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PubMed1997

Analgesic effects of codeine-6-glucuronide after intravenous administration.

Centrally administered codeine glucuronide has been shown to exhibit antinociceptive properties with decreased immunosuppressive effects compared to codeine. In this study, codeine-6-glucuronide was administered to rats, and its analgesic effect was compared to that of codeine. The concentrations of codeine and its metabolites in plasma and brain were also determined at the peak response time after administration of each compound. Receptor-binding studies with rat brain homogenates and affinity profiles were also determined. Intravenous administration of codeine-6-glucuronide resulted in approximately 60% of the analgesic response elicited by codeine itself. Analysis of plasma and brain showed that codeine-6-glucuronide is relatively stable in vivo, with only small amounts of morphine-6-glucuronide being detected in addition to unchanged codeine-6-glucuronide. The receptor affinity of codeine-6-glucuronide was similar to that of codeine. It is concluded that intravenously administered codeine-6-glucuronide possesses analgesic activity similar to that of codeine, and may have clinical benefit in the treatment of pain

Journal Article↗
PubMed1992

Pharmacokinetics and metabolism of codeine in humans.

Codeine (30 mg phosphate) was metabolized by eight human volunteers to the following six metabolites: codeine-6-glucuronide 81.0 +/- 9.3 per cent, norcodeine 2.16 +/- 1.44 per cent, morphine 0.56 +/- 0.39 per cent, morphine-3-glucuronide 2.10 +/- 1.24 per cent, morphine-6-glucuronide 0.80 +/- 0.63 per cent, and normorphine 2.44 +/- 2.42 per cent. Two out of eight volunteers were unable to O-dealkylate codeine into morphine and lack therefore the cytochrome P450 IID6 isoenzyme. The half-life of codeine was 1.47 +/- 0.32 h, that of codeine-6-glucuronide 2.75 +/- 0.79 h, and that of morphine-3-glucuronide 1.71 +/- 0.51 h. The systemic clearance of codeine was 2280 +/- 840 ml min-1, the renal clearance of codeine was 93.8 +/- 29.8 ml min-1, and that of codeine-6-glucuronide was 122 +/- 39.2 ml min-1. The plasma AUC of codeine-6-glucuronide is approximately 10 times higher than that of codeine. Protein binding of codeine and codeine-6-glucuronide in vivo was 56.1 +/- 2.5 per cent and 34.0 +/- 3.6 per cent, respectively. The in vitro protein binding of norcodeine was 23.5 +/- 2.9 per cent; of morphine, 46.5 +/- 2.4 per cent; of normorphine, 23.5 +/- 3.5 per cent; of morphine-3-glucuronide, 27.0 +/- 0.8 per cent; and of morphine-6-glucuronide, 36.7 +/- 3.8 per cent.

Adult↗
PubMed1996

Codeine disposition in human hair after single and multiple doses.

OBJECTIVE: We studied the dose-proportion and time-course relationships for the incorporation of codeine into human hair after the administration of three different groups. SUBJECTS: Male volunteers, with dark hair, were given oral codeine either as a single dose of 60 mg (n = 7) or 120 mg (n = 12) or as multiple doses of 30 mg 3 times daily for 5 days (n = 7) (450 mg total dose). METHODS: Blood and urine were collected for various times for up to 72 h after dosing. Scalp hair was collected initially by plucking (up to 4 weeks) and later by cutting for up to 10 weeks. Plasma, urine, proximal 1 cm of hair and distal hair were each analyzed for codeine and its metabolites by positive-ion chemical ionization ion trap gas chromatography/mass spectrometry. RESULTS: Codeine was detected in the proximal 1 cm of hair within 30 min of an oral 120-mg dose. Codeine was not detected in the distal hair segment until 3 weeks after receiving a dose of codeine. Codeine was detected in distal hair segments for at least 10 weeks at 30 pg mg-1 hair following a single 120 mg codeine dose and at 90 pg mg-1 hair following 30 mg codeine 3 times a day for 5 days. Morphine or the glucuronides of codeine or morphine were not detected in the hair specimens of these subjects. CONCLUSION: Codeine is rapidly distributed into the germanitive elements of hair in a dose-proportional manner. A portion of the codeine remains bound as the hair grows and can be detected in distal hair for up to 10 weeks after a single dose.

