Research In Nursing
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With a brief summary of selected literature identi- fied by a multidisciplinary panel of subject matter experts, the authors share their experience with the development of an institutional perioperative pain management guideline for patients on maintenance medication for addiction treatment (MAT), stressing the importance of perioperative continuation of opioid agonists such as methadone and partial agonists such
as buprenorphine; and the discontinuation of opioid antagonists, such as naltrexone. The authors’ protocol is appended as an example of a standardized approach to perioperative management of patients on MAT.
Keywords: Anesthesiology, medication for addiction treatment, pain management, perioperative manage- ment, substance use disorder.
Perioperative Management of Patients on
Maintenance Medication for Addiction Treatment:
The Development of an Institutional Guideline
Gillian A. Beauchamp, MD
Jill L. Hanisak, DNP, CRNA
Alexandra M. Amaducci, DO
Andrew L. Koons, DO
Jason Laskosky, PharmD, BCPS
Bernadette M. Maron, RN, BHCM
Thomas M. McLoughlin, Jr, MD
P ublic health in the United States is challenged by the intertwined relationship of the morbid- ity associated with chronic pain syndromes and the mortality associated with a crisis of opioid overdoses.1-4 Factors contributing to this crisis
are multifactorial and extensively described in the existing literature, but include the influence of the pharmaceutical industry, pressure from medical governing bodies to link pain relief with patient satisfaction, and a historical lack of adequate screening and monitoring for at-risk patients.5 Given that the majority of opioids prescribed in the post- operative setting go unused, and are neither stored nor disposed of properly, over-prescribing has undoubtedly contributed to the risk of harmful opioid use, the develop- ment of iatrogenic opioid use disorder, and the alarming rate of opioid overdoses which surpassed 50,000 deaths in 2019.6,7
Managing pain in the context of the ongoing crisis of overdose deaths remains a challenge that involves weigh- ing the risks and benefits of pain management modalities while assessing risk related to medical issues, psychiatric comorbidities, and substance use disorder (SUD).2 The medical community continues to explore how to safely and effectively manage perioperative pain while minimiz- ing the risk of iatrogenic opioid use disorder or exacerba- tion of existing SUD.3
Efforts to reduce risk have included opioid-sparing modalities for pain management, reduction in post- operative prescribed opioids, and screening patients for
SUD risk factors.4 Standardized approaches to risk as- sessment for harmful substance use and recurrence of use are lacking in many settings where opioids are used to manage pain.8,9
The use of medications such as methadone, buprenor- phine, and naltrexone to support recovery from SUD, also known as medication for addiction treatment (MAT) is supported by the existing literature and considered the standard of care for management of SUD.10 The periop- erative management of patients on maintenance warrants effective pain control without substantially increasing risk of recurrence of substance use.11 Specifically, non- opioid or opioid-sparing multimodal approaches to perioperative pain management are an important consid- eration and may include agents such as nonsteroidal anti- inflammatory medications (NSAIDs), gabapentinoids, ketamine, and neuraxial and regional anesthesia.12,13
Institutional guidelines directing SUD-focused periop- erative considerations should include: assessing psycho- logical support needs, multimodal approaches, dosing strategies that account for potential opioid tolerance, withdrawal management, avoiding hyperalgesia, assess- ing risk of recurrence of use, deciding whether to con- tinue MAT, and cautious monitoring.11,14-17
Description of Project With a brief summary of selected literature identified by a multidisciplinary group of institutional subject matter experts, the authors share their experience with
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the development of an institutional perioperative pain management guideline for patients on MAT, stressing their recommendations around the importance of peri- operative continuation of opioid agonist MAT and the discontinuation of opioid antagonist MAT.16,18-20 The protocol is appended (See Figures 1-3) as an example of a standardized approach to perioperative management of patients on MAT. A perioperative plan that includes ef- fective multimodal pain management and opioid sparing strategies, while managing withdrawal and decreasing risk factors for recurrence of substance use, is essential for effective care for patients on maintenance MAT.21
Discussion MAT: Methadone Methadone is a full mu opioid receptor agonist with additional N-methyl-d-aspartate (NMDA) receptor an- tagonism and reuptake inhibition of serotonin and norepinephrine, utilized for patients with opioid use disorder and/or moderate to severe chronic pain.18,22,23 Methadone and other medications to support recovery are intended to reduce harm from chronic opioid use, prevent withdrawal, and reduce patient preoccupation
with opioids and cravings.24 Methadone’s elimination is biphasic, with a short analgesic phase (8-12 hours) and a long sub-analgesic and withdrawal suppression phase (30-60 hours).18,25 The equianalgesic conversion ratio for methadone to and from other opioids is variable and nonlinear.25
