Perioperative Naltrexone Management

Naltrexone is a pure, nonselective opioid receptor antagonist that was developed in 1963 for its use in treating opioid use disorder.  It was designed to mimic the same opioid antagonist mechanism exhibited by naloxone, except with longer-lasting effects due to a modified ethylene side chain, thereby conferring its anticraving properties.  In the case of alcohol use disorder, naltrexone’s opioid antagonist properties are harnessed to reduce the rewarding effects of alcohol, which are partially mediated through the opioid system.  Although intramuscular naltrexone is currently approved by the U.S. Food and Drug Administration (Silver Spring, Maryland) and Health Canada (Ottawa, Canada) for alcohol use disorder and opioid use disorder, its oral formulation is approved for alcohol use disorder only.  Furthermore, a fixed-dose combination of naltrexone and bupropion is Food and Drug Administration–approved for obesity.  For patients who are prone to binge drinking, taking naltrexone 1 h before the consumption of alcohol decreases the reward and cravings for alcohol, which helps curb the development of alcohol use disorder. When prescribed for alcohol use disorder or opioid use disorder, oral naltrexone is typically dosed in the range of 50 to 100 mg daily. Different formulations of naltrexone are outlined in table 1.

Naltrexone can be orally administered and has a well-established pharmacokinetic profile. After ingestion, it is rapidly absorbed through the gastrointestinal system and undergoes first-pass metabolism in the liver, primarily to its active metabolite, 6β-naltrexol.  The terminal (elimination) half-life of oral naltrexone ranges from 3.9 to 10.3 h.  For extended-release injectable formulations, naltrexone has a longer half-life of 5 to 10 days (due to reduced first-pass metabolism, less of its effect is attributable to the active metabolite 6β-naltrexol), ensuring a sustained therapeutic effect. Pharmacodynamically, naltrexone functions as a competitive antagonist, binding to opioid receptors in the brain, thereby blocking the reinforcing effects of opioids and endorphins. In alcohol use disorder, it diminishes the pleasurable response to alcohol, helping to curb cravings and reduce the likelihood of relapse.  Low prescribing rates, poor patient adherence and compliance, and low monthly refill rates led to the development of the extended-release formulation, which is injected once monthly.  Additionally, low-dose naltrexone at 1 to 5 mg daily has demonstrated anti-inflammatory effects and shows promise in managing certain chronic pain conditions through modulation of glial cells. 

The relevance of alcohol use disorder cannot be overstated, with a substantial impact on public health and individual well-being. In a 2021 report by the Substance Abuse and Mental Health Services Administration it was revealed that 16.5% of people aged 12 or older in the United States (46.3 million individuals) were affected by alcohol use disorder during the last year, and the burden of this disorder extends worldwide. Naltrexone, through its role in reducing alcohol cravings and reinforcing abstinence, has emerged as an effective treatment option for individuals battling alcohol use disorder. Moreover, emerging expert opinion in the perioperative arena has sought to clarify the importance of maintenance of substance use disorder recovery (i.e., risk of return to use) in the perioperative period alongside the need for optimal acute postsurgical pain management.  Given naltrexone’s unique pharmacologic profile, as well as the contemporary evolution of perioperative management strategies of other opioid partial agonists or antagonists there is a special need to understand the perioperative implications of continuing or discontinuing naltrexone.

This review centers on naltrexone, specifically exploring its relevance and management in the perioperative period. The review was registered with PROSPERO (in 2023 under identifier no. CRD42023417511, available at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023417511, accessed June 5, 2024). We acknowledge that there are myriad applications of naltrexone, such as alcohol use disorder, opioid use disorder, and low-dose use in pain management, which may warrant focused investigations.

To address the perioperative management of naltrexone, we aim to summarize the existing evidence and elucidate its clinical implications. By exploring the pharmacokinetics and pharmacodynamics of naltrexone in the perioperative setting, we aspire to provide valuable insights for clinicians and anesthesiologists, thereby informing best practices and contributing to the development of guidelines in this context. Specifically, we hope to better elucidate the pharmacologic profile of the various formulations of naltrexone and its specific implications on the maintenance of recovery of an substance use disorder during the perioperative period.

