Cannabinoid-based Medications for Pain Raymond M. St. Marie, Raphael J. Leo, 2021

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22 juillet 2021 GRECC 0

Cannabinoid-based Medications for Pain

Raymond M. St. Marie, MD; Raphael J. Leo, MA, MD

Current Psychiatry, 2021, 20(5), 21-33.

Abstract and Introduction

Introduction

Against the backdrop of an increasing opioid use epidemic and a marked acceleration of prescription opioid–related deaths,[1,2] there has been an impetus to explore the usefulness of alternative and co-analgesic agents to assist patients with chronic pain. Preclinical studies employing animal-based models of human pain syndromes have demonstrated that cannabis and chemicals derived from cannabis extracts may mitigate several pain conditions.[3]

Because there are significant comorbidities between psychiatric disorders and chronic pain, psychiatrists are likely to care for patients with chronic pain. As the availability of and interest in cannabinoid-based medications (CBM) increases, psychiatrists will need to be apprised of the utility, adverse effects, and potential drug interactions of these agents.

The endocannabinoid system and cannabis receptors

The endogenous cannabinoid (endocannabinoid) system is abundantly present within the peripheral and central nervous systems. The first identified, and best studied, endocannabinoids are N-arachidonoyl-ethanolamine (AEA; anandamide) and 2-arachidonoylglycerol (2-AG).[4] Unlike typical neurotransmitters, AEA and 2-AG are not stored within vesicles within presynaptic neuron axons. Instead, they are lipophilic molecules produced on demand, synthesized from phospholipids (ie, arachidonic acid derivatives) at the membranes of post-synaptic neurons, and released into the synapse directly.[5]

Acting as retrograde messengers, the endocannabinoids traverse the synapse, binding to receptors located on the axons of the presynaptic neuron. Two receptors—CB1 and CB2—have been most extensively studied and characterized.[6,7] These receptors couple to Gi/o-proteins to inhibit adenylate cyclase, decreasing Ca2+ conductance and increasing K+ conductance.[8] Once activated, cannabinoid receptors modulate neurotransmitter release from presynaptic axon terminals. Evidence points to a similar retrograde signaling between neurons and glial cells. Shortly after receptor activation, the endocannabinoids are deactivated by the actions of a transporter mechanism and enzyme degradation.[9,10]

The endocannabinoid system and pain transmission

Cannabinoid receptors are present in pain transmission circuits spanning from the peripheral sensory nerve endings (from which pain signals originate) to the spinal cord and supraspinal regions within the brain.[11-14] CB1 receptors are abundantly present within the CNS, including regions involved in pain transmission. Binding to CB1 receptors, endocannabinoids modulate neurotransmission that impacts pain transmission centrally. Endocannabinoids can also indirectly modulate opiate and N-methyl-d-aspartate (NMDA) receptors involved in pain relay and transmission.[15]

By contrast, CB2 receptors are predominantly localized to peripheral tissues and immune cells, although there has been some discovery of their presence within the CNS (eg, on microglia). Endocannabinoid activation of CB2 receptors is thought to modulate the activity of peripheral afferent pain fibers and immune-mediated neuro­inflammatory processes—such as inhibition of prostaglandin synthesis and mast cell degranulation—that can precipitate and maintain chronic pain states.[16-18]

Evidence garnered from preclinical (animal) studies points to the role of the endocannabinoid system in modulating normal pain transmission (see Manzanares et al[3] for details). These studies offer a putative basis for understanding how exogenous cannabinoid congeners might serve to ameliorate pain transmission in pathophysiologic states, including chronic pain.

Cannabinoid-based medications

Marijuana contains multiple components (cannabinoids). The most extensively studied are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Because it predominantly binds CB1 receptors centrally, THC is the major psychoactive component of cannabis; it promotes sleep and appetite, influences anxiety, and produces the “high” associated with cannabis use. By contrast, CBD weakly binds CB1 and thus exerts minimal or no psycho­active effects.[19]

Cannabinoid absorption, metabolism, bioavailability, and clinical effects vary depending on the formulation and method of administration ().[20-22] THC and CBD content and potency in inhaled cannabis can vary significantly depending on the strains of the cannabis plant and manner of cultivation.[23] To standardize approaches for administering cannabinoids in clinical trials and for clinical use, researchers have developed pharmaceutical analogs that contain extracted chemicals or synthetic chemicals similar to THC and/or CBD.

