Low Dose Naltrexone – Can it hurt the liver?

Low Dose Naltrexone – Can it hurt the liver?

The FDA Warning for liver when taking very large doses (300 mg) of Naltrexone
& Clinical Trials about it safety in the liver

Unfortunately, the FDA Naltrexone ‘black box’ warning about the possibility of liver issues can be very misleading when investigating Naltrexone or Low Dose Naltrexone because it does not provide the scope or dosage on which the warning is based.   The below is information about the Black Box warning – it is based on a clinical study where patients were taking extremely high dosages of Naltrexone (300 mg a day) and a sub-set of obese patients developed some liver anomalies.  Additionally, included below are 4 subsequent National Institutes of Health / National Library of Medicine Clinical Studies or Articles that specifically discuss the safety of Naltrexone to the liver, when used below 300 mg a day.

Therefore, according to the below studies, the dosages of Low Dose Naltrexone (LDN), which are a very small fraction of either a regular or high dosage of Naltrexone, could be presumed to have no negative affect of the liver.   Note: The normal LDN dosage for adults is 4.5 mg or less per day, which is 1/66th of the maximum safe dosage level.  For children the normal dose is between 1 mg (1/300th of the maximum safe dosage) to 3 mg (1/100th of the maximum safe dosage).

Also, the immune modulating affect of the opioid antagonist, Naltrexone, have been shown to improve the liver’s condition, including reducing ALT/AST levels, cholestasis-induced liver injury, liver fibrosis, and hepatitis.   Those clinical trails will be posted separately.

The following is an excerpt from the National Institutes of Health/National Library of Medicine/Daily Med Website (http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=4682)

“Evidence of the hepatotoxic potential of naltrexone is derived primarily from a placebo controlled study in which naltrexone hydrochloride was administered to obese subjects at a dose approximately five-fold that recommended for the blockade of opiate receptors (300 mg per day)..”

*Note:  Patients with end-stage liver disease, severe cirrhosis, or in an acute hepatic state, should carefully consider with their doctor which drugs (including LDN) will adversely affect their liver given its extremely distressed state.*

The below four (4) clinical studies are quoted from the National Institutes of Health / National Library of Medicine/Pub Med Website:   (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed).

Study 1 –

Study of hepatotoxicity of naltrexone in the treatment of alcoholism.

Alcohol. 2006 Feb;38(2):117-20. Links

Yen MH, Ko HC, Tang FI, Lu RB, Hong JS.
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.

Since a black box warning was issued by the Food and Drug Administration regarding the use of the opiate antagonist naltrexone (NTX), many clinicians have been concerned about current labeling of the potential hepatotoxicity risk of NTX in the treatment of opiate dependence and alcoholism. Despite many reports that demonstrated that the use of NTX did not cause elevation of liver enzymes, controversy concerning whether NTX is hepatotoxic continues. The current study monitored 74 alcoholic patients who received 25mg of NTX daily in the first week and then 50mg of NTX daily for the rest of the 12-week period. After the 12-week treatment, levels of the hepatic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) did not show any elevation, except in one subject, and the results strongly support that NTX did not induce abnormalities in liver function tests or elevate the liver enzymes. Instead, a statistical significance of decreasing levels of ALT and AST in the liver was shown throughout the study. These findings provide further support that NTX is not hepatotoxic at the recommended daily dose and may be beneficial for patients with elevated liver enzymes.

PMID: 16839858 [PubMed – indexed for MEDLINE]

Study 2 –

High-dose naltrexone and liver function safety.

Am J Addict. 1997 Winter;6(1):21-9.Links

Marrazzi MA, Wroblewski JM, Kinzie J, Luby ED.
Department of Psychiatry, Harper-Grace Hospitals, Detroit, MI, USA.

Studies have found naltrexone useful in the treatment of diseases other than opiate addiction in which endogenous opioids presumably play a role, such as alcoholism and eating disorders. Some of these studies involve high doses (100-200 mg bid). Because investigational studies with high doses (300 mg/day) reported clinically significant increases in liver enzyme levels, the authors measured a spectrum of liver function parameters in response to high doses of naltrexone in a double-blind, crossover trial (100 mg bid) followed by an open-label period (200 mg bid). They observed no adverse clinical or laboratory changes in liver function in association with high-dose naltrexone therapy in eating disorders.

PMID: 9097868 [PubMed – indexed for MEDLINE]
Study 3 –

Naltrexone: report of lack of hepatotoxicity in acute viral hepatitis, with a review of the literature.

Addict Biol. 2004 Mar;9(1):81-7. Links

Brewer C, Wong VS.
The Stapleford Centre, London, UK. [email protected]

Many clinicians appear to be concerned about the potential hepatotoxicity of the opiate antagonist naltrexone (NTX) and this may be one reason why it is not used more widely in treating both heroin and alcohol abusers. Some much-quoted early studies noted abnormalities in liver function tests (LFTs) in very obese patients taking high doses, although there was no evidence of clinically significant liver dysfunction. These concerns may be reinforced by advice in the UK product information sheet to perform LFTs before and during treatment, by high infection rates with hepatitis C virus (HCV) among injecting heroin addicts and by the frequency of abnormal LFTs in alcohol abusers. We describe a heroin abuser in whom clinical and laboratory manifestations of acute hepatitis B and C appeared a few days after the insertion of a subcutaneous naltrexone implant. A decision was made not to remove the implant but the hepatitis resolved completely and uneventfully well within the normal time-scale. A review of the literature indicates that even when given at much higher doses than are needed for treating heroin or alcohol abusers, there is no evidence that NTX causes clinically significant liver disease or exacerbates, even at high doses, serious pre-existing liver disease. During the past decade, NTX has been shown to be safe and effective in the treatment of pruritus associated with severe jaundice caused by severe and sometimes life-threatening cirrhosis and other liver diseases. Its safety, even in these extreme conditions, is particularly reassuring. We suggest that it may be more appropriate and economical to advise patients to report promptly any suspected side effects than to perform regular LFTs, which may be misleading.

PMID: 15203443 [PubMed – indexed for MEDLINE]
Study 4 –

Safety of high-dose naltrexone treatment: hepatic transaminase profiles among outpatients.

Clin Neuropharmacol. 2006 Mar-Apr;29(2):77-9. Links

Kim SW, Grant JE, Yoon G, Williams KA, Remmel RP.
Department of Psychiatry, Medical School, University of Minnesota, Minneapolis, 55454-1495, USA. [email protected]

OBJECTIVES: This study was carried out to test the hypothesis that the hepatic safety profile of prolonged high-dose oral naltrexone (150 mg/d) is acceptable if over-the-counter analgesic use is restricted.

METHODS: Data from 41 consecutive outpatients with impulse-control disorder receiving naltrexone therapy were analyzed.

RESULTS: The mean treatment duration was 328 days and the mean naltrexone dose was 142 mg/d. Pretherapy/posttherapy mean aspartate transaminase and alanine transaminase levels in the naltrexone-alone group were 21.79/22.54 and 21.74/21.49 U, respectively (all within reference range).

CONCLUSIONS: Although limited in scope, these findings support the hypothesis that long-term use of high-dose oral naltrexone is safe in otherwise healthy patients with impulse-control disorders who restrict their intake of acetaminophen, aspirin, or nonaspirin nonsteroidal anti-inflammatory drugs (NSAID). However, confirming studies are needed.

PMID: 16614539 [PubMed – indexed for MEDLINE]

Note regarding National Institutes of Health / National Library of Medicine Copyright / Public Domain information – quoted from (http://www.nlm.nih.gov/copyright.html).

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