Brazilian Journal of Pain
https://brjp.org.br/article/doi/10.5935/2595-0118.20230051-en
Brazilian Journal of Pain
Review Article

Phytocannabinoids and the individualization of treatment. Why is there no level of evidence?

Fitocanabinoides e a individualização do tratamento. Por que não há nível de evidências?

Ricardo Ferreira de Oliveira e Silva; André dos Santos Costa e Silva

http://dx.doi.org/10.5935/2595-0118.20230051-en BrJP, vol.6, nSuppl. 2, p.126-130, 2023
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Abstract

BACKGROUND AND OBJECTIVES: The individualization of treatment has been recognized as essential in medical practice, especially due to the demand for different therapeutic approaches for similar situations. However, the complex and variable nature of the phytocannabinoids present in the cannabis plant presents challenges for the application of traditional models for testing the efficacy and safety of new drugs. The objective of the present study was to highlight the particularities of cannabis, including genetic variety, cultivation and production, which make it difficult to comply with traditional drug registration protocols, and the importance of individualizing treatment in the use of cannabis for the control of pain.
CONTENTS: Traditional models for testing the efficacy and safety of new drugs are based on a rigid methodology, divided into development and post-market phases. However, the complexity of the cannabis plant, with hundreds of actives that can vary according to the genetic variety, cultivation and production process, makes the application of these models difficult. In addition, international rules do not allow the registration of patents on cannabis products, due to the consideration that they are natural products and the extraction methods are already used in the industry for other plant actives. The individualization of treatment is fundamental in the use of cannabis for pain control, given the complexity of the plant and the limitations of traditional models of testing and drug registration.
CONCLUSION: The particularities of cannabis, such as genetic variability and the impossibility of registering patents, make compliance with current protocols difficult. However, the individualization of treatment allows adapting therapies to the needs of each patient, considering effectiveness and tolerance of side effects. Therefore, there is a need to rethink research and registry models to allow for a more flexible and personalized approach in the field of cannabis medicines.

Keywords

Cannabinoids receptors, Cannabis, Evidence-based pharmaceutical practice, History, Medical marijuana, Pain

Resumo

JUSTIFICATIVA E OBJETIVOS: A individualização do tratamento tem sido reconhecida como essencial na prática médica, especialmente devido à demanda por diferentes abordagens terapêuticas para situações semelhantes. No entanto, a natureza complexa e variável dos fitocanabinoides presentes na cannabis apresenta desafios para a aplicação dos modelos tradicionais de testes de eficácia e segurança de novos fármacos. O objetivo deste estudo foi destacar as particularidades da cannabis, incluindo a variedade genética, o cultivo e a produção, que dificultam a conformidade com os protocolos tradicionais de registro de medicamentos, e bem como a importância da individualização do tratamento na utilização da cannabis para o controle da dor. 
CONTEÚDO: Os modelos tradicionais de testes de eficácia e segurança de novos fármacos são baseados em uma metodologia rígida, dividida em fases de desenvolvimento e pós-mercado. No entanto, a complexidade da planta de cannabis, com centenas de ativos que podem variar de acordo com a variedade genética, o cultivo e o processo de produção, torna difícil a aplicação desses modelos. Além disso, as regras internacionais não permitem o registro de patentes de produtos canábicos, devido à consideração de que são produtos naturais e os métodos de extração já são utilizados na indústria para outros ativos vegetais. A individualização do tratamento é fundamental na utilização da cannabis para o controle da dor, dada a complexidade da planta e as limitações dos modelos tradicionais de testes e registro de fármacos. 
CONCLUSÃO: As particularidades da cannabis, como a variabilidade genética e a impossibilidade de registro de patentes, dificultam a conformidade com os protocolos atuais. No entanto, a individualização do tratamento permite adaptar as terapias às necessidades de cada paciente, considerando a efetividade e a tolerância aos efeitos colaterais. Portanto, é necessário repensar os modelos de pesquisa e registro para permitir uma abordagem mais flexível e personalizada no campo dos fármacos canábicos.

Palavras-chave

Cannabis, Dor, História, Maconha medicinal, Prática Farmacêutica baseada em evidências, Receptores de canabinoides

References

1 Fillingim RB. Individual differences in pain: understanding the mosaic that makes pain personal. Pain. 2017;158(Suppl 1):S11-S18.

