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Management of Opioid Agonist Treatment for Opioid Use Disorder in the Setting of Solid Organ Transplant

Joyal, Kayla PharmD1; Peckham, Alyssa M. PharmD, BCPP2,3; Wakeman, Sarah E. MD4; Zlotoff, Daniel MD, PhD4; Lewis, Gregory D. MD5; D’Alessandro, David MD6; Crowley, Jerome C. MD7; Waldman, Georgina PharmD2

Author Information
doi: 10.1097/TP.0000000000003926
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INTRODUCTION

The opioid overdose (OD) crisis is a devastating public health concern that has resulted in >81 000 OD deaths from June 2019 to May 2020.1 Untreated opioid use disorder (OUD) plays a significant role in the perpetuation of this crisis.2 OD death accounted for 13.4% of all deceased organ donation in 2017, a significant increase from 1.1% in 2000.3 However, further effort is needed toward improving equity through increased access to life saving transplants among individuals with OUD and end-stage organ failure.4

A 2017 survey of liver transplant centers with a 53.5% response rate (61 programs) found that 1 program considered methadone or buprenorphine use (herein referred to as opioid agonist therapy [OAT]) an absolute contraindication to transplant, whereas 37.7% considered it a relative contraindication. This disparity violates the National Organ Transplant Act, which requires that all medically qualified patients receive equitable access to transplant. In that same survey, nearly 50% of centers believed there should be a national consensus policy addressing OAT use in the setting of transplant. These results suggest knowledge gaps or lack of evidence-based guidelines may contribute to inconsistent access to transplantation in patients on OAT.5-7

Management of OAT during transplant can be complex but is necessary to avoid OAT discontinuation. There is an overwhelming body of literature demonstrating that patients with OUD treated with OAT have a higher incidence of achieving remission, less use of nonprescribed substances, and are at a reduced risk of all cause and OD-related mortality. Compliance to OAT and adequate social supports are key in achieving this success. Premature discontinuation of OAT can lead to return to opioid use rates of up to 90% and increased mortality.8 Transplant centers must collaborate with addiction medicine specialists to manage OAT before, during, and after transplant to prevent interruptions in treatment and stability. Stopping OAT to meet unclear transplant eligibility criteria could increase mortality or OUD relapse in patients who could otherwise successfully receive organ transplants.

Current data surrounding the safety and efficacy of OAT use in transplant populations is scarce. A 2003 retrospective chart review of 36 liver recipients transplanted while receiving methadone at a median dose of 50 mg concluded that patient and graft survival rates were similar to the national average.9 Rodgman et al detailed the experience of a 29-y-old female with OUD secondary to chronic cardiac pain who was initially managed with opioids after ventricular assist device implantation but after successful transition to buprenorphine-naloxone received a heart transplant while maintained on OAT.10

Given the significant knowledge gaps and evidenced based guidelines, this article aims to provide insight on safe and effective management of OAT throughout the transplant process.

PHARMACOLOGY OF OAT

OAT can broadly be classified into 2 categories: full or partial agonists. Full agonists (eg, methadone) activate mu opioid receptors (MOR) in the brain like other opioids. Partial agonists (eg, buprenorphine) also activate the MOR in the brain but to a lesser extent than full agonists, which renders a “ceiling effect.” Both methadone and buprenorphine reduce opioid withdrawal symptoms, opioid cravings, and OD mortality in patients with OUD.

Methadone has a long half-life of approximately 8–59 h based on individual patient characteristics. It has a biphasic elimination pattern in which the alpha elimination phase (8–12 h) is responsible for analgesia, whereas the beta elimination phase (30–60 h) is responsible for withdrawal suppression. Methadone need only occupy approximately 30% of MOR to provide withdrawal suppression, providing opportunity for receptor binding and effective analgesia with opioid analgesics perioperatively. When used for OUD, methadone should be given in a single daily dose. Concomitant use of methadone and CYP3A4, CYP2C19, and CYP2D6 inhibitors, which are often included in posttransplant antimicrobial prophylaxis regimens, can increase concentrations of methadone leading to excessive sedation. Pharmacist management of these interactions is imperative to avoid risk of sedation.

Buprenorphine is a partial agonist with high affinity for the MOR and a long half-life, ranging from 20 to 70 h. Unlike methadone, buprenorphine has less incidence of euphoria and respiratory depression due to its partial agonism and ceiling effect. With high binding affinity for the MOR, it can displace other full opioids from receptors which may precipitate withdrawal.

