The Impact of Perioperative Cannabis Use: A Narrative Scoping Review

Abstract

As countries progressively embrace the legalization of both medicinal and recreational cannabis, there remains a significant knowledge gap when it comes to the perioperative uses of cannabis, as well as the management of cannabis users. This review summarizes the information available on the subject based on existing published studies. Articles outlining the physiological changes occurring in the human body during acute and chronic use of cannabis (outside the context of anesthesia) are also taken into consideration as understanding these changes allows a more calculated approach to better anticipate patients' needs in the perioperative setting. Common questions facing the anesthesiologist at each phase of the perioperative period will be addressed and a systematic approach to the effect of cannabinoids on various organ systems will also be presented. Issues unique to cannabis use such as cannabis withdrawal syndrome and alterations in post-operative pain processing will also be discussed. To date, the number of studies available for guidance is small and study designs are markedly heterogenous, if not limited, making conclusions challenging. While the currently available information can assist in making decisions, further studies of larger scale are eagerly anticipated to help guide future patient care.

Introduction

According to the United Nations World Drug Report 2018, cannabis is the most common recreational drug used worldwide.¹ Their last global consensus in 2016 estimated that 192.2 million people or 3.9% of the world's population used the substance. That represented an overall 16% increase over the preceding decade. Most recently, Canada has embraced the legalization of adult recreational cannabis—second only to Uruguay. At present, 10 U.S. states and the District of Columbia have legalized recreational use, with several other states expressing desire to follow suit. Cannabis has also been decriminalized in Portugal, Israel, and the Netherlands, while other countries such as Zimbabwe, Jamaica, St. Vincent, and the Grenadines and Lesotho have legalized its use only medically.

With increasing popularity and social acceptance of the substance, it is imperative that the medical community stays current with the health implications of cannabis use. Psychoactive effects are common and may include psychosis, altered perception, impaired memory, and anxiety.^2,3 A wide variety of effects on major organ systems are also frequently observed.

One must also recognize the fact that cannabis contains more than 120 phytocannabinoids and other phytochemicals; and recreational cannabis-derived products can have a wide concentration range of these, each with a distinct pharmacological profile.⁴ While several of these compounds might be inconsequential due to their very low concentration, several compounds, including major phytocannabinoids such as Δ⁹-tetrahydrocannabinol (Δ⁹-THC), cannabidiol (CBD), and cannabigerol could have direct impact on patients.

Certain regulated preparations of cannabis are also licensed for use in mainstream medicine. Nabiximols and nabilone are examples of such. Nabiximols is available as an oromucosal spray and is approved for conditions such as cancer pain, which is not responsive to opioids, and muscular spasticity and neuropathic pain in patients with multiple sclerosis. Derived from the Cannabis sativa plant, it consists of a mixture of CBD and Δ⁹-THC in a 1:1 molecular ratio, terpenoids and flavonoids. The presence of CBD, a negative allosteric modulator of CB1 receptors, attenuates the euphoria and paranoia that is associated with Δ⁹-THC, making nabiximols a target for study in the area of cannabis use disorders.^5,6 Nabilone, an oral preparation of synthetic Δ⁹-THC, is prescribed regularly as an antiemetic in patients receiving chemotherapy and as a third-line agent for the treatment of neuropathic pain.

Today's anesthesiologists, given the potential challenges regarding control of consciousness and systemic interactions, need to understand how cannabis in its various forms affects their anesthetic practice. This systematic narrative review seeks to (1) summarize the published findings available to date that shed light on how anesthesiologists might tailor their practice to optimally care for cannabis users in the perioperative period and (2) review the potential uses of cannabinoids as therapeutic agents around the time of surgery.

Methods

While the use of cannabis dates back to ancient times, scientific studies exploring its use perioperatively have only occurred recently. We chose a scoping review study design to examine the full breadth of knowledge in this area across study designs, as well as identify gaps in knowledge to inform future research directions. The specific research question was developed through an iterative process. Initially, we sought to examine studies specific to chronic cannabis users presenting for surgery. However given the few studies identified, we chose to broaden the scope of the review to examine therapeutic uses of cannabis in the perioperative period and physiologic changes of cannabis that would be of relevance to the practicing anesthetist.

