Naltrexone Hydrochloride

(BANM, rINNM)
Synonyms: EN-1639A; Hidrocloruro de naltrexona; Naltreksonihydrokloridi; Naltreksono hidrochloridas; Naltrexone, chlorhydrate de; Naltrexon-hydrochlorid; Naltrexonhydroklorid; Naltrexoni hydrochloridum.
Cyrillic synonym: Налтрексона Гидрохлорид.

💊 Chemical information

Chemical formula: C20H23NO4,HCl = 377.9.
CAS — 16676-29-2.
ATC — N07BB04.
ATC Vet — QN07BB04.

Pharmacopoeias.

In Eur. and US.

Ph. Eur. 6.2

(Naltrexone Hydrochloride). A white or almost white, very hygroscopic, powder. Freely soluble in water; slightly soluble in alcohol; practically insoluble in dichloromethane. Store in airtight containers. Protect from light.

USP 31

(Naltrexone Hydrochloride). Store in airtight containers.

💊 Adverse Effects

Difficulty in sleeping, loss of energy, anxiety, dysphoria, abdominal pain, nausea, vomiting, reduction in appetite, joint and muscle pain, and headache may occur with naltrexone. Dizziness, constipation, diarrhoea, skin rashes, and reduced potency and ejaculatory difficulties have also been reported. Some adverse effects may be associated with opioid withdrawal. Thrombocytopenic purpura has occurred rarely. High doses may cause hepatocellular injury. Injection site reactions, including abscesses and tissue necrosis, have been reported with use of the intramuscular preparation.

Effects on the liver.

Increased liver enzyme values were reported in 6 of 40 obese patients given naltrexone 50 or 100 mg daily for 8 weeks.1 Five of the 6 patients had minimally abnormal liver function before naltrexone was given and liver function tests returned to baseline values or better on stopping naltrexone. Raised transaminase levels were noted in 5 of 26 obese patients after 3 weeks of treatment with naltrexone 300 mg daily; transaminase activity returned to normal when treatment was stopped.2
1. Atkinson RL, et al. Effects of long-term therapy with naltrexone on body weight in obesity. Clin Pharmacol Ther 1985; 38: 419–22
2. Mitchell JE. Naltrexone and hepatotoxicity. Lancet 1986; i: 1215.

Effects on the muscles.

Asymptomatic rhabdomyolysis has been reported1 in a patient receiving naltrexone; the condition resolved when naltrexone was withdrawn.
1. Zaim S, et al. Rhabdomyolysis associated with naltrexone. Ann Pharmacother 1999; 33: 312–3.

💊 Precautions

Naltrexone should be avoided in patients receiving opioids therapeutically, or in those misusing them, as an acute withdrawal syndrome may be precipitated. Withdrawal symptoms may develop within 5 minutes and last up to 48 hours. Naltrexone should be discontinued at least 48 hours before elective surgery involving opioid analgesia. For further precautions when using naltrexone as an adjunct in the treatment of opioid dependence, see Uses and Administration, below. When analgesia is required, larger doses than usual of opioids will be needed and there is an increased risk of respiratory depression and other adverse effects. Naltrexone should be used with caution in patients with hepatic impairment and is contra-indicated in patients with acute hepatitis or hepatic failure. Regular monitoring of hepatic function has been recommended. Naltrexone should be given with caution to patients with renal impairment.

💊 Pharmacokinetics

Naltrexone is well absorbed from the gastrointestinal tract but is subject to considerable first-pass metabolism and may undergo enterohepatic recycling. It is extensively metabolised in the liver and the major metabolite, 6β-naltrexol, may also possess weak opioid antagonist activity. Maximum plasma concentrations of naltrexone and 6β-naltrexol are achieved in about 1 hour and naltrexone is about 20% bound to plasma proteins at therapeutic doses. The elimination half-life of naltrexone is approximately 4 hours and that of 6βnaltrexol about 13 hours. Naltrexone and its metabolites are excreted mainly in the urine. Less than 1% of an oral dose of naltrexone is excreted unchanged.

Hepatic impairment.

A study1 in 11 patients with hepatic cirrhosis found that the systemic availability of naltrexone was significantly increased, particularly in those with decompensated disease.
1. Bertolotti M, et al. Effect of liver cirrhosis on the systemic availability of naltrexone in humans. J Hepatol 1997; 27: 505–511.

