Treatment of opioid use disorder in patients with liver disease

Key Points

1. What is the impact of opioid use disorder (OUD) among patients with chronic liver disease?

2. How is OUD diagnosed, and what evidence-based treatment options exist—in general, and among those with chronic liver disease?

3. What are the implications of opioid use and opioid use disorder with regard to liver transplantation (eligibility for transplantation, outcomes after transplantation, perioperative management of pain in the setting of opioid agonist treatment or chronic opioid exposure)?

INTRODUCTION

OUD is a chronic, relapsing, and treatable condition characterized by continued opioid use despite negative consequences. Approximately 2.7 million people in the United States are affected by OUD.¹ The disorder has genetic, neurobiological, social, and environmental contributors. OUD is associated with structural brain changes involved in the reward system and memory formation.² Left untreated, OUD can lead to serious mental, physical, and social complications. Due to its chronic nature, long-term treatment is typically required.

Although the incidence of prescribed opioid misuse has decreased, nonprescribed opioid misuse and overdose mortality are climbing, driven by illicitly manufactured fentanyl and concurrent stimulant use. More than 80,000 Americans died of opioid-involved overdoses in 2021, an increase of 61% compared to 2 years prior.³ Black, Hispanic, and American Indian communities are disproportionately affected by OUD harms and overdose deaths and are less likely to receive treatment.⁴

OUD is associated with conditions that cause liver disease, including alcohol use disorder and viral hepatitis. Understanding the diagnosis, treatment, and complications of OUD is essential for all health care professionals caring for individuals with liver disease.

DIAGNOSIS AND TREATMENT

OUD is diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition criteria.⁵ People who use opioids and demonstrate at least 2 signs or symptoms from the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition criteria are diagnosed with OUD with severity graded by the number of symptoms (Box 1).

BOX 1.

DSM-5 Criteria for OUD

1. Opioids are often taken in larger amounts or over a longer period than was intended. 2. There is a persistent desire or unsuccessful efforts to cut down or control opioid use. 3. A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects. 4. Craving or a strong desire or urge to use opioids. 5. Recurrent opioid use resulting in a failure to fulfill major role obligations at work, school, or home. 6. Continued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids. 7. Important social, occupational, or recreational activities are given up or reduced because of opioid use. 8. Recurrent opioid use in situations in which it is physically hazardous. 9. Continued opioid use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance. 10. Tolerance, as defined by either of the following: (a) A need for markedly increased amounts of opioids to achieve intoxication or desired effect; or (b) A markedly diminished effect with continued use of the same amount of an opioid 11. Withdrawal, as manifested by either of the following: (a) The characteristic opioid withdrawal syndrome; or (b) Opioids are taken to relieve or avoid withdrawal symptoms Mild: 2–3 symptoms present Moderate: 4–5 symptoms present Severe: 6 or more symptoms present

Abbreviation: DSM-5, Diagnostic and Statistical Manual of Mental Disorders Fifth Edition; OUD, opioid use disorder.

Evidence-based OUD treatment is highly effective, and long-term pharmacotherapy is the standard of care. The 3 FDA-approved medications for opioid use disorder (MOUD) are methadone (full opioid agonist), buprenorphine (partial opioid agonist), and naltrexone (full opioid antagonist). Methadone, buprenorphine, and extended-release naltrexone have been shown to reduce morbidity and mortality, with the 2 opioid agonist treatments (ie, methadone and buprenorphine) having the strongest evidence. The best medication for an individual depends on their medical co-morbidities, prior treatment response, pharmacologic factors, and social needs. Table 1 provides a comparison of the 3 MOUD options to help guide clinical decision-making.

TABLE 1.

