Actions

Naltrexone

Also known as

ReVia, vivitrol, depade, nalorex, opizone

Overview

Naltrexone reverses the effects of opioids and is used as a relapse prevention tool. It is not a maintenance treatment and should not be mistaken for one [1].

This is an antagonist that has the ability to evacuate and occupy the relevant receptor sites in the brain, it reverses the effects of opioids among dependent individuals. Naltrexone Hydrochloride is a non-addictive substance with a variety of applications (such as an abstinence reinforcing agent in problem drinking), not to be confused with Naloxone, the emergency treatment for opioid overdose.

While some patients do well with the oral formulation, it must be taken daily, preferably supervised and a patient whose cravings become overwhelming can start using again simply by skipping a dose before resuming opiate use. Oral naltrexone in opioid dependence is limited by the low retention in treatment, despite its approval by NICE. Oral naltrexone is optimal among specific opioid-dependent populations, usually the ones with an unusually stable social situation and high motivation (e.g. dependent health care professionals). Naltrexone treats the physical dependence on opioids, but further psychosocial interventions (such as counselling and group therapy) are often required to enable people to maintain abstinence.

Rapid Antagonist Induction (RAI) or Ultra Rapid Opiate Detoxification (UROD) is an inpatient procedure currently unavailable on the NHS, that offers the most painless method for coming off opiates yet devised. In short, you are sedated with intravenous or oral anaesthesia and withdrawal is induced by an opiate antagonist (naloxone/ Narcan). Some premedication is taken 12 hours before admission. A range of further medications such as clonidine (a relative of lofexidine) and octreotide (an anti-diarrhoea medication) are administered. Although patients are often disorientated on regaining consciousness, most can be discharged within 48 hours of admission, although some units retain patients for five days, only commencing Naltrexone, as 'blocker' on around day three.

It is usual for a range of take-home medications to be distributed to a responsible carer. The problem with this is that Naltrexone is only available (i.e. licensed) as a tablet at the moment. While the technology for an implant and a depot injection exists, they are very difficult to access in the UK [1].

Derivative of noroxymorphone that is the N-cyclopropylmethyl congener of naloxone. It is a narcotic antagonist that is effective orally, longer lasting and more potent than naloxone, and has been proposed for the treatment of heroin addiction [2].

Medical usage

In the long term treatment of opiate dependence once individuals are 7 - 10 days opiate free, and also used in the treatment for alcohol dependence [3].

Used as an adjunct to a medically supervised behaviour modification program in the maintenance of opiate cessation in individuals who were formerly physically dependent on opiates and who have successfully undergone detoxification. Also used for the management of alcohol dependence in conjunction with a behavioural modification program [2].

What does it look like?

The tablet is Naltrexone hydrochloride, Nalorex 50mgs peach, film coated. Tablets, implants [1].

Source

Diverted from manufacturers, pharmacies, GP's prescriptions [3].

Why take it?

Sought after effects

  • least painful detox yet,
  • symptoms abate very quickly [1].

Undesired effects

  • cost,
  • NHS licensing in most cases when medicated [1].

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. The plasma half-life of naltrexone is about 4 hours, for 6-β-naltrexol 13 h. The 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.

The best way to imagine the way Naltrexone works is to picture trying to open a door with a Chubb key that has a key in the locked position on the other side. You can't get it in. This, crudely, is how opiates find the receptor site that is occupied by Naltrexone.

How long should you take it? It really depends on how confident you are that you can stay off on will-power and support. If in doubt you should probably stay on the medication. If you do come off opiates for a while and then go back, be very aware that your tolerance has now dropped and if the Naltrexone is out of your system you are at great risk of overdose [1]..

Pharmacodynamics

Naltrexone, a pure opioid antagonist, is a synthetic congener of oxymorphone with no opioid agonist properties. Naltrexone is indicated in the treatment of alcohol dependence and for the blockade of the effects of exogenously administered opioids. It markedly attenuates or completely blocks, reversibly, the subjective effects of intravenously administered opioids. When co-administered with morphine, on a chronic basis, naltrexone blocks the physical dependence to morphine, heroin and other opioids. In subjects physically dependent on opioids, naltrexone will precipitate withdrawal symptomatology [2].

Absorption

Well absorbed orally [2].

Bioavailability

Oral bioavailability estimates ranging from 5% to 40% [2].

Metabolism

Hepatic. When administered orally, naltrexone undergoes extensive biotransformation and is metabolised to 6 beta-naltrexol (which may contribute to the therapeutic effect) and other minor metabolites [2].

Half-life

4 hours for naltrexone and 13 hours for the active metabolite 6 beta-naltrexol [2].

Elimination

Both parent drug and metabolites are excreted primarily by the kidney (53% to 79% of the dose), however, urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose and faecal excretion is a minor elimination pathway. The renal clearance for naltrexone ranges from 30 to 127 mL/min and suggests that renal elimination is primarily by glomerular filtration [2].

Lethal dosage

In the mouse, rat and guinea pig, the oral LD50's were 1,100 - 1,550 mg/kg; 1,450 mg/kg; and 1,490 mg/kg; respectively [2].