A literature search was performed by M.E. involving MEDLINE (1946 to June 14, 2023), MEDLINE In-process/ePubs (June 14, 2023), Embase Classic + Embase (1947 to June 14, 2023), and the American Psychological Association’s PsycINFO (1806 to June, Week 1, 2023), all via the Ovid platform; and the Web of Science Core Collection (1900 to June 15, 2023; Clarivate Analytics) to identify studies in which patients on naltrexone therapy underwent surgery. The search was completed on June 15, 2023. Search terminology included blocks of terms (controlled vocabularies as well as text words) for (naltrexone, generic and trade names) + (perioperative, including preoperative, intraoperative, postoperative, and surgery-related terms). The search strategies were not limited by study type; conference materials were limited to 2021 to present where possible. Searches were limited to human studies, adults, and to the English or French language. Nonjournal materials (books, chapters, preprints, among others) were removed via the search strategies. The retrieved citations were imported to Endnote (Clarivate Analytics). Studies were imported into Covidence and were initially screened by M.W., B.K., and M.I. All relevant studies were considered, including randomized controlled trials, observational studies including case control studies and cohort studies, case series, and case reports. Guidelines and institutional recommendations were extracted for summarization as well. All human participants were above the age of 18 yr old and were on naltrexone therapy before undergoing surgery. All reports involving the perioperative management of patients taking naltrexone in the preoperative period were included. Information about descriptors of management was collected where possible, including (1) the rationale for preoperative naltrexone use, (2) the maintenance dose and preparation of naltrexone, and (3) the rationale for continuation or discontinuation. This scoping review did not aim to pool data. Outcomes are reported in descriptive terms, and pertinent results are summarized below. Specific outcome variables were reported when relevant and available. These included postoperative pain scores, adverse events including acute postoperative pain and/or recurrence of underlying substance use disorder, and perioperative departure from hospital against medical advice. Eligible studies were uploaded into Covidence and were grouped into observational studies, randomized studies, and guidelines/practice recommendations. The data extracted for the various prespecified outcomes were collated, interpreted, and summarized into a narrative format. Standardized forms were used to collect data. This was performed by two persons (B.K. and M.W.) in duplicate, and the data were compared to ensure uniformity. Conflicts were assessed by the supervising expert (A.G.). Figure 1 and the appendix outline the search strategy.

The scoping review yielded 4,833 results on our initial search. After duplicates were removed, 4,145 studies were moved onto the abstract and title screening phase. During the initial screening phase, 4,053 studies were excluded because they were irrelevant. The remaining 92 studies were selected for the full text review, and 75 studies were excluded at this stage (duplicate, n = 1; wrong setting, n = 27; wrong outcomes, n = 5; wrong intervention, n = 17; wrong study design, n = 14; wrong patient population, n = 1; no full text/abstract found, n = 8; inadequate information, n = 2), resulting in 17 studies being included in our final review, as shown in figure 1. The 17 included studies included 3 randomized controlled trials, 1 case report, and 13 guidelines. Table 2 summarizes the randomized and observational studies, whereas table 3 summarizes pre-existing guidelines on this topic.

Two of the randomized controlled trials analyze the effects of postoperative oral naltrexone on intrathecal or epidural morphine-related pruritus after cesarean section. The authors also sought to study naltrexone’s effects on postoperative pain levels. Hersh et al. examined the effect of preoperative naltrexone administration on the effectiveness of oral codeine and ibuprofen. The single included case report included a patient who was taking preoperative naltrexone for opioid use disorder.  Of note, although excluded from our review due to inadequate information, naltrexone for weight loss has been described. Of the four studies in total, only two studies looked at the specific patient subset that matched our primary objective, which was to examine the reported perioperative concerns in patients taking naltrexone for an substance use disorder.  None of the clinical studies explicitly investigated naltrexone for the management of alcohol use disorder.

Three of four studies reported on perioperative oral naltrexone.  Of these three studies, two of the studies reported on “low-dose” naltrexone (less than 12 mg orally daily) whereas Hersh et al  reported a single 50-mg orally administered dose of naltrexone. Only Curatolo and Trinh reported on the perioperative use of extended-release naltrexone.

One randomized controlled trial examined varying doses of postoperative naltrexone (9 mg vs. 6 mg vs. placebo) among 45 women with no known substance use disorder undergoing cesarean section.  Adverse events and pain control were monitored between groups. The authors concluded that naltrexone reduced the rate of effective epidural morphine-related analgesia in a dose-dependent fashion (1 of 15 patients in the 6-mg group vs. 5 of 15 patients in the 9-mg group experienced inadequate analgesia; P < 0.05). In addition, 9 mg naltrexone was noted to be protective with respect to the ventilatory responses to carbon dioxide compared to 6 mg or placebo.

A second randomized controlled trial by the same authors sought to examine varying postoperative oral naltrexone doses (6, 3, and 0 mg) when administered to 35 patients undergoing cesarean section under intrathecal morphine (250 μg).  The authors concluded that naltrexone dose did not have a statistically significant effect on the duration of analgesia but was effective as oral prophylaxis against pruritus and vomiting.

