Can naltrexone be given to patients with liver impairment?

Comment by InpharmD Researcher

Despite naltrexone being metabolized via the liver, expert opinion suggests using it can be used with caution in patients with liver impairment as the risk of further liver injury is minimal. Additionally, naltrexone is often given to patients with a high background rate of liver disease, and there have been no proven cases of clinically apparent liver injury due to naltrexone. Studies evaluating use of naltrexone in patients with liver disease have found it can be safely used without risk for further toxicity, but overall, the data are of low-quality and require further investigation in larger, randomized controlled trials.

Background

According to the LiverTox database, naltrexone is typically given to patients with a high background rate of liver disease (injection drug use or alcoholism) and has been associated with variable rates of serum enzyme elevations (0% to 50%), with values above 3 times the upper limit of normal occurring in approximately 1% of patients and occasionally leading to drug discontinuation. However, several studies have found that the rate of alanine aminotransferase (ALT) elevations during naltrexone therapy is similar to that with placebo. Notably, most serum aminotransferase elevations during naltrexone therapy are mild and self-limiting and often resolve even with continuation of therapy. While there have been rare reports of acute, clinically apparent liver disease in patients taking naltrexone, the role of the medication in liver injury has not always been clear. Additionally, no clear description of the clinical features of the injury are given. Overall, while naltrexone has often been considered hepatotoxic, it has not been definitively linked to cases of clinically apparent liver injury. [1]

A recent review published in 2022 discussing treatment of alcohol use disorder in patients with liver disease suggests using naltrexone with caution in cirrhosis patients since the medication is metabolized via the liver. Mild liver injury has been reported in approximately 1% of patients, but there have been no proven cases of clinically apparent liver injury. [2]

A 2005 pharmacokinetic study evaluated the influence of mild and moderate hepatic impairment on naltrexone pharmacokinetics following long-acting naltrexone 190-mg administration. Subjects with mild (Child-Pugh grade A) and moderate (Child-Pugh grade B) hepatic impairment (n= 6 in each group) and matched control subjects (n= 13) were included in the study. Naltrexone concentrations in subjects with mild hepatic impairment were higher or equal to those of matched healthy control subjects, but mean concentrations in subjects with moderate hepatic impairment were lower or equal to those of the respective healthy control group. Total naltrexone exposure was similar across all groups. Long-acting naltrexone was well tolerated in all subjects, but adverse events were more common in patients with mild hepatic impairment (5 of 6) and moderate hepatic impairment (4 of 6) compared with healthy subjects (3 of 13). However, most adverse events were mild in severity, with headache being the most frequently reported adverse event; there were no trends or clinically meaningful changes from baseline observed in mean or median clinical laboratory values including hepatic enzymes. Mean ALT and aspartate aminotransferase (AST) levels increased 28 days after long-acting naltrexone injection (30.3 and 24 U/L change from baseline, respectively) in subjects with moderate hepatic impairment, but this increase primarily reflected changes in 2 subjects whose enzyme levels were variable and were thought to be associated with their underlying medical conditions (hepatitis C and alcohol-induced cirrhosis of the liver). Based on the study findings, it was concluded that the long-acting naltrexone dosage does not need to be adjusted in patients with mild or moderate hepatic impairment. [3]

References:

[1] LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Naltrexone. [Updated 2020 Mar 24]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548583/
[2] Nielsen AS, Askgaard G, Thiele M. Treatment of alcohol use disorder in patients with liver disease. Curr Opin Pharmacol. 2022;62:145-151. doi:10.1016/j.coph.2021.11.012
[3] Turncliff RZ, Dunbar JL, Dong Q, et al. Pharmacokinetics of long-acting naltrexone in subjects with mild to moderate hepatic impairment. J Clin Pharmacol. 2005;45(11):1259-1267. doi:10.1177/0091270005280199
Relevant Prescribing Information

Hepatotoxicity
Cases of hepatitis and clinically significant liver dysfunction were observed in association with naltrexone hydrochloride exposure during the clinical development program and in the postmarketing period. Transient, asymptomatic hepatic transaminase elevations were also observed in the clinical trials and postmarketing period. When patients presented with elevated transaminases, there were often other potential causative or contributory etiologies identified, including pre-existing alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other potentially hepatotoxic drugs. Although clinically significant liver dysfunction is not typically recognized as a manifestation of opioid withdrawal, opioid withdrawal that is precipitated abruptly may lead to systemic sequelae, including acute liver injury. Patients should be warned of the risk of hepatic injury and advised to seek medical attention if they experience symptoms of acute hepatitis. Use of naltrexone hydrochloride should be discontinued in the event of symptoms and/or signs of acute hepatitis. [4]
Hepatic Impairment
An increase in naltrexone AUC of approximately 5- and 10-fold in patients with compensated and decompensated liver cirrhosis, respectively, compared with subjects with normal liver function has been reported. These data also suggest that alterations in naltrexone bioavailability are related to liver disease severity. [4]

References:

[4] Naltrexone hydrochloride. Prescribing information. Chartwell RX, LLC; 2022.
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Can naltrexone be given to patients with liver impairment?

