Evaluation and Treatment of Pain With Medicinal Cannabis

Function

The cannabis plant belongs to the family Cannabaceae and contains hundreds of compounds called cannabinoids. These compounds have been isolated and discovered, with the most relevant being tetrahydrocannabinol (THC) and cannabidiol (CBD). Research in the late 20th century identified the first cannabinoid receptor.[4] To date, there are two endocannabinoid receptors that function as G–protein-coupled receptors—cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2).[5][6] 

CB1 receptors are commonly found in the central nervous system (CNS), whereas CB2 receptors are generally found in the peripheral immune and hematologic systems.[7] The distribution of these inherent receptors is important. Cannabinoids modulate pain perception through various receptor pathways and mediators, including the endocannabinoid system. These compounds can inhibit mast cell degranulation, modulate nociceptor response, and change afferent activity.[8] THC is a partial agonist of both CB1 and CB2 receptors, primarily recognized for its psychomimetic properties and its effects on pain modulation, digestion, and other physiological processes.[9] Specifically, THC can inhibit glutamate release, decrease 5-hydroxytryptamine release, and alter dopaminergic function, all of which have been shown to influence pain.[10][11][12]

Conversely, CBD acts as a negative allosteric modulator of CB1 and influences other endogenous systems, including the vanilloid receptor (TRPV1) and adenosine A2A. CBD has anti-inflammatory, analgesic, and anti-psychotic effects.[13] Specifically, CBD has been shown to decrease reactive oxygen species, suppress tumor necrosis factor, and inhibit T-cell proliferation.[14][15][16]

Issues of Concern

Although medicinal cannabis is a potential treatment option for pain, it, like any medication, carries the risk of adverse effects. A systematic review of 31 clinical studies conducted over 40 years identified the most serious effects as relapsing multiple sclerosis, vomiting, and urinary tract infections. Dizziness was noted as one of the most common benign effects.[17]

Short-term cannabis use can lead to altered motor coordination, impaired judgment, and psychosis, particularly at high doses, as indicated by previous studies.[18] Long-term use may contribute to cognitive disorders such as depression or schizophrenia, although further high-quality studies are needed to quantify these risks.[19] In addition, the metabolism of certain cannabinoids, such as CBD, occurs in the liver, posing a risk of drug-drug interactions when used alongside CYP3A4-altering medications.[20] Due to their metabolism, cannabinoids can also affect the liver; therefore, it is essential for practitioners to routinely assess liver function tests.

There are several routes to administer THC and CBD, including inhalational, oral, oromusocal sprays, and topical application.[21] The general approach in initiating any new medication, including medicinal cannabis, is to start low and go slow. Careful titration can minimize adverse effects, although the length of time varies for each patient until adequate pain control is achieved. Patients often receive preparations with CBD predominance and low THC to maximize symptom control. The antipsychotic effects of CBD can balance the psychotic effects of THC. However, higher doses of CBD-predominant preparations may be needed.[22] The majority of patients use between 1 and 3 g of cannabis daily, although doses should be individualized.[23]

Clinical Significance

Cannabis has been shown to have potential benefits in treating certain types of pain. Studies have shown that the type of pain dictates the response to treatment. In a randomized, double-blinded study of 40 patients undergoing abdominal hysterectomy, patients were subjected to 2 groups—one receiving 5 mg of oral THC and the other a placebo. Postoperative assessments of pain reduction indicated that there were no benefits from analgesic treatments.[24] Another study involving 41 patients compared oral cannabis to placebo following surgery. Primary outcome measures included morphine consumption and pain scores, showing no difference between groups.[25] Further studies have shown no improvement in acute pain from medicinal cannabis administration.[26] 

Although medicinal cannabis has not shown efficacy in treating acute pain, it has demonstrated benefit in treating chronic pain. A systematic review and meta-analysis involving 43 randomized control trials found that inhaled cannabis significantly reduced pain in patients with chronic pain (P<.0001). The study also concluded that medicinal cannabis may be particularly effective for chronic neuropathic pain.[27] 

Another systematic review of 18 trials was conducted to evaluate the use of cannabinoids in treating non-cancer pain. More than 80% of the trials reported a significant analgesic effect, and 4 trials specifically demonstrated the benefits of smoked cannabis for neuropathic pain.[28] In addition, the meta-analysis found certain adverse effects, including alterations in perception; mood disturbances, such as euphoria; and events affecting cognitive function.[21] Cannabis has also been studied in cancer pain. A literature review of 5 trials conducted between 1975 and 2017 examined the use of cannabinoids for cancer pain. All studies revealed improvement in cancer pain with THC or THC:CBD mixture through various administration routes.[29]

Several clinical trials have examined the effects of smoked cannabis specifically for pain management. A clinical study evaluated 56 patients with fibromyalgia, and results revealed pain reduction on the visual analog scale before and after 2 hours of self-administered cannabis.[30] Many adverse effects were observed in this study, including somnolence, dry mouth, sedation, and dizziness. In another study involving 21 patients with chronic posttraumatic or postsurgical neuropathic pain, patients were given varying concentrations of THC three times daily for 5 days, with dosages of 0%, 2.5%, 6%, and 9.4%. The findings revealed that patients using the highest concentration of 9.4% THC experienced a statistically significant reduction in pain intensity compared to those receiving 0% THC (P=.023). However, these patients were also more likely to experience adverse effects, such as headaches and dry eyes.[31] 

A clinical trial involving 28 HIV-positive patients with chronic neuropathic pain smoked cannabis 5 days a week for 2 weeks or placebo. There was a significant difference in pain relief with the cannabis group versus the placebo group (P=.016).[32] Further studies were also conducted and revealed pain benefits with smoked cannabis.[33][34][35] Overall, the benefits of medicinal cannabis in managing chronic pain may be partly offset by certain adverse events.

