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 »  Abstract
 » Introduction
 »  Pain Management ...
 » Cannabinoids
 »  Palliative Effec...
 »  Pharmacogenomics...
 » Conclusion
 »  References
 »  Article Tables

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Table of Contents 
Year : 2020  |  Volume : 26  |  Issue : 1  |  Page : 129-133

Cannabinoids as an alternative option for conventional analgesics in cancer pain management: A pharmacogenomics perspective

Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India

Date of Submission03-Sep-2019
Date of Acceptance10-Sep-2019
Date of Web Publication28-Jan-2020

Correspondence Address:
Dr. Mahadev Rao
Professor and Head, Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal - 576 104, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPC.IJPC_155_19

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 » Abstract 

The global cancer burden is significantly increasing at an alarming rate affecting patients, relatives, communities, and health-care system. Cancer patients require adequate pain relief and palliative care throughout the life course, especially in terminal illness. Although opioid treatment is successful in majority of patients, around 40% do not achieve enough analgesia or are prone to serious side effects and toxicity. The treatment of medical conditions with cannabis and cannabinoid compounds is constantly expanding. This review organizes the current knowledge in the context of SNPs associated with opioids and nonopioids and its clinical consequences in pain management and pharmacogenetic targets of cannabinoids, for use in clinical practice.

Keywords: Cancer pain, cannabinoids, nonopioids, opioids, pharmacogenomics

How to cite this article:
Jose A, Thomas L, Baburaj G, Munisamy M, Rao M. Cannabinoids as an alternative option for conventional analgesics in cancer pain management: A pharmacogenomics perspective. Indian J Palliat Care 2020;26:129-33

How to cite this URL:
Jose A, Thomas L, Baburaj G, Munisamy M, Rao M. Cannabinoids as an alternative option for conventional analgesics in cancer pain management: A pharmacogenomics perspective. Indian J Palliat Care [serial online] 2020 [cited 2021 May 12];26:129-33. Available from:

 » Introduction Top

Cancer malignancies are among the primary reasons of morbidity and mortality globally, with new cases reaching 18.1 million and fatality rate to 9.6 million in 2018. The global cancer burden is significantly increasing at an alarming rate affecting patients, relatives, communities, and health-care system.[1] Cancer-related pain is the most frequent and unsolved problem faced by cancer patients. Pain can be due to the cancer itself, where a tumor compressing and destroying nearby tissues or from diagnostic or therapeutic procedures or by immune responses. 55% of patients receiving chemotherapy and 66% of patients in terminally ill stage experience pain, of which one-third of all patients experience moderate-to-severe pain intensity.[2] Frequent reassessment of pain is necessary in cancer patients as pain intensity varies in accordance with disease condition, cancer treatments, and psychosocial status. Suboptimal pain management negatively impacts patients to carry out activities of daily living and reduces the quality of life, thereby causing mental distress to patients.[3] Hence, cancer patients require adequate pain relief and palliative care throughout the life course, especially in terminal illness.

 » Pain Management in Cancer Patients Top

Multidimensional approach interventions in pharmacological and nonpharmacological aspects are essential to treat pain in patients with life-limiting health conditions.[4] In 1986 and 1997, the World Health Organization (WHO) proposed a pain relief ladder approach for cancer patients.[5],[6] According to pain severity in patients, ladder model proposes treatment algorithm starting from nonopioids such as nonsteroidal anti-inflammatory drugs (NSAIDs) to weak opioids and ending in potent opioids. In 2018, the WHO has established guidelines for “pharmacological and radio therapeutic management of cancer pain in adults and adolescents” to offer evidence-based guidance in initiating and managing cancer pain.[7] Generally used medications for treating pain comprise opioids such as codeine, morphine, hydromorphone, oxycodone, fentanyl, and methadone and nonopioids including paracetamol and NSAIDs with adjuvant therapies such as antidepressant and anticonvulsant agents.

