Abstract
Even prior to the COVID-19 pandemic, rates of ambulatory surgeries and ambulatory patients presenting with substance use disorder were increasing, and the end of lockdown has further catalyzed the increasing rates of ambulatory patients presenting for surgery with substance use disorder (SUD). Certain subspecialty groups of ambulatory procedures have already established protocols to optimize early recovery after surgery (ERAS), and these groups have subsequently enjoyed improved efficiency and reduced adverse outcomes as a result. In this present investigation, we review the literature as it relates to substance use disorder patients, with a particular focus on pharmacokinetic and pharmacodynamic profiles, and their resulting impact on the acute- or chronic user ambulatory patient. The systematic literature review findings are organized and summarized. We conclude by identifying areas of opportunity for further study, specifically with the aim of developing a dedicated ERAS protocol for substance use disorder patients in the ambulatory surgery setting.
Key Summary Points
- Healthcare in the USA has seen an increase in rates of both substance use disorder patients and separately in ambulatory surgery cases.
- Specific perioperative protocols to optimize outcomes for patients who suffer from substance use disorder have been described in recent years.
- Agents of interest like opioids, cannabis, and amphetamines are the top three most abused substances in North America.
- A protocol and recommend further work should be done to integrate with concrete clinical data, in which strategies should be employed to confer benefits to patient outcomes and hospital quality metrics like those enjoyed by ERAS protocol in other settings.
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Introduction
Substance abuse in the USA threatens nearly 10% lifetime prevalence rate, and the rate is worsening considerably in this past decade. In 2017, the US Department of Health and Human Services specifically declared that the opioid abuse epidemic was a public health emergency [1]. The numbers have continued to dramatically worsen; the 2020 survey of the National Survey on Drug Use and Health marked the first time using the newer criteria of diagnosing substance use disorders (SUD) by the DSM-5 as opposed to its DSM-4 predecessor. Under these new criteria, the year 2020 saw 14.5% prevalence rate of Americans suffering from SUD [2].
Reviews have already identified the COVID-19 pandemic as the ideal catalyst for this substance abuse epidemic [3], yet there are no signs that this trend is subsiding in congruence with “post-covid” society. Furthermore, the COVID-19 pandemic placed a unique pressure on ambulatory surgery centers to receive higher acuity cases, especially in the immediate post-lockdown era. The United Nations Office on Drugs and Crime annual Drug Use Report cites in 2021 that North America continues to represent the highest rates of use for the most popular drugs of abuse (cannabis, opioids, and amphetamines) compared to other regions of the world [4]. This establishes precedent for a new level of acuity and a new level of care that can be expected in the ambulatory setting [5]. The most recent US Ambulatory Surgery Center Market Report valuated the market at USD 34.8 billion in 2021 and projected an annual growth rate of 6% for the remainder of the decade to 2030 [6]. The rising share of ambulatory surgery in the market in the post-COVID era is enough to warrant timely investigation of subpopulations of patients receiving care in this sector.
Providers should expect that this increasing prevalence of substance use disorder will impact their practice, and in the case of surgical patients undergoing anesthesia, it is reasonable to conclude that anesthesiologists will need to adapt their practices to accommodate this swiftly growing subset of the population as they enter under their care. A challenge of pain control in the ambulatory setting in recent years has already been identified [7, 8], and suggestions for opioid optimization and multimodal analgesia have already been posited [9]. The management of chronic pain patients in ambulatory surgery centers has already received increased attention [10], and so it stands to reason that increased attention should also be paid to SUD patients, as these patient populations commonly overlap. Here, we review current practices and then propose specific perioperative protocols to optimize outcomes for patients who suffer from substance use disorder.
Review of ERAS Protocol
Implementation of perioperative protocols for the purpose of optimizing patient recovery is hardly a novel concept. Namely, ERAS (early recovery after surgery) protocols aim to provide a framework for just that reducing postoperative and hospital recovery time with the primary goal of improving patient outcomes. An additional, self-serving aspect of ERAS protocols is that they help to streamline complex surgical procedures, thus optimally migrating them from an inpatient to outpatient surgery setting [11]. ERAS protocols are not usually applicable to any certain patient population in principle; rather, they represent an overall approach to the perioperative patient to optimize convalescence, but they leave the nuanced details of patient care to the discretion of the specific physicians to utilize as appropriate to each case. For this reason, ambulatory procedures are likely the most reliant on ERAS protocols to ensure expedient discharge to home.
For example, recovery after colorectal surgery has enjoyed the implementation of ERAS protocol. They aim for early oral intake and postoperative mobilization and encourage several interventions such as the avoidance of mechanical bowel preparation and modified preoperative oral intake with attention to the nature of current laparoscopic surgical techniques. They also include nutrition counseling for the patient and provider team and implement the start of patient carbohydrate loading 2 h preoperatively. These are all implemented with the recognition that early return of bowel function and mobility, along with adequate post-surgical pain control in the colorectal patient, leads to a decrease in postoperative morbidity and decreases the postoperative length of stay [12].
Many other examples of successful ERAS protocols exist as designed by certain hospital systems and for their unique subset of surgical patients. Patients undergoing gynecologic surgery—a patient population which is often sourced from the ambulatory setting—already enjoy the benefits of ERAS protocol [13]. Recently, gynecological patients under ERAS protocol demonstrated lower intra- and postoperative opioid use, and this correlated to less postoperative staff burden on follow-up visits and calls [14]. It is evident that postoperative pain management is an integral part of all ERAS protocols, specifically highlighting the value of multimodal analgesic therapy [15]. Still, there is a paucity of examples of ERAS protocols in practice as they relate to SUD patients, or which are engineered to consider the growing US population of substance users who present for surgery.