Cannabis-based medicines have been investigated for their potential to relieve pain and other symptoms in adults with cancer. Pain is a common issue among cancer patients, significantly impacting their quality of life. Opioid medications are commonly used to manage moderate-to-severe cancer pain but may not provide sufficient relief for 10% to 15% of patients. Therefore, there is a need for alternative analgesics to supplement or replace opioids.

The benefits and potential adverse effects of cannabis-based medicines, including medical cannabis, compared to placebo or other established analgesics for cancer pain in adults have been assessed. The search for relevant studies followed standard Cochrane methods, and the latest search was conducted in January 2023.

The selection criteria included double-blind, randomized controlled trials (RCTs) with at least 10 participants per treatment arm. The primary outcomes of interest were the proportions of participants reporting no worse than mild pain, patient global impression of change, and withdrawals due to adverse events. Secondary outcomes included pain relief, sleep problems, depression and anxiety, opioid dosage, and dropouts due to lack of efficacy.

A total of 14 studies involving 1823 participants were identified. Five RCTs focused on oromucosal nabiximols or THC alone for moderate-to-severe pain despite opioid therapy. Meta-analysis was conducted on 4 of these studies, and the findings indicated no clinically significant benefit for a patient global impression of change and no difference in withdrawals due to adverse events. There was also no difference in the frequency of serious adverse events between the cannabis-based medicines and placebo. Nabiximols and THC did not differ from placebo in reducing mean pain intensity.

The evidence regarding synthetic THC analogs (nabilone) and CBD oil was limited. A study found that nabilone was not superior to placebo in reducing pain associated with chemotherapy or radiochemotherapy. Synthetic THC analogs were shown to be superior to placebo but not superior to low-dose codeine in reducing moderate-to-severe cancer pain. CBD oil did not add value to specialist palliative care alone in reducing pain intensity.

No studies using herbal cannabis were found, and the overall conclusions were based on moderate- or low-certainty evidence. Oromucosal nabiximols and THC were found to be ineffective in relieving opioid-refractory cancer pain. Nabilone was also ineffective in reducing pain associated with chemotherapy or radiochemotherapy. Synthetic THC analogs had limited superiority over placebo, and CBD did not provide additional pain relief in advanced cancer.

Notably, the reviewed studies had limitations regarding study design, sample size, and duration. The evidence was insufficient to determine the place of cannabis-based medicines in the World Health Organization analgesic ladder for cancer pain. 

In conclusion, cannabis-based medicines did not show significant efficacy in relieving cancer pain that did not respond to opioids. The current evidence does not support the widespread use of these medicines in the management of cancer pain.[36]

Other Issues

Many randomized clinical trials involving medicinal cannabis consisted of small sample sizes, ultimately leading to low statistical power. Additional trials are needed to further validate the extent of pain benefit. However, the paucity of data may partially be due to cannabis being a Schedule I controlled substance. Legalization remains a controversial topic within the medical community. Furthermore, ethical, societal, and cultural reasons are implicated with cannabis. Being cognizant of state regulations is essential, as most states have approved the recommendation or authorization of medicinal cannabis. However, there are still several states that have yet to approve the use of medicinal cannabis.

Not all states have approved both THC and CBD. Some states have only approved CBD in the form of CBD oil.[37] In addition, clinicians undergo additional training to write a recommendation for medical cannabis for patients to pick up at an appropriate dispensary. Regulations may vary across states. Clinicians are unable to prescribe medicinal cannabis due to its classification by the federal government. Before recommending medicinal cannabis, developing a doctor-patient relationship, as with any patient encounter, is essential. This relationship helps clinicians record an adequate history and avoid contraindications to medicinal cannabis, including addiction, psychiatric disorders, or liver disease. The patient's support system, family dynamics, and other psychosocial elements should be sought out, and a follow-up plan should be established to maintain continuity of care. Follow-up appointments should be monitored for medication efficacy, adverse effects, drug-drug interactions, functional improvement, and improved quality of life. Clinicians can also provide patients with questionnaires or other forms regarding the quality of life to monitor symptom improvement.

Enhancing Healthcare Team Outcomes

The evaluation and treatment of pain require a multidisciplinary approach. Pain is purely subjective, and its complexity requires an adequate history and physical examination. Imaging is often necessary to rule out any underlying anatomical sources of pain. After a comprehensive assessment, a team-based model should be ensured to care for the patient. Social workers; physical therapists; psychologists; consultants, such as pain management clinicians; neurologists; physiatrists; and addiction specialists are all involved. The integrated team must understand the risks and benefits of using medicinal cannabis as it is a Schedule I controlled substance due to its high potential for abuse.

Skills

Knowledge of issues with medicinal cannabis use is essential.

Strategy

Maintaining continuous closed-loop communication among all members of the perioperative care team is essential to address the need, technique, and potential management challenges associated with medicinal cannabis use.

Ethics

Before considering medicinal cannabis, informed consent must be obtained from either the patient or, if the patient lacks capacity, from their designated and authorized decision-maker. All team members should feel empowered to voice any concerns to the team and/or the patient, as this fosters stakeholder buy-in and provides additional layers of review and insight into potential issues at the earliest opportunity.

Responsibilities

All team members must communicate their concerns, responsibilities, and activities with other team members contemporaneously and as indicated throughout the perioperative period based on their professional discretion.

Interprofessional Communication

All team members should respect the free flow of information and concerns among team members without allowing or producing an environment of hostility.

Care Coordination

All team members are responsible for supporting seamless collaboration by ensuring their actions do not disrupt the work of others or unintentionally create additional challenges or workload for other team members.