Parkinson’s disease and cannabinoids Part II
December 10, 2021
Cannabinoid Biosynthesis
January 28, 2022Scientific information for healthcare professionals
Author : Ana Rita Gaspar,
Bachelor’s degree in Biomedical Sciences
Member of the R&D team
Piauhy Labs
Cannabinoids used in Pain Management | Definition, pathophysiology and current therapeutic options
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.
Cannabinoids used in Pain management | Nociceptive pain definition
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:
- Transduction: begins when the stimulus is converted into chemical events in human tissues, after which the latter are converted into electrical events in neurons, culminating in action potentials, which are translated as chemical events in the synapses, in the form of a nerve impulse;
- Conduction: the nerve impulse is conducted along the length of the first-order neurons until they reach the synapse with the second order neuron;
- Transmission: corresponds to the transmission of electrical events along neuronal pathways, while neurotransmitters transmit information in the synaptic cleft between the first-order neuron and the second-order neuron in the dorsal root of the spinal cord;
- Perception: the true conscious experience of pain;
- Modulation: it is the event that occurs at all levels of the nociceptive pathways through the first order afferent neuron, dorsal root of the spinal cord and superior cerebral center. The result allows you to feel the painful sensation triggered by the stimulus.
Cannabinoids used in Pain management | Pain classification
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. …
Cannabinoids used in Pain management | Clinical analysis of pain
It is extremely important to know the origin, characteristics and symptoms that a patient has in relation to the pain they feel so that an adequate diagnosis can be made and, consequently, a careful treatment. Patients may commonly experience: • Acute pain: activation of nociceptors at the tissue injury site results in this type of pain, and the environment where the damage exists may subsequently change the characteristics of these nerve endings, for example. • Chronic pain: persistent pain usually associated with other pathological conditions such as diabetes, which induce prolonged and chronic tissue inflammation or alter the properties of peripheral nerves (neuropathic pain). • Allodynia: pain arising from a harmless stimulus, either by skin sensitization or by damage to peripheral nerves that induces changes in its structure. • Hyperalgesia: arises when a noxious stimulus generates exaggerated pain, whose proposed mechanisms are the same as the allodynia condition. • Referred pain: occurs when pain is perceived in a region that does not correspond to the location of the noxious stimulus, which happens, for example, during a myocardial infarction, since the pain resulting from it is emitted by the neck, shoulders and back.Cannabinoids used in Pain management | Inflammatory pain
Inflammation is a biological process that occurs in the body's tissues in response to dangerous stimuli, so that tissue repair is started. Thus, the first cells to migrate to the injured site are neutrophils, which are followed by the release of chemical mediators that further contribute to the inflammatory microenvironment.Pain that is adjacent to inflammation can be classified into two types: acute pain and chronic pain. The first is characterized as intense and occurs in a short period of time, starting after the harmful stimulation of myelinated Aδ fibers. On the other hand, prolonged inflammation leads to so-called chronic inflammatory pain, which is mediated by unmyelinated C fibers, and which lasts longer than expected recovery time.
Inflammatory pain induces an increase in afferent input at the dorsal root of the spinal cord and this leads to the development of central sensitization. Some inflammatory chemical mediators are produced at the site of tissue damage, including 5-HT, histamine, neural growth factor (NGF), ATP, glutamate, leukotrienes, nitric oxide (NO), and protons. During inflammation, these are produced by necrotic tissue and interact to activate nociceptors around inflammation.
Cannabinoids used in Pain management | Historical perspective of medicinal cannabis for pain
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 used in Pain management | Role of endocannabinoid system in pain relief
Regarding therapeutic options for pain relief, these options commonly may result in depression of the nociceptive system or stimulation of the antinociceptive system. In fact, they can be defined as non-opioid analgesic (acetaminophen, non-steroidal anti-inflammatory drugs, antidepressant agents or anti-epileptic agents) agents and opioid agents.
Related to opioid drugs, they are a broad class of drugs with structural similarity to the natural plant alkaloids found in opium. These drugs are, in fact, recognized as the most effective and most used to treat severe pain. However, taking these agents is controversial, as they have great potential for dependence.