In particular, the volume of ambulatory (same day) surgeries performed in the USA has grown consistently over the past quarter century. This can be attributed to improved technology allowing less invasive surgical procedures as well as improvements in perioperative care. With this rise in ambulatory cases, it is critical that the migration of procedures from an inpatient to outpatient setting does not compromise the quality of care and patient safety.
Patient safety following ambulatory surgery is maintained via strict discharge criteria from the post-anesthesia care unit (PACU). This requires assessment of the patient’s mental status, respiratory and cardiovascular function, pain control, level of nausea and vomiting, fluid balance, temperature conservation, and wound sites—in other words, ERAS protocols. When these criteria are not met, the length of PACU stay increases, or else results in an unanticipated hospital admission. This confers an increased cost to the patient to the hospital from the resulting complication.
There are several conditions that are associated with high unplanned admission rates; these include chronic pulmonary disease, congestive heart failure, diabetes mellitus, renal failure, liver disease, peripheral vascular disease, deficiency anemia, depression, and substance abuse. In one study of 6189 patients diagnosed with substance use disorder who underwent non-cardiac ambulatory surgery, 9.7% had an unanticipated hospital readmission within 30 days [16].
Earlier studies on PACU length of stay suggested that postoperative pain and postoperative nausea and vomiting are the two most critical factors for prolonged stay after ambulatory surgery [17]. Among a study of 16,411 surgical patients undergoing ambulatory surgery, the type of surgery, type of anesthesia, and specific adverse events such as excessive pain, postoperative nausea and vomiting, dizziness, drowsiness, and cardiovascular events prolonged stay. Patients receiving general anesthesia had a 50-min longer stay than those receiving monitored anesthesia care. Patients undergoing strabismus, transurethral, or otorhinolaryngological/dental procedures had the longest postoperative stay. A more recent study of 3152 patients showed increased PACU length of stay for intraoperative blood loss, increased volume of infused colloids, female gender, advanced age, longer duration of surgery, intubation, spinal anesthesia, high pain score, and nausea and vomiting [18].
ERAS protocol in the ambulatory setting also aims to reduce unexpected postoperative hospital admissions. In one recent report, the overall incidence of unexpected admissions in a study population of over 200,000 ambulatory surgery candidates was 0.11% [19]. Certain predictive factors were identified which included male gender, ASA physical status of II or III, a prolonged duration of surgery, procedures finishing after 3 pm, postoperative bleeding, excessive pain, nausea and vomiting, and excessive dizziness or drowsiness. Subsets of patients on the ENT, urology, and chronic pain services demonstrated the highest rates of unanticipated admissions.
Substance Abuse
Substance abuse disorders (SUD) present unique challenges in the perioperative planning of ambulatory surgery. Substance abuse is associated with refractory pain, decreased functional status, increased length of stay, increased readmission rates, and increased economic costs. Enhanced recovery after surgery (ERAS) protocols for the general population have been shown to significantly reduce postoperative complications and risk of readmission. At the current moment, there is no ERAS protocol specifically targeting substance abuse disorders. The goal of this review article is to establish recommendations and create an ERAS protocol for these patients. We will focus on specific drugs and the perioperative management required to increase the quality of care of these patients. Substance abuse is seen with prescription drug misuse (PDM) and non-prescription substances [20]. Prescription drug prevalence rates arise from the most misused medication classes: opioids, sedatives, tranquilizers, and stimulants [21].
ERAS protocols for control of pain in patients with history substance abuse are truly a challenge. There has been more research in opioid abuse compared to other commonly abused substances. It has been seen in ERAS that early multimodal therapy for analgesia provides significant benefits over the use of opioids alone for post-surgical pain. Hydrocodone and oxycodone are two of the most common prescription opioids that are associated with abuse, diversion, and overdose in the US [22].
Ideal multimodal analgesic regimens for patients with history of substance use disorder are still being determined. Due to the several classes of substances abused and the paucity of research in pre-existing non-opioid SUD patients, there has been difficulty in designing an effective multimodal analgesic therapy in this population.
Substance use disorder leads to chronic diseases of the brain [23]. It has been shown that these patients need specialized treatment modalities such as cognitive behavioral therapy and may additionally require pharmaceutical synergistic treatment with agents such as buprenorphine, methadone, and naltrexone in cases of opioid use disorder [24].
Several non-opioid analgesics have been used in multimodal analgesia in ERAS protocols and have shown to decrease PONV as well as decrease pain in patients undergoing surgery. These non-opioid adjuvants include gabapentin, lidocaine, pregabalin, ketamine, and acetaminophen as well as regional anesthesia. For patients with substance abuse, the ERAS protocols must be modified with considerations according to the types of substances abused to provide safe anesthesia and pain control in ambulatory surgery patients.
Opioids in the Perioperative Setting
Morphine and Other Strong Opioids
Up to 60% of opioids misused in the USA are deviations from original prescriptions written by legitimate medical prescribers, whereas the additional sources are from close relations or illicit drug dealers [25]. When substance users first utilize the opiate, it triggers mesolimbic activation of opioid receptors in the brain and is the primary mechanism by which a substance user’s reward system is reinforced. Acutely, activated dopaminergic pathways induce a sense of analgesia and euphoria originating in the ventral tegmental area of the midbrain, eventually communicating to the nucleus accumbens to release dopamine to generate pleasure. This process is akin to the reward process that humans experience when engaging in basic life-preserving functions like eating or sex. Ancillary pathways such as the endogenous opioidergic and GABA-ergic systems also play roles in these motivating pathways, many through interactions by mu-opioid and GABA-ergic interneurons [26]. Eventual inactivation of the opioid moiety either by the liver or kidney eventually leads to elimination of the metabolites by the kidney or, in some combination by feces, in a relatively direct manner.
