Cannabinoids are a group of compounds with a range of medical applications. Although linked to the plant in which they are principally produced, cannabinoids are of three types. First are phytocannabinoids which are produced by the plant Cannabis Sativa, whereas those endogenous to human or animal tissues are endocannabinoids. The third category is synthetic cannabinoids. ¹
There are more than 60 active phytocannabinoids. Amongst them, tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most known ones. THC is well-known for its intoxicating effect. CBD, a non-psychoactive cannabinoid, on the other hand, is known for its analgesic, neuroprotective, anti-inflammatory, antipsychotic, and anticonvulsant properties. ²
Anandamide and 2-arachidonylglycerol are two of the common endocannabinoids and affect various neurotransmitter systems governing pain, movement, muscle tone, memory, and emotion. Anandamide which is the first discovered endocannabinoid, has demonstrated analgesic potential at the spinal level.
Cannabinoids are being used medicinally since ancient times primarily for pain, mood disorders, and other conditions.
Analgesic History of Cannabinoids
The use of plant-based cannabis could be traced back to more than 5000 years ago. In the US, cannabis was widely used in the 19th and 20th centuries. However, later after the Marihuana Tax Act in 1937, restrictions were put on the use of cannabis. Many years later, in 1996, California became the first state to permit legal access to and use of botanical cannabis for medicinal purposes under physician supervision with the enactment of the Compassionate Use Act. In recent years, medicinal cannabis is again getting attention as a potential therapeutic option for a variety of medical conditions. ³
Animal preclinical studies have demonstrated blocking of pain response with cannabinoid treatment. Cannabinoids were effective against thermal, mechanical, and chemical pain in models of acute pain. ⁴ Despite these pieces of evidence on the analgesic efficacy of cannabinoids, they are not widely accepted as a routine analgesic treatment. This could be due to a lack of information about the molecular pharmacology of cannabinoids, behavioral suppression in pain models, and psychoactivity issues.
Cannabinoids as an Alternative to Opioids
Opioids are considered the most effective pain-relieving drugs. On the other hand, they are widely feared compounds owing to their association with abuse and addiction. ⁵ Opioids for the treatment of back pain is so common that it contributed to the opioid epidemic. A 2017 study from the US reports an alarming 67.8% of drug-related deaths involving opioids. Owing to this significant risk of morbidity and mortality associated with opioid use, there is a direct need for non-opioid medication in pain management.6 Cannabinoids could be an option to decrease opioid dosing. ⁶
How do Cannabinoids Work?
Cannabinoids act via cannabinoid receptors which are present in the pain pathway at the peripheral and central levels. ⁷
Cannabinoid receptors are of two types, namely, the cannabinoid -1 receptor (CB-1) and the cannabinoid -2 receptor (CB-2).CB-1 receptors are predominantly expressed on the neurons, whereas CB-2 receptors are expressed on cells of the immune system and seen in several areas of the brain.
Cannabinoids block the detection of painful stimuli and also reduce sensitivity to pain. These antinociceptive and anti-hyperalgesic effects are exerted at the peripheral as well as central levels.
Binding of cannabinoids to CB-1 results in the reduction of synaptic transmission. As per the latest studies, CB-1 receptors are also present on mast cells and hence may exert an anti-inflammatory response as well.
CB-2, on the other hand, is traditionally thought to modulate immunologic response. However, it has been observed that it also contributes to antinociception by inhibiting the release of pro-inflammatory factors by non-neuronal cells located near nociceptive neuron terminals. For this reason, activation of CB-2 produces antinociception response in case of inflammatory hyperalgesia and neuropathic pain.
CB-1 receptor activation is associated with central side effects, but activation of selective CB-2 receptors has the potential to treat pain without eliciting centrally mediated side effects. CB-2 receptors have novel pain control actions. Cannabinoid compounds can modulate hyperalgesia of various origins, and they are effective even in inflammatory and neuropathic pain.
Evidence From the Literature
Cannabinoids and Management of Cancer Pain
Cannabinoids and their derivatives may be able to be used as an alternative to opioids and non-steroidal anti-inflammatory drugs (NSAIDs) in cancer pain management, particularly in patients who are unable to take opioids and NSAIDs. ⁸
A review published in 2017 has documented the effectiveness of THC and CBD in cancer pain management. Clinical studies conducted between 1975 and 2014 have shown a reduction in chronic and neuropathic pain with the use of medical cannabis in patients with advanced cancer. ⁹
Another study in 2012 has demonstrated a significant improvement in pain score in patients with advanced cancer who are refractory to opioid treatment, with nabiximols, a novel cannabis extract. ¹⁰
Cannabinoids for Back Pain
Cannabinoids are being looked up as an alternative to opioids in the treatment of back pain. A 2018 study reports significant improvement in pain, mood, and sleep in patients with failed back surgery syndrome when given THC/CBD orally. ¹¹
Nabilone, a synthetic cannabinoid, has shown significant improvement in non-oncologic spine pain refractory to NSAIDs and/or opioids.