NSAIDs, paracetamol, morphine, and other opioids are considered the mainstays for pain management. As per the WHO consideration, patients should have access to a wide range of opioid analgesics, because there are known clinical differences in patient's response to specific analgesics.[7] Although opioid treatment is successful in majority of patients, around 40% do not achieve enough analgesia or are prone to serious side effects and toxicity. Even if opioid rotation is an option, it is highly time consumable which is challenging to hospice patients. As stated by Van Den Beuken-Van Everdingen et al., even though universal opioid consumption rate doubled in 2018 in comparison with 2012, one-third of the patients received no pain medication proportional to their rates of pain intensity.[2] This indicates that dose, dosage, or drug that effectively controls pain for one patient will not be the same for others. Among all other reasons of opioid failures, pharmacogenetic interindividual variability significantly affects the analgesic response and toxicity of the drugs.[8]

Genetic variability due to polymorphism in enzyme metabolizers and transporter genes chiefly accounts for drug sensitivity, response, and predisposition to side effects. One such example is the variation in response to codeine among highly polymorphic cytochrome P450 2D6 variants. Based on the genotype with that of phenotype, patients are categorized as poor (PMs), intermediate, extensive, or ultrarapid metabolizers (UMs). Robust evidence of unsatisfactory pain control and serious side effects of morphine in patients taking codeine urged the Clinical Pharmacogenetics Implementation Consortium to make recommendation to avoid codeine in PMs and UMs.[9] Similarly, various other genes in the family of cytochrome P450, cyclooxygenases, opioid receptors, phospholipase, HLA DQB1 have noteworthy role in affecting analgesic response of conventionally used pain medications.[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22] SNP's associated with opioids and nonopioids and their respective clinical consequences are depicted in [Table 1]. Because pain relief is considered as a basic human right,[23],[24] poor success rate of traditional analgesics and adjuvant therapies throws light on the urgent necessity of alternative therapies, considering pharmacogenetic interindividuality among patients.
Table 1: SNPs associated with nonopioids and opioids and its clinical consequences in pain management

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 » Cannabinoids Top

Cannabis sativa and Cannabis indica plants of family Cannabaceae contain approximately 100 cannabinoids, in which the active ingredient Delta-9-tetrahydrocannabinol (THC) is effective in the psychoactive properties. Cannabidiol (CBD) is another chief constituent that lacks the psychotropic effects, but carries antiemetics, antiepileptic, as well as other effects.[25],[26] Cannabinoid receptors, to date, CB1 and CB2, have been recognized where CB1 is located in the brain region and CB2 in the immune cells.[27]

Cannabinoids in cancer pain management

Cannabinoids produce analgesic effect by activating CB1 receptors present in CNS and nerve terminals. Furthermore, peripheral CB2 receptors facilitate analgesia, by blocking the production of pain and inflammatory mediators, which is important in managing cancer pain.[28] A selective review study by Blake et al. included clinical studies performed between 1975 and 2014 that evaluated the effectiveness of THC and CBD and reported that cannabinoids with decreased cancer pain were significantly associated in four out of five trials.[29] A double-blind randomized clinical trial (RCT) measuring the impact of nabiximols, a novel cannabis extract, showed substantial improvements in pain in patients with advanced cancer with opioid refractory pain.[30] In other RCT of 177 cancer patients who have unsatisfactory clinical response to opioids, the authors compared the effectiveness of THC: CBD extract and THC extract with placebo. THC: CBD extract presented statistically significant modification in baseline score in numerical pain rating scale compared with placebo.[31] These evidences supported the use of cannabinoids and their derivatives to use as an alternative or substitute in patients who are unable to take opioids and NSAIDs in cancer pain management.

 » Palliative Effects of Cannabinoids Top

Inhibition of nausea and vomiting

Nausea and vomiting are one of the devastating after effects of cancer chemotherapy. Despite the routinely administering antiemetics, the incidence of chemotherapy-induced nausea and vomiting (CINV) is relatively high.[32] Antiemetic property of cannabinoids is well established in animal models. Suggested mechanisms of antiemesis are through cannabinoid-mediated acetylcholine blocking and inhibiting digestive tract motility or through acting on CB1 receptors present in dorsal–vagal complex of the brain stem. Dronabinol and nabilone are already approved to treat chemotherapy-associated nausea and emesis. Moreover, there is evidence that cannabinoids are efficient in reducing nausea and vomiting during the delayed chemotherapy stage that is poorly regulated by the 5-HT receptor antagonist.[33],[34]

Appetite stimulation

Anorexia is one of the most disturbing symptoms of patients with advanced cancer that leads to major weight loss. Numerous studies revealed that THC and other cannabinoids at low-to-moderate doses have stimulatory effects on appetite and increase food consumption in animals. Dronabinol has already approved for AIDS wasting syndrome.[35]