For patients on chronic opioid therapy, tolerability of the drug class is usually dictated by the gastrointestinal side effects. These include effects such as nausea, vomiting, and constipation. Opioid-induced constipation is the most experienced and is the most impactful on daily quality of life and can be a barrier to discharge for an ambulatory patient as previously discussed [27]. Other side effects such as dizziness, somnolence, and urinary retention have been identified as well as various hormonal disturbances. Respiratory depression is the most feared complication; however, in properly monitored settings, the actual incidence is quite low [28].
For these reasons, morphine and its closely related analogues are highly useful in the perioperative period for managing acute surgical pain. Substances like morphine, fentanyl, and hydromorphone afford significant pain relief and minimized risk of adverse effects when given in a properly monitored setting, even when dose adjusting for CKD and ESRD patients [28]. In fact, when considering CKD patients for ambulatory surgery, the use of opioids should not be a deterrent to surgical candidacy, as literature shows that these patients with chronic pain have higher rates of undertreated pain, either by way of an abundance of caution or by frank unfamiliarity with the agents by non-pain specialists [29]. In the peri-surgical setting, eventual transition to oral morphine derivatives such as oxycodone or long-acting contemporaries allows for expedient disposition of post-surgical patients to home to convalesce in a monitored, outpatient setting.
In contrast to a monitored healthcare setting, the use of opioids in the absence of acute pain only reinforces the pleasure pathway without utilizing the intended purpose of analgesia. This scenario highlights the recreational environment wherein opiate habituation is present. As this reward system is repeatedly triggered, it compounds beyond the simple pleasure drive. As substance users progress into the chronic stage, they develop a physiologic need for additional dosing to achieve the same (remembered) effect, thus developing physiologic opioid tolerance. Insidiously, this physiologic dependence also bolsters a negative reinforcement schema should the user abstain, since the resulting withdrawal symptoms are highly unpleasant to experience thereby rendering the user with opioid dependence. Finally, higher-order and executive functioning of the prefrontal cortex—which normally exercises inhibitory capacity over the mesolimbic system—suffers from decreased mu receptor sensitivity, thus modulating the glutamate and GABA pathways, thus reducing the user’s ability to inhibit compulsory urges [30]. Eventually, the phenotypical expression of compulsive, drug-seeking behaviors resulting from this pathophysiology is the hallmark of chronic opioid addiction [31]. While this overall pathogenesis is well-studied and demonstrated across all persons and the pharmacokinetic and pharmacodynamic profiles of agents remain unchanged, it is important to note that variations do exist within the population, thus offering one likely explanation as to why certain patients are more susceptible to developing opioid use disorder compared to other genotypic or environmental variants.
One pharmacokinetic (PK) factor of particular importance is the rate of administration of the drug, which has implications for the substance users and their chosen source. In short, faster administration achieves higher plasma levels and thus greater drug effect, greater opioid agonism, and thus a more robust drug reward [32]. In principle, this confers a reduction in risk of abuse potential when extended-release formulations are used [33]. Additionally, absorption rate is a PK parameter that is potentially extorted by substance users, namely, by manipulation of the agent. For example, crushing a morphine (or ER) morphine tablet and ingesting it have been shown to manipulate time to maximum plasma concentration and thus correlate to the peak effect and euphoric reward of the drug [34]. This explains the wide variety of prescription and illicit opioid substances that are available to users depending on the desired effects, although the overall pharmacological principles remain the same. In sum, the overall impact of chronic opioid use on the ambulatory patient is increased opioid need compared to their naïve counterpart, more intense noxious sensation of untreated pain, and a dose-dependent reliance on a steady supply of equipotent oral morphine equivalents (OMEs) to stave off withdrawal symptoms.
Methadone
Additional pharmacological and physiologic parameters are considered when reviewing certain synthetic opioid agents. For example, methadone confers the benefit of being a full-opioid agent with rapid effect, yet the maximum effect can take up to 5 days [35]. It demonstrates a high degree of tissue redistribution due to its lipophilic nature, and so it affords a long duration of action by releasing slowly back into plasma circulation. This has been demonstrated as wide variability in terms of drug half-life up to 65 h. Further, analgesia begins within 30 min of ingestion, and duration can last up to 6 h [36]. It exerts additional antagonistic action on NMDA receptors and inhibition of serotonin reuptake at the synaptic junction [37]. It can be taken via a daily regimen and is therefore favored for controlled opioid dependence weaning programs, as its profile tends to subvert the undesired withdrawal effects.
When a patient presents to preoperative clinic on methadone, they are usually a chronic methadone patient for the purposes of opioid weaning therapy protocol. Treatment regimens for patients are highly individualized, and therefore, titration for discontinuation can vary based on providers. A general guideline is a gradual 10–25% reduction of dosage stepwise every 2 to 3 days (or longer if the case warrants, as no difference in withdrawal symptoms was found in one study between a 5- and 10-day weaning protocol [38]), with the goal of reaching a daily dose of 10–15 mg. This patient can be considered optimized pre-surgically for postoperative pain, and further weaning to discontinuation can be considered if appropriate. At any point, withdrawal symptoms during taper can be easily treated with an immediate-release methadone dose to help reduce taper intensity. In cases of surgical emergency, methadone may be reversed as other full-opioid agonists with naloxone. It is important to note that redosing may be necessary and patients should be monitored closely for re-narcotization, warranting an additional dose, as naloxone has a half-life of 30 min, much shorter than that of methadone [39].