Another randomized controlled trial sought to evaluate the effect of preoperative 50 mg oral naltrexone versus placebo on pain scores after complicated dental extractions. Patients self-administered 60 mg codeine, 400 mg ibuprofen, or placebo for postoperative pain. The authors concluded that pretreatment with naltrexone “reduced the analgesic response to both placebo and codeine” perhaps through blockade of both endogenous and exogenous opioids. No other adverse events were reported.

Curatolo and Trinh described in their case report the pain management of a 22-yr-old female maintained on extended-release naltrexone for opioid use disorder undergoing a total thyroidectomy and unilateral neck dissection. Her extended-release naltrexone was held 24 days preoperatively, and her postoperative pain was well controlled with intra- and postoperative analgesia. She required no additional pain medications upon discharge and was abstinent from opioids for 3 months before resuming extended-release naltrexone and has since continued naltrexone for maintenance therapy with no relapse or cravings. Although other authors have published case reports of other naltrexone formulations (i.e., Contrave and extended-release naltrexone) and their management in the perioperative period, the authors of this review excluded these articles due to inadequate information. 

Of the 13 guidelines summarized in table 3, 7 report specific indications for the perioperative management of oral naltrexone. Eight guidelines report specific indications for perioperative patients on extended-release naltrexone and 3 guidelines have nonspecific indications with respect to formulations or timelines for perioperative management.  Seven guidelines report opioid use disorder as the primary indication for naltrexone, 1 guideline reports general substance use disorder, and 5 guidelines have no indications listed. There is no set of published guidelines specific to the perioperative management of alcohol use disorder.

Of the guidelines that discuss the perioperative management of naltrexone, nine guidelines recommend the discontinuation of oral naltrexone 48 to 72 h preoperatively. The authors claim that the relatively short half-life of oral naltrexone (3.910.3 h) allows for its complete washout after 48 h of interruption, thereby facilitating postoperative analgesia. Two guidelines state that oral naltrexone can be stopped the morning of the operation.  These authors do not provide a rationale for their recommendations.

With respect to the extended release intramuscular formulation of naltrexone, all seven guidelines recommend longer washout periods when compared to the oral formulation. Five guidelines suggest stopping extended-release naltrexone 28 days before surgery. One guideline suggests a 21-day washout period, and another  suggests 24 to 30 days. None of the retrieved studies addressed specifics of opioid-related analgesic management or reinstitution of naltrexone.

There is a distinct lack of high-quality evidence that can currently guide clinicians with respect to the perioperative management of naltrexone, whether it is administered for opioid use disorder, alcohol use disorder, or chronic pain. Only four studies met our final inclusion criteria. We are unable to make definite statements due to a lack of overall research. We were able to analyze 13 different guidelines that mentioned naltrexone and its management; however, there is no isolated set of guidelines that focus on naltrexone; instead, they tended to group naltrexone with other substance use disorder pharmaceuticals (i.e., methadone, buprenorphine). The original purpose of this study was to investigate existing guidance on the perioperative use of naltrexone in the setting of alcohol use disorder. Throughout the screening process, we were unable to find any study or guideline document that investigated this subset of patients. Moreover, there are no existing guidelines currently based on a systematic review of the existing literature or a Delphi process. Given the paucity of clinical evidence and appropriate guidelines, we are unable to make specific perioperative recommendations at this time. Some important considerations follow.

Perioperative administration of naltrexone (up to 9 mg) was associated with a shorter duration of analgesia when the main analgesic agent was intravenous morphine or intrathecal morphine.  Furthermore, perioperative naltrexone administration may also have effects through blockade of both endogenous and exogenous opioids. In general, multimodal analgesia and increased doses of opioids eventually allowed for optimal analgesic control. The singular case report in which extended-release naltrexone was maintained demonstrated no recurrence of the opioid use disorder during the entire perioperative period. 

The vast majority of existing guidelines recommend cessation of oral naltrexone 3 days before surgery and not restarting until 7 to 10 days have elapsed after acute administration of opioids for perioperative pain. Many guidelines recommend against undergoing elective surgery within 28 days of intramuscular naltrexone administration. The vast majority of guidelines appear to focus on perioperative acute pain as the major primary endpoint as opposed to maintenance of substance use disorder recovery.

