Author : Ana Rita Gaspar,
Bachelor’s degree in Biomedical Sciences
Member of the R&D team
Piauhy Labs
Nowadays, chronic pain is a common and non-visible disease in most patients. Pain can behave as nociceptive pain, neuropathic pain and inflammatory pain. Harmful stimuli, or the pain feeling experienced by patients, are interpreted by central and peripheral nervous systems - which means that all the body (organs, bones, muscles, joints, skin) is involved. Pharmacological evidence shows the analgesic effect of cannabinoids and cannabinoid receptors, and also how somatic, visceral and neuropathy pain is relieved by cannabis plant compounds. Cannabinoids used for pain management can enhance the activity of our endocannabinoid system and deal beneficially with severe or chronic pain. Each of these types of pain and its treatment to alleviate symptoms will be defined and explained in further detail in this article.
According to the International Association for the Study of Pain (IASP), the definition of pain is the unpleasant feeling or emotional experience associated, in general, with tissue damage, which is also considered subjective. On the other hand, The notion of “Nociception” is the process that is induced by harmful stimuli, involving receptors, nerves and the central nervous system. It must be underlined that pain is usually caused by nociceptive activity; however, it can occur independently of it.
The sensation of pain arises when there is an activation of nerve endings, which are not very specialized and are called nociceptors. These transduce various stimuli into receptor potentials, which lead to action potentials. Nociceptors originate from cell bodies in the dorsal root ganglia or the trigeminal ganglion, emitting one axon to the periphery and another into the spinal cord or brainstem.
The axons associated with nociceptors can carry information at various speeds, so those that carry it at 5-30 m/s correspond to myelinated Aσ fibers, while those that carry it at 2 m/s correspond to unmyelinated C fibers. Thus, it is understood that myelinated Aσ fibers (faster conduction) respond to mechanical or thermal stimuli of dangerous intensity. In turn, unmyelinated C fibers respond to thermal, mechanical and chemical stimuli, and are therefore called polymodal.
Nociceptors remain in homeostasis in the absence of pain, however, they are activated when a noxious stimulus appears. When a thermal, mechanical or chemical stimulus reaches a noxious level of intensity suggestive of injury, then it is detected by nociceptors.
The injured tissue releases and produces numerous factors, which activate the nerve endings. These factors include globulin, protein kinases, arachidonic acid, histamine, nerve growth factor (NGF), substance P, calcitonin gene-related peptide (CGRP), among others. These factors stimulate transduction channels, such as transient receptor potential channels (TRP).
These channels Its function as voltage-dependent potassium channels and therefore help initiate receptor potentials, which consequently induce an action potential in nerve fibers.
What happens is that under resting conditions, the pore of these channels remains closed, however, when activated, the pore opens and these receptors allow an influx of sodium and calcium, which leads to the induction of action potentials in the nociceptive fibers. Thus, nerve impulses are propagated along the afferent fibers to the dorsal root of the spinal cord and later to the brain.
For the brain to detect pain and produce a targeted response to the threat, it requires the perception of a series of sensory events. Simultaneously, three phases for pain perception are involved: 1st pain sensitivity; 2nd signals transmitted from the peripheral nerves to the dorsal root of the spinal cord, through the peripheral nervous system; 3rd transmission of signals to the brain, through the central nervous system.
Signal transmission occur by two pathways for signal transmission to occur: the called ascending pathway, which allows the transmission of sensory information from the body to the brain, through the spinal cord, and the descending pathway, which transmits information from the brain to the organs, via the spinal cord.
Therefore, the central and peripheral nervous systems are both involved in pain perception mechanisms. The central nervous system comprises the brain and spinal cord, and it is mainly responsible for interpreting and integrating the information that is sent by the peripheral nervous system, coordinating all the activities of our body to produce a response to the effector organs. In turn, the peripheral nervous system refers to the nerves and ganglia that lie outside the brain and spinal cord, which connect the central nervous system to effector organs and body limbs.
Nociceptors are found in visceral organs, skin, joints, bones, muscles, but not in the brain. The harmful stimuli that lead to nociception depend on the different types of tissue in the human body: in the case of the skin, the harmful stimulus is thermal, mechanical and chemical in nature; in the case of joints, the harmful stimulus originates from mechanical stress and chemical inflammation; in the case of visceral organs, the harmful stimulus is mechanical distension; in the case of muscles, the harmful stimulus is strenuous mechanical effort, for example.