Over the last decade, there has been a crisis in the treatment of pain, which is justified by the use and abuse of opioid drugs that lead to overdose fatality, as well as the accentuated adverse effects when taking non-steroidal anti-inflammatory drugs. Thus, from a medical and clinical point of view, the void has been filled by medicinal cannabis, which, supervised by professionals, can balance human body main receptors (CB1 and CB2) – that is, endocannabinoid system.
The endocannabinoid system regulates many physiological processes such as immune function, endocrine function, antinociception, cognition, behavior, appetite, digestion, the autonomic nervous system and inflammation. That said, it works as a homeostatic regulator. Essentially, it regulates receptors, which are known as the Cannabinoid Receptor Type 1 (CB1) and the Cannabinoid Receptor Type 2 (CB2) and which have as ligands, phytocannabinoids and endocannabinoids.
The first receptor is found in the brain, spinal cord, trigeminal ganglion, macrophages, mast cells and epidermal keratinocytes and regulates effects of cannabinoid neurotransmitters in the central nervous system. In turn, the CB2 receptor predominates in the periphery of hematopoietic stem cells, spleen macrophages and other immune cells and can act on several fronts: regular neuroimmune interactions protecting neurons from pathogens; interfering with inflammatory mediators that increase the sensitivity of sensory neurons to noxious stimuli; respond to peripheral nerve damage.
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.
Cannabinoids used in Pain management |Cannabinoids and cannabinoid receptors | Endogenous cannabinoids
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.
Cannabinoids used in Pain management | Endocannabinoid system and mechanisms to alleviate pain
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.
Cannabinoids used in Pain management | The different targets of cannabinoids
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
Cannabinoids used in Pain management | Evidence of beneficial effects of cannabis in chronic pain management
Given the study of the benefits of medicinal cannabis on pain in animal models, evidence from behavioral studies demonstrates that synthetic agonists of the cannabinoid receptor or plant derivatives are effective in the treatment of acute pain. However, when the focus is on the results obtained from studies in humans, it appears that cannabinoids may be more effective in the treatment of chronic pain, compared to acute pain. Additionally, many of the targets already identified in animal models have not yet been confirmed in clinical trials. These are, for example, the absence of significant effects with CB2 receptor agonists, as well as the promising effect of FAAH inhibitors seen in animal studies. Obviously, this difference in realities is justified by the difference of the different species and methodologies, for example.Indeed, the "National Academy of Sciences, Engineering and Medicine" has reviewed more than 10,000 abstracts of scientific articles and has stated that, in fact, there is "conclusive or substantial evidence" for treating chronic pain in adults with medicinal cannabis. Likewise, the “PDQ Integrative Alternative and Complementary Therapies Editorial Board'' states that the use of cannabis/cannabinoids leads to the benefit of pain relief in people with cancer, in addition to its antiemetic effects, appetite stimulation and improved sleep.
“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
Regarding neuropathic pain data, the systematic review “Selective Cannabinoids for Chronic Neuropathic Pain: A Systematic Review and Meta-analysis”, published in 2017, reveals that oral cannabinoids are modestly effective in reducing this type of pain and, for this purpose, the treatment must last at least 2 weeks. This study, which involved 11 randomized controlled trials, with a total of 1219 participants, where oral cannabinoids were compared with standard pharmacological treatments or placebo in patients with neuropathic pain, further concluded that there are improvements in quality of life, sleep and an increased patient satisfaction.
Cannabinoids used in Pain management | Piauhy Labs mission
Regarding this situation, Piauhy Labs intend is progressing by its research with cannabinoids and terpenes, in order to study the effect of these compounds in the relief of pain in different situations, from various diseases. As a result of the research and development processes, Piauhy Labs intends to create patents and originate intellectual property, with the ultimate objective of producing effective medicines based on the Cannabis plant – mainly focused on management of patients’ chronic pain.