Opioid antagonism by naltrexone can typically be overcome by large enough doses of opioids to facilitate optimal analgesia. One study in mice has demonstrated that this critical threshold to overcome naltrexone’s antagonistic effects may be approximately 10 to 20 times the typically observed clinical dose.  However, the implications of chronic naltrexone administration may be different from its acute administration.  Indeed, chronic naltrexone administration results in an absence of agonist activity that may reduce the patient’s tolerance to the effects of opioid agonists. Studies have demonstrated an upregulation of brain opioid receptors after chronic naltrexone administration, which may suggest a mechanism behind the potentially increased sensitivity to agonist opioids observed in mice.  Therefore, exposure to full agonists of opioids in a patient that has recently stopped taking naltrexone may result in an exaggerated agonist response (i.e., analgesia or respiratory depression).

The plasma concentration typically detected after monthly injections of extended-release naltrexone (380 mg) are typically fourfold that after daily oral naltrexone dosing (50 mg).  Indeed, existing reports have highlighted the potential for opioid withdrawal in patients that have used opioid agonists within days of extended-release naltrexone administration.  Furthermore, the Food and Drug Administration has previously suggested that patients should remain opioid-agonist free for 7 to 10 days before their next extended-release naltrexone dose.  Angst explains in an editorial that extended-release naltrexone may effectively block opioid receptors for 3 weeks and that patients receiving extended-release naltrexone may be “unlikely to respond to opioids for about 3 weeks after injection.” Angst goes on to suggest that patients may demonstrate an exaggerated response to opioids after the fourth week, perhaps due to receptor upregulation secondary to prolonged receptor blockade. Indeed, the case report by Curatolo and Trin supports this theory, given that the patient experienced adequate pain relief 3 weeks after explant of the extended-release naltrexone. Needless to say, some reviews recommend administrating full-agonist opioids in a monitored setting to account for the potentially exaggerated effect in the context of respiratory depression.  Certainly rapidly acting full-agonist opioids like remifentanil have been suggested by some to account for this lack of certainty.

The timing, recency, dosing, chronicity, and formulation of naltrexone are all factors that may influence perioperative pain management. Although there is a paucity of evidence in the perioperative arena, the three randomized controlled trials and one case report in our scoping review support the notion that perioperative pain management may be more challenging in the context of perioperative naltrexone continuation. Higher-than-expected doses of full-agonist opioids may be required to overcome the effects of naltrexone. If enough time has lapsed since naltrexone administration, then patients may be at risk of an exaggerated analgesic and adverse effect response to full agonists. Care should be taken to monitor these patients in the immediate postoperative period for these exaggerated effects. Overall, physicians must be alert to the increased sensitivity or increased tolerance to opioid agonists for the perioperative management of acute pain.

There is little discussion in existing studies of the potential effects of perioperative naltrexone discontinuation on return to use in alcohol use disorder or opioid use disorder. Although existing guidelines and evidence support the notion that perioperative pain management is more challenging in the context of an opioid antagonist, there is no guidance on the destabilizing effects of discontinuing or temporarily holding one’s naltrexone therapy on maintaining recovery, a subject that is arguably of equal importance to the perioperative clinician, as we have discussed elsewhere.

Finally, there were no studies retrieved in our scoping review that sought to address the impact of low-dose naltrexone on perioperative pain. Extrapolating from chronic pain literature, however, it would appear that chronic administration of low-dose naltrexone appears to prolong the μ-opioid receptor potential of full agonists at ultra-low doses. This phenomenon is described as “hormesis” by some authors, whereby a low dose of an antagonist paradoxically acts as a weak agonist while a full dose acts as an antagonist.  Further studies are required to better understand the effects of naltrexone on the perioperative utility of μ-opioid receptor agonists for the management of acute pain, including in the perioperative period.

In line with existing guidelines, observational studies, and randomized controlled trials, this review does not equivocally support the discontinuation of naltrexone throughout the perioperative period for patients with alcohol use disorder or opioid use disorder. There are few studies examining the effects of naltrexone discontinuation or continuation of the maintenance of substance use disorder recovery. Extrapolating from guidelines and evidence pertaining to other opioid replacement therapies (i.e., buprenorphine), preoperative cessation of naltrexone may have untoward effects on a patient’s substance use disorder stability; however, data derived from this review to support this theory were sparse. The postoperative effects of full-agonist opioids may be unpredictable at best. It may be advisable to monitor these patients with greater acuity in the immediate postoperative period. Although many guidelines exist on this topic, none are designed on the basis of a systematic literature review. Certainly, optimal management of these complex patients necessitates effective communication between anesthesiologists, outpatient teams, and addiction specialists to ensure substance use disorder stability.