Published: Journal of Analytical Toxicology, ISSN 0146-4760, Volume 25, Number 6 September 2001, pp. 486-487

LETTER TO THE EDITOR: Concentration Ratios of Codeine-to-Morphine in Plasma after a Single Oral Dose (100 mg) of Codeine Phosphate

To the Editor:
It is widely recognized that codeine undergoes demethylation to produce morphine in a reaction catalyzed by hepatic CYP2D6 enzymes (1–3). Morphine is the ubiquitous metabolite of several opiates including the illicit drug heroin (2). Interpreting results of forensic drug testing for opiates is not easy, and definitive proof of heroin use often remains an open question. Both heroin and its metabolite 6-acetylmorphine (6-AM) have short elimination half-lives, making it difficult to identify these compounds in blood samples above limits of detection by current gas chromatographic–mass spectrometric (GC–MS) methods (4,5). Failure to identify 6-AM in blood specimens submitted for toxicological analysis means that drug-impaired drivers and others can claim that the presence of morphine and codeine in body fluids reflect intake of a prescription drug containing codeine and not abuse of heroin (6). The source of codeine is attributed to hydrolysis of acetylcodeine, which exists as an impurity in the illicit heroin preparation used (7).

It was recently suggested that examining the concentration ratio of morphine-to-codeine in blood samples from impaired drivers might aid in interpreting results of opiate analysis, high ratios being associated with intake of heroin and low ratios speaking in favor of taking codeine medication (8).

In connection with a study dealing with the incorporation of codeine into hair (9), nine healthy Caucasian subjects (three men and six women) received a single oral dose of codeine phosphate (100 mg) after an overnight fast. The volunteers were university students with a mean body weight of 63 kg, and all were classified as extensive metabolizers by genotyping the CYP2D6 enzyme (9). This communication compares the plasma concentration-time profiles of codeine with its pharmacologically active metabolite morphine.

Both morphine and codeine were determined in plasma by GC–MS. This involved addition of deuterium-labeled internal standards and solid-phase extraction. Prior to GC–MS, the PFPA derivatives were prepared and quantitative analysis was based on mass fragment ratios 445.2/448.2 for codeine/codeine-d3 and 414.2/417.2 for morphine/morphine-d3. The qualifier ions m/z 282.2 for codeine and m/z 361.2 and m/z 577.2 for morphine were also routinely monitored. The limit of detection of codeine and morphine by this GC–MS method was 1.0 ng/g plasma. Calibration plots were linear and the assay precision, expressed as between-run coefficients of variation, were 5.9% for codeine and 6.3% for morphine at a concentration of 20 ng/g in plasma.

Figure 1 shows a plot of the concentration-time profiles of codeine and morphine (lower part) as well as codeine-to-morphine ratios (upper part) from 0 to 23 h postdosing. Because of large interindividual variation the median concentrations are shown on the plot. The maximum concentrations of codeine and morphine occurred between 30 and 120 min (median 60 min) post-dosing. The median concentration of codeine at the maximum was 183 ng/g (range 114–326), being on the average 32 times higher (range 24–49) than the median peak concentration of morphine 5.9 ng/g (range 2.9–13.7). The peak concentration of morphine in plasma was only 3.2% of the peak codeine concentration. Importantly, at each sampling time point for up to 23 h post-dosing, the plasma concentration of codeine always exceeded that of morphine. The median areas under the concentration time curves (trapezoidal method) were 772 ng/h ¥ g for codeine compared with 34 ng/h ¥ g for morphine, which gives a codeine-to-morphine ratio of 23:1. The morphine AUC represented only 4.4% of the codeine AUC. At 23 h post-dosing, when the absolute concentrations of the opiates were close to LOD of the method, the codeine-to-morphine ratio was 2.1 to 1.

The concentration-time course of codeine and morphine in plasma observed in this single-dose study (100 mg codeine) agreed well with an earlier work in which 60 mg codeine had been given (1). Indeed the 32:1 ratio of peak codeine-to-morphine concentration in our study agreed well with the ratio of 33:1 after a dose of 60 mg codeine was administered (1). Quiding et al. (10) used a GC–MS method to determine morphine and codeine in plasma and reported that the morphine metabolite represented only 2–3% of the codeine concentration after a single oral dose of 60 mg and also during steady-state multiple dose conditions (10). Moreover, the concentration ratio of codeine-to-morphine in plasma remained greater than 1.0 even after seven repeated doses of 60 mg codeine phosphate (10). In subjects with diminished capacity for enzymatic O-demethylation one would expect to find an even greater codeine-to-morphine concentration ratio in plasma after administration of codeine (3).

The results of our study will prove useful when presence of opiates in blood or plasma are interpreted. Finding a high codeine-to-morphine concentration ratio strongly suggests a person has taken a prescription drug containing codeine (11). On the other hand, if heroin had been taken, the codeine-to-morphine concentration ratio would have been much less than unity (8) because of the higher concentration of morphine metabolite in blood under these conditions. If an individual ingested codeine together with heroin or codeine combined with morphine, making a correct interpretation of results of toxicological analysis of opiates becomes very difficult.

R. Kronstrand and A.W. Jones
Department of Forensic Toxicology
University Hospital
581 85 Linköping
Sweden

References
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 2. E.J. Cone, P. Welch, B.D. Paul, and J.M. Mitchell. Forensic drug testing for opiates: 111. Urinary excretion rates of morphine and codeine following codeine administration. J. Anal. Toxicol. 15: 161–166 (1991).
 3. Q.Y. Yue, J. Hasselström, J.O. Svensson, and J. Säwe. Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparison between extensive and poor hydroxylators of debrisoquine. Br. J. Clin. Pharmacol. 31: 635–642 (1991).
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 6. E.J. Cone, P. Welch, J.M. Mitchell, and B.D. Paul. Forensic drug testing for opiates: 1. Detection of 6-acetylmorphine in urine as an indicator of recent heroin exposure; drug and assay considerations and detection times. J. Anal. Toxicol. 15: 1–7 (1991).
 7. C.L. O’Neal and A. Poklis. The detection of acetylcodeine and 6-acetylmorphine in opiate positive urines. Forensic Sci. Int. 95: 1–10 (1998).
 8. A.W. Jones. Heroin use by motorists in Sweden confirmed by analysis of 6-acetylmorphine in urine. J. Anal. Toxicol. 25: 353–355 (2001).
 9. R. Kronstrand, S. Förstberg-Peterson, B. Kågedal, J. Ahlner, and G. Larson. Codeine concentrations in hair after oral administration is dependent on melanin content. Clin. Chem. 45: 1485–1494 (1999).
10. H. Quiding, P. Anderson, U. Bondesson, L.-O. Boréus, and P.Å. Hynning. Plasma concentrations of codeine and its metabolite morphine after single and repeated oral administration. Eur. J. Clin. Pharmacol. 30: 673–677 (1986).
11. D. Pearce, S. Wiersema, M. Kuo, and C. Emery. Simultaneous determination of morphine and codeine in blood by use of select ion monitoring and deuterated internal standards. Clin. Toxicol. 14: 161–168 (1979).

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