Opioids in chronic non-malignant pain: Methadone

The majority of the opioids used to treat acute and chronic pain have a high clearance, a relatively short half- life (between 2 and 6 hrs) and are extensively metabolised, predominantly in the liver. Methadone is the exception with a relatively low clearance (0.1- 0.3 Umin) and a long and variable half -life with a mean value of approx 30 hrs (range 6-150 hrs).

Methadone has good oral bioavailability, its metabolism is controlled by the amount of functional Cytochrome P450 isoform 3A4 activity in the liver (the content of this isoform can vary 50 fold between individuals and is responsible for the metabolism of r;' approximately 50% of currently used drugs) while its metabolites are not considered to have analgesic activity. Thus, methadone metabolism can be either stimulated (phenytoin, carbamazepine and rifampicin) or inhibited (fluconazole, HIV -1 protease inhibitors and some SSRI antidepressants [particularly fluvoxamine)) by the concurrent administration of other drugs.

Traditional teaching indicates that a convenient starting point is to have the dosing interval similar to the elimination half-life (contains the fluctuations in blood concentrations to an acceptable level during the dosing interval). The m-receptor binding profile, potency, good oral bioavailability and generally long half-life accounts for the use of methadone as a replacement therapy in drug dependent patients and why some clinicians believe it is a valuable opioid in the treatment of acute and chronic pain.

However, methadone pharmacology is more complicated and clinicians contemplating the prescription of this drug need to understand its peculiarities.

Methadone is usually administered as a racemate (ie 2 chemical entities called enantiomers that spatially, are the mirror image of each other). While the I -enantiomer is the biologically active species at the m-receptor (is 50 times as potent as an analgesic as the d -enantiomer in man, both enantiomers are non-competitive antagonists at the NMDA receptor with an activity similar to dextromethorphan and therefore would be expected to block the phenomenon of windup -clinically, these findings suggest that methadone may be more valuable than other opioids in the treatment of chronic pain which is characterised as neuropathic in origin. This is another analgesic example where the administration of the racemate may prove to be superior to the opioid active enantiomer (only available clinically in Germany) because the commonly believed" inactive" enantiomer interacts with a complementary system to possibly produce an enhanced outcome. Thus, some clinicians would suggest that methadone is relatively under-ulitised in the treatment of both cancer and chronic pain.

Nevertheless, methadone is different from other m -receptor agonists and the novice prescriber can easily get into difficulties of either under -dosing (leading to inadequate analgesia) or overdosing (resulting in toxicity) because of the highly variable terminal half-life. It has been suggested that the conversion ratio of oral opioids to methadone at steady state is different (much lower) than the usually accepted acute potency ratios would indicate. The clear message to physicians contemplating using methadone is to prescribe it regularly to become familiar with its nuances and they will then find it a valuable addition to their opioid repertoire.