2 Hui D, Bruera E. A personalized approach to assessing and managing pain in patients with cancer. J Clin Oncol. 2014;32(16):1640-6.

3 Hylands-White N, Duarte RV, Raphael JH. An overview of treatment approaches for chronic pain management. Rheumatol Int. 2017;37(1):29-42.

4 Crews KR, Monte AA, Huddart R, Caudle KE, Kharasch ED, Gaedigk A, Dunnenberger HM, Leeder JS, Callaghan JT, Samer CF, Klein TE, Haidar CE, Van Driest SL, Ruano G, Sangkuhl K, Cavallari LH, Müller DJ, Prows CA, Nagy M, Somogyi AA, Skaar TC. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy. Clin Pharmacol Ther. 2021;110(4):888-96.

5 Vieira CMP, Fragoso RM, Pereira D, Medeiros R. Pain polymorphisms and opioids: an evidence-based review. Mol Med Rep. 2019;19(3):1423-34.

6 Ting S, Schug S. The pharmacogenomics of pain management: prospects for personalized medicine. J Pain Res. 2016;9:49-56.

7 Rosenberger DC, Blechschmidt V, Timmerman H, Wolff A, Treede RD. Challenges of neuropathic pain: focus on diabetic neuropathy. J Neural Transm (Vienna). 2020;127(4):589-624.

8 Finnerup NB, Kuner R, Jensen TS. Neuropathic pain: from mechanisms to treatment. Physiol Rev. 2021;101(1):259-301.

9 Gilron I, Baron R, Jensen T. Neuropathic pain: principles of diagnosis and treatment. Mayo Clin Proc. 2015;90(4):532-45.

10 Moisset X, Bouhassira D, Attal N. French guidelines for neuropathic pain: an update and commentary. Rev Neurol (Paris). 2021;177(7):834-7.

11 Glickman A, Sisti D. Prescribing medical cannabis: ethical considerations for primary care providers. J Med Ethics. 2020;46(4):227-30.

12 Sagy I, Peleg-Sagy T, Barski L, Zeller L, Jotkowitz A. Ethical issues in medical cannabis use. Eur J Intern Med. 2018;49:20-2.

13 Singh AR, Singh SA. Guidelines, editors, pharma and the biological paradigm shift. Mens Sana Monogr. 2007;5(1):27-30.

14 González de la Aleja J, Martínez-Salio A, Bermejo-Pareja F. Continuing medical education in neurology: a necessary challenge. Neurologia. 2008;23(5):306-12.

15 Hogans BB, Watt-Watson J, Wilkinson P, Carr ECJ, Gordon DB. Perspective: update on pain education. Pain. 2018;159(9):1681-2.

16 Gatchel RJ, McGeary DD, McGeary CA, Lippe B. Interdisciplinary chronic pain management: past, present, and future. Am Psychol. 2014;69(2):119-30.

17 Keßler J, Geist M, Bardenheuer H. Treatment-refractory pain. Dtsch Med Wochenschr. 2018;143(19):1372-80.

18 Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013;46(2):207-18.

19 Moulin D, Boulanger A, Clark AJ, Clarke H, Dao T, Finley GA, Furlan A, Gilron I, Gordon A, Morley-Forster PK, Sessle BJ, Squire P, Stinson J, Taenzer P, Velly A, Ware MA, Weinberg EL, Williamson OD; Canadian Pain Society. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res Manag. 2014;19(6):328-35.

20 Machado-Duque ME, Gaviria-Mendoza A, Machado-Alba JE, Castaño N. Evaluation of treatment patterns and direct costs associated with the management of neuropathic pain. Pain Res Manag. 2020;30;2020:9353940.

21 Kaito T, Matsuyama Y, Yamashita T, Kawakami M, Takahashi K, Yoshida M, Imagama S, Ohtori S, Taguchi T, Haro H, Taneichi H, Yamazaki M, Inoue G, Nishida K, Yamada H, Kabata D, Shintani A, Iwasaki M, Ito M, Miyakoshi N, Murakami H, Yonenobu K, Takura T, Mochida J; Project Committee of the Japanese Society for Spine Surgery and Related Research (JSSR). Cost-effectiveness analysis of the pharmacological management of chronic low back pain with four leading drugs. J Orthop Sci. 2019;24(5):805-11.

