Article: Naltrexone

Naltrexone
Systematic (IUPAC) name
17-(cyclopropylmethyl)-4,5α-epoxy- 3,14-dihydroxymorphinan-6-one
Identifiers
CAS number	16590-41-3
ATC code	N07BB04
PubChem	5360515
DrugBank	APRD00005
Chemical data
Formula	C20H23NO4
Mol. weight	341.401 g/mol
Physical data
Melt. point	169°C (336°F)
Pharmacokinetic data
Bioavailability	5-40%
Protein binding	21%
Metabolism	hepatic
Half life	4 hours (naltrexone), 13 hours (6-β-naltrexol)
Excretion	renal
Therapeutic considerations
Pregnancy cat.	Category B3 (Australia)
Legal status	Schedule 4 (Australia)
Routes	oral hepatic

Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. It is marketed as its hydrochloride salt, naltrexone hydrochloride, under the trade name Revia. In some countries, an extended-release formulation is marketed under the trade name Vivitrol.

Chemical Structure

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

Pharmacology

Naltrexone, and its active metabolite 6-β-naltrexol, are competitive antagonists at μ- and κ-opioid receptors, and to a lesser extent at δ-opioid receptors. This blockade of opioid receptors is the basis behind its action in the management of opioid dependence—it reversibly blocks or attenuates the effects of opioids.

Its use in alcohol (ethanol) dependence has been studied and has been shown to be effective. Its mechanism of action in this indication is not fully understood, but as an opioid-receptor antagonist is likely to be due to the modulation of the dopaminergic mesolimbic pathway which ethanol is believed to activate.

Rapid detoxification

Naltrexone is sometimes used for rapid detoxification ("rapid detox") regimens for opioid dependence. The principle of rapid detoxification is to induce opioid-receptor blockade while the patient is in a state of impaired consciousness so as to attenuate the withdrawal symptoms experienced by the patient. Rapid detoxification under general anaesthesia involves an unconscious patient and requires intubation and external ventilation. Rapid detoxification is also possible under sedation. The rapid detoxification procedure is followed by oral naltrexone daily for up to 12 months for opioid dependence management. There are a number of practitioners who will use a naltrexone implant placed in the lower abdomen, and more rarely, in the posterior to replace the oral naltrexone. This implant procedure has not been show scientifically to be successful in "curing" the subject of their addiction, though it does provide a better solution than oral naltrexone for medication compliance reasons. Naltrexone implants are made by at least three companies (Wedgewood/Australian, ???[New Jersey]/USA, and Fidelity Capital/Russian), though none are FDA approved. There is currently scientific disagreement as to whether this procedure should be performed under local or general anethesia, due to the rapid, and sometimes severe withdrawal, that occurs from the naltrexone displacing the opiates from the receptor sites.

Rapid detoxification has been criticised by some for its questionable efficacy in long-term opioid dependence management. Rapid detoxification has often been misrepresented as a one-off "cure" for opioid dependence, when it is only intended as the initial step in an overall drug rehabilitation regimen. Rapid detoxification is effective for short-term opioid detoxification, but is approximately 10 times more expensive than conventional detoxification procedures. Aftercare can also be an issue, since at least one well-known center (check before you assume they will take you) in the United States reported that they will remove an implant from any patient arriving in their facility before admission.

Alcohol dependence

Depot injectable naltrexone (Vivitrol ®, formerly Vivitrex, but changed after a request by the FDA) was approved by the FDA on April 13, 2006 for the treatment of alcoholism. This version is made by Alkermes, and will be jointly marketed by Cephalon, Inc.. The preparation will be injected into the posterior and lasts for up to 30 days. Clinical trials for this medication were done with a focus on alcohol, presumably due to the larger number of alcoholics that it could be used to treat; however, Alkermes was asked to run a safety study for the off-label use of the injection for opiate addicts. This was found to be a successful use of the medication in patients who were single drug abusers, though multi-drug abusers would generally decrease their opiate use and increase their use of other drugs (i.e. cocaine) while on the injection. Other studies (Schmitz et al., 2001), however, provide evidence that naltrexone with the right protocol can be effective in treating cocaine addiction.

Safety

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 sensitising 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. This effect reinforces the necessity of monitoring of therapy and provision of patient support measures by medical practitioners.

Low-dose naltrexone (LDN)

Low Dose Naltrexone (LDN), where the drug is used in doses approximately one-tenth those used for drug/alcohol rehabilitation purposes, is being used by some as an "off-label" experimental treatment for certain immunologically-related disorders. Evidence of safety and efficacy are currently lacking, with no published data from randomised controlled trials in humans. The use of LDN for such diseases as cancer was discovered and developed by Ian Zagon and championed by Bernard Bihari.

There is some in vitro data that indirectly suggest the potential benefits of LDN therapy. Anecdotal accounts and case reports have also been cited in favour of LDN therapy. Some of the conditions where LDN has been reported as beneficial include multiple sclerosis, Crohn's disease, HIV/AIDS, chronic fatigue syndrome, fibromyalgia, AD in children (Elchaar GM, et al. 2006) and cancer. Several clinical trials have been planned.

In multiple sclerosis

Specifically in multiple sclerosis, LDN has been theorized to work in multiple modalities. Without formal studies, there is no formal conclusion as of yet, but the generally accepted theory posited originally by Dr. Bihari is as follows. Dr. Bihari generally observed that multiple sclerosis patients have lower levels of beta-endorphins than healthy controls. Beta-endorphins, in turn, are important regulators of the immune system. The Low Dose Naltrexone dose causes an artificial blockade of the endorphin receptors in the brain. The normal dose of Naltrexone for addiction (~50mg) maintains this blockade continuously, preventing any derived pleasure from taking the forbidden drugs, but the Low Dose of Naltrexone (~3 - 6mgs) is only effective for a short duration. During that time, the body cannot get endorphins to attach to the receptors and apparently overcompensates by creating more. Once the Low Dose Naltrexone dose has been metabolized, the body is left with a "normal" amount of endorphins as compared to healthy controls, which consequently normalizes the immune function. [1]