Administration, Oral↗
PubMed1996

Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects.

OBJECTIVE: Codeine O-demethylation to morphine is catalysed by the genetic polymorphic sparteine oxygenase (CYP2D6). The objective of the present study was to assess the analgesic effect of codeine on different types of experimental pain in relation to sparteine phenotype. METHODS: Fourteen extensive (EMs) and 14 poor metabolizers (PMs) of sparteine completed a randomized, double-blind, three-way, cross-over study with a single oral dose of codeine (75 or 100 mg) against morphine (20 or 30 mg) and placebo. Pain tests performed before and 1, 2, 3, and 4 h after medication included the cold pressor test and pain thresholds for heat and pressure stimulation. Adverse effects were rated by a structured interview. RESULTS: After morphine, morphine and morphine-6-glucuronide were present in equal amounts in plasma of PMs and EMs. After codeine, neither morphine nor morphine-6-glucuronide could be detected in 13 of the 14 PMs, whereas at least one of the compounds could be detected in all EMs. Peak pain and discomfort rated on a VAS scale during the cold pressor test were significantly reduced by morphine in both EMs and PMs, with a median peak change of 8.5 and 7.0 mm, respectively, for peak pain, and 11.5 and 15.5 mm, respectively, for discomfort. Codeine only reduced these pain measures significantly in EMs, with a median peak change of 5.5 mm for peak pain and 10.5 mm for discomfort. Pain detection and tolerance thresholds to heat and pressure were not consistently altered by either morphine or codeine. In PMs, adverse effects were significantly more pronounced on morphine than on codeine and only showed a slight difference between codeine and placebo. In EMs, there was no difference between codeine and morphine and more pronounced adverse effects on both drugs as compared to placebo. CONCLUSION: This study confirms that codeine O-demethylation depends on CYP2D6; it shows that the 6-glucuronidation of morphine is independent of CYP2D6; it supports the theory that the analgesic effect of codeine depends on its O-demethylation; and it indicates that this is probably also the case for the adverse effects. The results lend no support to the suggestion of a non-opioid analgesic effect of codeine.

Adult↗
PubMed1982

Codeine disposition in smokers and nonsmokers.

The bioavailability of codeine and extent of its transformation to morphine were stated in 12 smoking and 11 nonsmoking subjects after single doses 60 mg IM codeine and 60 mg codeine sulfate orally, given 1 wk apart. Codeine and morphine plasma concentrations over the 12-hr period after drug were determined by radioimmunoassay (RIA). No differences were found between smokers and nonsmokers with respect to maximum plasma concentration (Cmax) of codeine, time to attain this concentration (tmax), codeine plasma half-life (t1/2), or areas under plasma concentration-time curves (AUC) for codeine or morphine. There was a faster, but clinically unimportant, mean apparent plasma clearance in smokers (52.8 +/- 2.3 (SEM) ml/min/70 kg) than in nonsmokers (45.0 +/- 2.1 ml/min/70 kg) after intramuscular injection only. Mean oral codeine bioavailability in smokers (54.8 +/- 4.9%) and in nonsmokers (50.2 +/- 2.1%) did not offer. Plasma morphine AUC values were higher after oral doses than after intramuscular injections, suggesting a first-pass O-demethylation of codeine. For six of these subjects plasma morphine AUC values were very low after both routes of administration, suggesting less O-demethylation of codeine in these than in the remaining 17 subjects. The observation of higher morphine AUC values after oral codeine, coupled with clinical reports of greater analgesic potency with intramuscular codeine, does not support the hypothesis that the analgesic properties of this drug are mediated entirely by biotransformation to morphine.