Finally, nociceptive pain can be subdivided into somatic nociceptive pain and visceral nociceptive pain. On the one hand, the first comprises five physiological processes:
This type of pain is described as a painful sensation resulting from nerve damage both in peripheral structures and in the central nervous system. It is often associated with allodynia, that is, when there is a change in the pain direction. Allodynia is a dysfunction of brain activity that manifests itself as a sensation of pain when, normally, the stimulus is not painful. The main reason is because the message from the nerve fibers is altered. Neuropathic pain can arise spontaneously or can be produced by mild stimuli that are common in everyday experience, such as light touch or pressure from clothing, or hot or cold temperatures. This condition can be described as “pathological pain” since neuropathic pain does not function as a defense or alert system for our body. The main causes of this type of pain can be inflammation or metabolic diseases such as diabetes, trauma, toxins, tumors, neurological diseases, etc. …
A Chinese encyclopedia of agriculture and medicine, entitled “The Shennong Ben Cao Jing”, presents the oldest record of the use of cannabis for medicinal purposes, in which it presents recommendations for rheumatic pain, for diseases of the female reproductive tract and for malaria. That said, the Chinese predominantly used the seeds of this plant, which have low levels of THC.
However, over time, other parts of the plant were also used medicinally in India: several preparations were conceived with different medicinal potential, the strongest being used as analgesics, hypnotics, tranquilizers and anti-inflammatory drugs. At the end of the 19th century, 100 publications that investigated the use of medicinal cannabis had already been published, however, in a more contemporary world, laws and restrictions emerged and conditioned the study of this natural product as a therapeutic potential.
Recently, research associated with medicinal cannabis has grown exponentially and its use for the treatment of pain is one of the most considered. Indeed, in a 2014 article entitled “Pharmacological Management of Chronic Neuropathic Pain: Canadian Pain Society Revised Consensus Statement”, the recommendation for the use of cannabis as a third line of pain treatment is stated. The same article also advertised the following analgesic agents as treatment: as 1st line of treatment recommended gabapentoids, tricyclic antidepressants and serotonin and noradrenaline reuptake inhibitors; as 2nd line of treatment comes tramadol and opioid analgesics for moderate to severe pain; as the 3rd line of treatment indicates cannabinoids.
However, the problem exists since the clinical trials, which aim to investigate the efficacy and safety of medicinal cannabis conducted so far, have been of short duration and involved limited resources. Furthermore, the diversity of formulations, preparations and routes of administration is very scarce, so there is an urgent need to overcome these, by carrying it out with high-quality prospective clinical trials to determine efficacy, safety and dosage.
Cannabinoids bind to cannabinoid receptors and act as agonists. Cannabinoid receptors are cell membrane receptors, members of G protein-coupled receptors. They are activated by three main groups of ligands: endocannabinoids, phytocannabinoids, and synthetic cannabinoids. So far, four subtypes of these receptors have been identified - two have been cloned (cannabinoid receptors CB1 and CB2), while the other two, WIN and abnormal cannabidiol receptors (abn-CBD), have been characterized pharmacologically.
The analgesic effect of cannabinoids as a result of the binding of cannabinoids to cannabinoid receptors has been confirmed, and the role of the endocannabinoid system in pain relief has been verified in several types of pain: somatic, visceral and neuropathy. Classic analgesics, nonsteroidal anti-inflammatory drugs or opioids, paracetamol and antidepressants (with an analytical effect in some conditions) increase the activity of the endocannabinoid system.
Phytocannabinoids are exogenous cannabinoids and, as an example, appear THC and CBD, which also have an ability to bind to cannabinoid receptors. On the one hand, THC is the cannabinoid that has the most effects at the cognitive level and, on the other hand, CBD has very low psychoactive properties and may also inhibit THC metabolism.
The endocannabinoids (anandamide and 2-AG), derived from arachidonic acid, are produced by neuronal and non-neuronal cells in damaged tissues. Its function is to modulate the neural conduction of pain signals, attenuating sensitization and inflammation, as they activate cannabinoid receptors, which are also targeted by THC (phytocannabinoid).
On the one hand, anandamide can act as an autocrine or paracrine messenger and can be broken down to arachidonic acid and ethanolamine, or it can undergo transformation by COX-2 activity to give rise to pro-algesic prostamides. Anandamide mobilizes in response to inflammation and nerve damage and modulates nociceptive signals by activating local CB1 receptors.
On the other hand, 2-AG results from the hydrolysis of phosphatidylinositol-4,5-biphosphate and plays a prominent role in downward modulation of pain during acute stress. Both endocannabinoids are recruited during tissue injury to provide a first response to nociceptive signals. By understanding the role of endocannabinoids, it is possible to understand the effectiveness of exogenous cannabinoids, such as those found in the cannabis plant, in treating pain.
The discovery of the endocannabinoid system and the development of animal models with different forms of pain have recently demonstrated the synergism between the opioid and cannabinoid systems. There is a large amount of preclinical data in animal models on the analgesic effect of cannabinoids, predominantly Δ9-tetrahydrocannabinol (THC), nabilone and dronabinol, or combinations of THC and cannabidiol (CBD) and some other synthetic cannabinoids; and analgesic effects in the treatment of cancer-related pain without serious side effects.