Table 1  Differences in THC bioavailability and effects between inhaled and ingested cannabinoid-based medications

Factor Inhaled CBM formulations (herbal cannabis) Ingested CBM formulations
Peak blood levels of THC
Bioavailabilitya
Rate of absorption
First-pass metabolism
Onset of THC effects
Psychoactive effects of THCb
Duration of THC effects		 Higher; achieved in minutes
Nearly 30%
Rapid
Minimal/none
Rapid
Relatively greater
Brief		 Lower; achieved in 1 to 4 hours
Approximately 4% to 20%
Slow
Extensive
Slow
Relatively less
Longer/sustained

aBioavailability is higher with vaporized cannabis as compared with combusted (smoked) cannabis; oromucosal sprays (sublingual) provide cannabinoids that escape first-pass metabolism and therefore have higher bioavailability than ingested formulations

bPsychoactive effects would depend on dosage (ie, the frequency of inhalations or breath holding with inhaled cannabis, or the amount/dose ingested of oral CBM)

CBM: cannabinoid-based medications; THC: delta-9-tetrahydrocannabinol

Source: Adapted from references 20-22

In this article, CBM refers to smoked/vaporized herbal cannabis as well as pharmaceutical cannabis analogs. summarizes the characteristics of CBM commonly used in studies investigating their use for managing pain conditions.

Table 2  Characteristics of cannabinoid-based medications used in pain research

Medication Brand name Route of administration Classification FDA statusa CSA schedule
Cannabidiol
Dronabino
Nabilone
Ajulemic acid
Nabiximolsb
Medicinal (herbal) cannabis		 Epidiolex
Marinol (capsule), Syndros (liquid)
Cesamet
Anabasum
Sativex
Various strains		 Oral, sublingual
Oral, sublingual
Oral
Oral		 Oromucosal spray
Inhaled		 CBD extract
Synthetic THC
Synthetic THC
Synthetic THC
THC:CBD, 1:1 plant extract
Multiple cannabinoids		 V
III
II
NA
NA
I

aNone of the agents listed in this Table are FDA-approved for the management of pain

bNabiximols is approved in numerous countries for chronic cancer pain and multiple sclerosis–related pain

CBD: cannabidiol; CSA: Controlled Substances Act; NA: not applicable; THC: delta-9-tetrahydrocannabinol

CBM for chronic pain

The literature base examining the role of CBM for managing chronic nonmalignant and malignant pain of varying etiologies is rapidly expanding. Randomized controlled trials (RCTs) have focused on inhaled/smoked products and related cannabinoid medications, some of which are FDA-approved ().

Table 2  Characteristics of cannabinoid-based medications used in pain research

Medication Brand name Route of administration Classification FDA statusa CSA schedule
Cannabidiol
Dronabino
Nabilone
Ajulemic acid
Nabiximolsb
Medicinal (herbal) cannabis		 Epidiolex
Marinol (capsule), Syndros (liquid)
Cesamet
Anabasum
Sativex
Various strains		 Oral, sublingual
Oral, sublingual
Oral
Oral		 Oromucosal spray
Inhaled		 CBD extract
Synthetic THC
Synthetic THC
Synthetic THC
THC:CBD, 1:1 plant extract
Multiple cannabinoids		 V
III
II
NA
NA
I

aNone of the agents listed in this Table are FDA-approved for the management of pain

bNabiximols is approved in numerous countries for chronic cancer pain and multiple sclerosis–related pain

CBD: cannabidiol; CSA: Controlled Substances Act; NA: not applicable; THC: delta-9-tetrahydrocannabinol

A multitude of other cannabinoid-based products are currently commercially available to consumers, including tincture and oil-based products; over-the-counter CBD products; and several other formulations of CBM (eg, edible and suppository products). Because such products are not standardized or quality-controlled,[24] RCTs have not assessed their efficacy for mitigating pain. Consequently, the findings summarized in this article do not address the utility of these agents.