Administration, Oral↗
PubMed2003

Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O- and N-demethylated metabolites at mu- and delta-opioid receptors.

Phenotypic differences in analgesic sensitivity to codeine (3-methoxymorphine) results from polymorphisms in cytochrome P450-2D6, which catalyzes O-demethylation of codeine to morphine. However, O-demethylation reportedly is not required for analgesic activity of the 7,8-saturated codeine congeners dihydrocodeine, hydrocodone, and oxycodone. This study determined the potency and efficacy of these compounds and their demethylated derivatives to stimulate mu- and delta-opioid receptor-mediated G-protein activation using agonist-stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTP gamma S) binding. Results showed that 7,8-saturated codeine congeners were more efficacious than codeine in activating mu-receptors, but only dihydrocodeine was more efficacious at delta-receptors. Hydrocodone and oxycodone were approximately 10-fold more potent than codeine and dihydrocodeine at either receptor. Morphine-like compounds with a 3-hydroxy group were approximately 30- to 100-fold more potent than their 3-methoxy analogs at the mu-receptor, and these compounds generally exhibited greater efficacy (e.g., morphine produced 2-fold greater maximal stimulation than codeine). Removal of the N-methyl group did not affect efficacy or potency of codeine congeners to activate mu-receptors, whereas this modification generally increased efficacy but decreased potency of morphine congeners. At the delta receptor, morphine congeners showed greater potency and structure-dependent differences in efficacy compared with codeine congeners, whereas removal of the N-methyl group had effects similar to those observed at the mu-receptor. These results demonstrate that 7,8-saturated codeine congeners are more efficacious than codeine, which may explain their lack of requirement for 3-O-demethylation in vivo. Nonetheless, because all 7,8-saturated codeine congeners were significantly less potent than their morphine derivatives, further research is needed to understand the relationship between metabolism and in vivo activity of these compounds.

Animals↗
PubMed1984

Induction of physical dependence on codeine in the rat by drug-admixed food ingestion.

The developmental process of physical dependence on codeine has been explored in rats treated with codeine-admixed food (0.5 mg/g food) during 1 to 7 days. In rats treated with codeine for more than 2 days, body weight loss was markedly observed after the abrupt codeine withdrawal. The intensity and time course of body weight loss increased according to the duration of codeine treatment. After the codeine withdrawal, behavioral signs such as diarrhea, ptosis and vocalization were observed. In the naloxone-precipitated withdrawal test, rats treated with codeine for 1 day manifested a loss of body weight after naloxone challenge, and the intensity of body weight loss increased according to the duration of codeine treatment. After naloxone injection, the codeine-treated rats showed abnormal behaviors such as diarrhea, ptosis, teeth chattering , salivation, body shakes, vocalization, nose bleed, irritability, lacrimation and writhing. The total score, evaluated by the ranking system for precipitated withdrawal behaviors, was correlated with the duration of codeine treatment. These results suggest that naloxone-precipitated withdrawal signs are powerful in comparison with that after codeine withdrawal, and the weight loss is a common index for quantitative assessment of physical dependence on narcotics in the natural and naloxone-precipitated withdrawal tests. It is concluded that the drug-admixed food ingestion method has the advantage of rapidly inducing a high degree of physical dependence on codeine.

Animals↗
PubMed2004

Modification by L-NAME of codeine induced analgesia: possible role of nitric oxide.