Buprenorphine
As a partial agonist of the mu-opioid receptor, the benefit of buprenorphine is that it suppresses both withdrawal symptoms and physiological craving responses. Its peculiar drug profile is what lends itself to be categorized as an “atypical” opiate. It is also a drug that is often encountered within the patient population as a chronic phenotype rather than an acute, abuse-potential drug. This property of partial agonism induces a ceiling effect for any unwanted mu-opioid receptor-mediated side effects [40]. Despite the partial agonism at the mu-receptor, its binding profile to the receptor itself is of higher affinity than most full-opioid antagonists. This allows the buprenorphine molecule to bind tightly to the receptor and prevent or displace the binding of the full-opioid antagonists [41].
This is a property that is exploited for the purposes of blunting euphoric effect or otherwise physiologic reward response if/should a full-opioid dose be taken. However, this high affinity property also allows buprenorphine to precipitate withdrawal in individuals if they are physiologically dependent; thus, these withdrawal symptoms are often coaxed to surface prior to administration of buprenorphine, as the emergence of withdrawal symptoms correlates to a time of greater receptor availability. The molecule exhibits great potency, slow dissociation from its target receptor, and a relatively long half-life. Sublingual, oral, and even implantable administration routes exist, although the adverse effect profile of above 50% leaves much to be desired [42, 43].
Related to these complexities, patients on chronic buprenorphine therapy have been the subject of many recent studies as they pertain to perioperative pain control. In 2019, a comprehensive clinical practice advisory for perioperative management of these patients was published, clarifying recommendations and guidelines throughout the perioperative period. Advisements were developed from a committee meta-review on this patient population; however, the systematic review revealed little in the way of randomized controlled trials or higher levels of evidence. As such, these recommendations mainly represent GRADE level 4 or level 5 evidence [44], meaning that they represent conclusions drawn from mainly case series, case studies, or observational studies without control groups. Still, the recommendations represent a significant leap in progress for management of these patients.
In short, the advisory board recommended: (1) continuation of buprenorphine therapy in the pre- and perioperative setting; (2) continuation of buprenorphine therapy in the postoperative period with (3) adjunct analgesia almost always appropriate for these patients (including opiate and non-opiate multimodal analgesics); (4) specific confirmation that it is almost always appropriate to supplement postoperative pain control with full mu-opioid receptor agents such as hydromorphone, morphine, or fentanyl; and (5) discharge from hospital with appropriate equianalgesic dose of buprenorphine, or otherwise full mu agonists with appropriate outpatient monitoring [45]. It bears repeating that the level 4 and level 5 evidence strength are further proof that more high-fidelity studies of these patient populations need to be conducted in order to further optimize perioperative pain management.
Non-Opioid Agents in the Perioperative Setting
NSAIDS
NSAIDS decrease PONV as well as postoperative opioid requirement [46]. There is synergy between NSAIDS, acetaminophen, and dexamethasone when given together with regard to decreasing pain postoperatively [47]. Both opioid reduction and decrease of pain are seen when COX-2 selective inhibitors (COXIBs) are given as an analgesic adjuvant. This has been seen in an RCT of laparoscopic cholecystectomy receiving Cox inhibitors [48]. Recent meta-analyses and Cochrane reviews reveal only low-certainty evidence as to their efficacy, namely, that they have shown to reduce postoperative pain, PONV, and postoperative opioid use. Furthermore, in cancer surgery patients, NSAIDs have been shown to improve disease-free and overall survival rates (mainly through perioperative use of ketorolac) [49].
One classically cited contraindication to perioperative NSAID use is the concern for bleeding. Previously, very little data existed on NSAID impact on postoperative bleeding outcomes [50]. A systematic review and meta-analysis conducted and published by the Journal of American College of Surgery reported that out of 151,000 patients, no significant difference was found between NSAID and non-NSAID groups regarding hematoma, take-backs for bleeding, or blood transfusion administration. This indicates that NSAIDs are unlikely to be the definitive cause of postoperative bleeding complications [51].
Acetaminophen
Acetaminophen works in synergy with NSAIDS and decreases opioid consumption. The exact mechanism remains elusive, though current hypotheses indicate a central nervous system inhibition of the prostaglandin signaling pathway [52]. The greatest effect of acetaminophen is observed when given in conjunction with NSAIDs and is scheduled before surgery and every 6 h following as congruent with current ERAS 2020 guidelines [53]. Discussion regarding cost of IV versus oral modalities is ongoing and is relegated to individual healthcare organizations as dictated by resource availability.
Studies consistently show benefit for management of mild to moderate postoperative pain. It is well-tolerated and has a favorable side effect profile with minimal drug-drug interactions [54]. However, the relative ubiquity of acetaminophen in both IV and oral formulations makes its clinical benefit obscured. One recent meta-analysis among cesarean section patients receiving neuraxial anesthesia and IV acetaminophen reported no significant benefit and that the use of long acting neuraxial opioids may render IV acetaminophen obsolete. However, it does note that as neuraxial analgesia weans, the oral formulation becomes more effective [55]. In patients undergoing cardiac surgery, one study reported a benefit of IV acetaminophen administration in the form of reduced incidence of AKI [56]. Generally, ERAS application of acetaminophen is widely applied to cases such as thoracic/lung surgery, open laparotomy, total hip and knee arthroplasties, cesarean sections, and even in liver transplantation [57].