Psychological effects

In vivo studies indicate that cannabinoids exert antianxiety effects at low doses. THC and nabilone provide positive psychological effects, reduction in anxiety and depression, and enhanced sleep. These potentially positive effects can impact the medical outcomes of patients with terminally ill cancer.[36]

Antineoplastic effects

In vitro studies showed that THC, synthetic cannabinoid agonists, naturally occurring cannabinoids (CBD and cannabinol), and endocannabinoids have anticancer effects in case of lung cancer, gliomas, skin cancer, lymphomas, breast cancer, prostate cancer, uterine cancer, neuroblastoma, and thyroid epithelioma.In vivo studies also showed that natural and synthetic cannabinoids exhibit anticancer effects in xenografts of lung cancer, thyroid, skin cancer, epitheliomas, lymphomas, and gliomas.[37],[38]

Cannabinoid-based pharmaceuticals

Nonimportance in medical field and risk of misuse restricted the use of cannabis and its derivatives until recently. Rapidly changing policy leads cannabis to be given for medicinal purpose in many countries. This paves the way for novel treatment openings for patients although it should be weighed up against risk factors.

Inhalation of smoke is the common route of administration of cannabinoids as the active components are absorbed by lung alveoli and delivered to CNS.[39] However, due to problems caused due to improper delivery and variable absorption of drug, other routes of administration are considered by pharmaceutical companies.[26] Cannabinoid derivatives of THC, CBD, or its combinations are used for therapeutic purpose. An oral spray containing THC and CBD (1:1 ratio) nabiximols (Sativex®) is approved for spasticity therapy in multiple sclerosis in many European nations.[40] Epidiolex®, an oral CBD solution, is currently approved in the USA for the treatment of Lennox–Gastaut syndrome and Dravet syndrome.[41]

Synthetically produced products such as dronabinol and nabilone typically mimic THC. Nabilone has more related structure to THC and more potent when compared to dronabinol. They are approved for the weight loss treatment in HIV patients and patients with CINV, who are nonresponders to traditional antiemetics.[42]

 » Pharmacogenomics of Cannabinoids Top

Amidst all the benefits of cannabinoids, the patient's response to the drug depends on the individual's genetic background. Cytochrome P-450 (CYP-450) enzymes are involved in the primary metabolism of several exogenous cannabinoids: THC (CYPs 2C9, 3A4); cannabidiol (CBD; CYPs 2C19, 3A4); and cannabinol (CBN; CYPs 2C9, 3A4). Clinical pharmacogenetic data supported cytochrome P450 2C9 as a major contributor to THC metabolism. UDP-glucuronosyltransferases was recognized as capable of catalyzing the cannabinoid metabolism of both primary (CBD and CBN) and secondary (THC) cannabinoid metabolism.[43] The glucuronidation rates of cannabinol was observed at high levels by UGT1A10 and to a lesser extent by UGT1A7, UGT1A9, and UGT2B7 enzymes.[44] Interestingly, majority of the SNPs associated with the cannabinoids metabolism are distinct from the SNPs associated with the conventional analgesics related to pain management.

 » Conclusion Top

Despite significant improvements in recent years in cancer pain assessment and management, still significant number of patients with poorly regulated pain are present. A complete, holistic treatment strategy which consists of pharmacological and pharmacogenetic-based precision therapy would be utmost beneficial. The medicinal use of cannabis for the therapeutic management of multiple diseases have been documented in several traditional ayurvedic literatures over different periods of Indian history.

Further pharmacogenomic research examining the heterogeneity of SNPs associated with benefits and failure of conventional analgesics would aid in deriving appropriate directions for potential precision therapy of cannabinoids for pain management in cancer patients.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 » References Top

