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Naltrexone

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Not to be confused with the related chemical naloxone.
Naltrexone(INN, BAN, USAN)
Clinical data
Trade namesRevia
AHFS/Drugs.comMonograph
MedlinePlusa685041
Pregnancy
category
  • AU: B3
Routes of
administration		Oral, intramuscular
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability5–40%
Protein binding21%
Metabolismhepatic
Elimination half-life4 h (naltrexone),
13 h (6-β-naltrexol)
ExcretionUrine
Identifiers
  • 17-(cyclopropylmethyl)-4,5α-epoxy- 3,14-dihydroxymorphinan-6-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.036.939 Edit this at Wikidata
Chemical and physical data
FormulaC20H23NO4
Molar mass341.401 g/mol g·mol−1
3D model (JSmol)
Melting point169 °C (336 °F)
  • O=C4[C@@H]5Oc1c2c(ccc1O)C[C@H]3N(CC[C@]25[C@@]3(O)CC4)CC6CC6
  • InChI=1S/C20H23NO4/c22-13-4-3-12-9-15-20(24)6-5-14(23)18-19(20,16(12)17(13)25-18)7-8-21(15)10-11-1-2-11/h3-4,11,15,18,22,24H,1-2,5-10H2/t15-,18+,19+,20-/m1/s1 checkY
  • Key:DQCKKXVULJGBQN-XFWGSAIBSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Naltrexone reverses the effects of opioids and is used primarily in the management of alcohol dependence and opioid dependence.[1] It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade names Revia and Depade. In some countries, including the United States, a once-monthly extended-release injectable formulation is marketed under the trade name Vivitrol. Also in the United States, Methylnaltrexone Bromide, a closely related drug, is marketed as Relistor, for the treatment of opioid induced constipation.

Naltrexone should not be confused with naloxone nor nalorphine, which are used in emergency cases of opioid overdose.

Medical uses

Alcohol dependence

The main use of naltrexone is for the treatment of alcohol dependence. Naltrexone has been shown to decrease heavy drinking.[2] This is true even in those who continue drinking while taking naltrexone, but then it is less effective in helping people to stop completely.[3]

Naltrexone was approved by the U.S. Food and Drug Administration (FDA) for the treatment of alcohol dependence in 1994, following publication of the first two randomized, controlled trials in 1992. Since then a number of studies have confirmed its efficacy in reducing frequency and severity of relapse to drinking.[4] The multi-center COMBINE study showed the usefulness of naltrexone in a primary care setting, without add-on psychotherapy.[5]

As noted in the Pharmacogenetics section below, studies since the early 21st century have identified a gene, which is prevalent in roughly 25-30% of the white population, that results in a much more effective response to the use of naltrexone in reducing or ending dependence on alcohol. This gene is rarely present among those of African descent; it is common among 60-70 percent of Asians.[6]

Opioid dependence

Naltrexone helps patients overcome opioid addiction by blocking the drugs’ euphoric effects. Unlike when used for alcohol dependence (discussed above), naltrexone has little effect on opioid cravings.[7] Naltrexone has in general been better studied for alcohol dependence than in treating opioid dependence. It is also more frequently used for alcohol, despite originally being approved by the FDA in 1984 for opioid addiction.[8]

A 2011 review of studies suggested that naltrexone was not superior to placebo or to no pharmacological intervention, nor was naltrexone superior to benzodiazepine or buprenorphine. Because of the poor quality of the reviewed studies, the authors concluded that there was insufficient evidence to support naltrexone therapy for opioid dependence.[9] While some patients do well with the oral formulation, there is a drawback in that it must be taken daily, and a patient whose cravings become overwhelming can obtain opioid intoxication simply by skipping a dose before resuming opioid use. Due to this issue, the usefulness of oral naltrexone in opioid dependence is limited by the low retention in treatment. Oral naltrexone remains an ideal treatment only for a small part of the opioid-dependent population, usually the ones with an unusually stable social situation and motivation (e.g., opioid-dependent health care professionals). Naltrexone treats the physical dependence on opioids, but further psychosocial interventions (such as counseling and group therapy) are often required to enable people to maintain abstinence.[10]

Adverse effects

The most common side effects reported with naltrexone are non-specific gastrointestinal complaints such as diarrhea and abdominal cramping.