💊 Uses and Administration

Naltrexone is a specific opioid antagonist with actions similar to those of naloxone; however, it is more potent than naloxone and has a longer duration of action. It is used in the management of opioid dependence and alcohol dependence, and has also been investigated in other addictive disorders. Naltrexone is used as the hydrochloride as an aid to maintaining abstinence after opioid withdrawal in detoxified, formerly opioid-dependent patients. Naltrexone treatment should not be started until the patient has been detoxified and abstinent from opioids for at least 7 to 10 days because of the risk of acute withdrawal; abstinence should be verified by analysis of the patient’s urine. A naloxone challenge test should then be performed to confirm the absence of opioid dependence, as follows: naloxone hydrochloride 200 micrograms is given intravenously and the patient observed for 30 seconds for evidence of withdrawal symptoms; if none occur, a further dose of 600 micrograms is given and the patient observed for 30 minutes. A confirmatory rechallenge with naloxone hydrochloride 1.6 mg intravenously may be considered if results are ambiguous. Sources in the USA suggest a naloxone challenge test with a single dose of 800 micrograms given subcutaneously as an alternative to the intravenous route. Once a negative naloxone challenge test has been obtained, naltrexone hydrochloride is given orally to maintain abstinence. Treatment may be initiated with a dose of 25 mg. If no signs of opioid withdrawal occur subsequent doses may be increased to 50 mg daily. The usual maintenance dose of naltrexone hydrochloride is 350 mg weekly given as 50 mg daily, but the dosing interval may be lengthened to improve compliance; for example, doses of 100 mg on Monday and Wednesday and 150 mg on Friday may be effective, and various other intermittent dosage regimens have been used. Patients should be carefully counselled and warned that attempts to overcome the opioid blockade with large doses of opioids could result in fatal opioid intoxication. Naltrexone hydrochloride is also used as an adjunct in the management of alcohol dependence at a recommended oral dose of 50 mg daily. Alternatively, naltrexone (as the base) may be given as a modified-release intramuscular injection in a dose of 380 mg once every 4 weeks.

Alcohol withdrawal and abstinence.

Naltrexone may be of use as an adjunct to psychotherapy in maintaining abstinence after alcohol withdrawal in patients with alcohol dependence. Two systematic reviews1,2 have concluded that oral naltrexone is safe and effective for the short-term treatment of alcohol dependence, although there is less evidence for longterm benefit. However, since the risk of relapse is particularly high early after alcohol withdrawal, treatment for at least 3 to 6 months has been recommended.2,3 Compliance with oral naltrexone may be a problem,1,2 and promising results4,5 have been reported with a long-acting intramuscular injection given monthly. Naltrexone appears to be more effective at reducing the amount of alcohol consumed than producing complete abstinence;1reports6 from patients who continued to drink during therapy suggest that naltrexone may reduce the pleasure associated with drinking, possibly by blocking the effect of endorphins released as a result of alcohol consumption. Although naltrexone does not appear to be hepatotoxic at the oral dosage of 50 mg daily used for alcohol dependence, caution is recommended in patients with liver disease;3 careful monitoring is recommended if it is given with disulfiram since hepatotoxicity could potentially be increased. Other opioid antagonists have also been studied. Preliminary results7,8 suggest that nalmefene may also be effective, although there is insufficient evidence to recommend its use.2
1. Carmen B, et al. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 2004; 99: 811–28
2. Srisurapanont M, Jarusuraisin N. Opioid antagonists for alcohol dependence. Available in The Cochrane Database of Systematic Reviews; Issu
1. Chichester: John Wiley; 2005 (accessed 04/10/05)
3. Berg BJ, et al. A risk-benefit assessment of naltrexone in the treatment of alcohol dependence. Drug Safety 1996; 15: 274–82
4. Garbutt JC, et al. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA 2005; 293: 1617–25. Correction. ibid.: 1978
5. Swainston Harrison T, et al. Extended-release intramuscular naltrexone. Drugs 2006; 66: 1741–51
6. Volpicelli JR, et al. Effect of naltrexone on alcohol "high" in alcoholics. Am J Psychiatry 1995; 152: 613–15
7. Mason BJ, et al. A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HCl for alcohol dependence. Alcohol Clin Exp Res 1994; 18: 1162–7
8. Mason BJ, et al. A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry 1999; 56: 719–24.

Autism.

Autistic disorders have been linked with abnormalities in the endogenous opioid system and there is some evidence1 that naltrexone may be of benefit in children with autism, especially in those with self-injurious behaviour.
1. ElChaar GM, et al. Efficacy and safety of naltrexone use in pediatric patients with autistic disorder. Ann Pharmacother 2006; 40: 1086–95.

Opioid dependence.