Gabapentinoids
Gabapentinoids have recently seen increased utility in the substance abuse space. A 2020 randomized control trial of alcohol use disorder patients who received gabapentin demonstrated a significant increase in rates of total abstinence and/or reduced drinking when compared to placebo. This effect was more intensely observed among patients who had more significant withdrawal symptoms [58]. This highlights the similarity of mechanism of action with the substance in question: the drug class binds to voltage-sensitive calcium channels at the alpha-2-delta-1 site of the GABA receptor, the same moiety affected in alcoholism [59].
Anti-epileptic drugs gabapentin and pregabalin have been used for the treatment of chronic pain. A randomized control trial has shown a decrease in the use of tramadol after hysterectomy after the use of gabapentin [60]. A similar decrease in the use of opioid medication within the first 24 h after receiving gabapentin has also been demonstrated in multiple surgical subpopulations [61, 62]. Thus, gabapentinoids previously were thought to be a useful tool at the disposal of the ERAS anesthesiologist in attenuating narcotic need during and after procedures [63]. However, a recent meta-analysis of perioperative gabapentin across 281 studies showed no clinically significant difference in acute, subacute, or chronic pain management across the perioperative period. Secondary findings included slightly lower nausea and vomiting incidence, however greater risk of visual disturbance and dizziness seen with gabapentin use [64]. Editorial review of this meta-analysis by Anesthesiology in 2020 posited whether the diminished evidence of benefit and increased evidence of harm warrant a shift in the perioperative paradigm[65]. The authors further point out that the FDA identified that the French Society of Anesthesiology no longer recommends the routine use of gabapentin in the perioperative period [66]. In short, the value of gabapentinoids in the perioperative period is most evident in patients who are chronic pain patients already on a gabapentin regimen; however, the initiation in a naïve patient is likely not beneficial.
NMDA Receptor Antagonists
Ketamine is the prototypical drug of abuse in this category [66]. Its merit as an intraoperative adjunct to analgesia and anesthesia is well-studied. In a meta-analysis by Laskowski et al. in 2011, including 4701 total patients, the use of ketamine was associated with decrease in pain control as seen by VAS scores, decreased opioid requirements postoperatively, and lengthened time to first rescue analgesic. Typical clinical application occurs in the form of an IV bolus for induction and/or a maintenance infusion for the purposes of adjunct anesthesia and analgesia. The typical adverse effect is a risk of post-ketamine emergence agitation akin to emergence delirium [67]. An increase in neuropsychiatric side effects was also noted [68]. This coincides with the added therapeutic benefit of inducing dissociative anesthesia and mood-controlling and mood-reinforcing properties [69]. Such properties have earned ketamine (and its enantiomer esketamine) increased focus in recent years as an emerging psychotherapeutic [70], yet these same properties prime the agent for abuse potential. Since ketamine works as a non-competitive antagonist of the NMDA receptor, it targets the neural effects of endogenous glutamate, a major excitatory neurotransmitter [71]. This induces a reward effect, and along with its metabolite derivative methoxetamine, the agent has been demonstrated to serve as a reinforcing stimulus, which potentiates the risk of self-administration and eventually abuse [72]. Acute ketamine use, in addition to a dissociative anesthetic and amnestic state, mimics a cardiovascular stimulant by inducing symptoms such as tachycardia and hypertension [73], though these symptoms have been observed to be transient and linked to the drug’s plasma half-life of 2–4 h [74].
Chronic users of ketamine present with more characteristic symptoms. Most notable are the schizophreinoid symptoms of dopamine positive and negative findings like visual and auditory hallucinations and detachment, delusion, and amotivation, respectively [75]. Related to its unique mechanism of action in contrast to other psychostimulants and opioids, ketamine is thought to activate central dopamine release, which results in chronic feedback inhibition of dopaminergic release by the nucleus accumbens [76]. This also indicates a potential for negative reinforcing effects synonymous with withdrawal symptoms, essentially encouraging continued use to avoid a slew of uncomfortable withdrawal symptoms [77]. Studies also show that chronic users endorse greater rates of abdominal and urinary symptoms and suggest that ketamine may cause suprapubic pain, dysuria, and hematuria [78]. It has been suggested that the effects are due to the direct metabolism and excretion of ketamine and metabolites (norketamine, methoxetamine), eventually causing renal toxicity [79]. Literature is sparse about chronic ketamine abuse treatment; however, some emerging treatments also suggest acute reversal of dependency which may prove useful in the intraoperative setting. Iatrogenic inhibition of glutamatergic pathways with agents such as lamotrigine has been shown to reduce both the dosage and frequency of daily ketamine needs by chronic users [80]. Most chronic effects of ketamine use are psychogenic in nature, and there is scarcity in modalities to treat or reverse this state. However, ketamine psychotherapy is currently proving to be a promising approach to the treatment of substance abuse disorder when the agent is not ketamine [81], and so the clinical use of ketamine in and of itself may prove to be beneficial for the substance abuse patient, although more research is needed in this area.