Objectives were to investigate the effect of nonselective nitric oxide synthase (NOS) inhibitor, L-NAME on codeine-induced analgesia and to see the role of NO in its antinociceptive effect. Also, to see if L-NAME can potentiate the antinociceptive response of sub-effective dose of codeine and to explore if opioid receptors have some role to play in L-NAME effects. Mice were injected with selected doses of codeine or other selected agents intraperitoneally and the latency to hot plate was recorded at zero, 15, 30, and 60 min of the treatments. The antinociceptive response of codeine (10 mg/kg, i.p.) was studied in comparison to those of the NOS inhibitor, L-NAME, and of nitric oxide donor, sodium nitroprusside (SNP). Assessment of nitrates and nitrites (NOx) in the sera of treated mice were also made. Codeine (20 mg/kg dose), induced analgesia significantly and dose dependently only after 15 min. L-NAME at 20, 40, and 80 mg/kg dose levels significantly changed the nonanalgesic effect of codeine (10 mg/kg) to highly significant analgesia. The effect of L-NAME 40 mg/kg was significantly higher than the other two doses and was almost equal to that of the higher dose of codeine. Naloxone itself did not show any intrinsic effect but almost abolished the L-NAME-codeine induced analgesia. Similarly, SNP (1 mg/kg) reversed the decrease in reaction time by L-NAME-codeine to its control values, significantly. Pretreatment with L-NAME rendered the nonanalgesic dose of codeine significantly analgesic almost in an equal potency to the high dose of codeine alone and indicate that the NO modulatory effect on the opioid analgesic codeine is probably, at least in part, through opioid receptors.

Analgesia↗
PubMed1987

Codeine-mediated hepatotoxicity in isolated rat hepatocytes.

Administration of codeine to freshly isolated rat hepatocytes resulted in cytotoxicity characterized by a dose- and time-dependent leakage of lactate dehydrogenase (LDH) out of the cells. Codeine also caused a decrease in hepatic reduced sulfhydryl content. Cytochrome P-450 content and NADPH levels were not changed. Induction and inhibition studies of several potential pathways of codeine biotransformation were carried out in order to determine if codeine must be metabolized to a reactive intermediate to elicit these hepatotoxic effects. Codeine hepatotoxicity as measured by LDH release was not changed after induction of cytochrome P-450 by phenobarbital and was decreased after cytochrome P-448 induction by beta-naphthoflavone. However, codeine hepatotoxicity was inhibited when an inhibitor of cytochrome P-450 metabolism, metyrapone, was added. Inhibition of the other major hepatic oxidative enzyme system, flavin adenine dinucleotide (FAD)-containing monooxygenase, increased the cytotoxicity of codeine. Inhibition of alcohol dehydrogenase had no effect on codeine hepatotoxicity. These results indicate that codeine hepatotoxicity is caused by a cytochrome P-450-generated intermediate of codeine, whereas FAD-containing monooxygenase may metabolize codeine to a nontoxic intermediate.

Alcohol Dehydrogenase↗
PubMed1976

Variable interval responding maintained by intravenous codeine and ethanol injections in the rhesus monkey.

Rhesus monkeys were trained to respond under a variable interval 2 min schedule for codeine or ethanol injections. Both codeine and ethanol were effective in the initiation of variable-interval responding; responding was maintained over a range of codeine (0.003-1.0 mg/kg/injection) and ethanol doses (32.0-560 mg/kg/injection). Maximum rates of responding were obtained at the 0.01 mg/kg/injection codeine dose (0.14 responses/sec) and at the 180 mg/kg/injection codeine dose (0.19 responses/sec). Rates of responsing were bitonic functions of the reinforcer dose for both codeine and ethanol; maximum rates were obtained at intermediate doses and lower rates occurred at the extremes of the dose range. Both codeine and ethanol showed within-session decreases in responding across the range of reinforcer doses. Codeine-reinforced responding declined in rate within the one-hour session without a similar change in the frequency of drug injection; in contrast, both ethanol-reinforced responding and the frequency of ethanol injections declined within each session across a range of doses. Increasing or decreasing the codeine dose half-way through the one-hour session resulted in increases or decreases in codeine responding compared to controls. These data indicate that the progressive decline in codeine-reinforced responding is not the result of a generalized disruption of responding.

Animals↗
PubMed1997

Indices and graphical approaches for the detection of interindividual and interethnic variations in codeine metabolism.

