Abstract
Purpose of review:
The increasing prevalence of opioid tolerant individuals, in combination with the expanding scope and utilization of non-operating room anesthesia (NORA) necessitates ongoing investigation into best clinical practice for managing surgical/procedural pain in this population. The purpose of this article is to review recent guidelines, challenges, and considerations of managing pain in patients who are opioid tolerant secondary to opioid use disorder (OUD), with or without medications for the treatment of opioid use disorder (MOUD).
Recent findings:
A comprehensive preoperative evaluation in conjunction with a multidisciplinary, multimodal pain approach is optimal. NORA adds unique situational and environmental challenges for optimizing acute on chronic pain control in tolerant individuals while maintaining safety. Direct and partial/mixed mu-agonists should typically be continued throughout the perioperative period, while mu-antagonists (naltrexone) should be held 72 hours. Post procedural discharge instructions and follow up must be carefully arranged and ensured.
Summary:
Clinical recommendations continue to evolve as new consensus guidelines are published, although institution specific guidelines are most often followed. This review focuses on most recent best practices, within NORA and operating room settings, for managing opioid tolerant patients, patients with OUD and those on MOUD.
Keywords: opioid tolerant, opioid use disorder, multimodal analgesia, medications for opioid use disorder, perioperative pain management
Introduction
The prevalence of chronic opioid use and opioid use disorder (OUD) is rising, and these patients will continue to present for procedures requiring anesthesia. Patients presenting for surgery may exhibit opioid tolerance secondary to chronic opioid therapy for chronic pain, active opioid use disorder, or a history of opioid use disorder treated with medication. In response to the opioid epidemic, an increasing number of patients with OUD are being transitioned to medications for the treatment of opioid use disorder (MOUD), formerly known as medication-assisted treatment (MAT) (1**). Medications approved for the treatment of opioid use disorder include buprenorphine (with or without naloxone), methadone, and naltrexone, all of which have unique implications and management strategies in the perioperative period.
In addition to the known risks associated with preoperative opioid use and abuse, pain management during the perioperative period can be extremely challenging, as these patients tend to develop tolerance, opioid-induced hyperalgesia, and higher postoperative pain scores, requiring up to 3 to 4 times higher doses of opioids compared to their non-tolerant counterparts (2). As a result of increased opioid requirements, these patients have an increased risk for perioperative complications, including but not limited to excessive sedation, respiratory depression, and increased hospital length of stay and costs (1**). As such, close monitoring and emergency equipment should be available when taking care of these patients in all settings, but special care should be taken in the ambulatory and non-operating room anesthesia (NORA) locations. Despite the increasing prevalence of chronic opioid use and OUD, there remains limited evidence-based protocols available to guide anesthesiologists and pain physicians in optimizing perioperative pain management. In this article, we review the risks and challenges associated with opioid tolerant patients and patients on MOUD. Appropriate perioperative strategies must also be employed for patients with alcohol use disorder; the perioperative period can precipitate recurrence of use secondary to either uncontrolled pain or interruption of pharmacological/behavioral maintenance programs. Below, we summarize key principles and recommendations regarding the safe and effective perioperative management of these patients. We provide an overview of general perioperative strategies that can be employed for all of these patients, and then subsequently outline specific considerations and recommendations for each patient population.
General Perioperative Strategies for Opioid tolerant Patients and Patients with Active and Treated Opioid Used Disorder
Similar general preoperative, intraoperative, and postoperative principles apply when taking care of opioid tolerant patients and patients with active or medically treated opioid use disorder, which will be reviewed here.
Preoperative Management
Early identification of patients treated with chronic opioids and those with either active OUD or MOUD is critical as it allows for the opportunity to not only optimize pain control and mitigate potential side effects, but also to intervene in cases of active OUD, and to deter relapse in MOUD cases (1**). The patient’s primary prescriber should always be involved in formulating a perioperative pain management plan and obtaining collateral information is encouraged. Details regarding the type and name of the drug, route and timing of administration, chronicity of use, last dose, baseline pain rating and characteristics, and comorbid substance use and psychological disorders should be obtained preoperatively as this information can impact the perioperative pain management plan (2). A preoperative physical exam allows for baseline characteristics of mobility and functionality, and in chronic pain populations, may allow for careful planning of intraoperative positioning in efforts to mitigate postoperative discomfort (1). Patients taking chronic mu-opioid receptor agonists like morphine, oxycodone, or hydromorphone should generally be advised to continue home doses up to and including the day of surgery (1**,2). Fentanyl patches should be identified, and care should be taken to avoid excessive heat or moisture to the patch area; if removed, a new patch may be applied with knowledge that effective levels are reached after 6-12 hours (2). Lastly, managing expectations and outlining strategies for coping mechanisms postoperatively are essential for creating a shared, collaborative goal with the patient; by engaging in this conversation, clinicians may maximize the chance of patients experiencing a successful recovery period.
