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Pharmacokinetics of Opioids

Abstract of a paper for
1st Pan African Congress on Pain
Alexandria 9-11 November

(see meetings sections)

Geoff Gourlay
Pain Management Unit, Flinders Medical Centre, Bedford Park, South Australia, AUSTRALIA 5042

The variability in binding affinity of the various opioids for the cloned human - receptor is perhaps less than expected from equivalent animal data. However, the relative efficacy of different opioids shows greater variability suggesting factors controlling the delivery opioids to their receptor(s) are very important. The major determinants of the rate of delivery are the physio - chemical characteristics and pharmacokinetic properties of the opioids. In addition, actions at other receptors, most notably the NMDA receptor, by some, but not all, commonly used opioids assumes particular importance in patients where their pain can be characterised has having neuropathic components. Not all opioids are capable of delivering the same degree of analgesia, even following dose optimisation.

The usual pharmacokinetic parameters (half-lives, clearance, volume of distribution etc.) of the opioids have been known for some time. More recently, interest has concentrated on the role of metabolites in modifying the pharmacodynamic response observed in patients, both in terms of contributing to analgesia and adverse effects. Opioids, like many drugs are principally metabolised in the liver via Phase I and /or Phase II biotransformations to form a diverse array of metabolites. The Phase I reactions include essentially N- and 0- dealkylations (usually demethylations) and we now know that specific isoforms of Cytochrome P450 (predominantly in the liver) are involved in these biotransformations. Fortunately, only two (of many) Cytochrome P450 isoforms (ie 2D6 and 3A4) accounts for essentially all opioid metabolism. However, these isoforms can be polymorphically expressed and patients who have an inability to undertake some of these reactions may be at a significant disadvantage in terms of not achieving analgesia (codeine >® morphine, Cytochrome P450 2D6). Alternatively, potentially dangerous drug interactions (fluvoxamine and methadone, Cytochrome P450 3A4) may occur with concomitantly administered drugs because of competitive metabolism. Phase II biotransformations involve conjugations (eg. morphine conjugates with glucuronic acid >® morphine-3-glucuronide and morphine-6-glucuronide) and these conjugated metabolites can be pharmacologically active.

An understanding of the impact of opioid pharmacokinetics on the analgesic response and the propensity for side effects will allow practitioners to more effectively use these important pharmacological agents.

See also:

New perspectives on the oldest drug
Evidence based analgesic league table

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