Both endocannabinoids and exogenous cannabinoids act on multiple stages of pain in the nervous system, in addition to cannabinoid receptors CB1 and CB2. The various mechanisms by which cannabinoids achieve this are: pain reduction through interaction with a G protein-coupled receptor, GPR55 or GPR18, which is also known as the N-arachidonoyl glycine (NAGly) receptor; also by interaction with opioid receptors or serotonin receptors; ability to modulate certain nuclear receptors (PPARs) or transient receptor potential (TRP) channels, among others.
Therefore, it is easy to understand that many of these receptors could be strategic therapeutic targets for the use of medicinal cannabis as pain treatment. Cannabinoid-mediated analgesia mechanisms include inhibiting the release of neurotransmitters and neuropeptides from presynaptic nerve endings, regulating the excitability of postsynaptic neurons, activating descending pain-inhibiting pathways, and reducing neuroinflammation
“In humans, pharmacodynamic studies have demonstrated the effect of cannabinoids on induced somatic pain (e.g., thermal stimulation), capsaicin-induced hyperalgesia, painful spasms in patients with multiple sclerosis (MS) and neuropathic pain in patients with HIV/AIDS.”
Ana Rita Gaspar
Ana Rita Gaspar,
Bachelor’s degree in Biomedical Sciences
Member of the R&D team
Piauhy Labs
References
Abrams, D. I. and Guzman, M. (2015). Cannabis in cancer care. Clin. Pharmacol. Ther. 97, 575–586. 10.1002/cpt.108.
Argueta, D.A.; Ventura, C.M.; Kiven, S.; Sagi, V. and Gupta, K. A Balanced Approach for Cannabidiol Use in Chronic Pain. Front. Pharmacol. 2020; 11: 561. Published 2020, Apr 30. doi:10.3389/fphar.2020.00561.
Chen, J.S.; Kandle, P.F.; Murray, I., et al. Physiology, Pain. [Updated 2021 Jul 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539789/.
de Vries, M.; van Rijckevorsel, D. C. M.; Vissers, K. C. P.; Wilder-Smith, O. H. G. and van Goor, H. (2017). Pain and nociception neuroscience research group. tetrahydrocannabinol does not reduce pain in patients with chronic abdominal pain in a phase 2 placebo-controlled study. Clin. Gastroenterol. Hepatol. 15, 1079–1086. 10.1016/j.cgh.2016.09.147.
Fitzcharles, M.A.; Baerwald, C.; Ablin, J. and Häuser, W. (2016). Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis): a systematic review of randomized controlled trials. Schmerz 30, 47–61. 10.1007/s00482-015-0084-3.
Hill, K.P.; Palastro, M.D.; Johnson, B. and Ditre, J.W. Cannabis and Pain: A Clinical
Review. Cannabis Cannabinoid Res. 2017;2(1):96-104. Published 2017, May 1. doi:10.1089/can.2017.0017.
Hohmann, A.G.; Suplita, R.L.; Bolton, N.M.; Neely, M.H.; Fegley, D.; Mangieri, R.; KreyJ.F.; Walker, J.M.; Holmes, P.V.; Crystal, J.D.; Duranti, A.; Tontini, A.; Mor, M.; Tarzia, G. and Piomelli, D. An endocannabinoid mechanism for stress-induced analgesia. Nature. 2005, Jun 23; 435(7045): 1108-12. doi: 10.1038/nature03658. PMID: 15973410.
Horvath, G.; Kekesi, G.; Nagy, E. and Benedek, G. The role of TRPV1 receptors in the antinociceptive effect of anandamide at spinal level. Pain. 2008, Feb;134(3):277-284. doi: 10.1016/j.pain.2007.04.032. Epub 2007, May 29. PMID: 17533116.
Khalida, A. Pathophysiology of pain, Disease-a-Month, Volume 62, Issue 9, 2016, Pages 324-329, ISSN 0011-5029, https://doi.org/10.1016/j.disamonth.2016.05.015. (https://www.sciencedirect.com/science/article/pii/S0011502916300505).
Kraft, B.; Frickey, N.A.; Kaufmann, R.M.; Reif, M.; Frey, R.; Gustorff, B. and Kress, H.G. Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers. Anesthesiology. 2008, Jul; 109(1): 101-10. doi: 10.1097/ALN.0b013e31817881e1. PMID: 18580179.
Lynch, M.E. and Campbell, F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br. J. Clin. Pharmacol. 2011, Nov; 72(5): 735-44. doi: 10.1111/j.1365-2125.2011.03970.x. PMID: 21426373; PMCID: PMC3243008.