Naltrexone has been reported to cause liver damage (when given at doses higher than recommended). It carries an FDA boxed warning for this rare side effect. Due to these reports, some physicians may check liver function tests prior to starting naltrexone, and periodically thereafter. Concerns for liver toxicity initially arose from a study of non-addicted obese patients receiving 300 mg of naltrexone.[11] Subsequent studies have suggested limited toxicity in other patient populations.

Naltrexone should not be started prior to several (typically 7-10) days of abstinence from opioids. This is due to the risk of acute opioid withdrawal if naltrexone is taken, as naltrexone will displace most opioids from their receptors. The time of abstinence may be shorter than 7 days, depending on the half-life of the specific opioid taken. Some physicians use a naloxone challenge to determine whether an individual has any opioids remaining. The challenge involves giving a test dose of naloxone and monitoring for opioid withdrawal. If withdrawal occurs, naltrexone should not be started.[8]

It is important that one not attempt to use opioids while using naltrexone. Although naltrexone blocks the opioid receptor, it is possible to override this blockade with very high doses of opioids. However this is quite dangerous and may lead to opioid overdose, respiratory depression, and death. Similarly one will not show normal response to opioid pain medications when taking naltrexone. In a supervised medical setting pain relief is possible but may require higher than usual doses, and the individual should be closely monitored for respiratory depression. All individuals taking naltrexone are encouraged to keep a card or a note in their wallet in case of an injury or another medical emergency. This is to let medical personnel know that special procedures are required if opiate-based painkillers are to be used.

There has been some controversy regarding the use of opioid-receptor antagonists, such as naltrexone, in the long-term management of opioid dependence due to the effect of these agents in sensitizing the opioid receptors. That is, after therapy, the opioid receptors continue to have increased sensitivity for a period during which the patient is at increased risk of opioid overdose.[citation needed] This effect reinforces the necessity of monitoring of therapy and provision of patient support measures by medical practitioners.

Contraindications

Naltrexone (50 mg per day) should not be used by persons with acute hepatitis or liver failure, or those with recent opioid use (typically 7–10 days).

Pharmacogenetics

A naltrexone treatment study by Anton et al., released by the National Institutes of Health in February 2008 and published in the Archives of General Psychiatry, has shown that alcoholics having a certain variant of the opioid receptor gene (G polymorphism of SNP Rs1799971 in the gene OPRM1) demonstrated strong response to naltrexone and were far more likely to experience success at cutting back or discontinuing their alcohol intake altogether, while for those lacking the gene variant, naltrexone appeared to be no different from placebo.[6] The G allele of OPRM1 is most common in individuals of Asian descent, with 60% to 70% of people of Chinese, Japanese, and Indian ancestry having at least one copy, as opposed to 30% of Europeans and very few Africans.[12]

Because of the characteristics of the patient group in the US, the first study was done on white patients, and the next without regard for ethnicity. Anton et al. found that patients of African descent did not have much success with naltrexone in treatment for alcohol dependence because of lacking the relevant gene.[6]

As white patients with the gene had a five times greater rate of success in reducing drinking when given naltrexone than did patients without the gene, when used in a protocol of Medical Management (MM), Anton et al. concluded,

"Because almost 25% of the treatment-seeking population carries the Asp40 allele, genetic testing of individuals before naltrexone treatment might be worth the cost and effort, especially if structured behavioral treatment were not being considered."[6] This would enable treatment to be targeted by genetics to patients for whom it would be most effective. They noted, "Naltrexone is relatively easy to administer and free of serious adverse effects and, as we observed in the Asp40 carriers we studied, it appears to be highly effective."[6]

Studies have found naltrexone to be more efficacious among certain white subjects, because of the genetic basis, than among black subjects, who generally do not carry the relevant gene.[13] A 2009 study of naltrexone as an alcohol dependence treatment among African Americans failed to find any statistically significant differences between naltrexone and a placebo.[14] Studies have suggested that carriers of the G allele may experience higher levels of craving and stronger "high" upon alcohol consumption, compared to carriers of the dominant allele, and naltrexone somewhat blunts these responses, leading to a reduction in alcohol use in some studies.[15]

