Introduction

Chronic pain is a growing widespread health concern across the United States. According to the CDC, chronic pain affects approximately 1 in every 5 Americans, with an estimated cost of $560 billion for medical care and disability.[1] Chronic pain is a multifaceted condition that induces physical, mental, and emotional stress on the body. Therefore, treatment of chronic pain also requires a multifaceted approach, including pharmacological, non-pharmacological, and interventional measures. In light of the recent opioid epidemic, medicinal cannabis has gained traction as a possible treatment for chronic pain. As more states legalize the use of medical marijuana, healthcare professionals must understand the mechanism of action, indications, contraindications, role, and controversy of medicinal marijuana in treating chronic pain.

Function

Cannabis consists of many compounds, most of which are 60 pharmacologically active cannabinoids that act upon endogenous cannabinoid receptors in the body.[2] Currently, the primary compounds in the highest concentration are tetrahydrocannabinol (THC) and cannabidiol (CBD). THC contributes to the psychoactive effects of marijuana, including euphoria and psychosis. On the other hand, CBD is not psychoactive and is considered to have anti-anxiety and anti-psychoactive properties.[3] The therapeutic effects of medicinal cannabis depend on both the concentration of THC and the THC to CBD ratio. Recreational cannabis tends to contain a higher concentration of THC, whereas medicinal cannabis contains a higher concentration of CBD to limit the psychoactive effects of the drug. 

There are 2 primary types of endocannabinoid receptors: cannabinoid receptors type 1 (CB1) and cannabinoid receptors type 2 (CB2). Both receptors are classified as G-protein coupled receptors. CB1 receptors are located in the central and peripheral nervous system, specifically in the centers of the brain involved in pain modulation, the nociceptive pathways of the spinal cord, and peripheral nerves.[4] In contrast, CB2 receptors are primarily located in the periphery, such as in the immune and hematological systems, and aid in decreasing inflammation. THC is a partial agonist at both CB1 and CB2 receptors and inhibits the release of glutamate, 5-hydroxytryptamine and alters dopaminergic function, thereby affecting pain pathways.[5] CBD is a negative allosteric modulator of CB1 receptors and also acts on serotonin, vanilloid, and other receptors.

Issues of Concern

Due to the increasing support for the use of medicinal cannabis, it is essential to understand the federal and state policies related to the legalization of marijuana. As of 2021, a total of 36 states have legalized marijuana for medical purposes. Accessibility to medicinal cannabis for chronic pain patients varies as different states regulate the number of dispensaries and restrict the proximities of dispensaries within each state. Although medical marijuana is legal in more than half of the United States and is considered a possible treatment for chronic pain, it is still classified as a Schedule 1 drug.[6] Schedule 1 drugs are considered to have a high potential for abuse and are not FDA-approved for medical use due to lack of safety and universal medical acceptance. As with any other medication, there are several adverse effects associated with medicinal cannabis. Acute adverse effects related to THC include anxiety, panic, disorientation, impaired attention, short-term memory, and driving performance. Hence, it is prudent to avoid medicinal cannabis in patients with psychiatric illnesses, such as schizophrenia, as it may exacerbate the condition. Additionally, in 1 study, about 50% of patients with cannabis-induced psychosis converted to schizophrenia or bipolar disorder.[7] The most common acute side effect of CBD is diarrhea. Additionally, CBD has potential drug interactions with conventional pharmacotherapies as it interacts with cytochrome P450 (CYP 450) enzymes involved in drug metabolism.[8]

Clinical Significance

The use of medical marijuana can be traced back to over 5000 years ago. It was used by early Chinese physicians to treat pain associated with childbirth, rheumatic pain, malaria, and even constipation.[9] As described in the United States Pharmacopoeia, medicinal cannabis was used widely in the 19th and 20th centuries. The first state to legalize the use of marijuana under the supervision of a physician was California in 1996 under the provision of the Compassionate Use Act.[10] For many years, there have been countless studies addressing the effectiveness of medicinal cannabis in treating chronic pain. One particular study evaluated chronic pain patients' perspectives on medical marijuana. The study included 984 chronic pain patients, including those with neuropathic pain, back pain, arthritis, post-surgical pain, headaches, and abdominal pain. In this particular study, two-thirds of patients reported pain relief as the main benefit of marijuana use. Improved sleep was the second most commonly reported benefit. On the other hand, the primary negative theme amongst these patients was the cost associated with medicinal cannabis. The average cost was about $2000 per year, depending on the formulation and preferred route of administration. Unlike other medications, medicinal cannabis is not covered by insurance companies, leading to increased costs. Other negative themes associated with medicinal cannabis use amongst these patients were adverse effects of the medication and perceived bias against marijuana use.[11] 