Intraoperative Management
Adjunctive medications, regional and neuraxial anesthesia, and a multimodal approach provide the foundation of designing an anesthetic plan for opioid tolerant patients and those with OUD or MOUD. Such multimodal adjuncts include nonsteroidal anti-inflammatory agents, acetaminophen, gabapentin, magnesium, dexmedetomidine, as well as low-dose ketamine and lidocaine infusions; it is important to note that improved outcomes are attributed to the composite effect of co-administration of all agents, and individual administration of only one medication is rarely sufficient to have engender clinically significant impact. When possible, regional or neuraxial techniques are preferred in this population, as they allow for targeted isolation of painful/noxious stimuli, thereby decreasing systemic requirements and mitigating side effects (2). For patients presenting for NORA, it is critical to first anticipate and identify potential escalating airway needs, including access to oxygen, equipment, and staff who may assist in an emergency. If opioids are used intraoperatively, careful titration should be guided by intraoperative monitoring in accordance with observed nociception, as indicated by vital signs, spontaneous respiratory rate, and pupillary assessment (3*).
Postoperative Management
The postoperative period, which extends from the immediate post-procedural phase through discharge, follows a course with changing analgesic requirements. Multimodal analgesic techniques should be continued throughout the perioperative period, and consults to the acute and/or chronic pain service(s), transitional pain service, and/or addiction medicine service should be considered early, with frequent communication between teams and involvement of the patient’s primary prescriber when appropriate (1**). If anxiety and depression are exacerbating the pain experience, it can also be helpful to consult the psychiatry service to incorporate cognitive-behavioral therapy, acceptance, and mindfulness strategies (4*). In the case of NORA and ambulatory surgery, it is important to consider regional anesthetic techniques that allow for discharge with disposable, indwelling catheters which provide pain coverage with local anesthesia. For uncontrolled pain not relieved by multimodal analgesic techniques, administration of full mu-opioid receptor agonists, particularly those with high affinity for the mu receptor, like fentanyl or hydromorphone, can be considered, however these patients should be monitored closely for side effects such as sedation, respiratory depression, constipation, and behavioral aspects such as mood and anxiety, sleep, and cravings or urges to use (2). Depending on pain management needs and home medications, these patients often require prolonged and/or more intensive postoperative monitoring periods given the increased risks of withdrawal, side effects, and overdose (2). Lastly, the decision to discharge a patient with opioids, while typically at the surgeon/proceduralist’s discretion, should involve a multidisciplinary team discussion, including both the patient and the patient’s primary prescriber. Close follow up care is essential; careful discharge instructions should be provided regarding medications and tapering plans, and postoperative appointments should be scheduled with the surgical team, the patient’s primary prescriber, and any other clinically appropriate teams (1**). As recovery goes on, a return to baseline functionality is the goal for these patients.
NORA Considerations for the Opioid Tolerant Population
NORA presents unique considerations and challenges for the general surgical population but especially for opioid tolerant individuals. Many procedures are minimally invasive and ultimately not painful, yet acute, transient pain can develop during key portions of a procedure (skin puncture, endoscope placement, etc.) (2). Anticipation of such events via clear communication with the proceduralist, and appropriate pharmacological timing of short-acting analgesics can mitigate the stimulating effects and provide a smooth anesthetic experience. An additional consideration in the opioid tolerant population is preparing for unanticipated extended lengths of procedures or interventions; unforeseen intraoperative events or challenging anatomy may delay timely completion of the procedures and necessitate escalating doses of opioids and adjuncts (5). When opioids are used in anesthetized patients (monitored anesthetic care, or general anesthesia with a natural airway), it is important to titrate medications to secondary indicators of pain, such as respirations, in order to ensure adequate oxygenation/ventilation (2). Clear identification of oxygenation sources and supply, adequacy of emergency equipment, and communication with team members who can assist with emergent intubation/resuscitation is critical. If procedures become lengthy or complicated, it may delay discharge; early communication with outpatient opioid providers and transitional discharge teams may be warranted to ensure appropriate and timely follow up for pain needs.
