Plasma concentrations of codeine and its metabolite, morphine, after single and repeated oral administration

Abstract

Plasma concentrations of codeine and its demethylated metabolite, morphine, were determined after single and repeated oral administration of codeine. Twelve healthy volunteers received two doses of codeine 60 mg, 2.8 h apart. In order to achieve steady-state conditions codeine 60 mg was then taken every 8 h for a further five doses. The plasma concentrations of codeine and morphine after the first, second and seventh doses were analyzed by GC-MS. The maximum plasma concentrations of codeine and morphine were reached about 1 h after administration and this time interval did not change on repeated administration. The peak plasma codeine was higher after the second dose of codeine than after the first and the concentration resembled that at steady-state. For morphine, the plasma concentration did not increase significantly after the second dose. Both after a single dose and during steady-state the plasma concentration of morphine was only 2-3% of that of codeine. It seems unlikely that morphine plays a significant role in the analgesic efficacy of single or repeated doses of codeine.

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…12). After oral administration, the exposure to codeine is almost 40-fold greater than that of morphine (Quiding et al, 1986). However, the potency of morphine at the m-opioid receptor is 600-fold greater (Volpe et al, 2011), thus the pharmacological effects of codeine administration are almost exclusively attributable to the active metabolite morphine (and its subsequent pharmacologically active glucuronide metabolites; see Section IV.B.15.).…”

Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration.

“…Although codeine has been widely used for about 150 years, its pharmacokinetics in man have been investigated mainly during the last 10 years (Guay et al, 1987;Findlay et al, 1977Findlay et al, , 1978Findlay et al, , 1986Quiding et al, 1986;Rogers et al, 1982). In two studies (Guay et al, 1987;Quiding et al, 1986) the plasma concentrations of codeine and its O-demethylated metabolite morphine were determined after single and repeated oral administration in healthy adult volunteers.…”

“…In two studies (Guay et al, 1987;Quiding et al, 1986) the plasma concentrations of codeine and its O-demethylated metabolite morphine were determined after single and repeated oral administration in healthy adult volunteers. The hypothesis that codeine acts through biotransformation to morphine was proposed over 40 years ago (Sanfilippo, 1948).…”

“…The analyses of unconjugated codeine and morphine in plasma were carried out by gas chromatography-mass spectrometry and the lower limits of determination were 3.3 and 1.4 nmol l-1, respectively. The analytical procedure has been described in detail elsewhere (Quiding et al, 1986). The disposition rate constants (Xi) for codeine and morphine were calculated from the plasma drug concentration-time curves using linear regression analysis.…”

Codeine O‐demethylation co‐segregates with polymorphic debrisoquine hydroxylation.

“…This may have clinical implications because these compounds appear to have analgesic activity in both animals and man. In fact, it has been suggested that codeine exerts its analgesic effect by transformation to M (Sanfilippo, 1948) but other hypotheses exist (Quiding et al, 1986). NM is also considered to be an active metabolite of codeine and M, being approximately onefourth as potent as M in relieving postoperative pain (Lasagna & Komfeld, 1958).…”