22 Russo EB. History of cannabis and its preparations in saga, science, and sobriquet. Chem Biodivers. 2007;4(8):1614-48.

23 Alexander SP. Barriers to the wider adoption of medicinal Cannabis. BrJP. 2020;14(2):122-32.

24 Zuardi AW. History of cannabis as a medicine: a review. Braz J Psychiatry. 2006;28(2):153-7.

25 Borchers AT, Hagie F, Keen CL, Gershwin ME. The history and contemporary challenges of the US Food and Drug Administration. Clin Ther. 2007;29(1):1-16.

26 Nishioka Sde A, Sá PF. A Agência Nacional de Vigilância Sanitária e a pesquisa clínica no Brasil [The National Health Surveillance Agency, ANVISA, and clinical research in Brazil]. Rev Assoc Med Bras (1992). 2006;52(1):60-2.

27 Pisanti S, Bifulco M. Modern history of medical cannabis: from widespread use to prohibitionism and back. Trends Pharmacol Sci. 2017;38(3):195-8.

28 Schlag AK. An evaluation of regulatory regimes of medical cannabis: what lessons can be learned for the UK? Med Cannabis Cannabinoids. 2020;3(1):76-83.

29 Crocq MA. History of cannabis and the endocannabinoid system . Dialogues Clin Neurosci. 2020;22(3):223-8.

30 Charitos IA, Gagliano-Candela R, Santacroce L, Bottalico L. The cannabis spread throughout the continents and its therapeutic use in history. Endocr Metab Immune Disord Drug Targets. 2021;21(3):407-17.

31 Rock EM, Parker LA. Constituents of Cannabis Sativa. Adv Exp Med Biol. 2021;1264:1-13.

32 ElSohly MA, Radwan MM, Gul W, Chandra S, Galal A. Phytochemistry of Cannabis sativa L. Prog Chem Org Nat Prod. 2017;103:1-36.

33 Lewis MA, Russo EB, Smith KM. Pharmacological Foundations of Cannabis Chemovars. Planta Med. 2018;84(4):225-33.

34 Grof CPL. Cannabis, from plant to pill. Br J Clin Pharmacol. 2018;84(11):2463-7.

35 Casiraghi A, Roda G, Casagni E, Cristina C, Musazzi UM, Franzè S, Rocco P, Giuliani C, Fico G, Minghetti P, Gambaro V. Extraction method and analysis of cannabinoids in cannabis olive oil preparations. Planta Med. 2018;84(4):242-9.

36 Radwan MM, Chandra S, Gul S, ElSohly MA. Cannabinoids, phenolics, terpenes and alkaloids of cannabis. Molecules. 2021;26(9):2774.

37 Odieka AE, Obuzor GU, Oyedeji OO, Gondwe M, Hosu YS, Oyedeji AO. The medicinal natural products of cannabis sativa linn.: a review. Molecules. 2022;27(5):1689.

38 Berdigaliyev N, Aljofan M. An overview of drug discovery and development. Future Med Chem. 2020;12(10):939-47.

39 Chen J, Luo X, Qiu H, Mackey V, Sun L, Ouyang X. Drug discovery and drug marketing with the critical roles of modern administration. Am J Transl Res. 2018;10(12):4302-12.

40 Gallego V, Naveiro R, Roca C, Ríos Insua D, Campillo NE. AI in drug development: a multidisciplinary perspective. Mol Divers. 2021;25(3):1461-79.

41 Klumpers LE, Thacker DL. A brief background on cannabis: from plant to medical indications. J AOAC Int. 2019;2(2):412-20.

42 Brodniewicz T, Grynkiewicz G. Preclinical drug development. Acta Pol Pharm. 2010;67(6):578-85.

43 Najmi A, Javed SA, Al Bratty M, Alhazmi HA. Modern approaches in the discovery and development of plant-based natural products and their analogues as potential therapeutic agents. Molecules. 2022;27(2):349.

44 Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P, Temml V, Wang L, Schwaiger S, Heiss EH, Rollinger JM, Schuster D, Breuss JM, Bochkov V, Mihovilovic MD, Kopp B, Bauer R, Dirsch VM, Stuppner H. Discovery and resupply of pharmacologically active plant-derived natural products: a review. Biotechnol Adv. 2015;33(8):1582-614.