In addition, another study showed a 64% reduction in opioid use amongst chronic pain patients who used medical marijuana.[12] These patients experienced fewer side effects and improved quality of life. Due to the ongoing opioid epidemic, medicinal cannabis as a possible alternative treatment has become increasingly important. Unlike opioids, marijuana does not cause respiratory depression, leading to lower mortality rates. A study analyzing the effects of marijuana dispensaries on the number of adverse outcomes due to opioid use demonstrated a 17% reduction in opioid-related fatalities.[13] Dispensaries also had a similar effect on opioid-related admissions to treatment centers, thereby highlighting the substitutability of medicinal marijuana. A different study highlighted the effectiveness of medical marijuana in treating chronic non-cancer pain, neuropathic pain, medication-rebound headaches, and allodynia. However, it did not appear to have the same effectiveness as non-opioid analgesics for the treatment of acute pain. Furthermore, in this particular study, medicinal cannabis was no more effective than a placebo for treating visceral pain and only provided minimal analgesic effect in cancer pain.[14] 

There have also been a few randomized controlled trials studying the dosing and administration of medicinal cannabis. In 1 specific study, experts across 9 different countries developed 3 different treatment protocols for the dosing and administration of cannabis when treating patients with chronic pain. In the routine treatment protocol, it was agreed that a 5-milligram CBD-predominant strain of cannabis taken twice daily should be the initiating form of treatment due to its safety profile. If greater than or equal to 40 milligrams of CBD per day failed to provide adequate pain relief, a starting dose of 2.5 milligrams of THC was deemed appropriate. As per the consensus, THC could be slowly titrated up to 2.5 milligrams every 2 to 7 days until a maximum of 40 milligrams daily is reached. Expert consultation from a cannabinoid specialist or experienced medicinal cannabis clinical was recommended if the dosing, as mentioned above, failed to provide adequate pain relief. In the conservative treatment protocol, the initiating CBD dose was 5 milligrams once or twice daily up to a maximum of 40 milligrams, followed by an initiating dose of 1 milligram of THC if the maximum CBD-predominant dose provided inadequate pain control. The THC dose could then be titrated up by 1 milligram every 7 days to reach a maximum dosage of 40 milligrams daily. Lastly, the rapid protocol involved a balanced CBD to THC type of cannabis. The initial starting dose was 2.5 to 5 milligrams of each cannabinoid once or twice daily. The dosage could be titrated up by 2.5 to 5 milligrams every 2 to 3 days once or twice daily until a maximum dosage of 40 milligrams of THC was reached.[15]

Other Issues

Many of the studies that have been performed analyzing the potential benefit of medicinal cannabis in treating chronic pain have small sample sizes. Marijuana's status as a Schedule 1 substance certainly contributes to the lack of ample data. However, as more states pass legislation legalizing marijuana, more studies with larger sample sizes will ensue. Cannabis use continues to be a politically charged topic. Regulations among states vary, contributing to the difficulty in prescribing medicinal cannabis to patients suffering from chronic pain. Although preliminary data has supported the use of medicinal cannabis in the treatment of chronic pain, it is quite evident that further research needs to be performed to fully determine its true role in the world of pain management. The interest in exploring alternative treatments for chronic pain spurred by the opioid epidemic has created an opportunity to find treatments outside of the norm, from cannabis to even psychedelics.

Enhancing Healthcare Team Outcomes

The treatment of chronic pain requires an interprofessional approach. As with any patient encounter, a thorough history and physical exam are essential when delineating appropriate treatment options for chronic pain patients. The complexity of treating chronic pain patients is attributable to the subjective nature of pain, the variability of pain tolerance amongst patients, and the psychosocial impact of chronic pain. Therefore, effective collaboration among various disciplines, including physiatrists, physical therapists, psychologists, pain management physicians, neurologists, psychiatrists, and social workers, is necessary to ensure the best possible outcome for patients. Questionnaires and other forms can be offered to patients to monitor symptomatic improvement in pain and quality of life after initiating cannabis use. Nonetheless, ongoing research and studies are required to determine the actual effectiveness of medicinal cannabis as a possible alternative treatment for chronic pain.