Chronic Pain

Chronic pain is defined by the International Association for the Study of Pain (IASP) as “An unpleasant sensory and emotional experience associated with, or resembling that associated with, an actual or potential tissue damage.”¹

Pain is generally considered as chronic when shown to be persistent or recurring for a period of time higher than 3 months. It is a very subjective and personal experience, and can compromise the patient on different levels, potentially causing physical disability, emotional disturbance, and social withdrawal. The estimation is that over 20% of the general population currently suffers from it.²

The etymology of chronic pain can be uncertain and its treatment can bypass traditional or conservative therapeutic procedures.³

CB1 and CB2 receptors, together with endogenous ligands and enzymes, compose the Endocannabinoid System, known to affect pain pathways. CB1 receptors are distributed throughout the nervous system, both central and peripheral. Some CB1 locations that are most relevant on pain signalling are the terminals of primary afferent neurons, the dorsal root ganglion (DRG), the dorsal horn of the spinal cord, the periaqueductal grey matter, the ventral posterolateral thalamus and cortical regions associated with central pain processing.4

The activation of CB1 receptors by endogenous ligands or phytocannabinoids leads to a very significant modulation of the pain pathway. In the PNS the inhibition of ascending nociceptive signalling is observed, together with the activation of inhibitory descending transmission in the CNS, resulting in a strong modulation of pain stimulus. Thus, the pain/emotion relationship is regulated.5

Through this mechanism and because of the presence of cannabinoid receptors in microglial cells, cannabinoid compounds also bring benefits to neuropathic pain, as they allow the reduction of microglial neural inflammation.6

Moreover, the emotional and cognitive effects of pain are affected by this modulation, since CB1 receptors are also found in the limbic system and cortical areas of the brain.6

As for CB2 receptor, it is found mainly at the periphery, as tissues and cells of the immune system, hematopoietic cells, bone, liver, peripheral nerve terminals and keratinocytes. CB2 activation at peripheral level leads to reduction in the release of pronociceptive molecules. CB2 receptors can also be found in brain microglia and at the spinal cord level,7 where its activation happens to modulate immune responses, leading to inhibition of neuronal sensitization during chronic pain.6 All those antinociceptive effects can be seen in acute, neuropathic, and inflammatory pain conditions.

Besides the modulation of CB1 and CB2 receptors by phytocannabinoids, those compounds are also believed to have activity over mast cells receptors, therefore inhibiting the release of inflammatory signalling cytokines and enhancing the release of endogenous opioids, leading to their analgesic activity. In such a way, cannabis extracts appear as a very relevant alternative for pain treatments. It is important to mention that the choice for this therapy also plays a significant role on preventing the abuse of conventional pain medicines and opioid overuse.8

Considering the endogenous cannabinoid ligands, anandamide and 2-AG, it is known that both are produced on demand in response to stressful situations, such as tissue damage. Anandamide acts modulating nociceptive signals, in response to an inflammatory stimulus or neuronal damage, while 2-AG acts mainly in the modulation of the descending pain pathway, in response to an acute stress stimulus.4 Therefore, it is clear that the pain modulation by cannabinoid compounds is already something that is inherent to the organism.

Evidences show that exogenous cannabinoid ligands can also produce analgesic, anxiolytic, antispasmodic, muscle relaxant, anti-inflammatory and anticonvulsant effects in the human body; as such effects can be verified in different phytocannabinoids based therapies, for instance.9

Researchers from the University of Iowa conducted a clinical study with 36 oncological patients who suffered with chronic cancer pain. A comparison was made between placedo, THC therapy (at 10 and 20mg dosage) and Codeine therapy (at 60 and 120mg dosage). The results showed that 10mg of THC would produce an analgesic effect comparable to 60mg of Codeine. Likewise, 20mg of THC would be comparable to 120mg of Codeine; a therapeutic effect that would last over a 7h observational period. Higher levels of THC might be limited by its sedative potential, a side effect that, though not desired, can still be less hazardous than Codeine side effects.10

Another study held with 177 cancer pain patients, who were refractory to opioid therapy, was carried out with a THC:CBD extract (27mg/ml THC and 25mg/ml CBD), with an isolated THC extract (27mg/ml THC) and with placebo. A greater pain relief was experienced by patients treated with THC:CBD combination, a therapy that left twice as many patients with ≥ 30% pain reduction, in comparison to the placebo and the isolated THC group.11