Lynch, M.E. and Ware M.A. (2015). Cannabinoids for the treatment of chronic
non-cancer pain: an updated systematic review of randomized controlled
trials. J. Neuroimmune Pharmacol. 10 293–301. 10.1007/s11481-015-9600-6.
Mallick-Searle, T. and St Marie, B. Cannabinoids in Pain Treatment: An Overview. Pain Manag. Nurs. 2019; 20 (2): 107-112. doi:10.1016/j.pmn.2018.12.006.
Meng, H.; Johnston, B.; Englesakis, M.; Moulin, D. E. and Bhatia, A. (2017). Selective cannabinoids for chronic neuropathic pain: a systematic review and meta- analysis. Anesth. Analg. 125, 1638–1652. 10.1213/ANE.0000000000002110.
Morales, P.; Hurst, D.P. and Reggio, P.H. Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog. Chem. Org. Nat. Prod. 2017; 103: 103-131. doi: 10.1007/978-3-319-45541-9_4. PMID: 28120232; PMCID: PMC5345356.
Moulin D.; Boulanger, A.; Clark, A.J., et al. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res. Manag. 2014; 19(6): 328-335. doi:10.1155/2014/754693.
NASEM (2017). National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: National Academies Press.
O'Sullivan, S.E. An update on PPAR activation by cannabinoids. Br. J. Pharmacol. 2016, Jun; 173(12): 1899-910. doi: 10.1111/bph.13497. Epub 2016, May 19. PMID: 27077495; PMCID: PMC4882496.
PDQ Integrative Alternative and Complementary Therapies Editorial Board (2018). Cannabis and Cannabinoids (PDQ®): Health Professional Version,” in: PDQ Cancer Information Summaries [Internet]. Bethesda, MD: National Cancer Institute.
Pertwee, R.G.; Howlett, A.C.; Abood, M.E.; Alexander, S.P.; Di Marzo, V.; Elphick, M.R.; Greasley, P.J.; Hansen, H.S.; Kunos, G.; Mackie, K.; Mechoulam, R. and Ross, R.A.
International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂. Pharmacol. Rev. 2010, Dec; 62(4): 588-631. doi: 10.1124/pr.110.003004. PMID: 21079038; PMCID: PMC2993256.
Queremel, M.D.A. and Davis, D.D. Pain Management Medications. [Updated 2021 Jul 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560692/.
Romero-Sandoval, E.A.; Kolano, A.L. and Alvarado-Vázquez, P.A. Cannabis and Cannabinoids for Chronic Pain. Curr. Rheumatol. Rep. 19, 67 (2017). doi.org/10.1007/s11926-017-0693-1.
Ross, R.A. Anandamide and vanilloid TRPV1 receptors. Br. J. Pharmacol. 2003, Nov;140(5): 790-801. doi: 10.1038/sj.bjp.0705467. Epub 2003 Sep 29. PMID:14517174; PMCID: PMC1574087.
Vučković, S.; Srebro, D.; Vujović, K.S.; Vučetić, Č. And Prostran, M. Cannabinoids and Pain: New Insights from Old Molecules. Front. Pharmacol. 2018; 9: 1259. Published 2018 Nov 13. doi: 10.3389/fphar.2018.01259.
Vulfsons, S., Minerbi, A. and Sahar, T. Cannabis and Pain – Treatment – A Review of
the Clinical Utility and a Practical Approach in Light of Uncertainty. Rambam Maimonides Med J. 2020;11(1):e0002. Published 2020 Jan 30. doi:10.5041/RMMJ.10385.
Whiting, P.F.; Wolff, R.F.; Deshpande, S.; Di Nisio, M.; Duffy, S.; Hernandez, A.V.; Keurentjes, J.C.; Lang, S.; Misso, K.; Ryder, S.; Schmidlkofer, S.; Westwood, M. and Kleijnen, J. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015, Jun. 23-30; 313(24): 2456-73. doi: 10.1001/jama.2015.6358. Erratum in: JAMA. 2015, Aug. 4; 314(5): 520. Erratum in: JAMA. 2015, Aug. 25; 314(8): 837. Erratum in: JAMA. 2015, Dec. 1; 314(21): 2308. Erratum in: JAMA. 2016, Apr. 12; 315(14): 1522. PMID: 26103030.
Yam, M.F.; Loh, Y.C.; Tan, C.S.; Khadijah, A.S.; Abdul, M.N. and Basir, R.G. Pathways of Pain Sensation and the Major Neurotransmitters Involved in Pain Regulation. Int. J. Mol. Sci. 2018;19(8):2164. Published 2018 Jul 24. doi:10.3390/ijms19082164.
