1.1 General information

What is methadone?
Effects of methadone
Pharmacokinetics
Withdrawal syndrome
Drug interactions
Safety
Formulations

What is methadone?

Methadone is a potent synthetic opioid agonist which is well absorbed orally and has a long, although variable plasma half life. The effects of methadone are qualitatively similar to morphine and other opioids.

Most people who have used heroin will experience few side effects from methadone. Once on a stable dose, tolerance develops until cognitive skills and attention are not impaired. Symptoms of constipation, sexual dysfunction and occasionally increased sweating can continue to be troubling for the duration of MMT.

Methadone is fat soluble and binds to a range of body tissues including the lungs, kidneys, liver and spleen such that the concentration of methadone in these organs is much higher than in blood. There is then a fairly slow transfer of methadone between these stores and the blood. Because of its good oral bioavailability and long half life, methadone is taken in an oral daily dose.

Methadone is primarily broken down in the liver via the cytochrome P450 enzyme system. Approximately 10% of methadone administered orally is eliminated unchanged. The rest is metabolised and the (mainly inactive) metabolites are eliminated in the urine and faeces. Methadone is also secreted in sweat and saliva.

Effects of methadone

Actions

  • Analgesia
  • Sedation
  • Respiratory depression
  • Euphoria (oral methadone causes less euphoria than intravenous heroin)
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Other Actions

  • Decreased blood pressure
  • Constriction of the pupils
  • Gastrointestinal tract actions
    • Reduced gastric emptying
    • Reduced motility
    • Elevated pyloric sphincter tone
    • Elevated tone of Sphincter of Oddi can result in biliary spasm
  • Skin actions
    • Histamine release
  • Endocrine actions including
    • Reduced Follicle Stimulating Hormone
    • Reduced Luteinising Hormone
    • Elevated Prolactin
    • Reduced Adreno-Cortico-Trophic Hormone
    • Reduced testosterone (Endocrine function may return to normal after 2-10 months on methadone)
    • Elevated Anti Diuretic Hormone
  • Antitussive

Side Effects

  • Sleep disturbances
  • Nausea and vomiting
  • Constipation
  • Dry mouth
  • Increased sweating
  • Vasodilation and itching
  • Menstrual irregularities in women
  • Gynaecomastia in males
  • Sexual dysfunction including impotence in males
  • Fluid retention and weight gain

Pharmacokinetics

There is wide individual variability in the pharmacokinetics of methadone but in general, blood levels rise for about 3-4 hours following ingestion of oral methadone and then begin to fall. Onset of effects occurs approximately 30 minutes after ingestion. The apparent half life of a single first dose is 12 – 18 hours with a mean of 15 hours. With ongoing dosing, the half life of methadone is extended to between 13 and 47 hours with a mean of 24 hours. This prolonged half life contributes to the fact that methadone blood levels continue to rise during the first week of daily dosing and fall relatively slowly between doses.

Methadone reaches steady state in the body (where drug elimination equals the rate of drug administration) after a period equivalent to 4-5 half lives or approximately 3-10 days. Once stabilisation has been achieved, variations in blood concentration levels are relatively small and good suppression of withdrawal is achieved. For some, however, fluctuations in methadone concentrations may lead to withdrawal in the latter part of the inter-dosing interval. If dose increases or multiple dosing within a twenty four hour period do not prevent this, other agonist replacement treatment approaches such as buprenorphine should be considered.
  • Onset of effects: 30 minutes
  • Peak effects: approx 3 hours
  • Half life (in MMT): approx 24 hours
  • Time to reach stabilisation: 3-10 days
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Figure 1 - Plasma levels of methadone during first 3 days of dosing*


Text equivalent below for Figure 1 - Plasma levels of methadone during first 3 days of dosing

*Preston A (1999) The New Zealand Methadone Briefing. Used with permission.

Text version of Figure1
The figure above shows the typical relative plasma concentration of methadone during the first three days of dosing. It shows that plasma levels rise shortly after ingestion of the first dose, peaking at about the 3 hour mark, and then decreases to about 25% of the peak level at the 24 hour mark, when the second dose is ingested. A similar rise in plasma levels follows the second dose, however after the peak, levels decrease by a smaller amount. A similar rise in plasma levels also follows the third dose at 48 hours, and after the peak the plasma levels decrease by an even smaller percentage.

Withdrawal syndrome

The signs and symptoms of the opioid withdrawal syndrome include irritability, anxiety, restlessness, apprehension, muscular and abdominal pains, chills, nausea, diarrhoea, yawning, lacrimation, piloerection, sweating, sniffing, sneezing, rhinorrhea, general weakness and insomnia. Signs and symptoms usually begin two to three half-lives after the last opioid dose, ie. 36 to 48 hours for long half-life opioids such as methadone, and 6 to 12 hours for short half-life opioids such as heroin and morphine.

Following cessation of heroin, symptoms reach peak intensity within 2 to 4 days, with most of the obvious physical withdrawal signs no longer observable after 7 days. The duration of methadone withdrawal is longer (5 to 21 days). This first, or acute, phase of withdrawal may then be followed by a period of protracted withdrawal syndrome. The protracted syndrome is characterised by a general feeling of reduced well-being. During this period, strong cravings for opioids may be experienced periodically.

The opioid withdrawal syndrome is rarely life-threatening. However, completion of withdrawal is difficult for most people. Untreated methadone withdrawal symptoms may be perceived as more unpleasant than heroin withdrawal, reflecting the more prolonged nature of methadone withdrawal. Factors that have been identified as having the potential to influence the severity of withdrawal include the duration of opioid use, general physical health, and psychological factors, such as the reasons for undertaking withdrawal and fear of withdrawal. Buprenorphine appears to have a milder withdrawal than other opioids.
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Drug interactions

Toxicity and death have resulted from interactions between methadone and other drugs. Some psychotropic drugs may increase the actions of methadone because they have overlapping, additive effects (e.g. benzodiazepines and alcohol add to the respiratory depressant effects of methadone). Other drugs interact with methadone by influencing (increasing or decreasing) metabolism (See Appendix 1). Drugs which induce the metabolism of methadone can cause a withdrawal syndrome if administered to patients maintained on methadone. These drugs should be avoided in methadone patients if possible. If a cytochrome P450 inducing drug is clinically indicated for the treatment of another condition seek specialist advice. Cytochrome P450-3A inhibitors can decrease the metabolism of methadone and cause overdose.

A full list of drugs which interact with Methadone appears at Appendix 1

Safety

The long term side effects of methadone taken orally in controlled doses are few. Methadone does not cause damage to any of the major organs or systems of the body and those side effects which do occur are considerably less harmful than the risks of alcohol, tobacco and illicit opiate use (see Section 4.1). The major hazard associated with methadone is the risk of overdose. This risk is particularly high at the time of induction to MMT and when methadone is used in combination with other sedative drugs. The relatively slow onset of action and long half life mean that methadone overdose can be highly deceptive and toxic effects may become life threatening many hours after ingestion. (see Section 4.2). Because methadone levels rise progressively with successive doses during induction into treatment, most deaths in this period have occurred on the third or fourth day of treatment.

Formulations

Two preparations are available for methadone maintenance treatment in Australia:
  • Methadone Syrup® from Glaxo Smith Kline. This formulation contains 5 mg/ml methadone hydrochloride, sorbitol, glycerol, ethanol (4.75%), caramel, flavouring, and sodium benzoate.
  • Biodone Forte® from McGaw Biomed. This formulation contains 5mg/ml methadone hydrochloride and permicol-red colouring.