AIMS: To evaluate the use of different graphical methods and statistical tests in the detection of interindividual and interethnic variations in codeine metabolism. Various urinary metabolic ratios (MR) for codeine O-demethylation were also compared for their ability to determine phenotype. METHODS: Frequency histograms, normal test variable (NTV) plots and admixture analysis were used to examine the distributions of the urinary MRs for codeine O-demethylation, N-demethylation and glucuronidation in 132 Caucasian and 222 Chinese subjects. RESULTS: In the Caucasian population, apparent bimodality was shown in both a frequency histogram and NTV plot of the log MR of codeine O-demethylation (codeine/(morphine (M) + M-3 and M-6-glucuronide (M3G and M6G) + normorphine (NM)). Admixture analysis confirmed the co-segregation of codeine O-demethylation and debrisoquine hydroxylation. The antimode for the codeine O-demethylation MR between extensive and poor metabolisers was located between 5.5 and 8.3. A simplified MR for codeine O-demethylation (codeine/M3G) demonstrated a similar correlation with the debrisoquine MR to the more complex MR, allowing a simplification of the analytical method for phenotyping. The Chinese population had significantly higher median MRs for codeine N-demethylation, O-demethylation and glucuronidation, which was shown clearly in the frequency histograms, but not in the NTV plots. CONCLUSION: A histogram seems preferable over a NTV plot for assigning phenotype using the codeine O-demethylation MR, because it is clear and simple. Interethnic difference in the metabolism of codeine are also better visualised from the histograms.

Adult↗
PubMed2002

Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability.

BACKGROUND: Codeine analgesia is wholly or mostly due to its metabolism to morphine by the cytochrome P450 enzyme CYP2D6, which shows significant genetic variation in activity. The aims of this study were to investigate genotype, phenotype and morphine production from codeine in children undergoing adenotonsillectomy, and to compare analgesia from codeine or morphine combined with diclofenac. METHODS: Ninety-six children received either codeine 1.5 mg kg(-1) or morphine 0.15 mg kg(-1) in a randomized, double-blind design. Genetic analysis was performed and plasma morphine concentrations at 1 h were determined. Postoperative analgesia and side-effects were recorded. RESULTS: Forty-seven per cent of children had genotypes associated with reduced enzyme activity. Mean (SD) morphine concentrations were significantly lower (P<0.001) after codeine [4.5 (0.3) ng ml(-1)] than after morphine [24.7 (1.5) ng ml(-1)], and morphine and its metabolites were not detected in 36% of children given codeine. There was a significant relationship between phenotype and plasma morphine (P=0.02). More children required rescue analgesia after codeine at both 2 (P<0.05) and 4 h after administration (P<0.01). Fifty-six per cent of children vomited after morphine and 29% after codeine (P<0.01). Neither phenotype nor morphine concentration was correlated with either pain score or the need for rescue analgesia (r=-0.21, 95% confidence interval -0.4, -0.01). CONCLUSIONS: Reduced ability for codeine metabolism may be more common than previously reported. Plasma morphine concentration 1 h after codeine is very low, and related to phenotype. Codeine analgesia is less reliable than morphine, but was not well correlated with either phenotype or plasma morphine in this study.

Analgesia↗
PubMed1995

The pharmacogenetics of codeine hypoalgesia.

Codeine is an old drug that is still widely used to treat mild and moderate pain. It is mainly metabolised by glucuronidation, but minor pathways are N-demethylation to norcodeine and O-demethylation to morphine. The latter pathway depends on the genetically polymorphic CYP2D6 which is absent in 7% of the white population (PM) and present in the remainder (EM). Lack of influence of codeine on experimental pain in PM as well as in EM treated with the CYP2D6 blocker quinidine, who are both practically unable to convert codeine to morphine, has supported an old hypothesis that codeine acts through metabolically formed morphine. Possibly, local codeine O-demethylation in the CNS is of major importance for its hypoalgesic effect. Such a local morphine formation from codeine, which supposedly is also catalysed by CYP2D6, could explain why the hypoalgesic effect of codeine stems from morphine despite relatively low plasma levels of morphine after standard hypoalgesic doses of codeine. Dependence of codeine hypoalgesia on morphine formation via CYP2D6 makes this effect liable to interaction with drugs that are inhibitors of CYP2D6. Examples of potent inhibitors of CYP2D6 are quinidine, some selective serotonin reuptake inhibitors and some neuroleptics. Less potent inhibitors, such as tricyclic antidepressants, will probably also reduce the pain relieving effect of codeine, since codeine has a low affinity for CYP2D6. Biosynthesis of morphine in humans may also include steps catalyse by CYP2D6. Experimental studies in large groups of EM and PM indicate that this may lead to interphenotype differences in pain tolerance.