Nowadays, chronic pain is a common and non-visible disease in most patients. Pain can behave as nociceptive pain, neuropathic pain and inflammatory pain. Harmful stimuli, or the pain feeling experienced by patients, are interpreted by central and peripheral nervous systems - which means that all the body (organs, bones, muscles, joints, skin) is involved. Pharmacological evidence shows the analgesic effect of cannabinoids and cannabinoid receptors, and also how somatic, visceral and neuropathy pain is relieved by cannabis plant compounds. Cannabinoids used for pain management can enhance the activity of our endocannabinoid system and deal beneficially with severe or chronic pain. Each of these types of pain and its treatment to alleviate symptoms will be defined and explained in further detail in this article.
According to the International Association for the Study of Pain (IASP), the definition of pain is the unpleasant feeling or emotional experience associated, in general, with tissue damage, which is also considered subjective. On the other hand, The notion of “Nociception” is the process that is induced by harmful stimuli, involving receptors, nerves and the central nervous system. It must be underlined that pain is usually caused by nociceptive activity; however, it can occur independently of it.
The sensation of pain arises when there is an activation of nerve endings, which are not very specialized and are called nociceptors. These transduce various stimuli into receptor potentials, which lead to action potentials. Nociceptors originate from cell bodies in the dorsal root ganglia or the trigeminal ganglion, emitting one axon to the periphery and another into the spinal cord or brainstem.
The axons associated with nociceptors can carry information at various speeds, so those that carry it at 5-30 m/s correspond to myelinated Aσ fibers, while those that carry it at 2 m/s correspond to unmyelinated C fibers. Thus, it is understood that myelinated Aσ fibers (faster conduction) respond to mechanical or thermal stimuli of dangerous intensity. In turn, unmyelinated C fibers respond to thermal, mechanical and chemical stimuli, and are therefore called polymodal.
Nociceptors remain in homeostasis in the absence of pain, however, they are activated when a noxious stimulus appears. When a thermal, mechanical or chemical stimulus reaches a noxious level of intensity suggestive of injury, then it is detected by nociceptors.
The injured tissue releases and produces numerous factors, which activate the nerve endings. These factors include globulin, protein kinases, arachidonic acid, histamine, nerve growth factor (NGF), substance P, calcitonin gene-related peptide (CGRP), among others. These factors stimulate transduction channels, such as transient receptor potential channels (TRP).
These channels Its function as voltage-dependent potassium channels and therefore help initiate receptor potentials, which consequently induce an action potential in nerve fibers.
What happens is that under resting conditions, the pore of these channels remains closed, however, when activated, the pore opens and these receptors allow an influx of sodium and calcium, which leads to the induction of action potentials in the nociceptive fibers. Thus, nerve impulses are propagated along the afferent fibers to the dorsal root of the spinal cord and later to the brain.
For the brain to detect pain and produce a targeted response to the threat, it requires the perception of a series of sensory events. Simultaneously, three phases for pain perception are involved: 1st pain sensitivity; 2nd signals transmitted from the peripheral nerves to the dorsal root of the spinal cord, through the peripheral nervous system; 3rd transmission of signals to the brain, through the central nervous system.
Signal transmission occur by two pathways for signal transmission to occur: the called ascending pathway, which allows the transmission of sensory information from the body to the brain, through the spinal cord, and the descending pathway, which transmits information from the brain to the organs, via the spinal cord.
Therefore, the central and peripheral nervous systems are both involved in pain perception mechanisms. The central nervous system comprises the brain and spinal cord, and it is mainly responsible for interpreting and integrating the information that is sent by the peripheral nervous system, coordinating all the activities of our body to produce a response to the effector organs. In turn, the peripheral nervous system refers to the nerves and ganglia that lie outside the brain and spinal cord, which connect the central nervous system to effector organs and body limbs.
Nociceptors are found in visceral organs, skin, joints, bones, muscles, but not in the brain. The harmful stimuli that lead to nociception depend on the different types of tissue in the human body: in the case of the skin, the harmful stimulus is thermal, mechanical and chemical in nature; in the case of joints, the harmful stimulus originates from mechanical stress and chemical inflammation; in the case of visceral organs, the harmful stimulus is mechanical distension; in the case of muscles, the harmful stimulus is strenuous mechanical effort, for example.