Perioperative Considerations: Methadone Prior studies have reported that patients on maintenance methadone may have an increased opioid tolerance con- comitant with a decreased tolerance for pain, and thus may need higher perioperative and post-operative ad- junctive opioid doses compared to patients who are not tolerant to opioids.23,26 In addition to its use as a medica- tion to support recovery from opioid use disorder, meth- adone has gained popularity for perioperative pain relief in patients undergoing painful surgical procedures.27
As a full mu receptor agonist, continuing baseline methadone dosing throughout the perioperative period assists with perioperative analgesia and is easily supple- mented with additional opioids as needed, providing a basal level of opioid support for patients accustomed to daily methadone dosing. Continuation of methadone in
Figure 1. Guidelines for Methadone
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the perioperative period is generally recommended.28 Maintaining doses of chronic full mu agonist medications like methadone likely reduces the risk of perioperative opioid withdrawal, labile intraoperative hemodynamics, and severe pain.29 Given a lack of definitive evidence to suggest superiority of one approach over another, the authors feel there are two feasible approaches to continu- ing a patient’s baseline methadone dose: the dose may be provided as a single morning (QAM) dose, as is typically the practice at methadone treatment programs; or the pa- tient’s total daily methadone dose could be divided three times a day (TID) or four times a day (QID) during the day of the surgery or procedure. The reason to continue QAM dosing is to avoid the occurrence of methadone withdrawal or anxiety related to a fear of withdrawal, as the patient enters the perioperative setting on the day of the procedure or operation. On the other hand, if the patient is amenable, dividing the total baseline daily dose TID or QID has potential to provide better pain control throughout the day of the surgery or procedure.
There is risk for additive effects of other sedative and analgesic medications in patients receiving methadone. Strategies for opioid sparing perioperative pain manage-
ment include a multimodal approach with regional an- algesia techniques when possible, while continuing the daily methadone maintenance dose. The NMDA receptor effects of methadone reduce hyperalgesia while also pro- viding anti-allodynic properties, and thus may help to avoid tolerance, reduce adjunctive opioid requirement, and reduce the duration of postoperative pain.27
MAT: Buprenorphine Buprenorphine is a semisynthetic opioid with complex pharmacology.30-32 Buprenorphine acts as a partial agonist at the mu receptor and an antagonist at the kappa receptor, lending to its description as a mixed opioid receptor agonist-antagonist.33,34 Clinical trial data have shown a dose-response effect with analgesia, but a ceiling effect for respiratory depression (eg, doubling the dose from 0.2 mg to 0.4 mg IV resulted in a 3.5 fold increase in analgesic effect, but no change in the mag- nitude of respiratory depression).35 Respiratory ceiling effects have been shown with the sublingual formulation whereby doses of 32 mg resulted in no more respiratory depression than 16 mg among patients without physical dependence.35
Figure 2. Guidelines for Buprenorphine
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Buprenorphine displays a bell-shaped analgesic effect in rodents, but a reduced analgesic effect at the upper range of normally prescribed doses has not been observed in humans.30,32 Buprenorphine possesses a high mu re- ceptor affinity resulting in a relative, but not absolute, inability of agents with lower mu receptor affinity (eg, morphine) to displace buprenorphine from receptor sites. Full mu opioid agonists with higher affinity, or at higher doses, can provide additional analgesia when administered to patients already receiving buprenorphine. Conversely, high receptor affinity explains why buprenorphine, when newly initiated in patients receiving full mu opioid ago- nists of lower affinity, can precipitate withdrawal due to net displacement of full mu agonists by buprenorphine.31 When given sublingually (SL), buprenorphine has a mean elimination half-life ranging from 24 to 42 hours permitting daily or twice daily maintenance dosing for withdrawal suppression.33 The reported duration of an- algesia (SL formulation) is considerably shorter at only 4-8 hours, so more frequent divided doses may be con- sidered for perioperative patients receiving maintenance buprenorphine for withdrawal suppression, eg, instead of standard BID dosing, half-dose QID may be considered.34
Other commercially available formulations of bu- prenorphine in the United States include: a long acting subdermal implant; a subcutaneous injection depot for- mulation intended for maintenance treatment of opioid use disorder; and a transdermal patch intended for man- agement of severe pain—all possess longer durations of action resulting from drug formulation rather than any change in in vivo metabolism.31
When administered SL, buprenorphine undergoes first pass metabolism to the active metabolite norbu- prenorphine by CYP isoenzymes.31 Routes of administra- tion that avoid the first pass effect (intravenous or intra- nasal) result in less norbuprenorphine formation, which may be of clinical relevance.31 Given hepatic metabolism via CYP3A4, consideration should be given to patients receiving concurrent CYP3A4 inhibitors and inducers given potential CYP mediated drug-drug interactions.33