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.  Back to cited text no. 1
Van den Beuken-van Everdingen MH, Hochstenbach LM, Joosten EA, Tjan-Heijnen VC, Janssen DJ. Update on prevalence of pain in patients with cancer: Systematic review and meta-analysis. J Pain Symptom Manage 2016;51:1070-90.  Back to cited text no. 2
Breivik H, Cherny N, Collett B, de Conno F, Filbet M, Foubert AJ, et al. Cancer-related pain: A Pan-European survey of prevalence, treatment, and patient attitudes. Ann Oncol 2009;20:1420-33.  Back to cited text no. 3
Liu WC, Zheng ZX, Tan KH, Meredith GJ. Multidimensional treatment of cancer pain. Curr Oncol Rep 2017;19:10.  Back to cited text no. 4
World Health Organization. Cancer Pain Relief. World Health Organization; (1986). Available from: [Last accessed on 2019 Aug 13].  Back to cited text no. 5
World Health Organization. Cancer Pain Relief: with a Guide to Opioid Availability. World Health Organization; 1996. Available from: [Last accessed on 2019 Aug 13].  Back to cited text no. 6
World Health Organization. WHO Guidelines for the Pharmacological and Radio Therapeutic Management of Cancer Pain in Adults and Adolescents. World Health Organization; 2018. Available from: [Last accessed on 2019 Aug 12].  Back to cited text no. 7
Cherny N, Ripamonti C, Pereira J, Davis C, Fallon M, McQuay H, et al. Strategies to manage the adverse effects of oral morphine: An evidence-based report. J Clin Oncol 2001;19:2542-54.  Back to cited text no. 8
Crews KR, Gaedigk A, Dunnenberger HM, Klein TE, Shen DD, Callaghan JT, et al. Clinical pharmacogenetics implementation consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 2012;91:321-6.  Back to cited text no. 9
Crews KR, Gaedigk A, Dunnenberger HM, Leeder JS, Klein TE, Caudle KE, et al. Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther 2014;95:376-82.  Back to cited text no. 10
Swen JJ, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee AH, Mulder H, et al. Pharmacogenetics: From bench to byte – An update of guidelines. Clin Pharmacol Ther 2011;89:662-73.  Back to cited text no. 11
Zwisler ST, Enggaard TP, Noehr-Jensen L, Pedersen RS, Mikkelsen S, Nielsen F, et al. The hypoalgesic effect of oxycodone in human experimental pain models in relation to the CYP2D6 oxidation polymorphism. Basic Clin Pharmacol Toxicol 2009;104:335-44.  Back to cited text no. 12
Su Y, Zhan YY, Wang BF, Wang SC, Dai DP, Hu GX, et al. In vitro assessment of 24 CYP2D6 allelic isoforms on the metabolism of methadone. Drug Test Anal 2017;9:216-20.  Back to cited text no. 13
Martínez C, Blanco G, Ladero JM, García-Martín E, Taxonera C, Gamito FG, et al. Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use. Br J Pharmacol 2004;141:205-8.  Back to cited text no. 14
St Germaine CG, Bogaty P, Boyer L, Hanley J, Engert JC, Brophy JM. Genetic polymorphisms and the cardiovascular risk of non-steroidal anti-inflammatory drugs. Am J Cardiol 2010;105:1740-5.  Back to cited text no. 15
Lee YS, Kim H, Wu TX, Wang XM, Dionne RA. Genetically mediated interindividual variation in analgesic responses to cyclooxygenase inhibitory drugs. Clin Pharmacol Ther 2006;79:407-18.  Back to cited text no. 16
Zhang H, Luo X, Kranzler HR, Lappalainen J, Yang BZ, Krupitsky E, et al. Association between two mu-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence. Hum Mol Genet 2006;15:807-19.  Back to cited text no. 17
Chatti I, Woillard JB, Mili A, Creveaux I, Ben Charfeddine I, Feki J, et al. Genetic analysis of mu and kappa opioid receptor and COMT enzyme in cancer pain Tunisian patients under opioid treatment. Iran J Public Health 2017;46:1704-11.  Back to cited text no. 18
Nagaya D, Zahari Z, Saleem M, Yahaya BH, Tan SC, Yusoff NM. An analysis of genetic association in opioid dependence susceptibility. J Clin Pharm Ther 2018;43:80-6.  Back to cited text no. 19
Beer B, Erb R, Pavlic M, Ulmer H, Giacomuzzi S, Riemer Y, et al. Association of polymorphisms in pharmacogenetic candidate genes (OPRD1, GAL, ABCB1, OPRM1) with opioid dependence in European population: A case-control study. PLoS One 2013;8:e75359.  Back to cited text no. 20