Finally, nociceptive pain can be subdivided into somatic nociceptive pain and visceral nociceptive pain. On the one hand, the first comprises five physiological processes:
This type of pain is described as a painful sensation resulting from nerve damage both in peripheral structures and in the central nervous system. It is often associated with allodynia, that is, when there is a change in the pain direction. Allodynia is a dysfunction of brain activity that manifests itself as a sensation of pain when, normally, the stimulus is not painful. The main reason is because the message from the nerve fibers is altered. Neuropathic pain can arise spontaneously or can be produced by mild stimuli that are common in everyday experience, such as light touch or pressure from clothing, or hot or cold temperatures. This condition can be described as “pathological pain” since neuropathic pain does not function as a defense or alert system for our body. The main causes of this type of pain can be inflammation or metabolic diseases such as diabetes, trauma, toxins, tumors, neurological diseases, etc. …
A Chinese encyclopedia of agriculture and medicine, entitled “The Shennong Ben Cao Jing”, presents the oldest record of the use of cannabis for medicinal purposes, in which it presents recommendations for rheumatic pain, for diseases of the female reproductive tract and for malaria. That said, the Chinese predominantly used the seeds of this plant, which have low levels of THC.
However, over time, other parts of the plant were also used medicinally in India: several preparations were conceived with different medicinal potential, the strongest being used as analgesics, hypnotics, tranquilizers and anti-inflammatory drugs. At the end of the 19th century, 100 publications that investigated the use of medicinal cannabis had already been published, however, in a more contemporary world, laws and restrictions emerged and conditioned the study of this natural product as a therapeutic potential.
Recently, research associated with medicinal cannabis has grown exponentially and its use for the treatment of pain is one of the most considered. Indeed, in a 2014 article entitled “Pharmacological Management of Chronic Neuropathic Pain: Canadian Pain Society Revised Consensus Statement”, the recommendation for the use of cannabis as a third line of pain treatment is stated. The same article also advertised the following analgesic agents as treatment: as 1st line of treatment recommended gabapentoids, tricyclic antidepressants and serotonin and noradrenaline reuptake inhibitors; as 2nd line of treatment comes tramadol and opioid analgesics for moderate to severe pain; as the 3rd line of treatment indicates cannabinoids.
However, the problem exists since the clinical trials, which aim to investigate the efficacy and safety of medicinal cannabis conducted so far, have been of short duration and involved limited resources. Furthermore, the diversity of formulations, preparations and routes of administration is very scarce, so there is an urgent need to overcome these, by carrying it out with high-quality prospective clinical trials to determine efficacy, safety and dosage.
Cannabinoids bind to cannabinoid receptors and act as agonists. Cannabinoid receptors are cell membrane receptors, members of G protein-coupled receptors. They are activated by three main groups of ligands: endocannabinoids, phytocannabinoids, and synthetic cannabinoids. So far, four subtypes of these receptors have been identified - two have been cloned (cannabinoid receptors CB1 and CB2), while the other two, WIN and abnormal cannabidiol receptors (abn-CBD), have been characterized pharmacologically.
The analgesic effect of cannabinoids as a result of the binding of cannabinoids to cannabinoid receptors has been confirmed, and the role of the endocannabinoid system in pain relief has been verified in several types of pain: somatic, visceral and neuropathy. Classic analgesics, nonsteroidal anti-inflammatory drugs or opioids, paracetamol and antidepressants (with an analytical effect in some conditions) increase the activity of the endocannabinoid system.
Phytocannabinoids are exogenous cannabinoids and, as an example, appear THC and CBD, which also have an ability to bind to cannabinoid receptors. On the one hand, THC is the cannabinoid that has the most effects at the cognitive level and, on the other hand, CBD has very low psychoactive properties and may also inhibit THC metabolism.
The endocannabinoids (anandamide and 2-AG), derived from arachidonic acid, are produced by neuronal and non-neuronal cells in damaged tissues. Its function is to modulate the neural conduction of pain signals, attenuating sensitization and inflammation, as they activate cannabinoid receptors, which are also targeted by THC (phytocannabinoid).
On the one hand, anandamide can act as an autocrine or paracrine messenger and can be broken down to arachidonic acid and ethanolamine, or it can undergo transformation by COX-2 activity to give rise to pro-algesic prostamides. Anandamide mobilizes in response to inflammation and nerve damage and modulates nociceptive signals by activating local CB1 receptors.
On the other hand, 2-AG results from the hydrolysis of phosphatidylinositol-4,5-biphosphate and plays a prominent role in downward modulation of pain during acute stress. Both endocannabinoids are recruited during tissue injury to provide a first response to nociceptive signals. By understanding the role of endocannabinoids, it is possible to understand the effectiveness of exogenous cannabinoids, such as those found in the cannabis plant, in treating pain.
The discovery of the endocannabinoid system and the development of animal models with different forms of pain have recently demonstrated the synergism between the opioid and cannabinoid systems. There is a large amount of preclinical data in animal models on the analgesic effect of cannabinoids, predominantly Δ9-tetrahydrocannabinol (THC), nabilone and dronabinol, or combinations of THC and cannabidiol (CBD) and some other synthetic cannabinoids; and analgesic effects in the treatment of cancer-related pain without serious side effects.