When patients are maintained on buprenorphine and in need of further pain management, it is important to consider that buprenorphine occupies 95% of opioid receptors with doses at or above 16 mg.11 Patients maintained on buprenorphine generally require at least 50%–60% opioid receptor occupancy to prevent withdrawal symptoms. Allowing patients to continue buprenorphine at a reduced dose during the perioperative phase offers the ability to control postoperative pain with additional opioid analgesics while minimizing risk of returning to other opioids. Similar to methadone, preclinical data suggest that buprenorphine is impacted by interactions with CYP3A4 inhibitors and inducers, although these have not been clinically proven in practice.12

Whether a patient is maintained on buprenorphine or methadone, it is important to remember that continuation of preprocedure daily OAT requirements must be met before attempting to achieve analgesia. Continuation of a patient’s daily dose of OAT avoids worsening of pain symptoms due to the increased sensitivity associated with withdrawal but does not provide analgesic relief to cover surgical pain. When considering adjunctive opioid pain medications for surgical and procedural pain management, morphine, fentanyl, and hydromorphone are preferred due to their highly competitive affinity for the MOR. Analgesic dosing should be scheduled rather than as needed to proactively prevent breakthrough pain rather than provide reactive dosing which risks OUD destabilization.13

OAT MANAGEMENT IN THE SETTING OF TRANSPLANT

Patients receiving OAT require advanced pain management planning to minimize risk of inadequate analgesia in the perioperative period, although such planning may not always be possible for urgent transplant evaluations. The subsequent recommendations, summarized in Figure 1, are intended for use in patients with a history of OUD currently on OAT therapy.

F1
FIGURE 1.:
Management of OAT before, during, and after transplant. MMTP, Methadone Maintenance Treatment Program; OAT, opioid agonist therapy.

Pretransplant Management

At the time of transplant evaluation, it is important to obtain an accurate medication history, which includes the type and duration of OAT use, current daily dose, as well as any relevant information from prior perioperative strategies and experiences. Addiction specialists can provide key insights regarding the patient’s OUD management and progress and can contribute to a multidisciplinary approach to transplant selection and eligibility planning. Although not every transplant center may have an addiction consult service, a pain service or anesthesiology may also provide valuable insight on the nuances of pain management in patients receiving OAT. Once an OUD management plan is established, the authors suggest clearly documenting the plan and contact information for involved parties, including outpatient providers, in the electronic health record to align all members of the team to a universal approach to perioperative management.

Peritransplant Management

The greatest challenge of perioperative management of OAT is that the timing of transplant is unpredictable as it is dependent on donor availability. When an organ offer is accepted by the patient, the pain or addiction consult service should be notified. On the day of the operation, patients should still receive their OAT but may require dose modification (Figure 1).14,15

Postoperative Management

Following transplant, it is imperative that all clinicians caring for the patient are aware of the use of OAT, which may necessitate higher-than-average dosing secondary to tolerance and hyperalgesia. Close monitoring for symptoms of withdrawal (including sweating, abdominal pain, diarrhea, and cravings) and treating withdrawal by increasing OAT dosing is crucial to preventing adverse outcomes such as splinting, respiratory complications, and altered mental status following transplant. Involvement of the pain service and utilization of varied pain management strategies including patient-controlled anesthesia may be considered, although it should be noted that significant doses and basal rates may be required. Additionally, multimodal analgesia with opioid-alternatives such as regional anesthesia techniques, acetaminophen, ketamine, and lidocaine where appropriate offer further support while avoiding renal damaging nonsteroidal anti-inflammatory drugs. The timing of the opioid taper plan and simultaneous up-titration of patient’s OAT is dependent on patient specific factors such as duration of intubation, intensive care unit stay, and complexity of their surgical case. If, for some reason, buprenorphine was stopped completely during the perioperative period, it should be carefully reintroduced to decrease risk of precipitated withdrawal. Strategies to minimize this risk include waiting for mild withdrawal from opioids or use of microdosing.12,16

Discharge Planning

Once a patient is transferred out of the intensive care unit to the floor, coordination among providers is imperative to ensure they return to their home regimen while allowing for adequate pain control. Upon discharge from the hospital, patients should continue to follow with pretransplant OAT providers to ensure continuity of care.

CONCLUSION

Inexperience and lack of empirical data with OAT in the setting of organ transplant has led to apprehension in listing and transplanting patients with OUD. This article aims to provide a systematic, multidisciplinary approach toward the management of these complex patients with the goal to increase organ transplant equity for patients in OUD remission on OAT. Collaborations between the transplant team and addiction or pain services provide valuable insight into safe management of OAT and opioid pain management in the setting of surgery and ensure that patients treated with these medications are able to continue their therapies without interruptions that could otherwise predispose them to risk of recurrence of OUD.

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