The following databases were searched from inception through the Ovid search interface: Medline (1946–November 21, 2018), Medline In-Process/ePubs (November 21, 2018), Embase (1947–November 21, 2018), Cochrane Central Register of Controlled Trials (2018 October), Cochrane Database of Systematic Reviews (2005–November 21, 2018), and PsycINFO (1809–November Week 3, 2018. The PubMed database (NLM) was searched with results limited to non-Medline citations. The Web of Science (Clarivate, 1900–November 22, 2018), Scopus (Elsevier, 1960–present), ClinicalTrials.Gov (NIH NLM), and ProQuest Digital International Dissertations were searched; and finally, the University of Toronto Summon discovery services was searched for books and/or book chapters. All the databases were searched on the same day, Friday, November 23, 2018.

The searching process followed the Cochrane Handbook⁷ and the Cochrane Methodological Expectations of Cochrane Intervention Reviews (MECIR)⁸ for conducting the search, the PRISMA guideline⁹ for reporting the search, and the PRESS guideline for peer reviewing the search strategies¹⁰ drawing on the PRESS 2015 Guideline Evidence-Based Checklist used to avoid potential search errors.

Preliminary searches were conducted and full text literature was mined for potential keywords and appropriate controlled vocabulary terms (Medical Subject Headings for Medline, EMTREE descriptors for Embase, and PsycINFO descriptors). The search strategy concept blocks were built on the topics of Cannabis AND Perioperative AND (Studies or Surveys or Questionnaires or Interviews), limited to the English language, where possible. Please see the provided Medline search strategy in the Supplementary Table S1 for details.

In total, the search yielded 6683 articles after deduplication. Abstracts and titles were initially screened independently by two authors (V.M. and A.-F.V.) for eligibility on the basis of their relevance to the impact of cannabis on any phase of the perioperative period. A second screening phase of the selected articles was done by detailed analysis of the full text of articles, where available. Further to this, referenced material in the articles chosen were also screened for relevance and were included where appropriate. Discrepancies in article inclusion/selection were resolved by a third author (K.L.).

Data extraction was performed using a unique form created specifically for the purposes of this review. For each included study, publication characteristics, study design, type of cannabis use, perioperative period studied, and main conclusions were abstracted. Given the heterogeneity of study designs as well as the consistently small sample sizes used, a narrative synthesis seemed the most appropriate means by which to present the literature as an amalgamated body. The results were subdivided into findings relevant to the pre-operative, intraoperative, and post-operative periods, this format being reflective of the demarcation of phases that anesthetists use when considering a case and the modifications that might be needed at each step. Given that the aim of the review was to explore the evidence, rather than evaluate the quality of individual studies, bias was not formally assessed. However, an overarching summary on the quality of the studies found is made in the “Discussion” section of this article.

Results

A total of 27 articles were identified and used for this scoping narrative review. Thirteen articles were randomized control trials, two articles were animal studies, eight were cohort studies, and five were case reports. Figure 1 displays the PRISMA diagram and Table 1 outlines the included studies.

FIG. 1.

Flow diagram of included articles.

Table 1.