In efforts to reduce potential for harmful use of SL and buccal buprenorphine, buprenorphine is most often prescribed as co-formulated with naloxone (ratio 4:1).33 Interestingly, SL naloxone has been shown to precipi- tate withdrawal in doses of more than 2 mg, but not at lower doses.36
Figure 3. Guidelines for Naltrexone Inj. (Vivitrol)
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Perioperative Considerations: Buprenorphine There are several published approaches for perioperative management and acute pain management of patients re- ceiving buprenorphine, but clear evidence to support any one approach is limited.37,38 Common practice at many institutions includes cessation of maintenance buprenor- phine 48-72 hours prior to surgery, yet this practice is based on scant data.39
Silva et al39 describe the properties of buprenorphine that have been extrapolated to develop poorly supported theories around perioperative management of MAT patients. First, because buprenorphine is a partial mu agonist, it is inferred that it is not a potent analgesic. Second, because buprenorphine has a ceiling effect on respiratory depression, some assume that it also has a ceiling effect on analgesia. Third, it has been assumed that buprenorphine acts as a “blockade” to the analgesic effects of other co-administered opioids due to its strong binding affinity. Although studies have demonstrated a ceiling effect for buprenorphine-induced euphoria and respiratory depression, a ceiling effect for analgesia has never been demonstrated.39
As recently as 2014, it was common for practitioners to believe that since buprenorphine is a partial opioid agonist with a high affinity for mu-opioid receptors, patients on buprenorphine were expected to require a higher dose of opioid during the perioperative period. It was also assumed that a standard opioid-based anesthesia plan may be insufficient for patients on buprenorphine, thus a patient’s buprenorphine would need to be discon- tinued and replaced with full agonist opioids to ensure proper pain management.40 However, more recent guide- lines recommend continuing a patient’s buprenorphine in the perioperative period. Acampora et al37 propose that continuing buprenorphine and adding a full agonist opioid (FAO) is safe and may provide increased analge- sia, thus reducing the perioperative FAO requirement and limiting risk of recurrence of harmful post-operative substance use in this population.
The lack of clear guidelines for the perioperative man- agement of patients on MAT may cause apprehension for both the patient and the medical team.37 Maintaining buprenorphine preoperatively has not been associated with worse clinical outcomes. In fact, discontinuation of opioid maintenance therapy can lead to recurrence of harmful opioid use, with estimates of up to 90% recur- rence of use when MAT is discontinued prematurely.15 In a multicenter trial of primary heroin or prescription opioid users seeking treatment for opioid dependence, 82% of the 516 participants enrolled had recurrence of harmful opioid use within one month following an inci- dence of perioperative buprenorphine cessation.41
Maintaining patients on buprenorphine at a dose that allows for a sufficient proportion of unoccupied mu re- ceptors will allow for binding of any full mu agonists that
are administered perioperatively.38 High-dose buprenor- phine therapy (described as 24 mg per day sublingually) may occupy too large a percentage of mu opioid receptors, and therefore render commonly used FAOs ineffective; however standard buprenorphine dosing is 8 mg BID. Consideration may be given for careful tapering to a lower, moderate daily dose of buprenorphine dose before painful, elective surgery in patients on daily doses of bu- prenorphine 24 mg/day.38 Receptor availability studies show that for high buprenorphine maintenance doses (24-32 mg daily), the availability of mu-opioid receptors is minimal whereas at lower doses (8-12 mg daily), there is still up to 20% mu-opioid receptor availability.15
Acampora et al37 suggest a structured dosing strategy throughout the perioperative period to avoid withdrawal and risk of recurrence of harmful substance use while maximizing pain management. They recommend 8 mg of buprenorphine/naloxone twice daily for a total of 16 mg of buprenorphine the day before surgery to prevent crav- ings, followed by 4 mg twice a day on the day of surgery and postoperatively to open some mu receptors for avail- ability to FAOs as needed. Because buprenorphine has a high affinity and long duration of effect at the mu recep- tor, it provides significant analgesia at relatively low sub- lingual doses. Analgesic doses of buprenorphine (ideally 4 mg BID) in combination with FAOs produce synergis- tic analgesia. Buprenorphine effects at the mu receptor are reversible, and within 24 hours after reducing the daily buprenorphine dose among patients on high-dose buprenorphine, 40% of opioid receptors become unoc- cupied again.37 It is the opinion of the authors that where stable buprenorphine dosing is maintained, or reduced from high dose regimens to increase the available mu re- ceptors for concomitant full mu-agonist administration, the continuation of buprenorphine in the perioperative period is effective in avoiding withdrawal, cravings, and risk of recurrence of harmful opioid use.