Ana Rita Gaspar,
Bachelor’s degree in Biomedical Sciences
Member of the R&D team
Piauhy Labs
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Cannabinoids used in Pain Management | Definition, pathophysiology and current therapeutic options
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.
Cannabinoids used in Pain management | Nociceptive pain definition
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:
- Transduction: begins when the stimulus is converted into chemical events in human tissues, after which the latter are converted into electrical events in neurons, culminating in action potentials, which are translated as chemical events in the synapses, in the form of a nerve impulse;
- Conduction: the nerve impulse is conducted along the length of the first-order neurons until they reach the synapse with the second order neuron;
- Transmission: corresponds to the transmission of electrical events along neuronal pathways, while neurotransmitters transmit information in the synaptic cleft between the first-order neuron and the second-order neuron in the dorsal root of the spinal cord;
- Perception: the true conscious experience of pain;
- Modulation: it is the event that occurs at all levels of the nociceptive pathways through the first order afferent neuron, dorsal root of the spinal cord and superior cerebral center. The result allows you to feel the painful sensation triggered by the stimulus.
Cannabinoids used in Pain management | Pain classification
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. …
Cannabinoids used in Pain management | Clinical analysis of pain
It is extremely important to know the origin, characteristics and symptoms that a patient has in relation to the pain they feel so that an adequate diagnosis can be made and, consequently, a careful treatment. Patients may commonly experience: • Acute pain: activation of nociceptors at the tissue injury site results in this type of pain, and the environment where the damage exists may subsequently change the characteristics of these nerve endings, for example. • Chronic pain: persistent pain usually associated with other pathological conditions such as diabetes, which induce prolonged and chronic tissue inflammation or alter the properties of peripheral nerves (neuropathic pain). • Allodynia: pain arising from a harmless stimulus, either by skin sensitization or by damage to peripheral nerves that induces changes in its structure. • Hyperalgesia: arises when a noxious stimulus generates exaggerated pain, whose proposed mechanisms are the same as the allodynia condition. • Referred pain: occurs when pain is perceived in a region that does not correspond to the location of the noxious stimulus, which happens, for example, during a myocardial infarction, since the pain resulting from it is emitted by the neck, shoulders and back.Cannabinoids used in Pain management | Inflammatory pain
Inflammation is a biological process that occurs in the body's tissues in response to dangerous stimuli, so that tissue repair is started. Thus, the first cells to migrate to the injured site are neutrophils, which are followed by the release of chemical mediators that further contribute to the inflammatory microenvironment.Pain that is adjacent to inflammation can be classified into two types: acute pain and chronic pain. The first is characterized as intense and occurs in a short period of time, starting after the harmful stimulation of myelinated Aδ fibers. On the other hand, prolonged inflammation leads to so-called chronic inflammatory pain, which is mediated by unmyelinated C fibers, and which lasts longer than expected recovery time.
Inflammatory pain induces an increase in afferent input at the dorsal root of the spinal cord and this leads to the development of central sensitization. Some inflammatory chemical mediators are produced at the site of tissue damage, including 5-HT, histamine, neural growth factor (NGF), ATP, glutamate, leukotrienes, nitric oxide (NO), and protons. During inflammation, these are produced by necrotic tissue and interact to activate nociceptors around inflammation.
Cannabinoids used in Pain management | Historical perspective of medicinal cannabis for pain
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 used in Pain management | Role of endocannabinoid system in pain relief
Regarding therapeutic options for pain relief, these options commonly may result in depression of the nociceptive system or stimulation of the antinociceptive system. In fact, they can be defined as non-opioid analgesic (acetaminophen, non-steroidal anti-inflammatory drugs, antidepressant agents or anti-epileptic agents) agents and opioid agents.
Related to opioid drugs, they are a broad class of drugs with structural similarity to the natural plant alkaloids found in opium. These drugs are, in fact, recognized as the most effective and most used to treat severe pain. However, taking these agents is controversial, as they have great potential for dependence.