45 Anthony AT, Rahmat S, Sangle P, Sandhu O, Khan S. Cannabinoid receptors and their relationship with chronic pain: a narrative review. Cureus. 2020;12(9):e10436.]

46 Pertwee RG. Pharmacological actions of cannabinoids. Handb Exp Pharmacol. 2005;(168):1-51.

47 Stasiłowicz A, Tomala A, Podolak I, Cielecka-Piontek J. Cannabis sativa L. as a natural drug meeting the criteria of a multitarget approach to treatment. Int J Mol Sci. 2021;22(2):778.

48 D’hooghe M, Willekens B, Delvaux V, D’haeseleer M, Guillaume D, Laureys G, Nagels G, Vanderdonckt P, Van Pesch V, Popescu V. Sativex® (nabiximols) cannabinoid oromucosal spray in patients with resistant multiple sclerosis spasticity: the Belgian experience. BMC Neurol. 2021;21(1):227.

49 Lowe H, Toyang N, Steele B, Bryant J, Ngwa W. The endocannabinoid system: a potential target for the treatment of various diseases. Int J Mol Sci. 2021;22(17):9472.

50 Muller C, Morales P, Reggio PH. Cannabinoid ligands targeting TRP channels. Front Mol Neurosci. 2019;11:487.

51 Capano A, Weaver R, Burkman E. Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: a prospective cohort study. Postgrad Med. 2020;132(1):56-61.

52 Bhaskar A, Bell A, Boivin M, Briques W, Brown M, Clarke H, Cyr C, Eisenberg E, de Oliveira Silva RF, Frohlich E, Georgius P, Hogg M, Horsted TI, MacCallum CA, Müller-Vahl KR, O’Connell C, Sealey R, Seibolt M, Sihota A, Smith BK, Sulak D, Vigano A, Moulin DE. Consensus recommendations on dosing and administration of medical cannabis to treat chronic pain: results of a modified Delphi process. J Cannabis Res. 2021;3(1):22.

53 Bloomfield MAP, Hindocha C, Green SF, Wall MB, Lees R, Petrilli K, Costello H, Ogunbiyi MO, Bossong MG, Freeman TP. The neuropsychopharmacology of cannabis: a review of human imaging studies. Pharmacol Ther. 2019;195:132-61.

54 MacDonald E, Farrah K. Medical cannabis use in palliative care: review of clinical effectiveness and guidelines – an update [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2019;29. PMID: 31873991.

55 Baron EP, Lucas P, Eades J, Hogue O. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort. J Headache Pain. 2018;19(1):37.

56 Baron EP. Medicinal properties of cannabinoids, terpenes, and flavonoids in cannabis, and benefits in migraine, headache, and pain: an update on current evidence and cannabis science. Headache. 2018;58(7):1139-86.

57 Rodriguez CEB, Ouyang L, Kandasamy R. Antinociceptive effects of minor cannabinoids, terpenes and flavonoids in Cannabis. Behav Pharmacol. 2022;33(2&3):130-57.

58 Aviram J, Pud D, Gershoni T, Schiff-Keren B, Ogintz M, Vulfsons S, Yashar T, Adahan HM, Brill S, Amital H, Goor-Aryeh I, Robinson D, Green L, Segal R, Fogelman Y, Tsvieli O, Yellin B, Vysotski Y, Morag O, Tashlykov V, Sheinfeld R, Goor R, Meiri D, Eisenberg E. Medical cannabis treatment for chronic pain: outcomes and prediction of response. Eur J Pain. 2021;25(2):359-74.

59 Romero-Sandoval EA, Fincham JE, Kolano AL, Sharpe BN, Alvarado-Vázquez PA. Cannabis for chronic pain: challenges and considerations. Pharmacotherapy. 2018;38(6):651-62.

60 Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain. 2013;14(2):136-48.

61 Sainsbury B, Bloxham J, Pour MH, Padilla M, Enciso R. Efficacy of cannabis-based medications compared to placebo for the treatment of chronic neuropathic pain: a systematic review with meta-analysis. J Dent Anesth Pain Med. 2021;21(6):479-506.

62 Maharajan MK, Yong YJ, Yip HY, Woon SS, Yeap KM, Yap KY, Yip SC, Yap KX. Medical cannabis for chronic pain: can it make a difference in pain management? J Anesth. 2020;34(1):95-103.
 

Submitted date:
06/17/2022

Accepted date:
06/21/2023

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