Buprenorphine preparations

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Transtec: 35mcg/h, 52.5mcg/h and 70mcg/h patches, which release the drug over a 3-4 day period

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BuTrans: 5mcg/h, 10mcg/h and 20mcg/h patches, which release the drug over a 7-day period

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Tabs (sublingual): 200mcg

Sublingual buprenorphine

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The absorption of buprenorphine from the sublingual mucosa is rapid, occurring within 5 minutes. However, the oral bioavailability of buprenorphine is very low (approximately 10%), and additional swallowing of buprenorphine contributes little to overall absorption

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Sublingual buprenorphine is often not tolerated by patients due to its adverse effects profile, which includes dizziness, nausea, vomiting, drowsiness and lightheadedness

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As a result, alternative oral opioids, such as i/r morphine, are generally used to provide breakthrough pain relief for patients using transdermal buprenorphine

Methadone

Methadone is a synthetic opioid agonist at the mu- and delta-opioid receptors, and is also an NMDA-receptor antagonist. Its NMDA-receptor antagonism has led to the clinical impression that methadone has a particular place in the management of neuropathic pain.

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It may be given by the p.o., p.r., IV and SC routes

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Oral administration is followed by rapid gastrointestinal absorption with measurable plasma levels at 30 minutes.

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It is a basic and lipophilic drug that is subject to considerable tissue distribution and sequestration, and it has a characteristically long half-life in plasma of around 24 hours (range 13–100 hours)³²^,³³^,³⁴^,³⁵^,³⁶

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Tissue accumulation of methadone with chronic administration results in the potential for toxicity. Also, there is considerable inter-individual variation in methadone pharmacokinetics, which means that dose conversion and titration is difficult to predict accurately

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Methadone is extensively metabolized in the liver by the cytochrome P450 CYP3A3/4 isoenzyme to inactive metabolites. It is then excreted mainly by the faecal route, and so does not accumulate in renal failure

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Methadone should only be used in the palliative care setting by specialists experienced in its use. Even among experienced physicians, occasional serious toxicity can occur during the administration of methadone.³⁷ Contrary to what would be expected, toxicity appears to occur more frequently in patients previously exposed to high doses of opioids than in patients receiving low doses

Side-effects

All the typical opioid side-effects can be expected. Methadone also has an antidiuretic effect.

Drug interactions

Methadone has the potential for numerous and complex drug interactions.³² Its metabolism is increased by a number of other drugs, and their use in combination with methadone may then precipitate pain flare and opioid withdrawal symptoms. Other interactions that inhibit metabolism can lead to overdose and toxicity (Table 6a.9).

Table 6a.9

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Interactions which interfere with methadone metabolism

Decrease methadone levels	Increase methadone levels
Phenytoin	Fluconazole
Phenobarbital	SSRIs
Carbamazepine (not sodiumvalproate or gabapentin)
Rifampicin

Use of methadone

Methadone is rarely used as a first-line analgesic in the UK since it has a long half life and is difficult to titrate safely. Equianalgesic ratios of morphine (and other opioids) to methadone are dose-dependent. In single dose studies these ratios may vary from 1:1 at low doses of an oral opioid to as high as 20:1 for those patients receiving oral morphine in excess of 300mg per day. Opioid rotation to methadone is difficult because of the wide variability of equianalgesic ratios, but there have been several guidelines published.³⁷ (The appropriate conversion ratios should be used when switching from other strong opioids.)

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