####Background Methadone was developed in Germany during the Second World War. It was not commercially produced until the USA took over the patent after the war. At first doctors thought methadone would be a revolutionary new painkiller, but by the early 1950s it was hardly being used at all. In 1964, two doctors from New York, Marie Nyswander and Vincent Dole, were looking for drugs to help heroin users. They found methadone helped their patients to stop using heroin and that tolerance was slow to develop – the methadone maintenance treatment was born. ####What is methadone? Methadone is an effective evidence-based medication used for the treatment of opioid dependence, most commonly street heroin. Methadone’s usefulness in the treatment of opioid dependence is the result of several factors. It has cross-tolerance with other opioids, including heroin and morphine, and a long duration of effect, which means methadone is effective in preventing patients from experiencing an opioid withdrawal syndrome. At high doses (60–80 mg +), methadone may reduce the euphoric effects of heroin and morphine, allowing patients on adequate doses to reduce or stop illicit opioid use. ####Maintenance treatment The evidence base for treating opioid-dependent patients with methadone has been well established and it has been proven to reduce illicit methadone use, reduce criminal behaviour and reduce risk-taking behaviour associated with its use.[1,2,3,4,5] A total of 22,000 adults in Scotland are on methadone, costing at least £25 million per year. Methadone is suitable for those who wish to stop using illicit opioids but who do not feel they can achieve total abstinence initially. It is also suitable for those who are motivated to detoxify from all opioids and achieve abstinence. Aspirations about patient progress within treatment (for which methadone is just a part) are outlined in the Scottish Government's *Road to Recovery* document,[6] which describes the treatment as ‘a process through which an individual is enabled to move on from their problem drug use towards a drug-free life and become an active and contributing member of society’. The most powerful evidence base for methadone is for long-term maintenance, with retention in treatment being an indicator of better outcomes.[7,8] Patients do not respond favourably to non-mutually agreed reductions in methadone or enforced detoxification regimes.[9,10] ####Methadone preparations The types of methadone available in the UK include methadone oral solution, methadone tablets and methadone injectable formulations. In Scotland, only methadone oral solution is used in maintenance programmes. This solution is a green liquid and 1 mg/ml is the formulation licensed for the treatment of opioid dependence. It is effective in alleviating withdrawal symptoms and can be administered in solution as a once-a-day dose (blood levels can be kept stable, thus eliminating post-dose euphoria and pre-dose withdrawal). Sugar-free formulations have been introduced in an attempt to reduce secondary dental caries. However, it is likely that the acidity rather than the sugar is responsible for the increased incidence of teeth decay. Good oral hygiene is required. ####Side effects The side effects of methadone are those associated with all opioids, including nausea, vomiting, constipation and drowsiness. Larger doses cause respiratory depression and hypotension. Sweating, dry mouth, headache and decreased libido may also occur. Some patients complain of aching muscles about 24 hours after dosing and this may signify a breakthrough withdrawal effect associated with low plasma levels of methadone. ####Methadone metabolism Oral use is detected (in blood) at 15–45 minutes, with peak plasma concentration at 2.5–4 hours. However, there is an up to 17-fold variation of peak concentration for a given dosage. Methadone is highly bound to plasma proteins, free fraction typically at 13%, but again with wide interindividual variation. Final bioavailability is 75% (range 36–100%). Plasma elimination half-life is 40 hours (range 5–130 hours), affected by the genetic activity of cytochrome P450 (CYP) 3A4 and co-administered drug enzyme induction or inhibition effects.[11] Recommended doses are between 60 and 120 mg,[12] but optimal doses reflect the dose relationship with effectiveness and vary widely in clinical practice. Genetic expression accounts for much of the variability and some patients may benefit for splitting the dose to twice daily or using an alternative opiate replacement (e.g. buprenorphine). ####Prescribing The UK guidelines on the treatment of drug problems recommend flexible doses of methadone rather than fixed doses. This approach is supported by many randomised trials that have examined the link between methadone dose and retention in treatment. Results showed that flexible doses (as opposed to fixed doses) significantly raised retention of patients in treatment over a one-year period, firstly by prescribing adequate doses for patients and secondly by determining dose according to individual patient response. Retention in treatment is associated with better health and crime outcomes for both patients and society.[13] ####Drug screening Screening can be carried out using oral swabs, urine samples or hair testing. Oral testing is least invasive and most convenient. Hair testing is more often used in employment or criminal cases, where abstinence needs to be demonstrated. In a urine sample, a maintenance methadone dose will be evident for seven to nine days, whereas heroin will be evident in urine for up to 48 hours. Over-the-counter preparations such as co-codamol or codeine phosphate can give a positive opioid result. False negatives can also occur with low doses and in pregnancy. ####Risk The national treatment guidelines outline the risks of overdose in relation to the commencement of methadone, specifically during its induction.