Over the last decade, there has been a crisis in the treatment of pain, which is justified by the use and abuse of opioid drugs that lead to overdose fatality, as well as the accentuated adverse effects when taking non-steroidal anti-inflammatory drugs. Thus, from a medical and clinical point of view, the void has been filled by medicinal cannabis, which, supervised by professionals, can balance human body main receptors (CB1 and CB2) – that is, endocannabinoid system.
The endocannabinoid system regulates many physiological processes such as immune function, endocrine function, antinociception, cognition, behavior, appetite, digestion, the autonomic nervous system and inflammation. That said, it works as a homeostatic regulator. Essentially, it regulates receptors, which are known as the Cannabinoid Receptor Type 1 (CB1) and the Cannabinoid Receptor Type 2 (CB2) and which have as ligands, phytocannabinoids and endocannabinoids.
The first receptor is found in the brain, spinal cord, trigeminal ganglion, macrophages, mast cells and epidermal keratinocytes and regulates effects of cannabinoid neurotransmitters in the central nervous system. In turn, the CB2 receptor predominates in the periphery of hematopoietic stem cells, spleen macrophages and other immune cells and can act on several fronts: regular neuroimmune interactions protecting neurons from pathogens; interfering with inflammatory mediators that increase the sensitivity of sensory neurons to noxious stimuli; respond to peripheral nerve damage.
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.
Cannabinoids used in Pain management |Cannabinoids and cannabinoid receptors | Endogenous cannabinoids
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.
Cannabinoids used in Pain management | Endocannabinoid system and mechanisms to alleviate pain
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.
Cannabinoids used in Pain management | The different targets of cannabinoids
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
Cannabinoids used in Pain management | Evidence of beneficial effects of cannabis in chronic pain management
Given the study of the benefits of medicinal cannabis on pain in animal models, evidence from behavioral studies demonstrates that synthetic agonists of the cannabinoid receptor or plant derivatives are effective in the treatment of acute pain. However, when the focus is on the results obtained from studies in humans, it appears that cannabinoids may be more effective in the treatment of chronic pain, compared to acute pain. Additionally, many of the targets already identified in animal models have not yet been confirmed in clinical trials. These are, for example, the absence of significant effects with CB2 receptor agonists, as well as the promising effect of FAAH inhibitors seen in animal studies. Obviously, this difference in realities is justified by the difference of the different species and methodologies, for example.Indeed, the "National Academy of Sciences, Engineering and Medicine" has reviewed more than 10,000 abstracts of scientific articles and has stated that, in fact, there is "conclusive or substantial evidence" for treating chronic pain in adults with medicinal cannabis. Likewise, the “PDQ Integrative Alternative and Complementary Therapies Editorial Board'' states that the use of cannabis/cannabinoids leads to the benefit of pain relief in people with cancer, in addition to its antiemetic effects, appetite stimulation and improved sleep.
“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
Regarding neuropathic pain data, the systematic review “Selective Cannabinoids for Chronic Neuropathic Pain: A Systematic Review and Meta-analysis”, published in 2017, reveals that oral cannabinoids are modestly effective in reducing this type of pain and, for this purpose, the treatment must last at least 2 weeks. This study, which involved 11 randomized controlled trials, with a total of 1219 participants, where oral cannabinoids were compared with standard pharmacological treatments or placebo in patients with neuropathic pain, further concluded that there are improvements in quality of life, sleep and an increased patient satisfaction.
Cannabinoids used in Pain management | Piauhy Labs mission
Regarding this situation, Piauhy Labs intend is progressing by its research with cannabinoids and terpenes, in order to study the effect of these compounds in the relief of pain in different situations, from various diseases. As a result of the research and development processes, Piauhy Labs intends to create patents and originate intellectual property, with the ultimate objective of producing effective medicines based on the Cannabis plant – mainly focused on management of patients’ chronic pain.
Ana Rita Gaspar,
Bachelor’s degree in Biomedical Sciences
Member of the R&D team
Piauhy Labs
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Nowadays, chronic pain is a common and non-visible disease in most patients. Pain can behave as nociceptive pain, neuropathic pain and inflammatory pain.