Summary of Included Perioperative Articles

Title	Reference	Study type	No. of participants	Relevant findings
Effects of Δ9-THC on halothane MAC in dogs	19	Animal Research		As intravenous dose of THC increased, MAC of halothane decreased
Effects of Δ9-THC on cyclopropane MAC in the rat	18	Animal Research		As intraperitoneal dose of THC increased, MAC of cyclopropane decreased
Cardiovascular effects of cannabinol during oral surgery	12	Case–Control and Retrospective Cohort	n=20	Dose-dependent tachycardia; T-wave depressions and hypotension with higher THC doses; post-operative tachycardia; increased anxiety pre-operative use
Emotional response to intravenous Δ9-THC during oral surgery	12	Case–Control	n=15	Intravenous THC as pre-medication associated with increased anxiety, dysphoria, psychosis, and paranoia
Evaluation of intramuscular levonantradol and placebo in acute post-operative pain	75	Double-Blinded Clinical Trial	n=56; levonantradol users=40	Observed significant analgesic effects compared to placebo (p<0.05). No significant dose–response was observed. Side effects were observed significantly more in the levonatradol group with drowsiness as the most frequent.
Cannabis smoking and anesthesia	20	Case Report	n=1	Larger than normal amounts of intravenous and volatile agents needed for anesthesia, possible seizure intraoperatively, difficult ventilation during surgery
Cannabis abuse and laryngospasm	39	Case Report	n=1	Laryngospasm post-extubation in a cannabis smoker
Lack of analgesic efficacy of oral Δ9-THC in post-operative pain	71	Randomized Controlled Trial	n=40	No evidence of analgesic effect of orally administered THC in post-operative pain
Effects of nabilone, a synthetic cannabinoid, on post-operative pain	74	Randomized Controlled Trial	n=41	Nabilone was associated with an increase in post-operative pain scores
Administration of nabilone for post-operative pain control in the cannabis addicted: Case study	70	Case Report	n=1	Nabilone optimized post-operative pain control and improved sleep in a habitual cannabis user
A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for post-operative pain management	69	Prospective Cohort	n=64	Dose-related improvements in post-operative with a number needed to treat similar to many routinely used analgesics
Δ9-THC and the opioid receptor agonist piritramide do not act synergistically in post-operative pain	72	Randomized Double-Blind Case–Control (abstract)	n=100	Neither a synergistic nor an additive antinociceptive interaction between THC and the micro-opioid agonist piritramide in a setting of acute post-operative pain
Induction dose of propofol in patients using cannabis	17	Randomized Controlled Trial	n=60, 30 cannabis users, 30 nonusers	Cannabis use increased the propofol dose required for satisfactory induction when inserting a laryngeal mask airway
A randomized, controlled study to investigate the analgesic efficacy of single doses of the cannabinoid receptor-2 agonist GW842166, ibuprofen, or placebo in patients with acute pain following third molar tooth extraction	78	Randomized Controlled Trial	n=123	Cannabinoid receptor-2 agonist GW842166 did not show significant analgesic efficacy in acute post-operative dental pain.
Post-operative analgesia in the Jamaican cannabis user	82	Randomized Controlled Trial	n=73, 42 cannabis users; 31 nonusers	Cannabis users required significantly more opioid rescue analgesia in the immediate post-operative period. Female cannabis users required significantly more analgesia than males
Evaluation of the analgesic efficacy of AZD1940, a novel cannabinoid agonist, on post-operative pain after lower third molar surgical removal	77	Randomized Controlled Trial	n=151; AZD1940 users=61	AZD1940 cannabinoid agonist did not reduce post-operative pain.
Diffuse alveolar hemorrhage induced by sevoflurane	40	Case Report	n=1	Observed alveolar hemorrhage in cannabis user thought to be sevoflurane induced.
Intravenous Δ9-THC to prevent post-operative nausea and vomiting: A randomized controlled trial	89	Randomized Control Trial	n=40	Intravenous THC administered at the end of surgery before emergence from anesthesia was not effective at reducing post-operative nausea and vomiting
The prescription of medical cannabis by a transitional pain service to wean a patient with complex pain from opioid use following liver transplantation: a case report	87	Case Report	n=1	Medical Cannabis achieved a reduction in opioid consumption in a patient with pre-operative chronic pain and acute post-operative pain, who was previously on high dose opioids.
A randomized controlled trial of nabilone for the prevention of acute post-operative nausea and vomiting in elective surgery	88	Randomized Control Trial	n=340	Oral nabilone given as a single dose before surgery is ineffective in reducing post-operative nausea and vomiting
Conscious sedation for transesophageal echocardiography in cannabis users	23	Retrospective Cohort	n=102; 18 cannabis users, 84 nonusers	Cannabis users had higher requirement for midazolam vs. nonusers, but similar fentanyl doses when undergoing conscious sedation
Comprehensive strategies for pre-operative optimization and management of spine surgery patients: a pilot study	16	Prospective Cohort	n=27	Patients with a positive cannabis urine screen test required more propofol for induction
Effects of cannabis extract pre-medication on anesthetic depth	21	Randomized Control Trial	n=27; high dose cannabis=6, low-dose cannabis=8, active placebo=6, placebo=7	Average bispectral index values were significantly higher in the high-dose cannabis treatment group
The effect of pre-operative cannabis use on opioid consumption following surgery: a cohort analysis	83	Retrospective Cohort	n=354; 42 cannabis users, 312 nonusers	Cannabis users required an additional 1.13 mg morphine equivalent per gram of daily cannabis used
Weeding out the problem: the impact of pre-operative cannabinoid use on pain in the perioperative period	84	Retrospective Cohort	n=310; 155 cannabis users and 155 non-cannabis users	Cannabis use was associated with higher pain scores and a poorer quality of sleep in the early post-operative period in patients undergoing major orthopedic surgery
Orthopedic surgery patients who use recreational cannabis have less pre-operative pain	13	Retrospective Cohort	n=937; cannabis users=40	Cannabis use was significantly associated with increased physical activity and decreased pain intensity at operative site
Post-operative shivering among cannabis users at a public hospital in Trinidad, West Indies	90	Retrospective Cohort	n=55; cannabis users=25	Higher incidence and intensity of shivering in cannabis smokers, although result was not statistically significant

Δ⁹-THC, Δ⁹-tetrahydrocannabinol; MAC, minimal alveolar concentration.