Goel et al20 report that the current level of evi- dence as described by the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) tool regarding perioperative management of patients on buprenorphine is weak. The number of studies to address this perioperative dilemma is limited, and few directly evaluate the question of continuing versus dis- continuing buprenorphine. They suggest with Level 5 evidence that it is almost always appropriate to continue buprenorphine at the preoperative maintenance dose and that it is rarely appropriate to reduce the buprenor- phine dose. Postoperatively, they suggest with Level 4 evidence that after analgesic adjuncts have been initiated, it is appropriate to consider a full mu agonist to manage pain. If inadequate analgesia persists in the perioperative setting, one can consider buprenorphine dose reduction in the context of full mu-agonist use. They also recom- mend always prescribing non-opioid adjunct analgesia,
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such as NSAIDs, acetaminophen, gabapentin/pregabalin, ketamine, dexmedetomidine, lidocaine, and regional an- esthesia when appropriate. In the post-operative setting, it is almost always appropriate to discharge patients with a plan to continue their pre-operative maintenance dose of buprenorphine, with close monitoring and com- munication with the patient’s outpatient buprenorphine prescriber.20 Quaye et al,42 reported a significant re- duction in the need for post-operative opioids, as well as improved early recovery pain scores, in patients for whom buprenorphine was continued versus held in the perioperative setting.
Elective procedures provide the luxury of time to adequately plan, counsel patients, and discuss avail- able strategies with an interdisciplinary team. However, emergent procedures allow much less flexibility and may require more urgent strategizing.38
MAT: Naltrexone Unlike the mixed receptor pharmacology of methadone and buprenorphine, naltrexone (like naloxone) is a pure opioid antagonist with high affinity for the mu recep- tor.34,43-45 While the mechanism of action of naltrexone in the management of opioid use disorder centers around mu receptor blockade, its efficacy in the management of alcohol use disorders hinges on its ability to blunt the en- dogenous opioid reward pathway resulting in decreased euphoria from ethanol.46
When administered in its oral formulation (tablet), na- ltrexone is typically prescribed daily and, after administra- tion for 7 days, the half-life is approximately 10 hours.43 Given extensive metabolism to an active metabolite (6 beta naltrexol) and dependence on renal elimination of both the parent compound and metabolite, hepatic and or renal insufficiency may prolong duration of action. In addition to an immediate release tablet, naltrexone has been more recently available as an extended release (monthly IM injection) formulation.47 Following IM in- jection, plasma concentrations peak within 1-2 hours, fall transiently and then demonstrate a second peak at higher concentrations by day 2-3. Beginning approximately 14 days after dosing, concentrations slowly decline, with measurable concentrations for greater than 1 month.46
Perioperative Considerations: Naltrexone Both oral and IM naltrexone yield full mu opioid antago- nism, but due to their differing pharmacokinetics, need to be treated differently in the perioperative setting. No consensus recommendations exist, and perioperative planning should be done on a case-by-case basis. In our opinion, specific risk-benefit decisions must be made between the surgical and anesthesiology teams as well as the naltrexone prescriber in regard to the timing for surgery, ability to use opioid-sparing techniques and, if needed, the timing for discontinuation and reinstitution
of naltrexone therapy. It may be prudent to continue nal- trexone for procedures that are expected to cause mild or no pain, or that can be managed with non-opioid modali- ties, especially in those patients deemed to be high-risk for recurrence of harmful use.
For surgical procedures that are expected to result in moderate to severe pain, it may be necessary to stop naltrexone pre-operatively to improve analgesia. To account for 5 half-lives, and allow for effective opioid agonist action, oral naltrexone should be discontinued 72 hours before surgery (or potentially longer in the setting of renal or hepatic insufficiency). The timeline for IM naltrexone is not as clear, but successful pain manage- ment with opioids is reported starting at least 21 days post-injection, with increased success as time progresses towards the end of the 28-day injection cycle.48 For those surgeries that are unplanned and emergent, and for which naltrexone discontinuation is not an option, the surgical and anesthesiology team must rely heavily on non-opioid analgesics and modalities such as regional anesthesia, since opioids are not likely to have their intended effect.
