Cannabis and Pain Management

Cannabis Forms and Routes of Use

Cannabis contains more than 100 different cannabinoids, but the 3 most well-known are tetrahydrocannabinol (THC), cannabidiol (CBD), and terpenes.² If a cannabis plant contains 0.3% or more THC, the product has been called marijuana, although now the use of the term marijuana is controversial due to associations of the term with racism and criminalization.³ THC is the psychoactive compound that is responsible for the “high” associated with cannabis use. (If the THC level is less than 0.3%, the product is hemp. Hemp has no restriction on growth in the US.) The Agricultural Improvement Act of 2018 removed hemp and hemp products from the Drug Enforcement Administration’s schedule of controlled substances.⁴ CBD products are extracted from hemp and are legal to grow and sell. CBD has little-to-no psychoactive effects and is thought to have anti-inflammatory and pain-relieving properties. Terpenes are aromatic products that share some properties with CBD, but they also have promising antibacterial, antifungal, and anticancer properties.⁵

Cannabis can be smoked as joints (hand-rolled cigarettes), blunts (emptied cigars or cigarettes that have been partly or completely refilled with cannabis), or in pipes or water pipes (bongs). Individuals can also vape, or use electronic delivery systems, in which THC is dissolved in a volatile solution, heated, and inhaled. Edible products are available as brownies, cookies, or candy, or brewed as a beverage. A method of ingesting high-potency THC is smoking or eating different forms of highly concentrated THC resins, sometimes called oils, budder, wax, or shatter.⁶

Cannabis and Pain: What Do We Know? What Is in the Literature?

Cannabis has been used for centuries to treat pain. To provide, practical information for family physicians, the authors reviewed the published literature since 2015 for meta-analyses and systematic reviews of randomized controlled trials of cannabis for analgesia; studies focusing on cancer and terminal illness pain were excluded. The 12 reviews that met these criteria examined conditions such as neuropathic, rheumatological, other noncancer chronic pain, acute and peri-operative pain, and experimental pain. The literature review for this article was conducted similar to a systematic review-style research on the topic of cannabis and pain. The PRISMA algorithm was employed to organize and attempt to standardized exclusion and inclusion of articles. In order to understand the body of research on cannabis and pain, only systematic reviews, meta-analyses, and randomized controlled studies were included. Due to the wide array of pain etiologies, disorders with unique pain schema were not included. These disorders/diseases that were excluded are cancer, cirrhosis, terminal illness and palliative care, psychological illness, and pediatric pain. The search engine was PubMed. Then 195 studies were selected to be reviewed based on their titles (addressing both cannabis and pain). Based on 195 studies, all of the abstracts were read. This further winnowed down the results to 120. THC and CBD are the most abundant and well-studied of the cannabinoids (phytochemicals in the marijuana flower or bud). Studies looking at CBD, THC, or both were included despite that both compounds are metabolized in different ways and may have differing effects on pain. All studies included had an experimental design. This was in order to understand the routes of administration in a clearer way, with experimentally rather than user reported. Based on the studies reviewed, categories was chosen from this search (10 articles) that included topics most relevant to family physicians.

Adverse Effects of Cannabis Used to Treat Pain

Johal et al. reviewed 35 studies with data on adverse events found an increased risk of mild or moderate adverse effects with cannabis (48%) compared with placebo (40%); serious adverse events were rare in both the cannabis and placebo groups (Johal et al., 2020).¹⁰ The most frequent side effects were dizziness (31%), application site discomfort (18%), asthenia (16%); fatigue (15%), increased appetite (15%), dry mouth (14%), drowsiness (14%), nausea (13%), and hallucinations (13%). Long-term side effects could not be evaluated given the short durations of the included studies. Another study found higher levels of dizziness and hypotension in patients receiving cannabis compared with those who received placebo. The majority of included reviews reported frequent mild adverse effects; serious adverse effects were rare.

Methodologic Limitations

There are many limitations of the current body of literature on cannabis and pain including short timelines (most under 6 months, many less than 1 month) and small sample sizes. Almost all RCTs compared cannabis with placebo rather than with common analgesics used for chronic pain such as NSAIDs or acetaminophen which limits usefulness for practitioners and patients in evaluating options for treatment of pain. Because of the heterogeneity of cannabis products (including different cannabinoids and lack of consistent THC:CBD ratios), dose, and routes of administration, findings from particular studies cannot be generalized to medical cannabis. Taken together, these studies demonstrate a lack of consistency in both method and outcome but suggest that cannabis has the potential to provide a small benefit relative to placebo in treating pain. The most promising aspect of the literature was for neuropathic pain, where there is weak but emerging evidence for potential benefit of cannabis. Most reviewers conclude that, at this time, evidence is insufficient to recommend cannabis to treat pain because the level of evidence for its benefit is not strong and adverse effects of cannabis are frequent.

Additional Emerging Cautions with Cannabis Use

Family physicians are at the front lines when patients present for complications of cannabis use.