Key clinical considerations guiding the choice of medication for opioid use disorder

	Methadone	Buprenorphine	Naltrexone
Mechanism of action	Full mu-opioid receptor agonist	Partial mu-opioid receptor agonist	Full mu-opioid receptor antagonist
Mortality benefit	Yes, strong evidence	Yes, strong evidence	Unknown; weak evidence
Need for withdrawal before initiation	No	Possible; can reduce withdrawal with certain initiation strategies	Yes; abstain from all opioids for 4–7 d before initiation
Formulation	Oral	Sublingual; monthly or weekly XR subcutaneous injection	Monthly XR IM injection; oral
Location and administration	Only dispensed in a licensed OTP; requires daily observed dosing, with “take-home” doses allowed based on patient stability.	Prescribed outpatient by DEA-registered practitioners. XR injection administered by a qualified clinician.	XR injection administered by a qualified clinician.
Risk of respiratory depression	Higher than buprenorphine. Increased risk during initiation, in combination with sedating substances, or with decreased hepatic clearance.	Lower than full opioid agonists (eg, methadone)	None
Considerations in severe hepatic dysfunction (Child-Pugh Class C)	Decreased clearance requiring cautious initiation (eg, half of the standard starting dose) and close monitoring.	Decreased clearance requiring cautious initiation, but lower overdose risk than methadone. Consider using buprenorphine-only formulation (rather than buprenorphine/naloxone).	Not indicated

Abbreviations: DEA, Drug Enforcement Administration; IM, intramuscular; OTP, opioid treatment program; XR-naltrexone, extended-release naltrexone.

Methadone

Methadone is a full mu-opioid receptor agonist that suppresses opioid withdrawal and cravings and blocks opioid-related euphoria. It has a slow onset of action, taking ~120 hours to reach a steady state, and a long, variable elimination half-life. Methadone treatment is associated with sustained recovery time, improved social functioning, decreased risk of HIV and hepatitis C, and lower mortality.⁶ In the United States, methadone for OUD can only be accessed through government-licensed opioid treatment programs, where patients present for daily observed dosing. Those who demonstrate prolonged stability can access “take-home” doses that reduce the frequency of required visits.

Methadone is metabolized in the liver by the cytochrome P450 (CYP) system. Genetic variations in liver metabolism and CYP-mediated drug interactions influence the plasma concentration. Methadone can prolong the QT interval and cause arrhythmias (eg, torsades de pointes) in patients taking higher doses or other QT-prolonging drugs and in those with congenital long QT syndrome. Methadone clearance is substantially reduced in patients with severe hepatic dysfunction (ie, Child-Pugh Class C) and should be initiated cautiously, starting with low doses (eg, half of the standard dose). For example, for a hospitalized patient with OUD and severe hepatic dysfunction in acute opioid withdrawal, initiating methadone 10 mg (compared to 20 mg for patients without hepatic dysfunction) may be appropriate. Repeated doses should be given until withdrawal symptoms abate up to a maximum dose of 40 mg/day with monitoring for sedation.

Buprenorphine

Buprenorphine is a partial mu-opioid receptor agonist that suppresses opioid withdrawal and cravings and blocks the opioid-induced euphoria. Buprenorphine’s mu-opioid receptor activation plateaus with increasing doses, resulting in a “ceiling effect” on respiratory and central nervous system depression; thus, it carries a significantly lower overdose risk than full opioid agonists. Buprenorphine improves recovery rates and psychosocial outcomes and is at least as effective as methadone in reducing mortality.⁷

Buprenorphine is available in sublingual formulation, alone or in combination with the opioid antagonist naloxone, and in 2 extended-release subcutaneous injections administered weekly or monthly by a medical professional. All practitioners registered by the Drug Enforcement Administration can prescribe buprenorphine for OUD in general health settings, making it more accessible than methadone. For patients with physical opioid dependence, buprenorphine must be initiated by an induction method to avoid precipitated withdrawal.⁸

Like methadone, buprenorphine is metabolized primarily by the CYP system. Observational data demonstrates rare transaminase elevations and no cases of DILI with buprenorphine treatment. Buprenorphine can be safely used in patients with severe hepatic dysfunction with cautious initiation and titration. Hepatic impairment reduces naloxone clearance, so sublingual buprenorphine/naloxone in patients with severe hepatic dysfunction can cause withdrawal; thus, the buprenorphine-only formulation may be preferred.⁹

Naltrexone

Naltrexone is a full mu-opioid receptor antagonist available as a daily oral tablet and a monthly extended-release intramuscular injection administered by a medical professional. I.M. naltrexone reduces opioid cravings, improves abstinence rates, and has a possible mortality benefit.¹⁰ Evidence on the efficacy of oral naltrexone is mixed with some studies showing no benefit over placebo.¹¹ Naltrexone is also FDA-approved for the treatment of alcohol use disorder. Individuals must abstain from opioids for at least 4–7 days before starting naltrexone to avoid precipitated withdrawal. This is a major barrier to starting naltrexone compared to methadone and buprenorphine and contributes to lower initiation rates. Because naltrexone reduces opioid tolerance, individuals who return to opioid use are at higher risk of fatal overdose.