Please see Tables 1-3 for your response.

 

Pharmacokinetics of Long-Acting Naltrexone in Subjects With Mild to Moderate Hepatic Impairment

Design

Randomized, double-blinded, parallel-group, multicenter, placebo-controlled, phase 3 study

N= 250

Objective

To evaluate the efficacy and safety of XR-NTX in treating patients who were dependent on opioids

Study Groups

Naltrexone XR (n=126)

Placebo (n=124)

Inclusion Criteria

 Diagnosis of opioid dependence; actively seeking treatment; recently received inpatient (up to 30 days) treatment for opioid detoxification

Exclusion Criteria

Patients with evidence of decompensated liver disease (e.g., ascites, jaundice, encephalopathy, or esophageal varices); an ALT or AST greater than three times the ULN at screening; baseline or total bilirubin greater than 10% above the ULN; patients with evidence of AIDS-defining illness; positive naloxone text during the study

Methods

Participants were randomized 1:1 to receive extended-release naltrexone 380 mg injections or placebo once monthly. To evaluate the safety of naltrexone XR, liver enzymes were compared with that of the placebo group in patients with liver disease and HIV infection. Liver enzymes were collected at baseline and before patients revived their monthly injections.

Duration

July 3, 2008, through October 5, 2009

Outcome Measures

Abnormal laboratory tests and incidence of treatment-emergent adverse events

Frequency of liver enzyme elevations (three times the Upper limit of Normal[ULN])

Baseline Characteristics

  

Naltrexone XR (n=126)

Placebo (n=124)

  

Age, years (mean SD)

 29.4 ± 4.8 29.7 ± 3.6  

Male

 88.0%  

Hepatitis C

HIV positive

88.8%

42%

  

While individual baseline characteristics were not reported for each group, the authors state they were equally distributed.

Results

Endpoint

Naltrexone XR (n=126)

Placebo (n=124)

p-value

ALT elevation

Baseline

Week 4

Week 12

Week 24

Any post-baseline elevation

 

0

10.7%

3.5%

4.4%

19.6%

 

0

6.2%

6.7%

4.2%

12.9%

 0.876

AST elevation

Baseline

Week 4

Week 12

Week 24

Any post-baseline elevation

 

0

8.7%

2.3%

2.9%

14.0%

 

0

6.2%

3.3%

3.8%

10.6%

 0.713

GGT elevation

Baseline

Week 4

Week 12

Week 24

Any post-baseline elevation

 

18.3%

17.5%

12.6%

8.8%

23.4%

 

20.2%

14.8%

13.3%

10.4%

21.2%

 0.811

Adverse Events

Common Adverse Events: not reported

Discontinued due to Adverse Events: 2 patients dropped out of the study when the liver enzymes were three times the ULN

Study Author Conclusions

Naltrexone extended release can be used safely in eligible patients with opioid dependence, including those with underlying mild to moderate chronic HCV and/or HIV infections. 

InpharmD Researcher Critique

Patients with liver impairments usually have fluctuations in liver enzymes, making it a challenge to interpret the liver enzyme results. However, this data was able to provide trends from both baseline and post-baseline levels. One limitation is the large amount of dropouts or exclusions during the 24-week trial. Other limitations may be due to the population of White Russian males at a single center, reducing the extrapolatability of these results to other populations.

It is also possible that any ALT elevations observed were adaptations rather than true liver injuries. Elevations in ALT occasionally resolve spontaneously in patients taking potentially hepatotoxic drugs.