MAINTENANCE. Naltrexone is a longacting, non-addictive oral opioid antagonist. It can be effective in maintaining abstinence in opioid addicts after detoxification, but compliance with therapy is difficult to maintain because although it blocks the euphoriant effects of opioids it does not block the craving for narcotics. It is thus most effective in highly motivated addicts with good sociological and psychological support to discourage impulsive use of opioids. Subcutaneous formulations have also been used but have been associated with serious complications (see Rapid Detoxification, below). For a discussion of the management of opioid dependence.
1. Gonzalez JP, Brogden RN. Naltrexone: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence. Drugs 1988; 35: 192–213
2. Minozzi S, et al. Oral naltrexone maintenance treatment for opioid dependence. Available in The Cochrane Database of Systematic Reviews; Issu
1. Chichester: John Wiley; 2006 (accessed 02/09/08)
3. NICE. Naltrexone for the management of opioid dependence: Technology Appraisal Guidance 115 (issued January 2007). Available at: http://guidance.nice.org.uk/TA115/guidance/pdf/ English (accessed 02/05/07
4. Lobmaier P, et al. Sustained-release naltrexone for opioid dependence. Available in The Cochrane Database of Systematic Reviews; Issu
2. Chichester: John Wiley; 2008 (accessed 21/07/08).
RAPID DETOXIFICATION. Naltrexone has been used in various regimens for rapid detoxification;1,2 opioid withdrawal may be achieved in only a few days, although benefits for longterm outcome are not yet established. It has also been used for ultrarapid detoxification under anaesthesia, although a systematic review3 concluded that the risks outweighed the benefits of using opioid antagonists in such procedures. A later study4 also failed to support the use of such a regimen. After detoxification, patients may be given oral naltrexone for maintenance; subcutaneous formulations of naltrexone have also been used in an attempt to improve compliance, although serious complications, including deaths, have been reported5-7 with their use.
1. O’Connor PG, Kosten TR. Rapid and ultrarapid opioid detoxification techniques. JAMA 1998; 279: 229–34
2. Gowing L, et al. Opioid antagonists with minimal sedation for opioid withdrawal. Available in The Cochrane Database of Systematic Reviews; Issu
1. Chichester: John Wiley; 2006 (accessed 02/09/08)
3. Gowing L, et al. Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal. Available in The Cochrane Database of Systematic Reviews; Issu
2. Chichester: John Wiley; 2006 (accessed 02/09/08)
4. Collins ED, et al. Anesthesia-assisted vs buprenorphine- or clonidine-assisted heroin detoxification and naltrexone induction: a randomized trial. JAMA 2005; 294: 903–13
5. Hamilton RJ, et al. Complications of ultrarapid opioid detoxification with subcutaneous naltrexone pellets. Acad Emerg Med 2002; 9: 63–8
6. Gibson AE, et al. Opioid overdose deaths can occur in patients with naltrexone implants. Med J Aust 2007; 186: 152–3
7. Lintzeris N, et al. Unplanned admissions to two Sydney public hospitals after naltrexone implants. Med J Aust 2008; 188: 441–4.

Pruritus.

For reference to the use of opioid antagonists, including naltrexone, in pruritus, see under Nalmefene.

💊 Preparations

USP 31: Naltrexone Hydrochloride Tablets.

Proprietary Preparations

Arg.: Revez; Austral.: Revia; Austria: Dependex; Ethylex; Nalone†; Naltrexin; Nemexin; Revia; Belg.: Nalorex; Braz.: Revia; Canad.: Revia; Chile: Nalerona; Cz.: Nemexin; Revia; Denm.: Revia; Fin.: Revia; Fr.: Nalorex; Revia; Ger.: Nemexin; Gr.: Nalorex; Hong Kong: Revia; Hung.: Antaxon; Nemexin; Revia; India: Nodict; Indon.: Nutrexon; Phaltrexia; Irl.: Nalorex; Revia; Israel: Revia†; Ital.: Antaxone; Nalorex; Narcoral; Malaysia: Trexan†; Mex.: Revia; Neth.: Nalorex; Revia; Norw.: Revia; NZ: Revia; Port.: Antaxone; Basinal; Destoxican; Nalorex; Rus.: Antaxone (Антаксон); S.Afr.: Revia†; Singapore: Trexan†; Spain: Antaxone; Celupan; Revia; Swed.: Revia; Switz.: Naltrexin; Nemexin; Thai.: Revia; UK: Nalorex; Opizone; USA: Depade†; Revia; Trexan; Vivitrol.
Published December 09, 2018.