Considering multiple sclerosis and the pain associated with it, a placebo-controlled study was carried out involving 259 MS patients for 12 weeks.12  The study had a dose titration period, which ranged from 5mg to 25mg of THC per day, varying for each patient. Results showed that 29.4% of patients who received cannabis extract reported relief from MS symptoms, while this percentage was 15.7% in the placebo group. The experienced relief concerned muscle stiffness, body pain, muscle spasms and sleep quality. At the end of the study period, only 24.5% of patients on cannabis therapy chose to take the maximum available dose (25mg), while in the placebo group, the percentage of patients opting for the maximum dose was 69.4%.

Pain is a very common symptom in cancer patients, which may result from the disease itself and/or from the chemotherapy and radiotherapy treatment. Commonly, the pharmacological recommendation is related to the use of opioids, which, in addition to their associated side effects, have a strong addictive potential, coming to be necessary other alternatives for pain control. It is worth highlighting the role of cannabinoid substances, which have shown clinical importance both in the reduction and in the weaning of opioid drugs.13

A study involving 2970 oncological patients, carried out in Israel, brought together relevant information related to the pain relief due to the use of medical cannabis as an adjuvant cancer therapy. At the beginning of the study, 52.9% of the patients involved reported a subjective pain level between 8 and 10 (on a 1-10 scale). After 6 months of study and cannabis treatment, the percentage of patients reporting this same pain intensity dropped to 4.6%.14

As aforementioned, chronic pain is represented by both unpleasant sensory experience and emotional experience. Epidemiological data shows that the susceptibility of patients with chronic pain to mood and anxiety disorders is 4 times higher than that of the general population.15 The opposite relationship is also true, that is, individuals with depression are more likely to have or to develop different types of pain. Such a causal association between these comorbidities is an important factor to be taken into account in therapeutic practice, even when only one of the conditions is in evidence. The pathophysiological processes behind this interrelationship still need to be better elucidated, but there are literature indications that reveal both an increase in sensitivity and a reduction in pain tolerability in individuals with mood disorders. Another point of association between pain and depression is that both share common secondary comorbidities, such as sleep disorders and anxiety.16

Still regarding the oncological area, another study carried out with women diagnosed with breast cancer evidentiated 257 participants who would use medical cannabis to relieve symptoms associated with the pathology or cancer therapy, such as pain (78%), insomnia (70%), anxiety (57 %), stress (51%), nausea and vomiting (46%). Between participants, 75% reported that cannabis was essential and necessary for the relief of these symptoms.17

It is known that THC acts as a partial agonist at cannabinoid receptors (CB1 and CB2).18 A very high binding affinity of THC with the CB1 receptor appears to mediate its modulatory activities in memory processing, motor control and also its psychoactive properties (changes in mood and consciousness).

Studies show that a number of THC side effects, including anxiety, impaired memory and immunosuppression, can be reversed by other constituents of the cannabis plant (cannabinoids, terpenoids, and flavonoids).19,20  In this scenario, comes the non-psychoactive analog of THC, cannabidiol (CBD). Besides having a significant analgesic, anti-inflammatory, anticonvulsant and anxiolytic activities, CBD displays an entourage effect (the mechanism by which non-psychoactive compounds present in cannabis modulate the overall effects of the plant), being capable of improving tolerability and also the safety of THC, by reducing the likelihood of psychoactive effects and antagonising several other adverse effects of THC (sedation, tachycardia, and anxiety)21. This synergistic activity between cannabinoid compounds is extremely important for allowing the therapeutic use of THC which, especially in pain control therapy, shows to be crucial for its success.

Regarding the dosage recommendations, the individual assessment of each case, patient and pathology is crucial. However, there are general recommendations that can guide the process. In 2021, protocols of recommendations for the administration of medical cannabis in chronic pain therapy were published. Such protocols were elaborated based on the results of a modified Delphi method developed by 20 global experts on the subject.22

The first consensus obtained with the applied method was that cannabis can be considered a therapeutic option in cases of neuropathic, inflammatory, nociplastic and mixed pain. The second consensus was to establish 3 different types of protocols (Rapid, Routine and Conservative Protocol), which are summarised in the following images:

It is noteworthy that such protocols are described by their developers and responsible specialists themselves as a guide, from which adaptations to all individual cases are possible and must be evaluated.

