Diagnosis of AUD

According to the DSM-V, the diagnosis of AUD requires at least two of the criteria shown in table 1 to occur within a 12-month period. This table defines alcohol use severity levels, including moderate drinking, binge drinking, heavy alcohol use, alcohol dependence and AUD (the DSM-V term for alcohol ‘addiction’).

Patients with AUD compulsively use alcohol regardless of its harmful effects.4 5 They frequently demonstrate cravings and are often unable to cease alcohol use despite failure to complete social, occupational, or financial obligations. Perpetuating this cycle is an increase in alcohol metabolism and clearance rate, progressively raising a patient’s tolerance.13 Like all SUDs, comprehensive AUD treatment involves pharmacological and psychosocial interventions (see online supplemental table 1).

Alcohol pharmacology

The metabolites of alcohol, referred to here as ethanol or ethyl alcohol, have significant effects on most organs in the body.14 The primary mechanism by which ethanol affects the central nervous system (CNS) is the manipulation of ligand-gated ion channels and voltage-dependent calcium channels, resulting in either an enhancing or inhibitory effect on neurotransmitter systems in the CNS, depending on the receptor type.15 Ethanol’s predominant effect is a result of gamma-amino butyric acid (GABA) A potentiation.16 GABA functions as the primary inhibitory neurotransmitter in the CNS and alcohol-induced potentiation of GABA-A receptors has a significant inhibitory effect on neuronal excitability, decreasing the amplitude and frequency of certain impulses in the brain.17 Ethanol’s effect on GABA-A has a similar mechanism to other medications like barbiturates, benzodiazepines and anesthetics.18

Physiological effects of alcohol use: clinical concerns and considerations

AUD has effects on many physiological processes. The significance of these effects should be considered. The effects have been summarized and stratified based on organ system in table 2. Additionally, see online supplemental table 2 for a complete list of considerations.

FDA-approved medication treatments for AUD

There are three FDA-approved medication treatments for AUD: disulfiram, acamprosate and naltrexone. Table 3 offers a summary of these medications.

Disulfiram, an older medication, and aversive agent approved by the FDA for alcohol dependence in 1951, inhibits the action of aldehyde dehydrogenase, an enzyme which functions to reduce the blood levels of acetaldehyde. Acetaldehyde is associated with ‘hangovers’ and can result in facial flushing, nausea and an increase in heart rate. The combination of disulfiram and ethanol can result in the symptoms described above as well as hypotension, vomiting, abdominal discomfort and, in rare cases, cardiovascular collapse. Because of its age and hepatotoxic effects, clinicians prefer acamprosate and naltrexone.

Acamprosate is thought to exert its effect on AUD via modulation of glutamatergic transmission and is FDA approved to maintain abstinence in patients with AUD who are abstinent at the time of treatment initiation.19 It is not known to be affected by most anesthetic drugs and can be continued perioperatively.20 21

Naltrexone, a non-selective opioid antagonist at the mu, kappa and delta receptors, is widely considered to be the current treatment of choice for AUD pharmacotherapy. The dose range for naltrexone is typically 50–150 mg daily. Multiple studies and meta-analyses support its use for pursuing abstinence as well as reducing heavy drinking days and quantity of alcohol consumed at each episode of drinking.22 23 One must be cautious when using naltrexone in the context of comorbid liver disease or concomitant use of opioids; initiation of naltrexone during opioid use may precipitate significant opioid withdrawal symptoms due to residual receptor blockade.4

Chronic pain physicians use LDN, dosed at 1.5–4.5 mg, in the management of chronic pain conditions such as arthritis and fibromyalgia.24 25 LDN, at 1/10th the dose of naltrexone used for treating AUD, has exhibited effects that are not seen in larger doses including analgesic and anti-inflammatory properties. The exact mechanism of LDN remains unclear. However, it is thought to modulate opioid receptors, via transient blockade, resulting in a positive feedback response that increases endogenous opioids and opioid receptors. It also reduces inflammatory mediators via antagonism of toll-like receptor 4 in microglial cells and macrophages found in the peripheral and CNS.24 25

There is interest in using LDN for AUD symptoms, but most studies for AUD evaluate at least a 50-mg dose of naltrexone; thus, data are limited.