The pre-operative period

Pre-operative anxiety and pain were explored separately in two articles. Cannabis is reputed to produce a feeling of calm, relaxation, and euphoria, a seemingly desirable property for its use in the anxious patient. In those naive to it, however, the opposite reaction can be elicited with uncontrolled anxiety, culminating in panic attacks. For those predisposed, aggravation of psychotic states may also occur.¹¹ Evidence of this finding specific to the pre-operative period was documented by Gregg et al. in 1977. Pre-operative administration of intravenous Δ⁹-THC to oral surgery patients resulted in heightened anxiety, dysphoria, and paranoia linked to a distorted sense of perception, delusions of the sensorium, and increased sensory receptiveness.¹²

In 2018, Medina et al. recruited 937 patients scheduled for orthopedic day case surgery in an effort to determine whether recreational cannabis users experienced more pre-operative pain at the operative site.¹³ Forty of the patients were cannabis users. Analysis of patients' self-reports showed significantly lower pre-operative numeric rating pain scores in cannabis users (pain score=3.73 vs. 4.97; p<0.05). Most of the cannabis users were those scheduled for arthroscopic knee arthroplasty/chondroplasty or multiple drilling or microfracture, although several types of procedures were included for analysis. The study also did not report when cannabis use was stopped before surgery. Further findings on cannabis and pain will be discussed later in this review's post-operative section.

The intraoperative period

Central nervous system

CB1 receptors are some of the most abundant that exist in the brain (especially in the neocortex, hippocampus, basal ganglia, cerebellum, and brainstem) and spinal cord. They are concentrated on the presynaptic endings of neurons, and by G-protein coupling, they affect hyperpolarization at nerve terminals, which, in turn, prevents neurotransmitter release. Brain neurotransmitters involved in mediating awareness and arousal such as acetylcholine, dopamine, noradrenaline, and serotonin are some of those inhibited from release by activation of CB1 receptors.^14,15 THC is a potent agonist of the CB1 receptor. It is therefore understandable why some researchers have hypothesized that anesthetic drug requirement may be affected by cannabis use.

Two studies showed a tendency for regular cannabis users to require higher doses of propofol for the induction of anesthesia. While Clavijo et al. were able to detect this as a general trend,¹⁶ Flisberg et al. demonstrated that, although the dose of propofol required for loss of consciousness with a bispectral index (BIS) of 60 or below was approximately the same for both cannabis and non-cannabis users, the average dose needed to allow insertion of a laryngeal mask airway was significantly higher in cannabis users ((314.0±109.3 vs. 263.2±69.5 mg, p<0.04).¹⁷

For maintenance of anesthesia, the effect of cannabis use on BIS and requirement for volatile agent have also been investigated. While earlier animal studies in rats and dogs suggested decreased fraction of minimal alveolar concentration (MAC) requirement when cannabis was administered in the acute setting,^18,19 human studies have demonstrated the opposite.

In 2002, Symons reported a case of a particularly “stormy” intraoperative course with a cannabis-using patient, who needed larger than usual amounts of volatile and intravenous agents to remain well anaesthetized.²⁰ Endorsing Symons' observations was a 2018, double-blinded, case–control Israeli study conducted by Ibera et al.²¹ Of 40 cannabis- naive patients undergoing elective or nonemergent orthopedic surgery, 27 were pre-medicated with nabiximols. All participants were given general anesthesia by anesthetists who used their own clinical judgment to keep the patient well anesthetized. The BIS was monitored for all patients and was found to be always significantly higher for a given fraction of MAC in the group given nabiximols. Anesthetists also generally used a higher fraction of MAC for the treatment group. Although this preliminary study suggested that, for humans, anesthetic requirements are higher in cannabis users, the researchers did acknowledge that BIS, being a byproduct of electroencephalogram analysis, could, in this case, be representative of cortical activity, and was possibly not a measure of anesthetic depth itself. This was compared to similar paradoxical patterns that are known to be characteristic on administration of ketamine. We must bear in mind, however, that the effects of nabiximols, being a regulated drug, could be quite different from cannabis or cannabis-derived products that are now available in the medical and recreational markets.

Other animal studies in the past have also suggested additive effects and/or cross-tolerance of cannabis with barbiturates, opioids, benzodiazepines, and phenothiazines.²² Thakkar et al. noted an increased need for midazolam in cannabis users undergoing conscious sedation, but admitted that this finding was limited by the small sample size (n=102; 18 cannabis users and 84 nonusers).²³ More human studies that properly define the effect of cannabis use on central nervous system depressants are needed. Studies on opioids and their cross-tolerance with cannabis are already ongoing and will be discussed later in this article.