Mechanism of action

Naltrexone and its active metabolite 6β-naltrexol are antagonists at the μ-opioid receptor (MOR), the κ-opioid receptor (KOR) to a lesser extent, and to a far lesser extent, at the δ-opioid receptor (DOR).[16] The Ki affinity values of naltrexone at the MOR, KOR, and DOR have been reported as 0.0825 nM, 0.509 nM, and 8.02 nM, respectively, demonstrating a KOR/MOR binding ratio of 6.17 and a DOR/MOR binding ratio of 97.2.[17]

The blockade of opioid receptors is the basis behind naltrexone's action in the management of opioid dependence—it reversibly blocks or attenuates the effects of opioids. Its mechanism of action in alcohol dependence is not fully understood, but as an opioid receptor antagonist is likely to be due to the modulation of the dopaminergic mesolimbic pathway (one of the primary centers for risk-reward analysis in the brain, and a tertiary "pleasure center") which is hypothesized to be a major center of the reward associated with addiction that all major drugs of abuse are believed to activate. [citation needed] Mechanism of action may be antagonism to endogenous opiates such as tetrahydropapaveroline, whose production is augmented in the presence of alcohol.[18]

Structure and pharmacokinetics

Naltrexone can be described as a substituted oxymorphone – here the tertiary amine methyl-substituent is replaced with methylcyclopropane. Naltrexone is the N-cyclopropylmethyl derivative of oxymorphone.

Naltrexone is metabolized mainly to 6β-naltrexol by the liver enzyme dihydrodiol dehydrogenase. Other metabolites include 2-hydroxy-3-methoxy-6β-naltrexol and 2-hydroxy-3-methoxy-naltrexone. These are then further metabolised by conjugation with glucuronide.

The plasma half-life of naltrexone and its metabolite 6β-naltrexol are about 4 hours and 13 hours, respectively.

Formulations

A naltrexone formulation for depot injection was approved by the FDA on April 13, 2006 for the treatment of alcohol dependence.[19] Alkermes manufactures and markets this version in the United States under the name Vivitrol (formerly Vivitrex, but changed after a request by the FDA); Johnson & Johnson markets it in Russia. Cephalon originally marketed the drug in the United States; however, Alkermes reclaimed Vivitrol commercialization rights in 2008.[20] The recommended dose of Vivitrol 380 mg is delivered intramuscularly once a month. The injection should be administered by a healthcare professional.[21]

Naltrexone Hydrochloride marketed as Naltima-50 (Intas Pharmaceuticals, India)

The clinical trial leading to the approval of Vivitrol showed that when compared with a placebo, 380 mg of Vivitrol resulted in a 25% decrease in the event rate of heavy drinking days and 190 mg resulted in a 17% decrease. The 6-month randomized, double-blind, placebo-controlled study was conducted between February 2002 and September 2003. Of the 899 individuals screened, 627 were diagnosed as alcohol-dependent adults and were randomized to receive treatment. The main outcome measure was the event rate of heavy drinking days in the intent-to-treat population. The study’s authors concluded that: “Long-acting naltrexone was well tolerated and resulted in reductions in heavy drinking among treatment-seeking alcohol dependent patients during 6 months of therapy.”[22]

The FDA approved Vivitrol on October 12, 2010 for the prevention of relapse to opioid dependence, following opioid detoxification. This injectable version was previously approved only for alcohol dependence. The phase 3 clinical study upon which the FDA granted approval for Vivitrol in treating opioid dependence had an enrollment of 250 patients and treated for six months. Primary outcome measures were percentage of weekly urine tests negative for opioids and length of study retention during the double-blind period. Alkermes presented positive results from this study at the American Psychiatric Association 2010 Annual Meeting in May 2010. The study met its primary efficacy endpoint and data showed that patients treated once-monthly with Vivitrol demonstrated statistically significant higher rates of opioid-free urine screens, compared to patients treated with a placebo, as measured by the cumulative distribution of clean urine screens (p<0.0002).[23][24]