[14] There is an increased risk of overdose and death during induction into methadone treatment. Sedative drugs such as alcohol and benzodiazepines potentiate the effects of opioids (respiratory depression and hypoventilation). Too high an initial dose of methadone can also lead to methadone toxicity that is often delayed for hours (maximum absorption occurs at four hours) or even days (steady state blood levels taking four to five days to establish). This is because of methadone’s slow oral absorption and long half-life. ####Drug interactions Methadone may be a risk factor for QT prolongation and *torsades de pointe* with a possible dose-dependent action. A QTc interval beyond the normal limits (440 ms for men and 470 ms for women) is associated with increased risk of cardiac arrhythmias and sudden death, especially above 500 ms. The Medicines and Healthcare Products Regulatory Agency recommends QT monitoring for patients on high-dose methadone (>100 mg daily). Screening before commencing methadone is not mandatory but needs consideration, and any QT prolongation requires investigation. Drug interactions can also slow or speed methadone metabolism. Medicines that increase opioid blood levels by an inhibition of the CYP3A4 enzyme include cimetidine, fluvoxamine, ciprofloxacin and erythromycin. Doses of methadone may need to be decreased to prevent withdrawal symptoms and increased to prevent withdrawal symptoms when the enzyme inducer is stopped. Anticonvulsants (e.g. phenytoin and carbamazepine), human immunodeficiency virus (HIV) medicines (e.g. efavirenz, nevirapine), rifampicin and St John’s wort have the opposite effect, decreasing blood levels of methadone by the induction of the CYP3A4 enzyme. Additionally, certain medicines such as tricyclic antidepressants and antipsychotics in combination with methadone can lead to *torsades de pointes* via prolongation of the QTc interval, so caution should be used with these combinations. ####Use of methadone in patients with co-existing psychiatric conditions Methadone is also used in patients with co-existing psychiatric illness. A third of opioid users suffer from mental health problems including depression and anxiety and, because of this, interactions of methadone with psychotropic drugs should always be borne in mind.[13] Pain management in drug users presents a particular challenge for doctors. Pharmacological intervention is only one aspect of pain management and non-pharmacological interventions, for example cognitive behavioural therapy, should be considered. Acute pain requires full analgesic management in patients dependent on opioids. These patients may have a lower tolerance of pain, together with a higher tolerance of opioid analgesic effects. For opioid-dependent patients with chronic pain, the development of joint working arrangements across services to assess this population is desirable. Advice on good practice in pain management and addiction medicine can be found in *Pain and substance misuse: improving the patient experience*.[11] ####Methadone in pregnancy Engagement in treatment services is key. Even where pregnant women continue to use illicit substances, it has been shown that by engaging them in treament programmes their own health and the health of their unborn babies is better than those women who are not engaged in any treatment.[15] The objective of management is to achieve stability. Risks and needs should be assessed early and a treatment plan agreed between patient and clinician. It is important to screen for poly-substance misuse in pregnancy as there is evidence that other substances such as benzodiazepines and amphetamines may have more serious effects than heroin on the fetus. Clinicians need to be aware that some of the effects of different drugs of misuse during pregnancy are broadly similar and are, for the most part, non-drug specific. The national treament guidelines address the management of this special patient group.[14] ####Driving and methadone The Royal College Of General Practitioners, in its *Guidance for the use of methadone for the treament of opioid dependence in primary care*,[16] outlines the legal responsibility of patients prescribed methadone: 'Patients have a responsibility to inform the DVLA [the UK's Driver and Vehicle Licensing Agency] that they are receiving a prescription for methadone. They can then drive for personal reasons while prescribed oral methadone after undergoing a short independent medical examination and a urine screen for drugs. The licence is issued for a year at a time and needs to be supported by a favourable medical report. Patients will be subject to revocation of their licence where it is shown that there has been persistent use of or dependency on heroin, morphine, methadone and/or cocaine.' 2009-09-28T13:22:45Z None declared 113 2009-09-28T00:00:00Z 2009-10-19T13:51:10Z methadone-for-the-treatment-of-opioid-dependence 2009-10-19T13:51:10Z

Methadone has been in use since the 1960s as an effective medication for opioid dependency - particularly heroin. In this article Dr Malcolm Bruce and Dr Siobhan Morris look at the treatment regimes for methadone, together with its side effects, interactions with other drugs and risks.

2009-10-19T13:51:10Z