It is important to note that this subset of patients is particularly prone to variability in their opioid response both peri- and postoperatively. Patients who are recently or remotely dependent on opioids can demonstrate a tolerance to their effects. However, when a patient starts naltrexone therapy, they become susceptible to both attenuation and enhancement of the opioid effect.18 Therefore, the authors recommend that opioids provided in this context be used at low doses and titrated to effect. Naltrexone has a higher affinity for mu-opioid receptors than full-mu agonists. It will displace and block the re- ceptor from opioid agonism and precipitate withdrawal if given when opioid agonists are still circulating in the pa- tient’s system.49 Thus, postoperatively, the patient should not be restarted on their naltrexone until 7-10 days after their last dose of opioid.50
Background At the authors’ institution, as the number of patients treated for substance use disorder continues to rise, provisions for the perioperative management of surgi- cal patients with substance use disorder are a priority. A multidisciplinary workgroup including representatives from anesthesiology, surgery, pharmacy, pain medicine, quality and safety, medical toxicology, and addiction medicine, collaborated in the development of a clinical guideline and treatment algorithm. The consensus of our multidisciplinary team is that discontinuing medications, such as buprenorphine and methadone, in the periopera- tive setting increases risk for withdrawal, recurrence of substance use, delays to re-initiation of post-operative MAT, and increased pain. Challenges and opportunities involved in the consensus process included ensuring that all stakeholders were familiarized with the literature as
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selected by our institutional subject matter experts, and implementing practice change, particularly around the notion of continuing perioperative buprenorphine. The authors’ pathway includes discontinuation of the mu antagonist naltrexone prior to surgery when possible, but continuation of partial or full mu agonist medications, such as buprenorphine and methadone, throughout the perioperative period. A multimodal approach for periop- erative pain management that included guidance around whether to continue MAT was developed to provide maximal pain relief with minimal risk of recurrence of harmful substance use. A limitation of guideline devel- opment was the leveraging of subject matter expertise in lieu of a systematic review and grading of the litera- ture. Clinician education and development of electronic medical record decision support related to this guideline is ongoing to further enhance the delivery of quality peri- operative care for patients on MAT. Future areas of study include assessing both effectiveness of, and barriers to, guideline implementation. The guidelines are shared with the hope that they may assist others in developing similar protocols (See Figures 1-3).
REFERENCES
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AUTHORS Gillian A. Beauchamp, MD, is an emergency physician, medical toxi- cologist, and addiction specialist, Department of Emergency and Hospital Medicine, Lehigh Valley Health Network/University of South Florida (USF) Morsani College of Medicine, Allentown, Pennsylvania. Email: Gil- lian.Beauchamp@lvhn.org.
Jill L. Hanisak, DNP, CRNA, is the education coordinator of the Department of Anesthesiology for Lehigh Valley Health Network.
Alexandra M. Amaducci, DO, is a medical toxicology fellow and emergency medicine physician, Department of Emergency and Hospital Medicine, Division of Medical Toxicology, Lehigh Valley Health Network/ University of South Florida (USF) Morsani College of Medicine.
Andrew L. Koons, DO, is an emergency physician and medical toxi- cologist, Department of Emergency and Hospital Medicine, Division of Medical Toxicology, Lehigh Valley Health Network/University of South Florida (USF) Morsani College of Medicine.
Jason Laskosky, Pharm D, BCPS, is a clinical pharmacy specialist in Critical Care, Department of Pharmacy, Lehigh Valley Health Network.
Bernadette M. Maron, RN, BHCM, is a quality nurse specialist and certified professional in Health Care Quality, Department of Anesthesia and Perioperative division at Lehigh Valley Health Network.
Thomas M. McLoughlin, Jr, MD, is chair of the Department of Anes- thesiology for Lehigh Valley Health Network/University of South Florida (USF) Morsani College of Medicine.
DISCLOSURES Name: Gillian A. Beauchamp, MD Contribution: This author made significant contributions to the concep- tion, synthesis, writing and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None Name: Jill L. Hanisak, DNP, CRNA Contribution: This author made significant contributions to the concep- tion, synthesis, writing and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None Name: Alexandra M. Amaducci, DO Contribution: This author made significant contributions to the concep- tion, synthesis, writing and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None Name: Andrew L. Koons, DO Contribution: This author made significant contributions to the concep- tion, synthesis, writing and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None Name: Jason Laskosky, Pharm D, BCPS Contribution: This author made significant contributions to the concep- tion, synthesis, writing and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None Name: Bernadette M. Maron, RN, BHCM Contribution: This author made significant contributions to the concep- tion, synthesis, writing and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None Name: Thomas M. McLoughlin, Jr, MD Contribution: This author made significant contributions to the concep- tion, synthesis, writing and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None The authors did discuss off-label use within the article. Disclosure state- ments are available for viewing upon request.
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