3 The technologies

3.1 Methadone

3.1.1 Methadone (Rosemont Pharmaceuticals, AAH Pharmaceuticals, Martindale Pharmaceuticals, and Thornton & Ross) is a synthetic opioid receptor agonist with pharmacological activity similar to that of morphine. The summary of product characteristics (SPC) for methadone states that it is indicated for 'use in the treatment of opioid drug addictions (as a narcotic abstinence syndrome suppressant)'.

3.1.2 The 'British national formulary' (BNF) states that methadone is to be used in opioid dependence at an initial dose of 10–40 mg daily, which is increased by up to 10 mg daily (with a maximum weekly increase of 30 mg) until no signs of withdrawal or intoxication are seen. The usual maintenance dose range is 60–120 mg daily.

3.1.3 Methadone is available as an oral solution (1 mg/ml), an oral concentrate (10 mg/ml), tablets or injectable ampoules. Only oral formulations of methadone are considered in this appraisal. Administering methadone orally avoids the risks associated with injecting. Methadone has a long elimination half-life (usually 20–37 hours), which allows for a once-daily dosing schedule. Methadone appears to have no serious long-term side effects associated with chronic administration. In people stabilised on a methadone maintenance regimen, the drug does not have the pronounced narcotic effects seen with shorter-acting opioids such as illicit diamorphine. Some drugs, including rifampicin, phenytoin, phenobarbital and some antiviral drugs used in the treatment of HIV infection, speed up the elimination of methadone from the body. Other drugs, such as fluvoxamine and fluoxetine, may have the opposite effect on methadone metabolism. Knowledge of these interactions usually enables the appropriate adjustment of methadone dose for effective treatment. For full details of side effects, contraindications and drug interactions, see the SPC.

3.1.4 Initiation of treatment with methadone presents a potential risk of respiratory depression and should be undertaken with care. Interactions between methadone and other respiratory depressants such as alcohol, benzodiazepines and the newer non-benzodiazepine hypnotics (Z-drugs), other sedatives or tricyclic antidepressants may also induce serious respiratory depression. There is a risk of death early in methadone treatment as a result of excessive initial doses, failing to recognise cumulative effects, giving methadone to people with impaired liver function (due to chronic hepatitis) or failing to inform patients of the dangers of overdose if they are using other drugs at the same time. The relatively slow onset of action and long half-life mean that methadone overdose and toxic effects may become life threatening several hours after a dose is taken. During the initiation phase, the methadone dose should be adjusted carefully in order to eliminate drug craving and prevent withdrawal while avoiding the risk of intoxication or overdose. This process needs to be monitored by a doctor or trained nurse, and may require regular visits by the patient to a community prescribing centre. Initially patients may need to be seen at least fortnightly, but when they are stable, the frequency of medical assessment can be reduced.

3.1.5 The cost of methadone oral solution (1 mg/ml) is £1.35 per 100 ml excluding VAT. The cost of methadone oral concentrate (10 mg/ml) is £12.01 per 150 ml excluding VAT (BNF, edition 51). Costs may vary in different settings because of negotiated procurement discounts.

3.2 Buprenorphine

3.2.1 Buprenorphine (Schering-Plough) has both partial opioid agonist and opioid antagonist activity, and provides a milder, less euphoric and less sedating effect than full opioid agonists such as diamorphine or methadone (although these effects are less pronounced with methadone than with diamorphine).

3.2.2 The SPC for buprenorphine states that it is indicated for 'substitution treatment for opioid drug dependence, within a framework of medical, social and psychological treatment'. Buprenorphine is available in the form of sublingual tablets, transdermal patches and injectable ampoules. In the management of opioid dependence, sublingual tablets are used at an initial recommended once-daily dose of 0.8–4 mg, adjusted according to response. In practice, a starting dose of more than 4 mg/day is often used, with an adequate maintenance dose being in the range 12–24 mg/day. The maximum daily dose is 32 mg.

3.2.3 Buprenorphine is chemically distinct from methadone. Buprenorphine has a high affinity for opioid receptors and this reduces the impact of additional illicit diamorphine or other opioid use by preventing these drugs from occupying the opioid receptors. The high affinity of buprenorphine for opioid receptors means that it has a prolonged duration of action at higher doses, which can allow alternate-day dosing regimens. Buprenorphine also has a relatively good safety profile. Even higher than normal therapeutic doses rarely result in clinically significant respiratory depression because of its partial agonist activity at the opioid receptor involved (mu). The safety of buprenorphine mixed with high doses of other sedative drugs such as alcohol or benzodiazepines remains unclear. Starting buprenorphine treatment in opioid-dependent people may precipitate symptoms of withdrawal because buprenorphine displaces any residual illicit opioid agonists from receptors and because its partial agonist activity reduces the stimulation of receptors. In addition, whereas methadone is an agonist, buprenorphine is an antagonist at the receptor subtype involved in mood (kappa), which may mean that it produces less dysphoria. For full details of side effects and contraindications, see the SPC. Buprenorphine has abuse potential, as tablets can be crushed and then injected.

3.2.4 The cost of buprenorphine is £2.88 per 8 mg tablet excluding VAT (BNF, edition 51). Buprenorphine is also available in 2 mg (£0.96 per tablet) and 400 micrograms (£0.23 per tablet) strengths (BNF, edition 51). Costs may vary in different settings because of negotiated procurement discounts.