Cannabis
According to the National Conference of State legislatures as of 9 November 2022, 37 US states, 3 territories, and the District of Columbia allow medial use of cannabis products. Furthermore, 21 states, 2 territories, and the District of Columbia have legislative measures allowing and regulating for non-medical (recreational) use [82]. Cannabis use at a recreational capacity is expected to see increased rates across the USA as legalization trends continue. Cannabis is an agent that is widely sought after for its well-known neurological and cognitive effects [83]. It has been previously suggested that regular users of cannabis experience acute effects (depending on route of administration). For example, patients who smoke cannabis have been observed to experience airway inflammation and mucosal injury, with increased reactive upper airway symptoms [84]. Independent of route, cannabis consumption triggers tachycardia and has been somewhat implicated in precipitating myocardial events [83, 85]. Endogenous cannabinoid receptor (CB) types 1 and 2 have been observed to be expressed in the liver, fat, muscle, and brain, whereas selectively CB type 2 receptors are found in myocytes, the spleen, and immune cells [83]. Pharmacological modulation of CB-2 receptors has demonstrated a cardioprotective and immunomodulating role [86]. Perioperative effects of self-reported cannabis use were studied in a small group of endoscopy patients (n = 46), and no statistically significant difference was found in anesthetic agent requirements between users and non-users [87].
However, it should be known that the breadth of literature regarding chronic use of cannabis as it relates to anesthesia has not definitively shown significant increased risk of any major adverse perioperative events and at best merely suggests a possible increased risk of sudden cardiac death [85, 87]. While cannabinoid-induced tachycardia from acute use implies arrhythmogenic properties, the suggested mechanism of vasodilation leading to reflex tachycardia makes its primary role in arrhythmogenicity dubious [88]. Furthermore, chronic cannabis use has been associated with low baseline heart rate and near resolution of orthostatic hypotension, along with a blunting of both sympathetic and parasympathetic activity [89]. Further investigations of case reports or case series have implicated cannabis as the cause for more severe cardiovascular sequela, atrial fibrillation, ventricular tachycardia in young patients, and in one case fatal ventricular fibrillation [90,91,92]. The poor power of these reports, along with author speculation of alternative mechanisms, makes the perioperative cardiovascular effects unclear at best [93]. Furthermore, a randomized control study of low-dose oral cannabinoid along with very low-dose ethanol (essentially mimicking the pharmacologic milieu of recreational use) did not show a significant change in physiological response or cognitive function [94]. Clearly, the effects of acute and chronic cannabis use in patients can be complex, but literature fails to demonstrate robust evidence of increased risk of adverse events. This highlights potential for additional areas of investigation, especially as perioperative healthcare can reasonably expect that recreational cannabis use will only become more frequent and more common, especially among the ambulatory population.
Benzodiazepines and Barbiturates
Associated with perioperative delirium, and especially in the elderly patient, benzodiazepines are a relic of perioperative anxiolysis and are generally no longer utilized in the surgical period unless specific indications exist. The American Geriatrics Society recommends minimization of benzodiazepines for older surgical patients to prevent delirium [95]. Interestingly, most general anesthetics and benzodiazepines are known to positively modulate GABA-a receptors to change neuronal activity in the brain, benzodiazepines were further studied and found to exhibit additional membrane binding sites, and thus, the allosteric mechanism of benzodiazepines is implicated in the side effect profile of the drug class [96, 97].
In general, recent studies demonstrate a lack of benefit to benzodiazepine administration, particularly among patients above the age of 50 years and age dependent (however, it is noted that current administration practices already limit benzodiazepine usage with patients 65 and older) [98]. Furthermore, patients who are previously benzodiazepine naïve and were prescribed perioperative benzodiazepines demonstrated a risk of developing persistent benzodiazepine use at an incidence rate of 1 in 5 [99]. Newer literature explores the possible benefit of replacing benzodiazepine anxiolysis in the perioperative setting with that of cannabis [100]. Still, current novelty and controlled substance management makes studies limited, and more data are needed to establish this change.
Like benzodiazepines, barbituates are known to interface with GABA-A receptors and induce several effects including sedation, anxiolysis, and hypnosis. Agents like phenobarbital are clinically popular for its anti-epileptic properties and more specifically for alcohol withdrawal prophylaxis [97, 101]. It is rare for perioperative patients in the ERAS setting to present on a chronic home barbiturate regimen. Still, clinical awareness of GABA modulation effects in conjunction with general anesthetics during surgery should be noted. Appropriate attenuation of MAC, accounting for patient age and adiposity, is an important factor to include when determining an anesthetic plan aimed at minimizing recovery time.
Alpha-2 Agonists
Agents like dexmedetomidine and clonidine have been implicated in various perioperative pharmacological properties such as anti-nociception, anxiolysis, nausea prophylaxis, anti-inflammation, and renal protection. Central pain modulatory pathways involving alpha-2 receptors associated with peripheral c-fiber signal transduction are the main mechanism of supraspinal and spinal anti-nociceptive effects [102]. Further review and meta-analysis identify dexmedetomidine to be a highly selective alpha-2 agonist with broad perioperative effects, including inhibition of endogenous adrenocorticoid release, decreased blood glucose, modulation of interleukin signaling, and improvement of natural killer, B cell, and CD4+ T cell ratios in addition to the previously mentioned benefits [103]. Modulation of neuroinflammation following spinal or brain injury by dexmedetomidine has also been studied [104].
The impact of clonidine and dexmedetomidine on postoperative pain and morphine requirements postoperatively has been studied. Findings included that both dexmedetomidine and clonidine decreased morphine requirements postoperatively as well as decreased PONV. However, one study found that patients who received clonidine had a higher rate of hypotension intraoperatively and postoperatively, while those who used dexmedetomidine were seen to have bradycardia [46].