Ayuso P, Plaza-Serón Mdel C, Doña I, Blanca-López N, Campo P, Cornejo-García JA, et al. Association study of genetic variants in PLA2G4A, PLCG1, LAT, SYK, and TNFRS11A genes in NSAIDs-induced Urticaria and/or angioedema patients. Pharmacogenet Genomics 2015;25:618-21.  Back to cited text no. 21
Cristallo AF, Schroeder J, Citterio A, Santori G, Ferrioli GM, Rossi U, et al. Astudy of HLA class I and class II 4-digit allele level in Stevens-Johnson syndrome and toxic epidermal necrolysis. Int J Immunogenet 2011;38:303-9.  Back to cited text no. 22
Brennan F. Palliative care as an international human right. J Pain Symptom Manage 2007;33:494-9.  Back to cited text no. 23
Lipman AG. Pain as a human right: The 2004 global day against pain. J Pain Palliat Care Pharmacother 2005;19:85-100.  Back to cited text no. 24
Perucca E. Cannabinoids in the treatment of epilepsy: Hard evidence at last? J Epilepsy Res 2017;7:61-76.  Back to cited text no. 25
Urits I, Borchart M, Hasegawa M, Kochanski J, Orhurhu V, Viswanath O, et al. An update of current cannabis-based pharmaceuticals in pain medicine. Pain Ther 2019;8:41-51.  Back to cited text no. 26
Abrams DI, Guzman M. Cannabis in cancer care. Clin Pharmacol Ther 2015;97:575-86.  Back to cited text no. 27
Walker JM, Huang SM. Cannabinoid analgesia. Pharmacol Ther 2002;95:127-35.  Back to cited text no. 28
Blake A, Wan BA, Malek L, DeAngelis C, Diaz P, Lao N, et al. Aselective review of medical cannabis in cancer pain management. Ann Palliat Med 2017;6:S215-S222.  Back to cited text no. 29
Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: A randomized, placebo-controlled, graded-dose trial. J Pain 2012;13:438-49.  Back to cited text no. 30
Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC: CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage 2010;39:167-79.  Back to cited text no. 31
Baburaj G, Abraham AM, George L, Shetty V, Thempalangad RM, Rajesh KS, et al. Astudy on utilization and evaluation of antiemetics in chemotherapy-induced nausea and vomiting. Indian J Med Paediatr Oncol 2017;38:334-9.  Back to cited text no. 32
[PUBMED]  [Full text]  
Robson P. Therapeutic aspects of cannabis and cannabinoids. Br J Psychiatry 2001;178:107-15.  Back to cited text no. 33
Di Carlo G, Izzo AA. Cannabinoids for gastrointestinal diseases: Potential therapeutic applications. Expert Opin Investig Drugs 2003;12:39-49.  Back to cited text no. 34
Berry EM, Mechoulam R. Tetrahydrocannabinol and endocannabinoids in feeding and appetite. Pharmacol Ther 2002;95:185-90.  Back to cited text no. 35
Walsh D, Nelson KA, Mahmoud FA. Established and potential therapeutic applications of cannabinoids in oncology. Support Care Cancer 2003;11:137-43.  Back to cited text no. 36
Hall W, Christie M, Currow D. Cannabinoids and cancer: Causation, remediation, and palliation. Lancet Oncol 2005;6:35-42.  Back to cited text no. 37
Guzmán M. Cannabinoids: Potential anticancer agents. Nat Rev Cancer 2003;3:745-55.  Back to cited text no. 38
Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers 2007;4:1770-804.  Back to cited text no. 39
Vermersch P, Trojano M. Tetrahydrocannabinol: Cannabidiol oromucosal spray for multiple sclerosis-related resistant spasticity in daily practice. Eur Neurol 2016;76:216-26.  Back to cited text no. 40
Freeman TP, Hindocha C, Green SF, Bloomfield MAP. Medicinal use of cannabis based products and cannabinoids. BMJ 2019;365:l1141.  Back to cited text no. 41
Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for medical use: A Systematic review and meta-analysis. JAMA 2015;313:2456-73.  Back to cited text no. 42
Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: A systematic review. Drug Metab Rev 2014;46:86-95.  Back to cited text no. 43
Mazur A, Lichti CF, Prather PL, Zielinska AK, Bratton SM, Gallus-Zawada A, et al. Characterization of human hepatic and extrahepatic UDP-glucuronosyltransferase enzymes involved in the metabolism of classic cannabinoids. Drug Metab Dispos 2009;37:1496-504.  Back to cited text no. 44


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