Methadone

Methadone is a synthetic drug structurally and pharmacologically similar to morphine; it acts mainly at the p-receptor. Methadone is largely metabolised to products that are excreted in the urine (tV2 8 h). The principal feature of methadone is its duration of action. Analgesia may last for as long as 24 h. If used for chronic pain in palliative care (12-hourly) an opioid of short t% should be provided for breakthrough pain rather than an extra dose of methadone.

The long duration of action also favours its use to cover opioid withdrawal (see before). Occupancy of opioid receptors by methadone reduces the desire for other opioids, and their effects, should any be taken; the slow offset diminishes the severity of the withdrawal. Addicts who are cooperative enough to take oral methadone feel reduced craving and less 'kick/buzz/rush' from i.v. heroin or morphine because their opioid receptors are already occupied by methadone and the i.v. drug must compete. Dependence occurs but this is less severe than with morphine or heroin. Reports of deaths in addicts entering prescribed methadone substitution programmes have been attributed to the cardiovascular effects of a membrane stabilising action, unlike morphine.

Vomiting is fairly common with methadone (though somewhat less so than with morphine) especially if the patient is ambulant, and sedation is less.

Methadone is also useful for severe cough. DIAMORPHINE (heroin)

This semisynthetic drug was first made from morphine at St Mary's Hospital, London in 1874. It was introduced in 1898 as a remedy for cough and for morphine addiction; later it was appreciated that it 'cured' morphine addiction by substituting itself as the addicting agent.

Pharmacokinetics. Diamorphine (diacetylmorphine) is converted in the body within minutes to morphine and 6-monoacetylmorphine, a metabolite of both drugs; the effects of diamorphine are principally due to the actions of morphine and 6-monoacetylmorphine on the p- and, to a lesser extent, the K-receptors. Diamorphine given par-enterally has a il/2 of 3 min. When given orally it is subject to complete presystemic or first-pass metabolism and only morphine (tV2 3 h) and the metabolites reach the systemic circulation. Thus oral diamorphine is essentially a prodrug. The greater potency of diamorphine (diamorphine 1 mg = morphine 1.5 mg) may be due to the metabolite 6-acetylmorphine and to the common use of morphine as sulphate and diamorphine as hydrochloride.

Use. Diamorphine is used medicinally for acute pain, e.g. myocardial infarction and chronic pain, e.g. in palliative care. Diamorphine provides a more rapid onset of pain relief than morphine because it is more lipid soluble and enters the brain more readily. Its duration of action is about the same and it may cause less nausea and hypotension. Diamorphine is more soluble than morphine to a useful degree.33 This, together with its greater potency (greater efficacy in relation to weight and therefore requiring a smaller volume) makes diamorphine suitable to deliver by s.c. infusion through a syringe driver when continuous pain control is required in palliative care and can no longer be achieved by enteral morphine (oral, buccal, suppository) (see Patient-controlled analgesia, p. 328).

Diamorphine is also used for severe cough (Diamorphine Linctus).

Abuse. It is commonly stated that diamorphine (heroin) is the 'most potent' of all dependence-producing opioids. Weight-for-weight it is certainly more effective than morphine, and this is of importance in illicit traffic as diamorphine takes up less space, but in so far as efficacy in inducing dependence is concerned, there is doubt.

In almost every country the manufacture of diamorphine, even for use in medicine, is now illegal. The first to try this prohibition as a remedy for widespread drug addiction was the USA, which

33 Solubility in water: morphine sulphate 1 in 21; diamorphine hydrochloride 1 in 1.6.

banned diamorphine manufacture in 1924, provoked by the magnitude of the addiction problem and not yet discouraged by the experience of this type of approach with alcohol prohibition (1919-1933).

An effort was made in 1953 to achieve a worldwide ban on diamorphine in medicine (so that any diamorphine, wherever it was found must be illegal) and many countries agreed. The UK did not agree because legitimate supplies for medicine were not than getting into illicit channels (it has since remained available for medicinal use but is not exported). A ban now would be pointless since illegal diamorphine is readily available worldwide.

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