Analgesics, Opioid↗
PubMed1999

Impact of ethnic origin and quinidine coadministration on codeine's disposition and pharmacodynamic effects.

CYP2D6 is polymorphically distributed so that in poor metabolizers enzyme activity is missing. The goal of this study was to compare the pharmacokinetics and pharmacodynamics of codeine with and without quinidine between Caucasian and Chinese extensive metabolizers of debrisoquin. Nine Caucasians and eight Chinese subjects received in random, double blind fashion, on two occasions, codeine 120 mg. with placebo or with quinidine 100 mg. Pharmacodynamic effects were determined over 6 h. Codeine-apparent clearance and partial metabolic clearance by O-demethylation were significantly greater in the Caucasian than in the Chinese subjects (1939 +/- 175 ml/min versus 1301 +/- 193 ml/min, p <.03 and 162.7 +/- 36.6 ml/min versus 52.7 +/- 12.7 ml/min, p <.02, respectively). Codeine's respiratory effects (except on resting ventilation) were significantly greater in the Caucasian than in the Chinese subjects (p <.05), but no interethnic differences were noted in codeine's effect on the digit symbol substitution test and pupillary ratio. No morphine or morphine metabolites were detected in plasma when codeine was coadministered with quinidine. Codeine O-demethylation was significantly reduced after quinidine in both ethnic groups; however, the absolute decrease was greater in Caucasians (115.8 +/- 25.9 ml/min versus 46.8 +/- 10.6 ml/min, respectively, p <.03). The diminished production of morphine after quinidine was associated in the Caucasians, but not in the Chinese, with a marked reduction in codeine's effects (p <.01). In conclusion, Chinese produce less morphine from codeine, exhibit reduced sensitivity to that morphine, and therefore might experience reduced analgesic effect in response to codeine. In addition, quinidine induced inhibition of codeine O-demethylation is ethnically dependent with the reduction being greater in Caucasians.

Adult↗
PubMedDate not supplied

Pharmacokinetics of codeine after parenteral and oral dosing in the rat.

The pharmacokinetics of codeine was examined in six male Sprague-Dawley rats following iv bolus (3 mg/kg) and oral (5 mg/kg) codeine in a randomized crossover design. Whole blood concentrations of codeine and its O-demethylated metabolite, morphine, were determined by HPLC with electrochemical detection. Following iv codeine administration, the distribution and elimination are best described by an open two-compartment model. The weight normalized volume of distribution of (Vdarea) and total body clearance (CL) were 5.1 +/- 1.7 liters/kg and 6.2 +/- 1.5 liters/kg/hr, respectively. Mean residence time of codeine averaged 34.1 +/- 6.9 minutes. The ratio of AUCmorphine/AUCcodeine was 0.05 +/- 0.02. The absolute bioavailability of codeine calculated was 8.3 +/- 3.2%, indicating extensive first pass metabolism of codeine. An equivalent amount of codeine and morphine were present in the rat following oral codeine. Thus, the amount of morphine formed following codeine administration depends on the route of codeine administration.

Administration, Oral↗
PubMed1996

Incorporation of codeine and metabolites into hair. Role of pigmentation.