Specific Perioperative Considerations for Patients with Active and Medically Treated Opioid Use Disorder
Patients with both untreated OUD and MOUD present unique anesthetic and pain management challenges, especially in NORA and ambulatory settings. As the number of patients with a history of OUD presenting for elective, urgent, and emergent surgeries continue to increase, more guidance is needed to optimize care for these patients during the perioperative period. In the ambulatory setting, such concerns include diminished environmental resources (limited access to additional qualified personnel, emergency airway/imaging equipment typically found in the OR, pharmaceutical options available via a central pharmacy, adequate space in case of emergency), the necessity of careful patient selection (avoiding patients with co-existing disease that increase the risk for admission, including pulmonary disease, active drug abuse, renal failure, etc), and ensuring office staff and hours are adequate to address any postoperative pain issues or PONV prior to discharge. Prior to discharge, clinical staff must be proficient in the careful coordination of post-discharge follow up with the patient’s PCP, surgeon/proceduralist, opioid prescriber, and any other affiliated teams such as addiction psychiatry. Furthermore, these NORA considerations must be re-addressed each time there is an addition to the ever-expanding list of procedures being performed in clinic/ambulatory setting. Below, we provide a summary of the recent literature and recommendations regarding the perioperative management of patients with untreated OUD and those receiving medications such as buprenorphine, suboxone, methadone, and naltrexone.
Buprenorphine (with or without naloxone)
Buprenorphine is a long-acting, mixed opioid agonist and antagonist that is available as a single agent or in combination with naloxone, an opioid antagonist (1). Various formulations of buprenorphine are FDA-approved for the treatment of both OUD and chronic pain. When buprenorphine is prescribed for the treatment of OUD [extended-release subcutaneous injection alone, or in combination with naloxone to produce a sublingual tablet (Suboxone) or film (Subutex)], buprenorphine is dosed in milligrams; however, when indicated for chronic pain [twice daily buccal film (Belbuca) or weekly transdermal patch (Butrans)], buprenorphine is dosed in micrograms (1). Historically, there have been many different approaches to the management of perioperative pain in patients on chronic buprenorphine, as comprehensive clinical evidence is limited (6).
A multi-society, multi-specialty Working Group on Opioid Use Disorder comprised of an expert panel recently published an extensive literature review and provided 2021 consensus recommendations regarding the perioperative management of patients on buprenorphine (with and without naloxone) who present for elective, urgent, and emergent surgery (1**). In contrast to previously published guidelines recommending the preoperative discontinuation of buprenorphine 48 to 72 hours prior to surgery, this working group recommends that buprenorphine (with or without naloxone) should be continued preoperatively as adequate analgesia can still be achieved, while discontinuing it may increase the risk of OUD recurrence or harm (grade B, moderate level of certainty) (1,7**). Regarding tapering patients on high doses of buprenorphine (>16mg daily) and in situations in which high levels of postoperative pain are expected, existing recommendations have been to either taper or continue at the prescribed dosage (8) but ultimately recommendations remain largely institution dependent. However, given that receptor availability studies and case reports suggest adequate analgesia can still be achieved even at high doses of buprenorphine, the working group recommends avoiding tapering buprenorphine doses preoperatively (grade B, moderate level of certainty). For example, supplementation during the intraoperative period with adjuncts such as sufentanil can be sufficient to achieve adequate analgesia for patients on buprenorphine. It is important to reference each individual institution’s guidelines and protocols on the perioperative management of patients on various buprenorphine formulations, as each institution may have differing recommendations given the lack of rigorous clinical evidence available to guide care.
For intraoperative and postoperative pain management, in addition to previously summarized strategies, the patient’s buprenorphine dose can be increased and/or divided into multiple doses given every 6 to 8 hours to ensure adequate coverage in the perioperative period (grade C, low level of certainty) (1**). All dose adjustments should be a shared decision made in coordination with the patient and the patient’s primary prescriber. If opioids are needed in the perioperative period, titration can be challenging and unpredictable, as increased doses of opioids may be required secondary to buprenorphine’s partial agonism at the mu-opioid receptor (9). Postoperatively, if a full mu agonist was initiated or if the patient’s maintenance buprenorphine dose was increased during the perioperative period, a post-discharge plan, including close coordination and follow up with the primary prescriber, should be provided to the patient with careful instructions on how to taper off the opioid or return to the preoperative dose of buprenorphine (grade A, moderate level of certainty) (1**).