Acute adverse effects of cannabis use include dizziness, drowsiness, nausea, increased heart rate, hyperemesis, psychomotor impairment, and increased risk of motor vehicle accidents.¹⁵ Long-term adverse effects of smoking marijuana include cannabinoid hyperemesis syndrome, and psychosis.¹⁶ Concerns are escalated for adolescents and young adults, particularly those engaging in regular, high potency cannabis use. Several studies are teasing apart whether associated effects on learning and risk of lowering thresholds for psychotic episodes and earlier appearance of schizophrenia are correlative or causative.^17,18

Cannabinoid Hyperemesis Syndrome (CHS) consists of severe recurrent nausea and vomiting in patients with prolonged chronic use of cannabis (more than weekly use), which typically presents in 3 phases. The prodromal phase consists of morning nausea, abdominal discomfort, and fear of vomiting. It may last months or years.¹⁹ The second or hyperemetic phase consists of severe, intense emesis with vomiting episodes throughout the day. Patients may present to emergency departments repeatedly, but their lab testing and imaging are often nonspecific. Weight loss may occur in this phase, which may continue for 24 to 48 hours. Relief is associated with hot-water bathing.²⁰ For patients to enter the recovery phase, complete cessation of cannabis use is required; This phase may take months while lipophilic cannabinoids are eliminated from the patient’s system.²¹

Medication Interactions with Cannabis

Family physicians also must remain vigilant about emerging data regarding drug interactives with cannabis. One tool useful for identify drug interactions, as well as preparing patients for surgical and other procedures requiring sedation is the American Society of Regional Anesthesia and Pain Medicine’s recently released consensus guidelines to assist in caring for patients who use cannabis/cannabinoid medications.²²

There are several potential interactions between THC and CBD and other medications, including those with similar psychoactive effects such as central nervous system depressants, benzodiazepines, opioids, alcohol, and antihistamines, which may result in increased sedation. In addition, coadministration of cannabis with tricyclic stimulants, sympathomimetics, and antidepressants may cause tachycardia. THC is metabolized by the CYP3A4 and CYP2C9 enzymes, whereas the metabolism of CBD involves the CYP3A4 and CYP2C19 enzymes. Table 1 outlines the various enzymes that are inhibited by THC and CBD. Coadministration of medications that involve these enzymes may affect THC and CBD or medication plasma levels.

The guidelines also highlight the potential for interactions between anticoagulant and antiplatelet medications with THC and CBD. Patients may be at risk for increased bleeding due to inhibition of CYP enzymes and P-glycoproteins resulting in increased levels of warfarin, direct-acting oral anticoagulants (DOACs), and clopidogrel. Other notable interactions include substrates of the CYP2D6 enzyme, which includes several opioids, antidepressants, antipsychotics, antiarrhythmic and β blocker medications. THC and CBD inhibition of CYP enzymes can result in increased drug levels. CBD may also cause increased levels of nonopioid analgesics (acetaminophen, NSAIDs) and propofol due to interactions with the UGT1A9 enzyme.

Beyond medication interactions, CBD and THC consumption can have a variety of impacts on a patient’s ability to tolerate sedation and anesthesia. The guidelines recommend universal screening for amount and frequency of cannabis use, type of cannabis product, time of last consumption, and route of administration (Grade A). In addition, procedures should be postponed if the patient experiences acute cannabis toxicity and has impairment in their decision making capacity (Grade A). The guidelines also recommend delaying elective surgery for 1 to 2 hours after acute cannabis smoking due to the potential increased risk of myocardial infarction (Grade C). Family physicians should educate their patients to share their cannabis use with their surgeons and anesthesiologists to minimize potential adverse outcomes.

Conclusion: So, What Do We Tell Our Patients?

Although we are learning much about cannabis and potential therapeutic roles of this plant, physicians should discuss risks and benefits of what is known and what we are learning.

The US literature on the efficacy of cannabis use for pain is scant. There are no published standards of therapeutic benefit of cannabis, such as number needed to treat. And much of the literature on the topic is limited by lack of consistency. Until we have better practice guidelines from scientific studies, we can still share possible promising practices. And we can certainly share ways to reduce harm—from abstinence to reducing risk according where a product is obtained and how it is consumed.

So, what medical advice can family physicians give in today’s world of mixed messages about medical-use cannabis and recreational/adult-use cannabis?

• Avoid early age initiation of cannabis use (i.e., definitively before the age of 16 years),

• Choose low-potency tetrahydrocannabinol (THC) or balanced THC-to-cannabidiol (CBD)–ratio cannabis products,

• Abstain from using synthetic cannabinoids,

• Avoid combusted cannabis inhalation and give preference to nonsmoking use methods,

• Avoid deep or other risky inhalation practices,

• Avoid high-frequency (e.g., daily or near-daily) cannabis use,

• Abstain from cannabis-impaired driving,

• Educate patients that some individuals have a higher risk for cannabis use–related health problems and should avoid use altogether. These include individuals with a personal or family history of schizophrenia, uncontrolled hypertension/coronary artery disease, chronic obstructive pulmonary disease or lung pathology (particularly with smoking and vaping), current immune treatment, and pregnancy

Until the Schedule 1 status of cannabis changes, researchers in the US will remain limited on the ability to conduct randomized, placebo-controlled, blinded, prospective studies, just as we do with the majority of products we call medications in the US. Until then, family physicians can educate patients and families on what we know, what we are learning, and how we can reduce harm around cannabis use.