis plant (5). These substances should be administrated as a spray under the tongue or on the buccal mucosa, orally or via inhalation in different formulations and concentrations. The high variability of systems and routes, along with the different concentrations of cannabinoids, make predicting efficacy very difficult. A series of preclinical and observational studies were conducted in order to examine the possible benefits of using cannabinoids in cancer pain management. However, their clinical efficacy is still not supported by high-quality clinical trials. The side effects of treatment with cannabinoids (mainly cognitive impairments) are mild with respect to those observed with opioid treatment. Nevertheless, Cannabis use is related to addiction. This review aims to provide an update on clinical studies on the use of cannabis-based medicines for cancer pain management. In addition, the current study aims to inform the medical oncology community about the use of cannabis as a possible therapeutic option for pain relief.
Cannabinoids: Classification and Biological Features
Cannabinoids, compounds derived from the Cannabis Sativa plant, include endogenous and exogenous substances that bind to specific inhibitory cannabinoid receptors (CB-Rs) differently distributed in the human body. To date, two receptors have been isolated and identified as CB1-R and CB2-R. CB1-R is expressed in the central nervous system. It has many biological functions, whereas CB2-R is expressed in peripheral cells and the immune system and can modulate immune cell migration and cytokine release (5). Both receptors, together with endocannabinoids and their metabolic enzymes, are contained in the endocannabinoid system (ECS). Cannabinoids can be divided into three types: endocannabinoids (compounds produced by the body interacting with cannabinoid receptors), phytocannabinoids (compounds derived from cannabis), and synthetic-related cannabinoids (manufactured compounds). The endo-cannabinoids are able to bind and modulate cannabinoid receptors. The principal endocannabinoids expressed in the brain are Arachidonoyglycerol (2-AG) and Anandamide (AEA) (6). AEA has a higher affinity for CB1-R than that for CB2-R, whereas 2-AG displays a moderate affinity for both receptors (7). Endocannabinoids modulate other receptors and channels such as several members of transient receptor potential (TRP) ion channel super-families, involved in different molecular signaling pathways in the nervous system (8). It has been demonstrated that endocannabinoids are also implicated in many pathological conditions (i.e., cancer, autism, Alzheimer’s disease) (9-12). The principal phytocannabinoids are Δ9-THC CBD (5). THC is a psychotropic component of C. Sativa, which acts as a partial agonist of CB1-R and CB2-R as has been shown in pre-clinical studies (13-19). Specifically, Δ9-THC activates the CB1-R by impairing the intracellular synthesis of cyclic adenosine monophosphate (cAMP) through a G-protein-mediated mechanism (20), determining analgesia, hypolocomotion, hypothermia, and catalepsy. Moreover, Δ9-THC is able to modulate the transient receptor potential cation channel subfamily V member 2, 3, and 4 (TRPV2, TRPV3, and TRPV4), and the transient receptor potential cation channel subfamily M member 8 (TRPM8) (21). CBD is a non-psychotropic component of C. Sativa (5) that is able to modulate negatively CB1-R and CB2-R activities, acting as a negative allosteric modulator (22). Accumulating evidence shows that CBD acts as an agonist of the transient receptor potential cation channel subfamily A member 1 (TRPA1), transient receptor potential vanilloid-1 (TRPV1), TRPV2, TRPV3 channels, while is an antagonist of G protein-coupled receptor 12 (GPR12), of G protein-coupled receptor 3 (GPR3), and G protein-couple receptor 6 (GPR6). Moreover, CBD is able to increase AEA levels (23, 24). Several pre-clinical and clinical studies have highlighted many biological effects (e.g., anti-inflammatory, neuroprotective, antioxidative, antiemetic, and analgesic effects) associated with CBD, varying according to its concentration and the study models adopted (25, 26). Cannabigerol (CBG) is a non-psychoactive phytocannabinoid with a low affinity for CB1-R and CB2-R but is able to inhibit AEA uptake impairing the ECS. CBG activates the α2-adrenergic receptor while moderately blocking the serotonine 5-hydroxytryptamine receptor 1A (5HT1A). It also interacts weakly with TRPV1, TRPV2, TRPA1, TRPV3 and TRPV4 (27, 28). This compound has anti-glaucoma properties and antiproliferative effects and it is effective in bladder pain (29). Cannabichromene (CBC), has a low affinity for CB1-R and CB2-R, but can inhibit the AEA uptake, thus, affecting the ECS (30). CBC interacts with TRPA1, TRPV3, TRPV4, and TRPV8. CBC has anti-inflammatory and anti-analgesic effects as reported in several studies (31, 32). Cannabidivarin (CBDV), also termed cannabidivarol or CBDV, is a non-psychoactive compound with anti-epileptic activity related to its interaction with TRPV1. CBDV is able to desensitize TRPV1, TRPV2 and TRPA1 channels (33). In addition to the cannabinoids, Cannabis also contains terpenes, which confer the diverse odors of its different strains and have therapeutic benefits (34). Accumulating evidence demonstrated that terpenes are able to contribute to the treatment of neuropathic pain in multiple sclerosis (MS) and spasticity (39). Marinol® and Syndros® are synthetic (−) trans-Δ9-THC-related drugs, also called Doranibol, mainly used in the oral formulation to alleviate acquired immune deficiency syndrome (AIDS)-related anorexia and for nausea and vomiting induced by chemotherapy in patients resistant to conventional antiemetic therapies (40, 41). Finally, Cesamet® and Canemes® are formed by Nabilone, which is an analogue of Δ9- THC used in the oral formulation to alleviate nausea and vomiting induced by chemotherapy in patients resistant to conventional antiemetic therapies (42).