Methadone
Methadone is a pure mu-opioid receptor agonist with higher risks of respiratory depression and overdose compared to buprenorphine. Methadone is prescribed once daily for the treatment of OUD, with effective daily doses varying between 60 and 120 mg per day. Methadone is also prescribed for chronic pain, typically in twice or three times per day dosing schedules. While consensus recommendations are to continue daily methadone doses during the perioperative period, home doses will not cover acute perioperative pain, and due to its long half-life, methadone can be difficult to titrate in the fluctuating setting of acute pain (3*,9). Preoperatively, if the patient is unable to receive the regular dose on the morning of surgery, it can be administered orally or the adjusted equivalent dose may be given intravenously during the preoperative or intraoperative period (3*). For patients prescribed methadone for OUD, dividing the maintenance dose into a three or four times a day dosing schedule may provide analgesic benefit (4*). If full mu-opioid receptor agonists are required, these patients may require significantly increased doses of opioids secondary to opioid cross-tolerance and the potential for opioid-induced hyperalgesia (9). Additionally, careful monitoring of the QTc-interval should be employed throughout the perioperative period, as these patients are at increased risk for potentially life threating cardiac arrhythmias (10).
Naltrexone
Naltrexone, a long-acting opioid antagonist, is FDA-approved for the use of OUD and alcohol use disorder among other indications. It is taken either orally once daily, or intramuscularly every 28 days. There remains variability across even recent literature and protocols, however, most recommend that patients hold oral naltrexone for 72 hours prior to surgery, and that patients receiving monthly injections should schedule surgery at least 3 to 4 weeks after the last dose, with a possible need for an oral bridge based on the timing of surgery (3*). After abrupt discontinuation of naltrexone, a selective upregulation of mu-receptors with enhanced opioid sensitivity may develop, thus necessitating extreme care and diligence when titrating opioids throughout the perioperative period (3,7**). In the case of urgent or emergent surgery for patients maintained on naltrexone, it is important to identify the timing of the last dose of naltrexone, and that all members of the perioperative care team communicate and understand the pain management plan. If the patient’s last dose of naltrexone was within 72 hours, higher doses of opioids will likely be required to outcompete the opioid-blocking effects of naltrexone at the cellular level. In contrast, when naltrexone is no longer occupying the receptors (toward the end of the month for patients on monthly injections or greater than 24 to 72 hours since last oral dose), opioid receptor upregulation can occur, resulting in increased sensitivity and an increased risk of side effects. As such, close postoperative monitoring is essential, and there should be a low threshold for postoperative overnight admission given the risk of rebound opioid sensitivity in patients maintained on oral naltrexone. Restarting naltrexone postoperatively is typically considered only after acute pain resolves and opioid agonists are discontinued, however this decision and plan should be carefully coordinated with the patient’s primary prescriber with close follow up arranged (3*,9).
Patients With Active Opioid Use Disorder
Many of the principles discussed above for patients with chronic pain and those with MOUD also apply to patients with active OUD. Despite diligent preoperative attempts to obtain a detailed history of the patient’s drug use, it remains exceedingly difficult to accurately quantify the amount of opioids patients with OUD actually consume, thus putting them at increased risk for withdrawal during the perioperative period. Furthermore, it is typical for patients actively abusing opioids to also take other recreational drugs, further complicating the clinical presentation and response to medications. The perioperative team should diligently monitor these patients for signs and symptoms of withdrawal, such as tachycardia, diaphoresis, restlessness/anxiety, pupillary dilation, rhinorrhea, gastrointestinal upset, tremor, yawning, and/or piloerection. Additionally, patients with OUD have been shown to have lower pain tolerance, increased opioid tolerance, and increased sensitivity to pain as a result of opioid-induced hyperalgesia, making perioperative pain management particularly challenging in this surgical population (4*). There has been a recent push for anesthesiologists, pain physicians, and other perioperative care team members to not only screen for OUD, but to also consider intervening and initiating MOUD in the perioperative period or arranging referral for initiation of MOUD upon discharge (1**,10).