Both endocannabinoids and exogenous cannabinoids act on multiple stages of pain in the nervous system, in addition to cannabinoid receptors CB1 and CB2. The various mechanisms by which cannabinoids achieve this are: pain reduction through interaction with a G protein-coupled receptor, GPR55 or GPR18, which is also known as the N-arachidonoyl glycine (NAGly) receptor; also by interaction with opioid receptors or serotonin receptors; ability to modulate certain nuclear receptors (PPARs) or transient receptor potential (TRP) channels, among others.
Therefore, it is easy to understand that many of these receptors could be strategic therapeutic targets for the use of medicinal cannabis as pain treatment. Cannabinoid-mediated analgesia mechanisms include inhibiting the release of neurotransmitters and neuropeptides from presynaptic nerve endings, regulating the excitability of postsynaptic neurons, activating descending pain-inhibiting pathways, and reducing neuroinflammation
“In humans, pharmacodynamic studies have demonstrated the effect of cannabinoids on induced somatic pain (e.g., thermal stimulation), capsaicin-induced hyperalgesia, painful spasms in patients with multiple sclerosis (MS) and neuropathic pain in patients with HIV/AIDS.”
Ana Rita Gaspar
Ana Rita Gaspar,
Bachelor’s degree in Biomedical Sciences
Member of the R&D team
Piauhy Labs
References
Abrams, D. I. and Guzman, M. (2015). Cannabis in cancer care. Clin. Pharmacol. Ther. 97, 575–586. 10.1002/cpt.108.
Argueta, D.A.; Ventura, C.M.; Kiven, S.; Sagi, V. and Gupta, K. A Balanced Approach for Cannabidiol Use in Chronic Pain. Front. Pharmacol. 2020; 11: 561. Published 2020, Apr 30. doi:10.3389/fphar.2020.00561.
Chen, J.S.; Kandle, P.F.; Murray, I., et al. Physiology, Pain. [Updated 2021 Jul 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539789/.
de Vries, M.; van Rijckevorsel, D. C. M.; Vissers, K. C. P.; Wilder-Smith, O. H. G. and van Goor, H. (2017). Pain and nociception neuroscience research group. tetrahydrocannabinol does not reduce pain in patients with chronic abdominal pain in a phase 2 placebo-controlled study. Clin. Gastroenterol. Hepatol. 15, 1079–1086. 10.1016/j.cgh.2016.09.147.
Fitzcharles, M.A.; Baerwald, C.; Ablin, J. and Häuser, W. (2016). Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis): a systematic review of randomized controlled trials. Schmerz 30, 47–61. 10.1007/s00482-015-0084-3.
Hill, K.P.; Palastro, M.D.; Johnson, B. and Ditre, J.W. Cannabis and Pain: A Clinical
Review. Cannabis Cannabinoid Res. 2017;2(1):96-104. Published 2017, May 1. doi:10.1089/can.2017.0017.
Hohmann, A.G.; Suplita, R.L.; Bolton, N.M.; Neely, M.H.; Fegley, D.; Mangieri, R.; KreyJ.F.; Walker, J.M.; Holmes, P.V.; Crystal, J.D.; Duranti, A.; Tontini, A.; Mor, M.; Tarzia, G. and Piomelli, D. An endocannabinoid mechanism for stress-induced analgesia. Nature. 2005, Jun 23; 435(7045): 1108-12. doi: 10.1038/nature03658. PMID: 15973410.
Horvath, G.; Kekesi, G.; Nagy, E. and Benedek, G. The role of TRPV1 receptors in the antinociceptive effect of anandamide at spinal level. Pain. 2008, Feb;134(3):277-284. doi: 10.1016/j.pain.2007.04.032. Epub 2007, May 29. PMID: 17533116.
Khalida, A. Pathophysiology of pain, Disease-a-Month, Volume 62, Issue 9, 2016, Pages 324-329, ISSN 0011-5029, https://doi.org/10.1016/j.disamonth.2016.05.015. (https://www.sciencedirect.com/science/article/pii/S0011502916300505).
Kraft, B.; Frickey, N.A.; Kaufmann, R.M.; Reif, M.; Frey, R.; Gustorff, B. and Kress, H.G. Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers. Anesthesiology. 2008, Jul; 109(1): 101-10. doi: 10.1097/ALN.0b013e31817881e1. PMID: 18580179.
Lynch, M.E. and Campbell, F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br. J. Clin. Pharmacol. 2011, Nov; 72(5): 735-44. doi: 10.1111/j.1365-2125.2011.03970.x. PMID: 21426373; PMCID: PMC3243008.