Preoperative evaluation

Obtaining the true amount of daily alcohol use at the surgical or anesthesia preoperative visit can potentially lend itself to engaging these patients in AUD services to reduce alcohol consumption and risk of complications. Some data demonstrate that drinking over 60 g daily (>4 standard U.S. drinks) is associated with a two-to-fourfold increase in postoperative complications.10 At least one randomized controlled trial demonstrates that reduction of alcohol consumption at least 4 weeks prior to surgery led to a dramatic reduction in postoperative complications.26 In addition, a remote history of risky drinking did not result in increased postoperative complications when compared with risky drinking in the few weeks leading up to surgery.27 Tapering or discontinuing AUD medication treatments (eg, naltrexone) to facilitate postoperative analgesia may have a much different result in an individual with remote AUD and strong recovery history, as compared with another with a history of multiple relapses and poor psychosocial functioning. If history is unavailable or unclear or if there is concern for polysubstance use, a urine toxicology screening can be beneficial. Breath or serum testing for alcohol levels may be more practical than testing for alcohol metabolites in urine, which requires expensive, time-consuming chromatographic testing.28 At least one device is validated for use in emergency departments for patients with differing levels of consciousness.29

The anesthesiologist taking care of a patient with AUD must be aware of the effects this disease has on the anesthetic plan. In an acutely intoxicated patient, informed consent presents a challenging conundrum as autonomy must be maintained if possible. While decision-making capacity is temporarily altered by acute alcohol use, it (depending on quantity) is not thought to result in a definite absence of capacity. If other contributors (eg, head trauma, polysubstance use) have been ruled out, it might be sufficient to document a capacity assessment. Every effort should be made to provide alternate care plans and discharge instructions. Documentation is important in the event of treatment refusal or patient-directed discharge (PDD). Individuals with SUDs and those in withdrawal have an increased incidence of PDD which is linked to an increased 30-day mortality rate.30 This is critical in the context of an already increased morbidity/mortality risk on hospital discharge for patients with SUD in general.31 One study following semistructured interviews of patients with SUD demonstrated four reasons for PDD: cravings or withdrawal symptoms, uncontrolled acute or chronic pain, stigmatization from staff, and lack of freedom of movement.30 We are unaware of data specific to postoperative PDD; however, early identification and intervention of individuals with SUDs (including treatment of uncontrolled pain and withdrawal symptoms) may prevent PDD and could improve outcomes.

A non-judgmental approach during preoperative discussions may help avoid stigmatizing patients and empower them to be honest and forthcoming about their substance use. Avoid stigmatizing language such as ‘addict’, ‘alcoholic’, and similar phrasing, as this can worsen outcomes.32 Considering the extent of a patient’s SUD journey (often including relapses, degradation of personal and familial relationships, financial hardships, etc) and referring to AUD as a treatable disease can aid in normalizing patients’ care.32

Postoperative pain control

Perioperative management of naltrexone

Naltrexone, a competitive mu-opioid receptor antagonist, is dosed orally from 25 to 150 mg daily or given as a once monthly 380 mg intramuscular suspension under the brand name Vivitrol.41 53 Patients may be resistant to opioids in the presence of naltrexone but may become overly sensitive to opioids as its effect diminishes.40 41 Patients planning to have surgery while taking this medication should consult their prescribing physician to determine the optimal perioperative drug schedule and discuss expectations.41 Based on receptor pharmacology studies, the half-life of naltrexone’s major active metabolite, 6-beta-naltrexol, is approximately 13–14 hours orally; thus, oral naltrexone should be stopped by the prescriber at least 72 hours prior to elective surgery (roughly five half-lives).40 54 For intramuscular depot-naltrexone administration, the concentration declines 14 days after last dose. The last intramuscular dose is recommended no less than 25 days prior to elective surgery.55 Oral naltrexone can be used as a replacement/bridge for the intramuscular formulation until 72 hours prior to surgery.56

While the pharmacology of naltrexone suggests that discontinuing naltrexone may be of immediate perioperative benefit, one must recognize that this cessation can also significantly increase risk of relapse, particularly in patients with higher severity AUD. Relapse risk must be weighed against the clinical risk of significant opioid antagonism resulting in uncontrolled postoperative pain. This clinical decision should be made on a case-by-case basis with the surgeon, the patient/family, and of course the primary SUD practitioner (if available). This will serve to both adjust patient expectations appropriately and establish a clear plan of postoperative care and coordination of follow-up.

While not explicitly addressed in literature, if the choice is made to discontinue naltrexone and if there is significant concern for relapse within 72 hours (for patients on either oral or extended-release naltrexone with temporary oral substitution), one should plan to bridge this gap using either disulfiram or acamprosate and/or maintaining close follow-up with the primary prescriber. The patient should be counseled extensively to avoid reinforcing locations, situations and triggers, and support from family or friends should be enlisted. In addition, 12-step programs and other previously useful behavioral interventions should be used more aggressively. If the concern for relapse is significant, presurgical admission should be considered. If cravings present during hospitalization and naltrexone initiation is unsafe at that time, using the above approaches (gabapentin, topiramate, counseling, etc) postoperatively is encouraged, as is using inpatient SUD consultants.48 51

While all surgeries are unique, in situations where opioid-free anesthesia and analgesia can reliably be accomplished using multimodal methods, the clinician should continue full-dose naltrexone; if a painful surgery is anticipated and opioids will likely be needed for pain control, the clinician should recommend discontinuation at the time intervals noted above. In either case, discussion with the SUD practitioner is of the utmost importance to carefully coordinate dates of stoppage, encouragement of other SUD treatment modalities as already noted, and restarting at appropriate time intervals if the medication is stopped.