 

References:

Turncliff RZ, Dunbar JL, Dong Q, et al. Pharmacokinetics of long-acting naltrexone in subjects with mild to moderate hepatic impairment. J Clin Pharmacol. 2005;45(11):1259-1267. doi:10.1177/0091270005280199

 

Naltrexone for alcohol use disorder: Hepatic safety in patients with and without liver disease

Design

Retrospective, observational, single-center, cohort study

N= 160

Objective

To evaluate the safety of naltrexone in those with liver disease (LD)

Study Groups

Without LD (n = 60)

With LD (n = 100)

Inclusion Criteria

Patients with prescriptions of naltrexone for alcohol use disorder (AUD)

Exclusion Criteria

Patients with naltrexone prescriptions for indications other than AUD; patients with other known chronic liver diseases including chronic hepatitis B or C infection

Methods

This was a retrospective study from a single center in California. Of 160 patients prescribed naltrexone for AUD, 100 (63%) had LD, and 47 (47%) of those with LD had cirrhosis (47% decompensated).

Duration

2015 to 2019

Outcome Measures

Differences in mean AST, ALT, ALP, and Tbili at three time points (before, during, and after naltrexone) were assessed overall and by group (without LD, LD without cirrhosis, and cirrhosis)

Mortality including deaths from all causes and alcohol-related hospitalizations included hospitalizations for alcohol withdrawal, alcohol-associated hepatitis, alcohol-induced gastrointestinal bleed or pancreatitis, and decompensated cirrhosis.

Baseline Characteristics

  

Without LD (n = 60)

With LD (n = 100)

p-value 

Age, years (IQR)

 46 (34–56) 51(41–58)  0.05
Male gender

70%

 86% 0.01

Ethnicity

Black

Caucasian

Asian

Unknown

Hispanic

 

10%

8%

3%

73%

52%

 

13%

2%

1%

1%

71%

 0.03

Comorbidities

Psychiatric history

Diabetes

Hyperlipidemia

 

80%

7%

12%

 

39%

21%

17%

 

<0.001

0.02

0.36

BMI, kg/m2 (IQR)

27 (24–29)

28 (23–31)

0.61

Oral naltrexone formulation

88%

 95% 0.40

Naltrexone dose prescribed

25 mg/day

50 mg/day

380 mg/month

 

3%

85%

12%

 

5%

90%

5%

0.27

>30 days of naltrexone

70%

63%

0.40

Alcohol-related hospitalization after naltrexone

7%

26%

0.003

Results

 

 Without LD (n = 60) With LD (n = 100)  

ALT, IU/L

Baseline

During treatment

After treatment

 

22

25

25

 

39

32

28

  

AST, IU/L

Baseline

During treatment

After treatment

 

25

27

27

 

59

46

39

  

ALP, IU/L

Baseline

During treatment

After treatment

 

70

65

97

 

98

94

100

  

Total bilirubin, mg/dL

Baseline

During treatment

After treatment

 

0.40

0.52

0.19

 

0.86

0.82

0.54

  

Mortality: Follow-up of 10 months (IQR, 4–18), eight patients died. Cumulative 2-year survival in patients without LD was 97.7% (95% CI, 84.6–99.7) compared to 95.4% (95% CI, 82.8–98.8; p = 0.93) for those with LD alone, 90.8% (95% CI, 73.5–97.0; p = 0.52) for those with cirrhosis, and 81.3% (95% CI, 51.2–93.8; p = 0.25) for those with decompensated cirrhosis

Alcohol-related hospitalizations: 30 patients (19%) had at least one subsequent alcohol-related hospitalization and no hospitalizations related to naltrexone hepatoxicity. Cumulative incidence of 2-year alcohol-related hospitalizations after naltrexone prescriptions was 8.2% (95% CI, 2.7–24.0) for those without LD compared to 27.7% for LD alone (95% CI, 16.6–44.0; p = 0.09), 40.5% for LD with cirrhosis (95% CI, 24.8–61.6; p = 0.006), and 41.7% (95% CI, 23.3–66.6; p = 0.005) for decompensated cirrhosis.  Alcohol-related hospitalization rates were highest among those with LD and shorter naltrexone prescriptions (45.3%; 95% CI, 28.6–66.0) and lowest in those without LD and shorter naltrexone prescriptions (0%) (p < 0.001)

Adverse Events

Not disclosed

Study Author Conclusions

 Naltrexone is safe for patients with underlying liver disease with a very low incidence of liver enzyme elevations and no evidence of hepatotoxicity.

InpharmD Researcher Critique

Some limitations in this study include liver enzyme elevations, severe liver enzyme elevations, transient elevations, and clinically meaningful hepatoxicity were detected only if laboratory values were checked. Adherence or gaps in prescriptions were not measured. Naltrexone prescriptions outside of the hospital system were not assessed.

Drinking history was not recorded in health records. Information regarding patient visits outside of the network hospital was lacking. The cohort was composed mainly of Hispanic subjects and this will limit the generalizability to the population. The cohort of decompensated individuals with cirrhosis was small, limiting the power of this analysis. The potential confounding effect of psychotherapy was not captured.