*For more information on medical cannabis for cancer pain, see the “Oncology” section.

References:
  1. DESANTANA, J. M. et al. Definition of pain revised after four decades. Brazilian Journal Of Pain, v. 3, n. 3, p. 197–198, 2020.
  2. DE SOUZA, J. B. et al. Prevalence of chronic pain, treatments, perception, and interference on life activities: Brazilian population-based survey. journal de la societe canadienne pour le traitement de la douleur [Pain research & management], v. 2017, p. 4643830, 2017.
  3. DELLAROZA, M. S. G. et al. Caracterização da dor crônica e métodos analgésicos utilizados por idosos da comunidade. Revista da Associacao Medica Brasileira (1992), v. 54, n. 1, p. 36–41, 2008.
  4. HILL, K. P. et al. Cannabis and Pain: A Clinical Review. Cannabis and Cannabinoid Research, v. 2, n. 1, p. 96–104, jan. 2017.
  5. ‌ÜBERALL, M. A. A Review of Scientific Evidence for THC:CBD Oromucosal Spray (Nabiximols) in the Management of Chronic Pain. Journal of Pain Research, v. 13, p. 399–410, 14 fev. 2020.
  6. ‌VUČKOVIĆ, S. et al. Cannabinoids and Pain: New Insights From Old Molecules. Frontiers in Pharmacology, v. 9, 13 nov. 2018.
  7. ‌ABRAMS, D.; GUZMAN, M. Cannabis in cancer care. Clinical Pharmacology & Therapeutics, v. 97, n. 6, p. 575–586, 17 abr. 2015.
  8. ‌ANTHONY, A. T. et al. Cannabinoid Receptors and Their Relationship With Chronic Pain: A Narrative Review. Cureus, 14 set. 2020.
  9. ‌ANDRE, C. M.; HAUSMAN, J.-F.; GUERRIERO, G. Cannabis sativa: The Plant of the Thousand and One Molecules. Frontiers in Plant Science, v. 7, 4 fev. 2016.
  10. NOYES, R. et al. The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clinical Pharmacology & Therapeutics, v. 18, n. 1, p. 84–89, jul. 1975.
  11. ‌JOHNSON, J. R. et al. Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Study of the Efficacy, Safety, and Tolerability of THC:CBD Extract and THC Extract in Patients with Intractable Cancer-Related Pain. Journal of Pain and Symptom Management, v. 39, n. 2, p. 167–179, fev. 2010.
  12. ‌ZAJICEK, J. P. et al. MUltiple Sclerosis and Extract of Cannabis: results of the MUSEC trial. Journal of Neurology, Neurosurgery & Psychiatry, v. 83, n. 11, p. 1125–1132, 1 nov. 2012.
  13. ‌LUCAS, P. Cannabis as an Adjunct to or Substitute for Opiates in the Treatment of Chronic Pain. Journal of Psychoactive Drugs, v. 44, n. 2, p. 125–133, abr. 2012.
  14. ‌PubMed. Disponível em: <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&>
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  17. ‌WEISS, M. C. et al. A Coala‐T‐Cannabis Survey Study of breast cancer patients’ use of cannabis before, during, and after treatment. Cancer, v. 128, n. 1, p. 160–168, 12 out. 2021.
  18. ‌PERTWEE, R. G. The diverse CB1and CB2receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. British Journal of Pharmacology, v. 153, n. 2, p. 199–215, jan. 2008.
  19. ‌RUSSO, E. B. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology, v. 163, n. 7, p. 1344–1364, 12 jul. 2011.
  20. ‌ANDRE, C. M.; HAUSMAN, J.-F.; GUERRIERO, G. Cannabis sativa: The Plant of the Thousand and One Molecules. Frontiers in Plant Science, v. 7, 4 fev. 2016.
  21. ‌ABRAMS, D.; GUZMAN, M. Cannabis in cancer care. Clinical Pharmacology & Therapeutics, v. 97, n. 6, p. 575–586, 17 abr. 2015.
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