Naltrexone is associated with variable liver enzyme elevations with very rare cases of liver injury. Naltrexone has demonstrated safety for use in alcohol-associated compensated cirrhosis; however, evidence in patients with severe hepatic dysfunction is limited, and naltrexone should only be used with caution in patients recovering from acute hepatitis.

Social, psychological, and behavioral treatments

Counseling, recovery coaching, and interventions to improve social determinants of health are important parts of OUD treatment. Harm reduction measures save lives and reduce stigma. Syringe service programs and overdose prevention centers (ie, safer consumption sites) reduce transmission of viral hepatitis and HIV, prevent overdose, and connect patients to OUD treatment. All individuals who use opioids should be given intranasal naloxone and counseling on overdose prevention.

LIVER TRANSPLANTATION CONSIDERATIONS

Patients with OUD may be referred for liver transplantation, given the high prevalence of co-morbid OUD and liver disease. Guidelines on liver transplantation evaluation recommend a psychiatric consultation to assess for mental health and substance use disorders.¹² There is no specific recommended abstinence requirement for patients with OUD being considered for liver transplantation. In comparison, at least 6 months of abstinence from alcohol use is commonly required for patients with alcohol-associated liver disease.¹² The guidelines reinforce that patients “should not be denied transplantation based on methadone use alone, and expectations of methadone reduction or discontinuation should not be a requirement for transplant listing (1-B).”¹²

There is significant variability across liver transplant centers with respect to the eligibility of patients taking MOUD. In a 2017 survey of liver transplant centers, only 1 program considered methadone or buprenorphine treatment an absolute contraindication to transplant, while 38% considered it a relative contraindication.¹³ One-third of centers required doses of methadone or buprenorphine below a certain threshold, which conflicts with OUD treatment standards of practice that recommend individualized dosing to improve quality of life and reduce opioid-related harm.

Published evidence on transplantation outcomes among patients on MOUD is promising, with most data coming from retrospective studies of patients on methadone. In the largest retrospective study, 36 liver transplant recipients receiving methadone had similar patient and graft survival rates to the national average, with only 4 documented single-time episodes of posttransplant injection drug use.¹⁴ Data on buprenorphine and transplant outcomes is more limited. There are 2 case reports of patients taking buprenorphine-naloxone who received liver transplants, both of whom maintained good graft function and abstinence from nonprescribed opioids within 18 months of transplant.¹⁵

Programs evaluating patients with OUD for liver transplantation should take an individualized approach and prioritize evidence-based treatment. Policies that require tapering or discontinuing MOUD put patients at risk of returning to nonprescribed opioid use, reducing their odds of ever receiving a transplant. Involving an addiction medicine specialist can help optimize treatment and establish longitudinal care to support the patient’s recovery posttransplant.

MANAGEMENT OF ACUTE AND PERIOPERATIVE PAIN IN PATIENTS WITH OUD AND LIVER DISEASE

Treating acute pain in patients with OUD can be challenging due to the complex and interrelated nature of pain and OUD. MOUD adds complexity because of their unique pharmacologic profiles and potential interactions with opioid analgesics. While methadone and buprenorphine may interfere with analgesic efficacy, current guidelines recommend continuing these medications during the perioperative period.¹⁶ Higher doses and shorter dosing intervals of opioid analgesics may be required due to increased pain sensitivity and cross-tolerance. Naltrexone blocks the effects of opioid analgesics. Therefore, oral naltrexone should be stopped 72 hours before and IM naltrexone 30 days before scheduled surgery.

CONCLUSION

OUD is prevalent and causes substantial morbidity and mortality. Long-term, evidence-based treatment with medications and psychosocial treatments are highly effective and decrease mortality. It is crucial to continue OUD treatment, including medications, during the perioperative period.