Xenobiotics circulating in the blood may become incorporated into growing hair. Melanin has affinity for many pharmacologically unrelated drugs and is responsible for the pigmentation in hair. To assess the role of pigmentation in the incorporation of drugs into hair, the distribution of codeine and its metabolites was studied in Sprague-Dawley (SD; white nonpigmented hair), Dark Agouti (DA; brown pigmented hair), and hooded Long-Evans (LE; both black pigmented and white nonpigmented hair) rats. Codeine was administered at a dose of 40 mg/kg/day i.p. for 5 days. Fourteen days after beginning the dosing protocol, hair was collected and analyzed for codeine, and its metabolite, morphine, by positive-ion chemical ionization GC/ion-trap MS. The plasma pharmacokinetics for codeine and morphine were also determined after a single 40 mg/kg injection (equivalent to first dose in 5-day dosing protocol) in all three strains of rats. Hair and plasma codeine and morphine concentrations were also determined after acid hydrolysis to evaluate the presence of glucuronide metabolites. Codeine concentrations in the hair of SD, DA, and pigmented LE hair were 0.98 +/- 0.10, 5.99 +/- 1.24, and 111.93 +/- 18.69 ng/mg hair, respectively; morphine concentrations were 0.34 +/- 0.04, 0.51 +/- 0.11, and 14.46 +/- 1.81 ng/mg hair, respectively; morphine glucuronide concentrations were 0.67 +/- 0.08, 1.04 +/- 0.37, and 13.80 +/- 3.60 ng/mg hair, respectively. Studies examining the in vitro binding of [3H] codeine and [3H]morphine to hair demonstrated both specific and nonspecific binding sites for codeine and morphine. Pigmented hair from LE rats possessed the greatest number of binding sites, white hair from SD rats contained the least, and brown hair from DA rats was intermediate. A time course study of codeine and its metabolites showed pigment-mediated differences in incorporation of codeine and metabolites within a few hours of drug administration. These data indicate that pigmented hair possesses a greater capacity to bind and incorporate codeine and its metabolites than does nonpigmented hair. Interpretation of hair concentrations of drugs should involve consideration of hair pigmentation.

Animals↗
PubMed1986

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

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.

Administration, Oral↗
PubMed2003

Codeine and clinical impairment in samples in which morphine is not detected.

OBJECTIVE: Codeine metabolises partly to morphine by the liver enzyme CYP2D6, which is subject to genetic polymorphism. It has been suggested that analgesic effects of codeine are due to the morphine metabolite. Codeine effects other than analgesia have been less investigated in this regard, but it has been suggested that sedation, for example, might be independent of morphine formation. The aim of our study was to investigate the influence of codeine alone, without concomitant presence of morphine, on a clinical test for drunkenness (CTD) performed in relation to suspected drugged driving. METHODS: Cases with detected codeine but not morphine, nor any other drug above the limit of detection, were selected from the database of suspected drugged drivers at National Institute for Forensic Toxicology, Oslo, Norway. Codeine blood concentration in these samples was compared with the conclusions from the corresponding individual CTD. RESULTS: Of the 43 cases fulfilling the selection criteria, 23 were judged as "not impaired", and 20 as "impaired". Mean blood codeine concentration in the "not impaired" group was 143 ng/ml (95% CI 48-238, median 63 ng/ml). Mean concentration in the "impaired" group was 213 ng/ml (95% CI 146-279, median 159 ng/ml). There was a statistically significant concentration difference between the two groups. Codeine blood concentrations were further grouped as "moderate", "medium high" and "high". When adjusted for age, gender and chronic use, the odds ratios for being judged as impaired were 6 (95% CI 1-32, P=0.04) and 19 (95% CI 2-182, P=0.01) for the "medium high" group and the "high" group, respectively, relative to the "moderate" group. CONCLUSION: Codeine appeared to have some dose-dependent effect on the central nervous system that may lead to impairment as judged from a CTD, independent of measurable blood morphine concentrations. This supports the view that some codeine effects do not seem to be mediated by morphine.

Adult↗