Efficacy of Cannabinoids in Cancer-related Pain Management: Update from Clinical Studies
Accumulating data from clinical studies highlighted the potential role of phytocannabinoids in cancer pain management and cancer-related symptoms (i.e., anxiety, depression, sleep disorders, fatigue, nausea and vomiting, oral mucositis) as reported previously by Coelho et al. (43). Chronic moderate to severe pain is common in patients with advanced cancer (44). Opioids represent the treatment of choice for cancer pain, but unfortunately, patients experience adverse side effects at the higher doses required to relieve cancer pain. A few randomized controlled clinical trials using cannabinoids as a therapeutic choice have been reported with discordant results. Noyes et al. (Table I), reported for the first time the analgesic effect of orally delivered THC in patients suffering from different types of cancer and cancer-related pain (45, 46). In a double-blind clinical trial, authors investigated the analgesic effect and side effects of THC (dose of 5 to 20 mg) on 10 patients with cancer at an advanced stage compared to patients treated with placebo. Pain relief was significantly superior to placebo at high doses of THC (15 and 20 mg), highlighting its analgesic role (45). Later on, Noyes et al. conducted another study aimed to compare the analgesic effect of THC (at doses of 10 and 20 mg) to that of codeine (at doses of 60 mg and 120 mg) in cancer patients with pain. Results indicated that pain was significantly relieved only in patients treated with THC and at high doses of codeine compared with placebo (46). Despite these encouraging results, these studies highlighted many side effects (i.e., sedation, mental disorder, blurred vision, and social withdrawal), which inhibited the use of THC in clinical practice. Thus, to overcome this issue, THC analogs (i.e., benzopyranoperidine and nitrogen-containing benzopyran derivative), were tested in two different studies (47, 48). Results from these studies highlighted poor outcomes in terms of amelioration of pain and adverse side effects. Subsequently, several clinical trials were conducted to dissect the adjuvant analgesic role of cannabinoids in cancer-related pain, by using nabiximols (THC: CBD) against THC extract and placebo in patients with cancer pain in order to relieve pain. Johnson et al. (49) studied the efficacy and safety of THC and THC:CBD extracts in patients with cancer-related pain unsuccessfully relieved by opioid treatment. Patients treated with CBD extract showed a significant reduction in pain (detected by Numerical range scale, NRS) compared to patients treated with placebo or with THC extract alone. Later, Portenoy et al. (50), showed that nabiximols (in an oral formulation containing cannabis extract) significantly relieved patients from pain only at lower doses, and showed a lower adverse effect profile (i.e., nausea, dizziness, vomiting) that differed from that of higher doses. Litchtman et al. (51) conducted a double-blind, randomized, placebo-controlled phase 3 study of nabiximols (in oral formulation, Sativex®) as an adjuvant agent in cancer patients suffering from severe pain unsuccessfully controlled by treatment with opioids. Data that emerged from this study showed that nabiximols was not superior to placebo on the primary efficacy endpoint (percent change in the average pain NRS score), while it was efficient in multiple secondary endpoints, particularly in patients from the U.S.A. who received lower doses of opioids at baseline than patients from the rest of the world. Moreover, the safety profile of nabiximols was consistent with previous studies in patients suffering from cancer at an advanced stage. Interestingly, Schleider et al. (52) conducted a long-term observational study of medical Cannabis in patients suffering from different types of cancer treated with a mixture of THC and CBD. Data reported from these studies showed that patients who completed the treatment (about 98%) reported an improvement in their general conditions, but they experienced at least one adverse effect (i.e., dry mouth, dizziness, sleep disorder). To date, an update on clinical trials on the effects of cannabinoids on the treatment of cancer pain is available at https://clinicaltrials.gov/ and is summarized in Table I. Altogether these few pieces of clinical evidence, highlight the potential role of cannabinoids in cancer pain management, although more high-quality clinical studies are necessary (53).
Cannabinoids in cancer pain management: an update from clinical trials.
Concluding Remarks and Future Perspectives
Cancer pain is a highly debilitating disease that dramatically affects QoL and it is very difficult to be treated by using the available therapeutic options. Although the results from preclinical trials are encouraging, few clinical studies have been conducted that are not sufficient to promote cannabinoids as therapeutic agents for cancer pain management. Further high-quality clinical trials are necessary to prove their clinical safety and efficacy. It is necessary to consider the putative interactions of cannabinoids with other drugs and to set up appropriate protocols of controlled trials by considering the co-morbidities of patients with cancer to minimize the risk of adverse effects, especially for patients subjected to immunotherapies. In this way, the oncologists will be more convinced of the cannabinoids’s therapeutic properties and will be more willing in prescribing cannabinoid therapies.
Acknowledgements
The Authors are grateful to Dr. Alessandra Trocino, Mrs. Mariacristina Romano and Dr. Mariacinzia Grizzuti from Istituto Nazionale Tumori IRCCS Fondazione Pascale for providing excellent bibliographic service and assistance. This work was (partially) supported by the Italian Ministry of Health Ricerca Corrente Project M4/3.
Footnotes
Authors’ Contributions
Conceptualization, S. Bimonte, M. Cascella, A. Cuomo; writing – original draft preparation: S. Bimonte; and writing – review and editing: M. Cascella. All Authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to disclose about this study.
- Received November 24, 2023.
- Revision received December 27, 2023.
- Accepted December 28, 2023.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