Mechanism of action

Naltrexone is a pure opiate antagonist and has little or no agonist activity. The mechanism of action of naltrexone in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. Naltrexone is thought to act as a competitive antagonist at mc, κ, and δ receptors in the CNS, with the highest affintiy for the μ receptor. Naltrexone competitively binds to such receptors and may block the effects of endogenous opioids. This leads to the antagonization of most of the subjective and objective effects of opiates, including respiratory depression, miosis, euphoria, and drug craving. The major metabolite of naltrexone, 6-β-naltrexol, is also an opiate antagonist and may contribute to the antagonistic activity of the drug [2].

Effects

Minor effects

More common

  • abdominal or stomach cramping or pain (mild or moderate),
  • anxiety,
  • nervousness,
  • restlessness,
  • insomnia,
  • headache,
  • joint or muscle pain,
  • nausea,
  • vomiting,
  • unusual tiredness [4].

Less common

  • chills,
  • constipation,
  • cough,
  • hoarseness,
  • runny or stuffy nose,
  • sinus problems,
  • sneezing,
  • sore throat,
  • diarrhoea,
  • dizziness,
  • fast or pounding heartbeat,
  • increased thirst,
  • irritability,
  • loss of appetite,
  • sexual problems in males [4].

Major effects

Less common

  • skin rash [4].

Rare

  • abdominal or stomach pain (severe),
  • blurred vision,
  • aching, burning, or swollen eyes,
  • chest pain,
  • confusion,
  • discomfort while urinating or frequent urination,
  • fever,
  • hallucinations,
  • itching,
  • mental depression or other mood or mental changes,
  • tinnitus,
  • shortness of breath,
  • oedema,
  • weight gain [4].

Common

  • sleep problems,
  • tiredness,
  • anxiety,
  • headache,
  • joint and muscle pains,
  • abdominal pain and cramps,
  • nausea,
  • vomiting [5].

Less common

  • feeling energetic,
  • loss of appetite,
  • thirst,
  • diarrhoea,
  • constipation,
  • depression,
  • irritability,
  • dizziness,
  • skin rashes,
  • decreased potency, delayed ejaculation,
  • chills [5].

Overdose

  • confusion,
  • hallucinations,
  • blurred vision,
  • severe vomiting,
  • diarrhoea [6].

Dose-related effects

Large doses of naltrexone may cause liver damage [5]. Seek medical advice immediately if any of the following symptoms are experienced -

  • excessive tiredness,
  • unusual bruising or bleeding,
  • loss of appetite,
  • pain in the upper right area of the abdomen that lasts more than a few days,
  • light-coloured bowel movements,
  • dark urine,
  • jaundice [5].

Drug testing

How long does naltrexone stay in the urine?

Naltrexone can be detected in the urine for 4 - 6 hours [6].

How long can naltrexone be detected in blood?

A blood test can detect Naltrexone for up to 24 hours [6].

How long can a saliva test detect naltrexone?

A saliva test can detect Naltrexone for up to 1 day [6].

How long can a hair test detect naltrexone?

Naltrexone, like many other drugs, can be detected with a hair follicle drug test for up to 90 days [6].

Harm reduction

Naltrexone should not be started prior to several 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, although of course with rapid detox this will already have happened. This period may depend on the half-life of the specific opioid previously used. Some doctors use a naloxone challenge to determine whether an individual has any opioids remaining in their system. The challenge involves giving a test dose of naloxone and monitoring for opioid withdrawal. If withdrawal occurs, naltrexone should not be started.

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, although this will usually be at least a gram of above average 'street' (40%) strength heroin. Similarly one will not show normal response to opioid pain medications when taking naltrexone. All individuals taking naltrexone are encouraged to wear a wristband, keep a card or a note in their wallet in case of an injury or another medical emergency that may require opioids. This is to let medical personnel know that special procedures are required if pain control is indicated.

There has been some controversy regarding the use of opioid-receptor antagonists, such as naltrexone, in the long-term management of opioid dependence due primarily to the emotional equilibrium of the ex-user. Many report periods of deep melancholy for months in early 'recovery'.

Sleep disturbance may endure for anything from 3 days to over a month (albeit reducing). For this reason, a course of benzodiazepines may be beneficial. Anti nausea medication and non opiate based painkillers such as Voltarol (diclofenac), deal with residual minor aches and pains and many ex opiate users find to their distress that their past use will have masked minor (and major) ailments that will require attention.

With the NHS only offering tablets, cost is an issue for most users and their families, despite the good results that this abstinence based treatment can deliver. However, it is not advised to attempt to purchase naltrexone on the 'black market', as you can't be certain of its origins or purity, and can do serious harm by self-administering [1].

History

Naltrexone was originally synthesised by Endo Laboratories (New York) in 1963 and a US patent was granted in 1967. The company had previously developed naloxone, but due to being a small firm was limited in its distribution and so did not market naltrexone. When Endo was bought out by the much larger DuPont Pharmaceuticals in 1969, there seemed little prospect of it being continued, but President Nixon's 'War on Drugs' and the 1972 Drug Abuse Office and Treatment Act made naltrexone a viable commercial product. It subsequently entered clinical trials for heroin addiction treatment in 1973, and despite early setbacks was finally marketed under the brand name 'Trexan' in 1984 [1]


References