INFLUENCE OF PLASMA-PROTEIN BINDING ON ANALGESIC EFFECT OF METHADONE IN RATS WITH SPONTANEOUS WITHDRAWAL

The effect of spontaneous withdrawal on alpha(1)-acid glycoprotein (AA G) levels and methadone protein binding has been studied in the rat. A nimals were made physically dependent on morphine by providing morphin e HCl in drinking water for three weeks. The natural opiate withdrawal was induced in rats by substituting the morphine solution with drinki ng water. The severity of the abstinence syndrome was assessed at vari ous time intervals. After 12 h of withdrawal, the animals showing abst inence signs and low morphine levels were injected with intravenous me thadone (0.35 mg kg(-1)) and the analgesic effect was measured by the tail-flick method and compared with animals receiving water. The oral administration of morphine produced an increase in AAG levels from 0.6 4 +/- 0.05 g L(-1) in control animals to 1.47 +/- 0.92 g L(-1) in expe rimental animals at the point of withdrawal and 1.21 +/- 0.09 g L(-1) 24 h after withdrawal. The percentage of methadone unbound was signifi cantly lower in morphine-treated than in control animals. A significan t correlation between AAG levels and percentage of methadone bound was observed. A parallel analgesic effect after intravenous methadone, as measured by AUC in the tail-flick test, was less in abstinence animal s than in control (287.6 +/- 24.8 compared with 401.0 +/- 37.06 s min) . We suggest that in the withdrawal syndrome an adjustment of methadon e dose may be necessary because of changes in protein binding.