CBM for non-cancer pain

Neuropathic pain. Randomized controlled trials have assessed the pain-mitigating effects of various CBM, including inhaled cannabis, synthetic THC, plant-extracted CBD, and a THC/CBD spray. Studies have shown that inhaled/vaporized cannabis can produce short-term pain reduction in patients with chronic neuropathic pain of diverse etiologies, including diabetes mellitus-, HIV-, trauma-, and medication-induced neuropathies.[22,25,26] Similar beneficial effects have been observed with the use of cannabis analogues (eg, nabiximols).[25,26-29]

Meta-analyses and systematic reviews have determined that most of these RCTs were of low-to-moderate quality.[26,30] Meta-analyses have revealed divergent and conflicting results because of differences in the inclusion and exclusion criteria used to select RCTs for analysis and differences in the standards with which the quality of evidence were determined.[25,30]

Overall, the benefit of CBM for mitigating neuropathic pain is promising, but the effectiveness may not be robust.[30,31] Several noteworthy caveats limit the interpretation of the results of these RCTs:

  • due to the small sample sizes and brief durations of study, questions remain regarding the extent to which effects are generalizable, whether the benefits are sustained, and whether adverse effects emerge over time with continued use
  • most RCTs evaluated inhaled (herbal) cannabis and nabiximols; there is little data on the effectiveness of other CBM formulations[25,26,30]
  • the pain-mitigating effects of CBM were usually compared with those of placebo; the comparative efficacy against agents commonly used to treat neuropathic pain remains largely unexamined
  • these RCTs typically compared mean pain severity score differences between cannabis-treated and placebo groups using standard subjective rating scales of pain intensity, such as the Numerical Rating Scale or Visual Analogue Scale. Customarily, the pain literature has used a 30% or 50% reduction in pain severity from baseline as an indicator of significant clinical improvement.[32,33] The RCTs of CBM for neuropathic pain rarely used this standard, which makes it unclear whether CBM results in clinically significant pain reductions[30]
  • indirect measures of effectiveness (ie, whether using CBM reduces the need for opioids or other analgesics to manage pain) were seldom reported in these RCTs.

Due to these limitations, clinical guidelines and systematic reviews consider CBM as a third- or fourth-line therapy for patients experiencing chronic neuropathic pain for whom conventional agents such as anticonvulsants and antidepressants have failed.[34,35]

Spasticity in multiple sclerosis (MS). Several RCTs have assessed the use of CBM for MS-related spasticity, although few were deemed to be high quality. Nabiximols and synthetic THC were effective in managing spasticity and reducing pain severity associated with muscle spasms.36 Generally, investigations revealed that CBM were associated with improvements in subjective measures of spasticity, but these were not born out in clinical, objective measures.[26,37] The efficacy of smoked cannabis was uncertain.37 The existing literature on CBM for MS-related spasticity does not address dosing, duration of effects, tolerability, or comparative effectiveness against conventional anti-spasm medications.[36,37]

Other chronic pain conditions. CBM have also been studied for their usefulness in several other noncancer chronic conditions, including Crohn’s disease, inflammatory bowel disease, fibromyalgia, and other rheumatologic pain conditions.[22,31,38-40] However, a solid foundation of empirical work to inform their utility for managing pain in these conditions is lacking.

CBM for cancer pain

Anecdotal evidence suggests that inhaled cannabis has promising pain-mitigating effects in patients with advanced cancer.[41-43] There is a dearth of high-quality RCTs assessing the utility of CBM in patients with cancer pain.[43-45] The types of CBM used and dosing strategies varied across RCTs, which makes it difficult to infer how best to treat patients with cancer pain. The agents studied included nabiximols, THC spray, and synthetic THC capsules.[43-45] Although some studies have demonstrated that synthetic THC and nabiximols have potential for reducing subjective pain ratings compared with placebo,[46,47] these results were inconsistent.[46,48] Oromucosal nabiximols did not appear to confer any additional analgesic benefit in patients who were already prescribed opioids.[31,45]

The benefit of CBM for mitigating cancer pain is promising, but it remains difficult to know how to position the use of CBM in managing cancer pain. Limitations in the cancer literature include:

  • the RCTs addressing CBM use for cancer pain were often brief, which raises questions about the long-term effectiveness and adverse effects of these agents
  • tolerability and dosing limits encountered due to adverse effects were seldom reported[43,45]
  • the types of cancer pain that patients had were often quite diverse. The small sample sizes and the heterogeneity of conditions included in these RCTs limit the ability to determine whether pain-mitigating effects might vary according to type of cancer-related pain.[31,45]
  • Despite these limitations, some clinical guidelines and systematic reviews have suggested that CBM have some role in addressing refractory malignant pain conditions.[49]

Psychiatric considerations related to CBM

As of November 2020, 36 states had legalized the use of cannabis for medical purposes, typically for painful conditions, despite the fact that empirical evidence to support their efficacy is mixed.[50] In light of recent changes in both the legal and popular attitudes regarding cannabis, the implications of legalizing CBM remains to be seen. For example, some research suggests that adults with pain are vulnerable to frequent nonmedical cannabis use and/or cannabis use disorder.[51] Although well-intended, the legalization of CBM use might represent society’s next misstep in the quest to address the suffering of patients with chronic pain. Some evidence shows that cannabis use and cannabis use disorders increase in states that have legalized medical marijuana.[52,53] Psychiatrists will be on the front lines of addressing any potential consequences arising from the use of CBM for treating pain.

Psychiatric disorders and CBM. The psychological impact of CBM use among patients enduring chronic pain can include sedation, cognitive/attention disturbance, and fatigue. These adverse effects can limit the utility of such agents.[22,29,45]

Contraindications for CBM use, and conditions for which CBM ought to be used with caution, are listed in [54,55].The safety of CBM, particularly in patients with chronic pain and psychiatric disorders, has not been examined. Patients with psychiatric disorders may be poor candidates for medical cannabis. Epidemiologic data suggest that recreational cannabis use is positively associated both cross-sectionally and prospectively with psychotic spectrum disorders, depressive symptoms, and anxiety symptoms, including panic disorder.56 Psychotic reactions have also been associated with CBM (dronabinol and nabilone).[57] Cannabis use also has been associated with an earlier onset of, and lower remission rates of, symptoms associated with bipolar disorder.[58,59] Consequently, patients who have been diagnosed with or are at risk for developing any of the aforementioned conditions may not be suitable candidates for CBM. If CBM are used, patients should be closely monitored for the emergence/exacerbation of psychiatric symptoms. The frequency and extent of follow-up is not clear, however. Because of its reduced propensity to produce psychoactive effects, CBD may be safer than THC for managing pain in individuals who have or are vulnerable to developing psychiatric disorders.

Table 3  Relative contraindications and precautions related to use of cannabinoid-based medicationsa

Contraindications
Adverse reactions to cannabis, including psychoactive effects History of addiction (personal or familial) History of psychosis (personal or familial) Severe cardiac (arrhythmia or MI) or stroke history Pregnancy/lactating
Precautions
History of bipolar disorder (personal or familial) Severe anxiety and/or depression Safety-sensitive jobs (driving, flying, operating heavy machinery Drug interactions (medications with potential for drug interaction with THC and CBD) Concurrent sedative/hypnotic use

aPsychotomimetic and mood effects are likely to be more salient with THC than CBD products

CBD: cannabidiol; MI: myocardial infarction; THC: delta-9-tetrahydrocannabinol

Source: Adapted from references 54,55

There is a lack of evidence to support the use of CBM for treating primary depressive disorders, general anxiety disorder, posttraumatic stress disorder, or psychosis.[60,61] Very low-quality evidence suggests that CBM could lead to a small improvement in anxiety among individuals with noncancer pain and MS.[60] However, interpreting causality is complicated. It is plausible that, for some patients, subjective improvement in pain severity may be related to reduced anxiety.62 Conversely, it is equally plausible that reductions in emotional distress may reduce the propensity to attend to, and thus magnify, pain severity. In the latter case, the indirect impact of reducing pain by modifying emotional distress can be impacted by the type and dose of CBM used. For example, low concentrations of THC produce anxiolytic effects, but high concentrations may be anxiety-provoking.[63,64]