Meanwhile, another study in 2008 evaluated the effect of dronabinol (a synthetic THC) in patients with chronic back pain. In phase 1 of the study, patients who were given 10 or 20 mg of dronabinol showed a statistically significant decrease in pain intensity. Patients who progressed to phase 2 of the study demonstrated a significant reduction in pain compared to baseline. ¹²
The involvement of neuropathic components is common in back pain. Opioids, anti-epileptics, and antidepressants are routinely used in neuropathic pain management. Cannabinoids are evolving as likely treatment options as they have demonstrated activity on important molecular pathways in neuropathic pain.
Many clinical studies support the use of inhaled cannabis in the treatment of neuropathic pain associated with multiple sclerosis, HIV neuropathy, spinal cord injury, and nerve injury. In such cases, inhaled cannabis could benefit the patient, and the patient could also rapidly self-titrate dosing to the desired effect.
Cannabinoids can be used for symptom management in urological disorders. ¹³
A 2014 study documents the use of cannabis in urology. Almost three-quarters of patients with Chronic Prostatitis (CP)/Chronic Pelvic Pain Syndrome (CPPS) reported using cannabis for symptomatic relief. Of these, 36.8% reported symptom improvement.
Cannabinoids in Rheumatic Diseases
Rheumatic diseases are common causes for chronic pain; however, current pharmacological interventions for chronic pain are not always helpful and safe for long-term use. The therapeutic effect of cannabis and cannabidiol in reducing pain associated with rheumatic diseases could be a ray of hope for patients suffering from chronic pain with these conditions. ¹⁴
Evidence for the use of cannabinoids in rheumatic diseases comes from an observational study conducted in 2011. The study involved the treatment of fibromyalgia patients with cannabis. Significant pain relief, reduction in stiffness, and increase in relaxation and perception of well-being were reported using cannabis. ¹⁵
A similar yet recent study in 2019 reports treatment response in 81.1% of patients along with a significant decrease in pain intensity with the use of medical cannabis in fibromyalgia patients. ¹⁶
Another recent retrospective review published in 2018 assessed the effect of medical cannabis in fibromyalgia patients. Cannabis treatment was given for a mean duration of 10.4 months, whereas the mean dose was 26 g per month. The treatment showed significant improvement in the condition, so much so that 50% of patients stopped using any other medical therapy for fibromyalgia. Additionally, the side effects were mild and were reported in 30% of the patients. ¹⁷
One study reports the use of cannabinoids to relieve pain associated with rheumatoid arthritis (RA). Cannabis-treated patients showed significant improvements in certain pain parameters and quality of sleep.
Cannabidiol (CBD) and Pain Management
CBD is one of the well-researched compounds among different cannabinoids. Several animal models advocate its analgesic effect in neuropathic pain. It is known to alleviate allodynia in sciatic nerve injury. It was also found effective in a chronic constriction injury animal model of neuropathic pain. ¹⁸
Analgesic and anti-inflammatory effects of cannabinoids, including CBD, are evident in several inflammatory-induced chronic pain models.
Intramuscular injection of CBD or cannabinol (CBN) was found beneficial in a rat model of myofascial pain and aided in the reduction of mechanical sensitization.
The Future of Cannabinoids as Analgesic Agents
The robust and enduring potential of cannabinoids is of great scientific interest. They are being looked up as a new area of medication development. The analgesic potential of cannabinoids is well documented and hence could be a promising treatment of pain management. Cannabinoids are on the path to progress from herbal medications to regulated prescription drugs. ¹⁹
The medical cannabinoid prescribing guidelines provide practical recommendations on the use of cannabinoids in primary care. According to these guidelines, medical cannabinoids could be considered for:
Refractory neuropathic pain if the patient is experiencing persistent problematic pain despite optimized analgesic therapy
Refractory pain in palliative cancer patients
The guidelines strongly recommend the use of pharmaceutically developed cannabinoids (nabilone or nabiximols) for pain management, whereas medical cannabinoids could be considered for the treatment of refractory chemotherapy-induced nausea and vomiting. They could also be considered in refractory cases of multiple sclerosis and spinal cord injury. ²⁰
Cannabinoids and COVID
The anti-inflammatory and analgesic potential of cannabinoids could be beneficial in the treatment of COVID-19 infections. With COVID-19 symptoms including body aches, sore throat, and headaches, pain relief would be welcome by many patients. Cannabinoids are proven pain relievers and thus could be used in COVID-19 treatment. However, there is no evidence yet to support its use in COVID -19 infection. ²¹
How are Cannabinoids Administered?
Cannabis products are generally used either by inhalation (smoking/ vaporization) or orally. Other interesting but minimally used routes include oromucosal, topical-transdermal and rectal routes. Intranasal cannabinoid sprays used as a low-dose adjuvant to patches aid in rapid absorption for systemic effects. Effective transdermal penetration in the case of topical applications improves therapeutic effectiveness.
Cannabinoids, either derived from a plant source, produced by the human body, or synthetic, have promising analgesic potential. Ever-increasing clinical trials advocate the analgesic potential of cannabinoids. Though guidelines permit limited use of cannabinoids, steadily progressing research and regressing myths about the psychoactivity of cannabinoids will open up doors for cannabinoids as conventional pain management agents in the future.