“This drug approval represents a significant advancement in addiction treatment,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research.[25] Nora Volkow, M.D., Director of the National Institute on Drug Abuse (NIDA), stated that: “As a depot formulation, dosed monthly, Vivitrol obviates the daily need for patients to motivate themselves to stick to a treatment regimen - a formidable task, especially in the face of multiple triggers of craving and relapse. This new option increases the pharmaceutical choices for treating opioid addiction, and may be seen as advantageous by those unwilling to consider agonist or partial agonist approaches to treatment. NIDA is continuing to support research on Vivitrol's effectiveness in this country, including a focus on criminal justice involved populations transitioning back into the community.”[26]

A newer option is the naltrexone implant, which must be surgically inserted under the skin. The implant provides a sustained dose of naltrexone to the patient, thereby preventing the problems which may be associated with missing doses. It must be replaced every several months. Naltrexone implants are made by at least three companies, though none have been approved by the U.S. Food and Drug Administration (FDA) or the Australian Therapeutic Goods Administration.[27] Naltrexone implants have been used successfully in Australia for a number of years as part of a long-term protocol for treating opiate addiction.[28]

Controversies

The FDA authorized use of injectable Naltrexone for opioid addiction using a single study.[29] This study was run out of Russia, a country where opioid agonists such as methadone and buprenorphine are not available. Therefore this single trial of natrexone was performed not by comparing it to the best available, evidence-based treatment (methadone or buprenorphine) but by comparing it with a placebo.[30] In addition, the study failed to follow-up on participants to document post-treatment overdose - a key measure for opioid substitution therapies.[31] These factors led to criticism of the study's design and ethics, and, by extension, of the FDA's approval of injectable naltrexone for opioid addiction based on this study.[32]

Research

Depersonalization disorder

Naltrexone is sometimes used in the treatment of depersonalization disorder. While studies have suggested it is less effective than naloxone for treating depersonalization, naloxone is impractical for daily use because it must be injected intravenously. A small (12 patients), open label, non-controlled 2005 naltrexone study demonstrated an improvement in 4 patients of depersonalization symptoms, as measured by 3 validated dissociation scales.[33]

Low-dose naltrexone

Main article: Low-dose naltrexone

"Low-dose naltrexone" (LDN) describes the "off-label" use of naltrexone at low doses for diseases not related to chemical dependency or intoxication, such as multiple sclerosis.[34] Much more research needs to be done before it can be recommended for clinical use.

Although there are scientific studies showing its efficacy in some conditions such as fibromyalgia,[35] other, more dramatic claims for its use in conditions like cancer and HIV have less scientific support.[34] This treatment has received significant attention on the Internet, especially through websites run by organizations promoting its use.[36]

Tobacco dependence

A study done by The Chicago Stop Smoking Research Project at the University of Chicago found that Naltrexone did not help to improve a subject's chance of attaining smoking cessation when compared to a placebo.[37]

Self-injurious behaviors

Some studies suggest that self-injurious behaviors present in persons with developmental disabilities (including autism) can sometimes be remedied with naltrexone.[38] In these cases, it is believed that the self-injury is being done to release beta-endorphin, which binds to the same receptors as heroin and morphine.[39] If the "rush" generated by self-injury is removed, the behavior may stop.

Behavioral addiction

There are indications that naltrexone might be beneficial in the treatment of impulse control disorders such as kleptomania, compulsive gambling, or trichotillomania (compulsive hair pulling), but there is conflicting evidence of its effectiveness for gambling.[40][41][42] A 2008 case study reported successful use of naltrexone in suppressing and treating an internet pornography addiction.[43]

Countering adverse effects of interferon alpha

Naltrexone is effective in suppressing the cytokine type mediated adverse neuropsychiatric effects of interferon alpha therapy.[44][45]

See also

References

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  3. ^ Pettinati, HM; O'Brien, CP; Rabinowitz, AR; Wortman, SP; Oslin, DW; Kampman, KM; Dackis, CA (December 2006). "The status of naltrexone in the treatment of alcohol dependence: specific effects on heavy drinking". Journal of clinical psychopharmacology. 26 (6): 610–25. PMID 17110818.
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  21. ^ Vivitrol Prescribing Information
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  • LDNscience.org, a website dedicated to promoting and studying the therapeutic indications of low dose naltrexone.
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