Lynch, M.E. and Ware M.A. (2015). Cannabinoids for the treatment of chronic
non-cancer pain: an updated systematic review of randomized controlled
trials. J. Neuroimmune Pharmacol. 10 293–301. 10.1007/s11481-015-9600-6.
Mallick-Searle, T. and St Marie, B. Cannabinoids in Pain Treatment: An Overview. Pain Manag. Nurs. 2019; 20 (2): 107-112. doi:10.1016/j.pmn.2018.12.006.
Meng, H.; Johnston, B.; Englesakis, M.; Moulin, D. E. and Bhatia, A. (2017). Selective cannabinoids for chronic neuropathic pain: a systematic review and meta- analysis. Anesth. Analg. 125, 1638–1652. 10.1213/ANE.0000000000002110.
Morales, P.; Hurst, D.P. and Reggio, P.H. Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog. Chem. Org. Nat. Prod. 2017; 103: 103-131. doi: 10.1007/978-3-319-45541-9_4. PMID: 28120232; PMCID: PMC5345356.
Moulin D.; Boulanger, A.; Clark, A.J., et al. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res. Manag. 2014; 19(6): 328-335. doi:10.1155/2014/754693.
NASEM (2017). National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: National Academies Press.
O'Sullivan, S.E. An update on PPAR activation by cannabinoids. Br. J. Pharmacol. 2016, Jun; 173(12): 1899-910. doi: 10.1111/bph.13497. Epub 2016, May 19. PMID: 27077495; PMCID: PMC4882496.
PDQ Integrative Alternative and Complementary Therapies Editorial Board (2018). Cannabis and Cannabinoids (PDQ®): Health Professional Version,” in: PDQ Cancer Information Summaries [Internet]. Bethesda, MD: National Cancer Institute.
Pertwee, R.G.; Howlett, A.C.; Abood, M.E.; Alexander, S.P.; Di Marzo, V.; Elphick, M.R.; Greasley, P.J.; Hansen, H.S.; Kunos, G.; Mackie, K.; Mechoulam, R. and Ross, R.A.
International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂. Pharmacol. Rev. 2010, Dec; 62(4): 588-631. doi: 10.1124/pr.110.003004. PMID: 21079038; PMCID: PMC2993256.
Queremel, M.D.A. and Davis, D.D. Pain Management Medications. [Updated 2021 Jul 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560692/.
Romero-Sandoval, E.A.; Kolano, A.L. and Alvarado-Vázquez, P.A. Cannabis and Cannabinoids for Chronic Pain. Curr. Rheumatol. Rep. 19, 67 (2017). doi.org/10.1007/s11926-017-0693-1.
Ross, R.A. Anandamide and vanilloid TRPV1 receptors. Br. J. Pharmacol. 2003, Nov;140(5): 790-801. doi: 10.1038/sj.bjp.0705467. Epub 2003 Sep 29. PMID:14517174; PMCID: PMC1574087.
Vučković, S.; Srebro, D.; Vujović, K.S.; Vučetić, Č. And Prostran, M. Cannabinoids and Pain: New Insights from Old Molecules. Front. Pharmacol. 2018; 9: 1259. Published 2018 Nov 13. doi: 10.3389/fphar.2018.01259.
Vulfsons, S., Minerbi, A. and Sahar, T. Cannabis and Pain – Treatment – A Review of
the Clinical Utility and a Practical Approach in Light of Uncertainty. Rambam Maimonides Med J. 2020;11(1):e0002. Published 2020 Jan 30. doi:10.5041/RMMJ.10385.
Whiting, P.F.; Wolff, R.F.; Deshpande, S.; Di Nisio, M.; Duffy, S.; Hernandez, A.V.; Keurentjes, J.C.; Lang, S.; Misso, K.; Ryder, S.; Schmidlkofer, S.; Westwood, M. and Kleijnen, J. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015, Jun. 23-30; 313(24): 2456-73. doi: 10.1001/jama.2015.6358. Erratum in: JAMA. 2015, Aug. 4; 314(5): 520. Erratum in: JAMA. 2015, Aug. 25; 314(8): 837. Erratum in: JAMA. 2015, Dec. 1; 314(21): 2308. Erratum in: JAMA. 2016, Apr. 12; 315(14): 1522. PMID: 26103030.
Yam, M.F.; Loh, Y.C.; Tan, C.S.; Khadijah, A.S.; Abdul, M.N. and Basir, R.G. Pathways of Pain Sensation and the Major Neurotransmitters Involved in Pain Regulation. Int. J. Mol. Sci. 2018;19(8):2164. Published 2018 Jul 24. doi:10.3390/ijms19082164.
Nowadays, chronic pain is a common and non-visible disease in most patients. Pain can behave as nociceptive pain, neuropathic pain and inflammatory pain.