Additional studies have demonstrated the perioperative use of dexmedetomidine for post-surgical pain. Dexmedetomidine administered at the end of the procedure offered better hemodynamic stability and improved pain response in comparison to ropivacaine. It also demonstrated early discharge from PACU and improved postoperative outcomes when used as part of ERAS protocol [105]. Still, certain subpopulations of surgical patients have not demonstrated significant benefit: a small, randomized study of lateral thoracotomy patients receiving dexmedetomidine infusions did not enjoy decreased analgesic requirements within the perioperative 72 h; however, it did result in decreased intraoperative opioid consumption and improved postoperative sleep quality [106]. In sum, utilization of either a perioperative bolus and/or a continuous infusion of 0.3–1.0 mcg/kg/h (most commonly 0.5 mcg/kg/h) in the meta-analysis by Wang et al. showed the abundance of benefit as described above and indicate the impressive potential for dexmedetomidine in the ERAS space [103].
Inhaled Solvents
Inhaled solvents represent a wide range of surfactants, propellants, and other diverse agents that are commonly found in household aerosolized or propelled products [107]. They are generally categorized into three subgroups by agent type: group I includes volatile solvents, fuels, and anesthetics; group II represents nitrous oxide; and group III includes volatile alkyl nitrates. These agents produce a quick and reliable high with rapid dissipation while boasting minimal negative withdrawal effects [108]. The sought-after CNS excitation and psychoactive effects are thus easily accessible and readily abused on their own, or they can also be utilized as carriers for other target drugs which do not readily vaporize at room temperatures so that they may be inhaled. Inhaled solvents represent some of the most abused substances in the USA within the last decade, specifically among adolescent population, although trends typically decrease somewhat into adulthood [109].
One prototypical example is the toxic difluoroethane which is commonly found in compressed air canisters for electronic cleaning. It is thought to exert its effect by stimulating GABA receptors but also by possible inhibition of NMDA receptors [110]. For this reason, volatile anesthetics most readily resemble the effects of acute alcohol intoxication [111]. The acute effects are thus an initial high or “rush” followed by lightheadedness and transient prefrontal cortex-mediated disinhibition and impulsivity. This effect can last several minutes but can be extended by repeat inhalation. Increasing doses can result in slurred speech, dizziness, visual disturbances, and ataxia. Prolonged and chronic use can stimulate visual hallucinations and time distortion [112]. While these effects are sometimes sought after, chronic users are more likely to report a mixed positive–negative or even noxious experience [113].
The pattern of acute versus chronic users can be organized as such, however with one exceptional morbidity and mortality risk which is present at any use regardless of frequency. The aptly named “sudden sniffing death syndrome” was attributed to as much as 22% of inhalant abuser deaths on their initial use of the substance and is thus the leading cause of death among all inhalant abusers [114]. It is postulated that the hydrocarbons, as well as other inhalants, sensitize the myocardium to epinephrine by stabilizing the cell membrane to depolarization. Since individual myocardial cell responses exist in the way that electrical impulses and sensitization is propagated, the net result is a disorganized electrical conductance circuit that increases the risk of sudden fatal arrhythmias [110]. These arrhythmias can occur even at physiological levels of circulating epinephrine; however, endogenous surges from a threat stimulus notably increase the risk. Most other side effects of inhalant abuse are relegated to chronic users and have general CNS declination symptoms such as loss of brain mass and visual or sensorineural hearing loss. Additional cases of cardiomyopathy, toxic hepatitis, and distal renal tubular acidosis have also been cited [108].
In summary, the acute effects of these agents are transient in nature and would likely have marginal effect on ambulatory substance use patients. However, care should be given to those in whom providers suspect chronic use phenotypes, as their GABA and NMDA receptor activation pathways may be effectively altered like that of a chronic alcohol user.
Neuraxial Anesthesia
Patients with chronic pain and substance abuse require greater analgesic doses. Intrathecal morphine that has been tried in laparoscopic colorectal surgery showed a shorter hospital length of stay for the intrathecal group in an RCT of intrathecal morphine compared to epidural analgesia. There was also early return to mobility and better postoperative pain control in the intrathecal group [115]. This could be an area of research for patients with pre-existing chronic pain and substance abuse for pain control undergoing laparoscopic surgery. However, in an open abdominal surgery gastrectomy RCT in 2014, this was not the case: the intrathecal group demonstrated opposite results suggesting inadequate pain control in the postoperative period for open cases [116].
Thoracic epidural analgesia has been effective in both open and laparoscopic abdominal surgeries, and faster return to bowel function and minimization of narcotic use has been observed [117]. A meta-analysis of postoperative pain control showed excellent efficacy with epidural analgesia compared to parenteral opioids[118]. Faster return of bowel function was again shown in patients with epidural analgesia in a 2016 Cochrane review [119]. However, there have been conflicting reports on patient length of stay with epidural analgesia in open procedures and laparoscopic procedures in patients who received epidurals [120, 121]. Understandably, neuraxial anesthesia remains a useful tool in the ERAS perioperative pathways, provided that the patient is an appropriate surgical candidate for this modality.
Regional Anesthetic Techniques
Thoracolumbar nerves are anesthetized in TAP blocks mostly done with the use of ultrasound between the transverse abdominis muscles and the internal oblique muscles [122]. A decrease in 24-h morphine requirement in patients undergoing laparoscopic surgery was noted in a randomized control trial but demonstrated an increase in PONV [123]. Generally, TAP blocks in abdominal surgery have not been associated with increased risk of PONV [124]. Studies for TAP blocks in the most common ambulatory setting (labor and delivery) remain conflicted. In one study of cesarean section patients in 2020, the combination of intrathecal morphine with TAP block using lysosomal bupivacaine and bupivacaine HCl has afforded opioid-reducing benefit [125]. However, as recently as 2021, an RCT of TAP block with or without intrathecal morphine demonstrated non-inferior post-opioid consumption through 72 h, with the additional benefit of reduced pruritus and more favorable safety profiles when intrathecal morphine is not administered [126]. Investigation of quadratus lumborum blocks in parturients who have received intrathecal morphine demonstrated no additional analgesic benefit [127]. Similar non-inferior or otherwise non-significant benefit was concluded from a RCT of ambulatory total laparoscopic hysterectomy patients receiving TAP blocks [128].