Some strengths in this study include hepatologists were not involved in prescribing naltrexone for those with LD, it is less likely that selection was based on liver disease severity. 



References:

Ayyala D, Bottyan T, Tien C, et al. Naltrexone for alcohol use disorder: Hepatic safety in patients with and without liver disease. Hepatology Communications. 2022;6(12):3433-3442.

 

Incidence and Progression of Alcohol-Associated Liver Disease After Medical Therapy for Alcohol Use Disorder

Design

Retrospective, observational, single-center, cohort study

N= 9635

Objective

To ascertain whether medical addiction therapy was associated with an altered risk of developing alcohol-associated liver disease (ALD) in patients with alcohol use disorder (AUD)

Study Groups

Treated (n=3906)

Untreated (n=5729)

Inclusion Criteria

Patients with ALD who had at least 1 of the following International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis codes: alcoholic hepatitis (K70.1), alcoholic cirrhosis of liver (K70.3), alcoholic hepatic failure (K70.4), alcoholic fibrosis and sclerosis (K70.2), other cirrhosis (K74.69), or unspecified cirrhosis (K74.60); received 3 prescriptions for at least 1 of the following: disulfiram, acamprosate, naltrexone, gabapentin, topiramate, or baclofen

Exclusion Criteria

None explicitly stated

Methods

Eligible patients were from a research institution in Massachusetts. Information was collected for patients meeting the inclusion criteria. The ICD-10 diagnosis codes used were alcohol abuse (F10.1) or alcohol dependence (F10.2). The cohort of patients was split into those treated with medical addiction therapy or not.

Duration

The mean duration of therapy for patients in the treated group was 4.1 years, whereas the mean follow-up duration from AUD diagnosis was 9.8 years in the treated group and 8.8 years in the untreated group.

Outcome Measures

Incidence of ALD and hepatic decompensation after medication addiction therapy

Baseline Characteristics

  

Treated (n= 3906)

Untreated (n= 5729)

Mean Age, years

 55 ± 15.3 54.7 ± 59.5

Female

44.4% 36.2%

White

 84.8% 82.5%
Viral hepatitis

16.2%

 9.9%
Nonalcohol substance use disorder

49.8%

 27.6%

Results

Any pharmacotherapy (e.g., gabapentin, topiramate, baclofen, naltrexone, disulfiram, or acamprosate) was associated with decreased odds of developing ALD after therapy (aOR, 0.37; 95% CI, 0.31-0.43; p< 0.001).

Naltrexone therapy was independently associated with decreased odds of developing ALD (aOR, 0.67; 95% CI, 0.46-0.95; p= 0.03) after medical addiction therapy.

The only agent that was not associated with decreased odds of ALD development was disulfiram (aOR, 0.86; 95% CI, 0.43-1.61; p= 0.66).

Any pharmacotherapy (e.g., gabapentin, topiramate, baclofen, naltrexone, disulfiram, or acamprosate) was associated with decreased odds of developing hepatic decompensation after therapy (aOR, 0.35; 95% CI, 0.23-0.53; p< 0.001).

Naltrexone therapy was independently associated with reduced incidence of hepatic decompensation in patients with cirrhosis (aOR, 0.27; 95% CI, 0.10-0.64; p= 0.005).

Baclofen (p= 0.91), acamprosate (p= 0.06), and disulfiram (p= 0.24) were the only studied agents not significantly associated with decreased hepatic decompensation; these three agents were associated with increased odds of developing hepatic decomensation.

Adverse Events

 N/A

Study Author Conclusions

Naltrexone is currently contraindicated in severe liver disease given the concern for hepatotoxicity and the precipitation of liver failure in these vulnerable patients. The results of this study suggest a benefit of naltrexone: it is a factor in not only preventing ALD but also limiting hepatic decompensation in patients with established cirrhosis.

InpharmD Researcher Critique

This study is not generalizable due to the patient population being majority white and there was not a balanced population of females and males. There were no subgroup analyses based on each studied medication and it was unreported if polypharmacy occurred with the studied agents. As a retrospective single-center study, there is a potential for confounding variables to influence these results. There was also no documentation on adherence to AUD pharmacotherapy.



References:

Vannier AGL, Shay JES, Fomin V, et al. Incidence and Progression of Alcohol-Associated Liver Disease After Medical Therapy for Alcohol Use Disorder. JAMA Netw Open. 2022;5(5):e2213014. Published 2022 May 2. doi:10.1001/jamanetworkopen.2022.13014