Cardiovascular system

The endocannabinoid system acts, in part, as a neuromodulator of the cardiovascular system. The effects of exogenous cannabinoids on the heart vary depending on the dose. For lower doses, a biphasic response is observed. Tachycardia (heart rate increase of 20–100%) for up to several hours as well as an increase in systolic and diastolic blood pressure and cardiac work characterize the first phase. This is thought to be mediated by beta-adrenergic receptor stimulation and vagal suppression. After this initial phase has ended, a second phase featuring bradycardia and hypotension ensues.^24–27 At high cannabis doses, bradycardia and postural hypotension are observed (although reflex bradycardia during the exhalation phase of the Valsalva maneuver is inhibited).^24,28

In small observational experiments by Mathew et al. on the effect of postural hypotension, cerebral artery flow velocity was found to be significantly compromised in volunteers experiencing dizziness during cannabis intoxication. This potentially raises concerns for patients who are vulnerable to cerebral ischemic disease.^29,30 Stroke, as related to cannabis use, is not very common. However, case reports have suggested a temporal relationship between cannabis use and cerebrovascular accidents. Similar mechanisms as described for myocardial infarct are proposed as reasons for this correlation.³¹

Electrophysiologic changes may also be observed with acute cannabis use. Sinoatrial and atrioventricular conduction velocities increase, while the refractory period decreases. Arrhythmias such as atrial fibrillation and ventricular and supraventricular tachycardia may be elucidated. Although there have been some case reports of sudden death due to myocardial infarction in young adult cannabis users,^32–34 increase in cardiac work is usually well tolerated in this age group. A history of coronary artery disease (typically in older patients), however, has been shown to make subjects susceptible to elucidation of symptoms of ischemia in the setting of acute cannabis use.

In a group of 10 habitual tobacco smokers, Aronow and Cassidy demonstrated that those who smoked a cannabis cigarette (19.8 mg Δ⁹-THC) before ergonometric testing were able to exercise on a bicycle for half the time (129.4 min) as those who smoked a regular tobacco cigarette (244.3 min). Increased myocardial oxygen demand and decreased oxygen delivery due to the presence of carboxyhemoglobin were more marked after cannabis than after tobacco use.³⁵ Supporting this finding is the observation of Mittleman et al. in 2001 after retrospective analysis of 3882 cases of acute myocardial infarction. Cannabis smoking was associated with a four to eight times increased risk of heart attack in the first 60 min after its use.³⁶ Coronary spasm, angiopathy, increased propensity for plaque rupture, and a prothrombotic effect have also been proposed mechanisms of cannabis-induced myocardial infarction.³¹

Considering these observations, it is has been suggested that caution is used when administering anesthetic agents that may compound myocardial depression such as volatiles. Avoidance of drugs that worsen tachycardia such as ketamine, atropine, pancuronium, and epinephrine was also encouraged by Hernandez et al.³⁷ Use of drugs such as clonidine, beta-blockers, physostigmine, and diazepam in those prone to orthostatic hypotension has also been discouraged by others.^22,28 As a practical measure, waiting, if reasonable, for the acute effects of cannabis (in nonchronic users) to subside before starting anesthesia and surgery has been suggested.^22,28 These suggestions are of course inference-based opinions of the individual authors. To date, no evidence or expert panel-based guidelines have been published.

Respiratory system

Despite a large body of literature discussing the effects of cannabis on the lungs, only a few case reports were found that suggested high airway reactivity or pulmonary damage in cannabis smokers in the perioperative period. A case of uvular edema attributed to cannabis smoking was documented by Mallat et al. in 1996. The edema was so severe post-operatively (10–12 cm long uvula) that the 17-year-old patient experienced airway obstruction as a result. Mallat also recorded effective treatment of the edema with 10 mg dexamethasone, which was chosen based on the precedent of its successful use in treating traumatic uvulitis and other forms of airway swelling.³⁸

In 2002, White recorded a case of laryngospasm on extubation of a patient who smoked cannabis before his operation. This patient was reintubated and topical lidocaine sprayed onto the vocal cords before he was safely extubated.³⁹ Kim et al. documented diffuse alveolar hemorrhage occurring in one patient, possibly due to sevoflurane.⁴⁰ The cause of hemorrhage in Kim's case report was disputed, however, by Murray et al. who postulated that antecedent injury to the epithelium and alveoli, and the anticoagulant effects of cannabis used by this patient, together with the mechanical assault associated with negative pressure pulmonary edema were the cause of inadvertent bleeding.⁴¹