Several potential pharmacokinetic drug interactions may arise between herbal cannabis or CBM and other medications ([65,66]). THC and CBD are both metabolized by cytochrome P450 (CYP) 2C19 and 3A4.[65,66] In addition, THC is also metabolized by CYP2C9. Medications that inhibit or induce these enzymes can increase or decrease the bioavailability of THC and CBD.[67]

Table 4  Potential drug interactions: Medications that can impact THC bioavailability

CYP3A4 inhibitors CYP3A4 inducers CYP2C9 inhibitors CYP2C9 inducers
Cimetidine
Ketoconazole
Nefazodone
Protease inhibitors
Tamoxifen
Verapamil		 Phenytoin
Rifampin
Topiramate		 Clopidogre
Fluoxetine
Fluvoxamine
Ketoconazole		 Carbamazepine
Phenobarbital
Phenytoin
St. John’s wort

CYP: cytochrome P450; THC: delta-9-tetrahydrocannabinol

Source: Adapted from references 65,66

Simultaneously, cannabinoids can impact the bioavailability of co-prescribed medications ([66,68]). Although such CYP enzyme interactions remain a theoretical possibility, it is uncertain whether significant perturbations in plasma concentrations (and clinical effects) have been encountered with prescription medications when co-administered with CBM.[69] Nonetheless, patients receiving CBM should be closely monitored for their response to prescribed medications.[70]

Table 5  Potential drug interactions: Medication metabolism influenced by THC effects on CYP enzymesa

CYP1A2 substrates CYP3A4 substrates CYP2C9 substrates
Clozapine
Duloxetine
Fluvoxamine
Melatonin
Mirtazapine
Olanzapine
Ramelteon		 Alprazolam
Amitriptyline
Aripiprazole
Buspirone
Carbamazepine
Citalopram
Cyclosporine
Haloperidol
Imipramine
Midazolam
Mirtazapine
Risperidone
Sertraline
Zolpidem		 Amitriptyline
Fluoxetine
Ibuprofen
Losartan
Phenobarbital
Phenytoin
Valproic acid
Venlafaxine

aThis is not an exhaustive list of substrates. THC inhibits CYP2C9 and CYP3A4, potentially increasing availability of the medications listed. THC induces CYP1A2, potentially reducing availability of the medications listed

CYP: cytochrome P450; THC: delta-9-tetrahydrocannabinol

Source: Adapted from references 66,68

Potential CYP enzyme interactions aside, clinicians need to consider the additive effects that may occur when CBM are combined with sympathomimetic agents (eg, tachycardia, hypertension); CNS depressants such as alcohol, benzodiazepines, and opioids (eg, drowsiness, ataxia); or anticholinergics (eg, tachycardia, confusion).[71] Inhaled herbal cannabis contains mutagens and can result in lung damage, exacerbations of chronic bronchitis, and certain types of cancer.[54,72] Co-prescribing benzodiazepines may be contraindicated in light of their effects on respiratory rate and effort.

The THC contained in CBM produces hormonal effects (ie, significantly increases plasma levels of ghrelin and leptin and decreases peptide YY levels)[73] that affect appetite and can produce weight gain. This may be problematic for patients receiving psychoactive medications associated with increased risk of weight gain and dyslipidemia. Because of the association between cannabis use and motor vehicle accidents, patients whose jobs require them to drive or operate industrial equipment may not be ideal candidates for CBM, especially if such patients also consume alcohol or are prescribed benzodiazepines and/or sedative hypnotics.[74] Lastly, due to their lipophilicity, cannabinoids cross the placental barrier and can be found in breast milk[75] and therefore can affect pregnancy outcomes and neurodevelopment.

Bottom Line

The popularity of cannabinoid-based medications (CBM) for the treatment of chronic pain conditions is growing, but the interest in their use may be outpacing the evidence supporting their analgesic benefits. High-quality, well-controlled randomized controlled trials are needed to decipher whether, and to what extent, these agents can be positioned in chronic pain management. Because psychiatrists are likely to encounter patients considering, or receiving, CBM, they must be aware of the potential benefits, risks, and adverse effects of such treatments.

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