Still, there exist many other regional anesthetic techniques that can decrease postoperative pain and improve patient recovery. These include upper extremity, lower extremity, truncal/abdominal blocks, and lower extremity blocks [129,130,131]. Application to ambulatory orthopedic and/or cosmetic procedures is readily apparent in these circumstances.
Alcohol
According to the 2019 National Survey on Drug Use and Health, 14.5 million people ages 12 and older had alcohol use disorder (AUD) in 2019. The large prevalence has many consequences including emergencies and deaths in the USA as well as the economic burden in the USA totaling $249 billion per year. For the human body, alcohol use, whether acute or chronic, poses many physiological implications that can be challenging for an anesthesiologist to manage in the perioperative setting.
Acute alcohol intoxication is a clinical condition following the ingestion of large amounts of alcohol. Clinical manifestations involve different organs including behavioral, cardiac, gastrointestinal, pulmonary, neurological, and metabolic. Symptoms are usually related to blood alcohol concentration (BAC). As the BAC increases, level of consciousness ranges from altered perception of the environment, to slurred speech, to coma, and death. In the perioperative setting, this will impair the ability to obtain informed consent.
Metabolic alterations of acute alcohol ingestion include hypoglycemia, lactic acidosis, hypokalemia, hypomagnesemia, hypoalbuminemia, hypocalcemia, and hypophosphatemia. Cardiovascular effects include tachycardia, peripheral vasodilation, and volume depletion leading to hypothermia and hypotension. Holiday heart syndrome is a colloquialization of such cardiovascular effects that can be characterized by atrial or ventricular tachyarrhythmias and new onset atrial fibrillation. Acute alcohol intoxication can result in respiratory depression and decreased airway sensitivity increasing the risk of aspiration and pneumonia. The gastrointestinal effects include nausea, vomiting, diarrhea, gastritis, peptic ulcers, and pancreatitis [132]. Since acute intoxication with alcohol closely resembles the mechanism of action for most sedating anesthetics (namely, at the central GABA receptors), anesthetic requirement is relatively decreased.
This contrasts with chronic alcohol users, who will develop tolerance and thus require more anesthetic compared to their sober counterpart. Additional concerns include vitamin B1 and thiamine deficiencies, cardiac arrhythmias, alcohol-induced diastolic cardiomyopathy, liver dysfunction, and sensitivity to fluid shifts. Endorphin release is also diminished in chronic AUD patients, and so analgesic dosing may need adjustment [133].
It is estimated that one in five surgical patients suffer from AUD [134]. Effects of alcohol intoxication are so vast and represent such a high fraction of the patient population in the ambulatory setting regardless of timing of ingestion that certain protocolizations of care by larger organizations have already occurred [135].
Specific anesthetic implications for acutely intoxicated patients in the ambulatory setting are as follows:
-
Delay surgery if not urgent/emergent.
-
BAC value varies and is therefore not a clinically useful value to obtain [136].
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Remain vigilant for cross-tolerance of alcohol with most sedating anesthetics [137].
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Assess for volume status and treat as indicated.
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Preoperative labs including complete blood count, liver function studies, and electrolyte panel may be necessary given nutritional status.
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Perioperative vitamin B1 and thiamine supplementation may be beneficial.
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Consider an electrocardiogram and echocardiography to assess cardiovascular function.
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Maintain normothermia: acutely intoxicated patients are more prone to hypothermia which poses increased infection risk.
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Patients may have increased PONV, and so a transdermal scopolamine patch 30 min prior to incision, with dexamethasone at induction, and ondansetron prior to emergence may be used in concert (adapted from [138]).
Conclusion
Even before the pandemic, the healthcare in the USA saw an increase in rates of both substance use disorder patients and separately in ambulatory surgery cases. The COVID-19 pandemic highlighted the importance of focus in these areas and catalyzed the rates of both populations. Here, a systematic literature review shows that a wealth of pharmacological and clinical precedent exists for the development of ERAS protocol for ambulatory surgery patients who concurrently suffer from substance use disorder. Agents of interest like opioids, cannabis, and amphetamines are the top three most abused substances in North America, and much is known about their pharmacokinetic and dynamic profiles with respect to the perioperative setting. NMDA antagonists and alpha 2 agonists are also well-researched. The utilization of gabapentinoids has fallen in recent years, owing to mounting evidence of lack of benefit. Opportunities remain to further solidify clinical guidelines for atypical opioids, with buprenorphine as a specific example. In summary, the richness of literature on this subject sets a precedent for developing a comprehensive ERAS protocol for substance use disorder patients in the ambulatory setting. Here, we establish a basis for developing such a protocol and recommend further work be done to integrate with concrete clinical data. Finally, implementation of this protocol is expected to confer benefits to patient outcomes and hospital quality metrics like those enjoyed by ERAS protocol in other settings.
Data Availability
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
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Zwolinski, N.M., Patel, K.S., Vadivelu, N. et al. ERAS Protocol Options for Perioperative Pain Management of Substance Use Disorder in the Ambulatory Surgical Setting. Curr Pain Headache Rep 27, 65–79 (2023). https://doi.org/10.1007/s11916-023-01108-3
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DOI: https://doi.org/10.1007/s11916-023-01108-3