Conclusion
As the number of patients presenting for surgery with a history of chronic opioid use or OUD continues to increase, it is essential to have protocols in place to guide the optimal perioperative management of these patients. Review of the recent literature and consensus recommendations serves to highlight the overall limited amount of evidence available to guide pain management of opioid tolerant patients and patients with MOUD. Overall, similar fundamental principles apply when taking care of these patients (Table 1). In all cases, the following are recommended: early identification of opioid tolerance and OUD with and without treatment, identification of route/dosage/timing of last use, interprofessional collaboration among providers with frequent communication and close post-discharge follow up, consultation of acute pain and addiction medicine services as appropriate, and the use of multimodal opioid sparing analgesic techniques throughout the perioperative period.
Table 1.
Perioperative Principles For Managing Opioid Tolerant Patients, OUD, MOUD, and NORA Considerations
| Medication | Perioperative Principles/Recommendations |
|---|---|
| Opioid therapy for chronic pain | -Continue throughout perioperative period -Prioritize multimodal/neuraxial/regional approaches |
| Buprenorphine (with or without naloxone) | -Continue throughout perioperative period -Consider taper to 16mg for patients >16mg/day if high postoperative opioid requirements anticipated |
| Methadone | -Continue throughout perioperative period -Consider dividing maintenance dose into BID/TID dosing to optimize coverage -Monitor QTc interval |
| Naltrexone | -PO: Hold for 72 hours prior to surgery -IM: Plan surgery 3-4 weeks after last injection -Urgent/emergent surgery considerations: may be resistant or hypersensitive to opioid agonists based on timing of last dose -Restart when acute pain resolves + opioid agonists discontinued |
| Active OUD | -Early identification, comprehensive preoperative exam/discussion is essential -Monitor for withdrawal symptoms -May require increased doses -Consider perioperative/postoperative initiation of MOUD -Consider consulting addiction, acute/chronic pain, and transitional discharge teams |
| NORA Considerations | -Mitigate the transient, stimulating portions of procedures with short-acting adjuncts -Titrate analgesics to respirations -Identify resources (equipment, oxygen, personnel) and have action plan for escalating sedation needs in opioid tolerant individuals |
Legend: Overview of recent recommendations for optimizing analgesia in opioid tolerant individuals. These patients require diligent perioperative monitoring in the setting of opioid titration, especially in the NORA context. Multimodal non-opioid regimens and/or neuraxial approaches are encouraged when possible. In all cases, refer to institution specific perioperative guidelines.
Given that patients on chronic opioids tend to develop tolerance, opioid-induced hyperalgesia, and higher postoperative pain scores, these patients often require higher doses of opioids, making them at higher risk of anesthetic complications, especially in NORA and ambulatory settings where resources are already limited. An increasing number of institutions are developing protocols to guide the perioperative management of opioid tolerant patients and patients with MOUD that present for elective, urgent, and emergent surgery, and is it important to defer to these institutional-specific practices. With future large-scale studies examining the perioperative management of these patients, current recommendations and guidelines are likely to evolve as clinical evidence grows, which will continue to have tremendous implications on the way we care for these patients.
Key Points.
A multidisciplinary approach (surgery, anesthesia, regional teams) in collaboration with the patient’s primary prescriber and/or addiction psychiatrist is recommended to guide the perioperative pain management of opioid tolerant patients and patients with OUD treated with medications.
Multimodal analgesic techniques including both pharmacologic and nonpharmacologic modalities and regional/neuraxial anesthesia should be employed when possible throughout the perioperative period.
Opioids prescribed for chronic pain should be continued throughout the perioperative period (especially long-acting opioids), including the morning of surgery.
For patients treated with medications for opioid use disorder, buprenorphine (with or without naloxone) and methadone should generally be continued throughout the perioperative period, while naltrexone (intramuscular or oral) should be held preoperatively.
Patients should be given detailed discharge instructions and close postoperative follow up with the primary provider/prescriber is essential.
Footnotes
Conflicts of Interest: Richard D. Urman reports funding/fees from Heron, Merck, Medtronic, Pfizer, AcelRx and the NIH. For the remaining authors none were declared.
References and Recommended Reading
Papers of particular interest, published within the period of review, have been highlighted as:
* of special interest
** of outstanding interest
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