From a broader perspective, two recent systematic reviews by Ribeiro and Tashkin provide helpful summaries of literature findings on the changes that have been found in the respiratory system due to the smoking of cannabis.^42,43 Overall, from these studies, cannabis smoking was found to be positively correlated to respiratory symptoms associated with chronic bronchitis, namely cough, sputum production, and wheeze (odds ratio=2.98).⁴³ Histologic examination justified this by confirming replacement of ciliated columnar epithelial cells with mucus-producing goblet cells, while bronchoscopy showed airway surface inflammation and increased secretions, similar to that seen in tobacco smokers. While most studies on cannabis smoking corrected for concurrent tobacco and cannabis use, Tan et al. and Macleod et al. noted that smoking both substances rather than one increased the risk of respiratory symptoms and chronic obstructive pulmonary disease.^44,45 Tashkin et al., however, found no increase in respiratory symptoms in subjects using both substances.

Evident assault to the lungs begs the question as to whether the cannabis smoker's airway is more reactive than normal. On this matter, only three studies were cited as having conducted experiments by either histamine or methacholine provocation.^46–48 Outcome measures were “histamine dose causing a 50% increase in specific airway resistance” and “methacholine dose causing a 20% reduction in forced expiratory volume in one second (FEV1).” None of the three studies showed a difference between cannabis smokers and nonsmokers. Tashkin et al. did, however, find increased airway reactivity in smokers of both tobacco and cannabis.

With respect to other spirometry measures, FEV1/forced vital capacity (FVC) ratios have been studied by various groups with different study designs. While there exist a variety of contradicting outcomes, the general consensus on the evidence supports no decrease in ratio. In fact, both FEV1 and FVC values appear to be higher in cannabis smokers, possibly due to the topography of cannabis smoking and the bronchodilatory effects of Δ⁹-THC.²⁸ All four studies investigating carbon monoxide transfer factor found no change in cannabis-only smokers as opposed to nonsmokers.^49–52 Airway conductance, however, was shown to be modestly decreased, supposedly as a result of airway edema.^49–52

Evidence for association with bullous lung disease, barotraumas, and pneumothoraces remains only at the level of case series or reports and larger studies are needed before definitive statements on the matter are made.

Having realized the dangers of inhaling combustive smoke, many are now resorting to vaping of cannabis. Vaping significantly decreases the exposure to toxic inhalants produced by smoking, but studies are emerging, which suggest that it may have its own drawbacks. Long-term studies on the health effects of vaping are also not readily available.^53,54

Gastrointestinal system

The gut is well known to be regulated, in part, by CB1 receptors. The effect is likened to “braking” by acetylcholine regulation. Exogenous cannabinoids therefore decrease gastric motility and colonic propulsion. Cannabis cessation/withdrawal has been shown to be associated with a hyperemesis syndrome in some. Whether or not this has an impact on the risk of aspiration in the perioperative period has yet to be studied.^55,56

Hematological system

The effect of cannabis on hemostasis is a subject of controversy. One study in rats has demonstrated a 1.5 to 2.0 increase in clotting time after administration of Δ⁹-THC and cannabinol extract.⁵⁷ Deusch et al., however, observed increased surface expression of glycoprotein IIb–IIIa and P-selectin in in-vitro studies on platelets exposed to Δ⁹-THC.⁵⁸ A systematic review on available literature conducted by Zakrzeska et al. noted that, while the effects of cannabis on the cannabinoid receptors may lead to an increased risk of thromboembolism (especially in the context of cardiovascular events), the evidence for cannabis having an anticoagulant effect remains relatively convincing.⁵⁹ This may raise concerns for the anesthetist with respect to blood loss, performance of neuraxial anesthesia, and deep blocks and the placement of invasive lines.

Pharmacology

Although no studies were found reporting altered pharmacodynamics or kinetics of common anesthetic drugs in the setting of cannabis use, it has been established that CBD is metabolized by the cytochrome P450 (CYP) pathway by at least seven isozymes. The CYP2C and CYP3A families are the most involved with the most inhibited superfamilies being CYP3A4 and CYP3A5.⁶⁰ The CYP3A4 enzyme is involved in the metabolism of at least 50% of drugs commonly used in medicine, including some benzodiazepines, opioids, and acetaminophen. Inhibition implies that drugs that are substrates of these enzymes could experience delayed metabolism leading to prolonged half-lives.⁶¹ In fact, at least four published case reports have provided preliminary suggestion that international normalized ratio (INR) in warfarin users may be increased by inhibition of CYP isoenzymes by both CBD and THC.⁶²