There are no data to specifically address reinitiation of naltrexone and each patient especially those deemed high risk should be managed on a case-by-case basis; naltrexone should not be reinitiated until at least 7–10 days after last opioid administration.41 If there is desire to reinitiate naltrexone earlier than this or if there is concern about potentially precipitating withdrawal, one can initiate a naloxone challenge test (administration of 0.2–0.8 mg naloxone intravenous with monitoring for 30–60 min for opioid withdrawal symptoms) to determine likelihood of precipitating withdrawal.57

Patients with a history of naltrexone use that is continued perioperatively (such as for urgent, emergent or trauma cases) may require additional monitoring for respiratory depression and hemodynamic compromise if opioids are used for postoperative pain, given potential for receptor upregulation and increased sensitivity to opioids in the context of continued antagonism.41 58 The duration of this effect has not been effectively studied to this point.40 In all patients receiving naltrexone (but particularly in those receiving the extended-release injectable version), continuous pulse oximetry monitoring is invaluable because some patients who are repeatedly administered high-dose full agonists to overcome receptor blockade and provide postoperative analgesia may suddenly develop respiratory depression59 (see online supplemental figures 2 and 3).

Perioperative management of LDN

The coadministration of LDN and an opioid is unlikely to result in clinically significant withdrawal symptoms; however, it could affect analgesia in the postoperative period or in settings where full mu agonists are needed.60 61 As discussed in the naltrexone section, continuation of LDN is acceptable if opioid-free anesthesia and analgesia are planned. If opioid agonist need is anticipated, discontinuation of LDN for 48 hours is recommended by the LDN Research Trust in order to ensure mu-opioid receptor liberation for treatment with full agonists.62 63 If opioid need is anticipated and LDN has not been discontinued, short-acting full mu agonists should be administered. At such low doses of naltrexone, opioid dosages will easily overcome the antagonistic effect of LDN.64–66

Notably, however, exogenous opioids are thought to alter the analgesic effects of LDN via disruption of the endogenous opioid system; for this reason as well as potential for precipitated withdrawal, it is advised that exogenous opioids be weaned and discontinued prior to initiating or reinitiating LDN for the management of chronic pain conditions.67–69 Specifically, the LDN Research Trust recommends at least 48 hours free from opioid agonists prior to reinitiation of LDN62 (see online supplemental figures 2 and 3).

Discharge considerations

Postoperatively, the clinician should advise the patient with AUD of an increased susceptibility to relapse of both alcohol and other substances of abuse. This is a vulnerable time for patients with AUD and there is significant mortality within the first 30 days after hospital discharge for this patient population.70 While it would certainly be ideal to avoid prescription opioids for discharge, weighing the risk of alcohol relapse due to uncontrolled pain versus use of full opioid agonists for pain control is important. Thus, reviewing the patient’s AUD history with the patient and providing an explanation of treatment options and goals is essential. Consistent messaging from multiple perioperative clinicians will best demonstrate consensus.

If the patient was using acamprosate or disulfiram preoperatively, it is reasonable to continue them postoperatively; the discharging provider should ensure the patient has an adequate supply of their medication. Naltrexone presents a unique challenge because reinitiation of it usually requires a period of abstinence as previously indicated; it is ideal if this can be reinitiated while inpatient. Awaiting this prior to discharge may result in much longer hospital stays.

In patients with a known history of AUD or other SUDs with an outpatient provider managing this disorder, the inpatient clinician should confirm appropriate follow-up and complete a ‘warm hand-off’ to ensure no lapses in care. If the patient has a newly diagnosed AUD, local SUD specialty care resources should be made available and ideally an appointment scheduled by the time the patient leaves the hospital; doing so can reduce morbidity and mortality risks.71

Unfortunately, more than 50% of patients discharged after a hospitalization involving alcohol withdrawal are readmitted an average of 1.8 times for alcohol-related issues within a year of their initial hospitalization, with readmission rates highest among patients who direct their discharge or have comorbid psychiatric disorders.72 Given the significant risk to patients with AUD within 30 days of discharge, one should ensure that patients with AUD are not experiencing withdrawal symptoms at the time of discharge.