Manini et al., however, published a study in 2016 demonstrating that concomitant use of CBD and intravenous fentanyl did not alter the pharmacokinetics of fentanyl.⁶³ The sample size for this study was only 17, however, which limits the value of the findings. Some have also mentioned enzyme induction by exogenous cannabinoids; however, robust in vivo human studies are again lacking.⁶⁴

Post-operative period

Pain

There are several published studies on the efficacy of cannabis in the treatment of acute pain.^65–79 At least two systematic reviews were found that evaluated the validity of the use of cannabis in the post-operative period. The first was published in 2001 by Campbell et al. and analyzed nine randomized controlled trials.⁸⁰ The second was published as recently as 2017 by Stevens and Higgins and included seven trials.⁸¹ Both articles distilled their conclusions to a lack of supportive evidence for the use of cannabis for acute pain in the post-operative period.

With respect to habitual cannabis users, some have been observed to use higher doses of opioids post-operatively. Within the Jamaican population, Jefferson et al. observed that regular cannabis users undergoing orthopedic surgery needed on average 31.1 mg more pethidine within the first 6 h post-operatively.⁸² Jamal et al. showed a similar trend in patients receiving surgery for inflammatory bowel disease, who used on average 1.13 mg morphine equivalents more per gram of cannabis used per day.⁸³

Most recently, Liu et al. published the findings of a study that propensity matched 155 cannabis users to nonusers coming for major orthopedic surgery. In the post-operative period, patients on pre-operative cannabinoids had a higher median pain numerical rating score at rest (5.0 vs. 3.0, p=0.010) and with movement (8.0 vs. 7.0, p=0.003), and a higher incidence of moderate-to-severe pain at rest (62.3% vs. 45.5%, p=0.004) and with movement (85.7% vs. 75.2%, p=0.021). Cannabis users in this study also had poorer sleep quality post-operatively.⁸⁴

While further studies are needed to corroborate these findings and confirm causality, the concept of cannabinoid modulation of the endogenous opioid system is familiar to scientists. Several theories that propose receptor—agonist “crosstalk,” including receptor heterodimerization and modification of signal transduction, are being considered and research is still ongoing in this field.⁸⁵

Interestingly, cannabis is currently used in transitional pain medicine clinics as one means of managing chronic or neuropathic post-surgical pain, especially in cases where patients need to decrease opioid consumption, but still maintain a level of pain control.^86,87

Post-operative adverse effects: nausea and vomiting and shivering

Although a recognized treatment for nausea and vomiting in patients receiving chemotherapy, preliminary studies showed that both oral nabilone and intravenous Δ⁹-THC fail to show definitive prevention of postoperative nausea and vomiting.^88,89 In the case of intravenous Δ⁹-THC, its negative side effect profile actually forced discontinuation of the trial. At present, no form of cannabis is used for this form of nausea and vomiting. No studies were found that suggested patients who smoke cannabis experience less nausea and vomiting.

One Trinidadian study (n=55) sought to establish whether cannabis use was linked to post-operative shivering. Despite the incidence being higher in cannabis users, however, statistical analysis was unable to show the difference to be significant.⁹⁰

Cannabis withdrawal syndrome

Although no studies were found on perioperative cannabis withdrawal in the initial literature search, it was considered appropriate to include a brief section on this subject, considering that it may be encountered and should be recognized and addressed in as timely a manner as possible. A separate informal search was done for this section using the PubMed database and the Google Scholar search engine.

According to the Diagnostic and Statistical Manual of Mental Disorders—Fifth Edition, cannabis withdrawal syndrome is part of the criterion used in the diagnosis of cannabis use disorder. Within 1 week of abruptly discontinuing cannabis, patients manifesting any three or more of the following symptoms are regarded as being in withdrawal: irritability, nervousness or anxiety, sleep difficulty, decreased appetite or weight loss, depressed mood, and any physical symptom, namely abdominal pain, shakes/tremors, sweating, fever, chills, or headache.⁹¹ Preliminary studies have shown benefit with the use of gabapentin, dronabinol, and nabiximols for control of these symptoms. Zolpidem and mirtazapine have also been shown to help with sleep difficulty.⁹²

In the case of habitual cannabis users who are having difficulty coping with pain, anxiety, or insomnia post-operatively, cannabis withdrawal syndrome should be considered. In one case study that showed nabilone administration to be effective in the pain management of a chronic cannabis user, the possibility of cannabis withdrawal occurring in the post-operative period was indeed a consideration of the author.⁷⁰ In cases where medical versions of cannabis prove effective, it is possible that cannabis receptors, previously occupied by the usual form of cannabis used by the patient, are re-agonized by the introduction of another form of cannabis.

Discussion

In summary, medical cannabis has not been proven to be of use in the pre-operative period and may in fact prove deleterious. Some surgical candidates who are habitual users of recreational cannabis may cope better with anxiety and pain by maintaining their use before surgery, but the use of medical cannabis in the cannabis naive for pre-operative anxiety is not recommended. The induction and maintenance of anesthesia appear to be more challenging, with cannabis users requiring increased amounts of intravenous and volatile agents to achieve the same depth of anesthesia as those who do not use cannabis. Cardiovascular lability may also be anticipated, with patients having a background of ischemic heart disease being at higher risk than average for an ischemic event.

Although associated with chronic bronchitis, cough, wheeze, and sputum production, smoked cannabis has not been proven to adversely affect lung function, neither does it result in airway hyperreactivity. Cannabis may also slow gastric emptying, but as to how this impacts precautionary measures for the prevention of aspiration remains to be studied, as does cannabis-drug interactions in humans.

Post-operatively, cannabis users appear to have higher pain scores and experience poor sleep, although this could also represent a manifestation of cannabis withdrawal syndrome. Medical cannabis appears to not be effective for the prevention or treatment of post-operative nausea and vomiting nor for the management of acute post-operative pain.

There are significant challenges in creating evidence-based direction at present when the role of cannabis in medicine and society seems to be evolving faster than rigorous scientific studies can be completed. Studies available are heterogenous in their design and sample sizes still relatively limited. The stigma surrounding cannabis use also impacts the reliability of data. In districts where cannabis use is illegal, for example, the validity of self-reported use or lack thereof can reasonably be questioned. Local custom or individual demographics may also dictate the method of cannabis intake and not all studies standardize for this factor that actually heavily influences pharmacodynamics.

Cannabis use is also at times treated as a binary entity, being either positive or negative, without documentation of the quantity and frequency of use. In some cases, even if patients do make an effort to quantify, the terms used such as “joint,” “roll,” or “spliff,” are nonspecific and highly variable in their interpretation. Similarly, the concentration of Δ⁹-THC and other cannabinoids varies greatly and is not always quantifiable. In the case of smoking, variables such as breath volume and length of breath hold are likely inconsistent among smokers and introduce even more uncertainty. Many cannabis users also use other recreational substances and to truly refine findings to be representative of the effect of cannabis, it is necessary to correct for these factors, if they are reported at all.

That being said, the authors of this article still feel that the information available at this point represents a sturdy foundation and is likely sufficient to give the anesthetist a general overview of the differences to anticipate in the cannabis user so that sound anesthetic plans can be made and specific challenges may be anticipated. In view of this, emphasis should be placed on getting as accurate a substance use history from patients as possible to adequately create an anesthetic plan.^20,22,93

Conclusion

The field of cannabis research in human health continues to evolve and Canadian health care providers are well positioned to lead this task granted the new legal framework. The current paucity of literature on the direct effects of cannabis on anesthesia and anesthetic concerns is a matter that must be addressed. Fortunately, several are rising to this research challenge as cannabis use becomes more accepted and prevalent in the local patient population. As bodies of evidence grow more definitive, conclusions and direction are anticipated to further refine anesthetic practice.

Abbreviations Used

Δ⁹-THC

Δ⁹-tetrahydrocannabinol

BIS

bispectral index

CBD

cannabidiol

CYP

cytochrome P450

FEV1

forced expiratory volume in one second

FVC

forced vital capacity

MAC

minimal alveolar concentration

THC

tetrahydrocannabinol

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work was funded by a grant received through the Health System Research Fund by the Ministry of Health and Long-Term Care. Drs. Ladha, Wijeysundera, and Clarke are supported, in part, by Merit Awards from the Department of Anaesthesia at the University of Toronto and the Health Services Research Fund from the Ministry of Health and Long-Term Care of Ontario. Dr. Wijeysundera is supported in part by a New Investigator Award from the Canadian Institutes of Health Research and the Endowed Chair in Translational Anesthesiology Research at St. Michael's Hospital and University of Toronto.

Supplementary Material

Supplementary Table S1

Cite this article as: Ladha KS, Manoo V, Virji A-F, Hanlon JG, Mclaren-Blades A, Goel A, Wijeysundera DN, Kotra LP, Ibarra C, Englesakis M, Clarke H (2019) The impact of perioperative cannabis use: a narrative scoping review, Cannabis and Cannabinoid Research 4:4, 219–230, DOI: 10.1089/can.2019.0054.