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

  • Pharmacodynamics
  • Published:
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Abstract

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.

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References

  1. Poulsen L, Brosen K, Arendt-Nielsen L, Gram LF, Elbaek K, Sindrup SH (1996) Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. Eur J Clin Pharmacol 51:289–295

    Article  CAS  PubMed  Google Scholar 

  2. Yue QY, Alm C, Svensson JO, Sawe J (1997) Quantification of the O- and N-demethylated and the glucuronidated metabolites of codeine relative to the debrisoquine metabolic ratio in urine in ultrarapid, rapid, and poor debrisoquine hydroxylators. Ther Drug Monit 19:539–542

    Article  CAS  PubMed  Google Scholar 

  3. Sindrup SH, Brosen K, Bjerring P, Arendt-Nielsen L, Larsen U, Angelo HR, Gram LF (1990) Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine. Clin Pharmacol Ther 48:686–693

    CAS  PubMed  Google Scholar 

  4. Sindrup SH, Brosen K (1995) The pharmacogenetics of codeine hypoalgesia. Pharmacogenetics 5:335–346

    CAS  PubMed  Google Scholar 

  5. Caraco Y, Sheller J, Wood AJ (1996) Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J Pharmacol Exp Ther 278:1165–1174

    CAS  PubMed  Google Scholar 

  6. Tyndale RF, Droll KP, Sellers EM (1997) Genetically deficient CYP2D6 metabolism provides protection against oral opiate dependence. Pharmacogenetics 7:375–379

    CAS  PubMed  Google Scholar 

  7. Kathiramalainathan K, Kaplan HL, Romach MK, Busto UE, Li NY, Sawe J, Tyndale RF, Sellers EM (2000) Inhibition of cytochrome P450 2D6 modifies codeine abuse liability. J Clin Psychopharmacol 20:435–444

    Article  CAS  PubMed  Google Scholar 

  8. Romach MK, Otton SV, Somer G, Tyndale RF, Sellers EM (2000) Cytochrome P450 2D6 and treatment of codeine dependence. J Clin Psychopharmacol 20:43–45

    Article  CAS  PubMed  Google Scholar 

  9. Quiding H, Lundqvist G, Boréus LO, Bondeson U, Öhrvik J (1993) Analgesic effect and plasma concentrations of codeine and morphine after two dose levels of codeine following oral surgery. Eur J Clin Pharmacol 44:319–323

    CAS  PubMed  Google Scholar 

  10. Sindrup SH, Arendt-Nielsen L, Brosen K, Bjerring P, Angelo HR, Eriksen B, Gram LF (1992) The effect of quinidine on the analgesic effect of codeine. Eur J Clin Pharmacol 42:587–591

    CAS  PubMed  Google Scholar 

  11. Hasselstrom J, Yue QY, Sawe J (1997) The effect of codeine on gastrointestinal transit in extensive and poor metabolisers of debrisoquine. Eur J Clin Pharmacol 53:145–148

    Article  CAS  PubMed  Google Scholar 

  12. Eckhardt K, Li S, Ammon S, Schanzle G, Mikus G, Eichelbaum M (1998) Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain 76:27–33

    Article  CAS  PubMed  Google Scholar 

  13. Bradley CM, Nicholson AN (1986) Effects of a mu-opioid receptor agonist (codeine phosphate) on visuo-motor coordination and dynamic visual acuity in man. Br J Clin Pharmacol 22:507–512

    CAS  PubMed  Google Scholar 

  14. Linnoila M, Hakkinen S (1974) Effects of diazepam and codeine, alone and in combination with alcohol, on simulated driving. Clin Pharmacol Ther 15:368–373

    CAS  PubMed  Google Scholar 

  15. Walker DJ, Zacny JP (1998) Subjective, psychomotor, and analgesic effects of oral codeine and morphine in healthy volunteers. Psychopharmacology 140:191–201

    Google Scholar 

  16. Redpath JB, Pleuvry BJ (1982) Double-blind comparison of the respiratory and sedative effects of codeine phosphate and (±)-glaucine phosphate in human volunteers. Br J Clin Pharmacol 14:555–558

    CAS  PubMed  Google Scholar 

  17. Saarialho-Kere U, Mattila MJ, Seppala T (1986) Pentazocine and codeine: effects on human performance and mood and interactions with diazepam. Med Biol 64:293–299

    CAS  PubMed  Google Scholar 

  18. Stacher G, Bauer P, Schneider C, Winklehner S, Schmierer G (1982) Effects of a combination of oral naproxen sodium and codeine on experimentally induced pain. Eur J Clin Pharmacol 21:485–490

    CAS  PubMed  Google Scholar 

  19. Liljequist R (1981) Codeine-induced memory changes: nature and relationship to opiate system. Eur J Clin Pharmacol 20:99–107

    CAS  PubMed  Google Scholar 

  20. Chesher GB (1985) The influence of analgesic drugs in road crashes. Accid Anal Prev 17:303–309

    Article  CAS  PubMed  Google Scholar 

  21. Drummer O, Chu M, Gerostamoulos J (1999) Involvement of drugs in accident causation. Report of AustRoad Working Group, Southbank, Australia. Victoria Institute of Forensic Medicine and Department of Forensic Medicine

  22. Ray WA, Thapa PB, Shorr RI (1993) Medications and the older driver. Clin Geriatr Med 9:413–438

    CAS  PubMed  Google Scholar 

  23. Leveille SG, Buchner DM, Koepsell TD, McCloskey LW, Wolf ME, Wagner EH (1994) Psychoactive medications and injurious motor vehicle collisions involving older drivers. Epidemiology 5:591–598

    Google Scholar 

  24. Zacny JP, Lichtor JL, Flemming D, Coalson DW, Thompson WK (1994) A dose-response analysis of the subjective, psychomotor and physiological effects of intravenous morphine in healthy volunteers. J Pharmacol Exp Ther 268:1–9

    Google Scholar 

  25. Bruera E, Macmillan K, Hanson J, MacDonald RN (1989) The cognitive effects of the administration of narcotic analgesics in patients with cancer pain. Pain 39:13–16

    CAS  PubMed  Google Scholar 

  26. WHO Collaborating Center for Drug Statistics Methodology (2000) Drug consumption in Norway 1996–2000.

  27. Christophersen AS, Morland J (1997) Drugged driving, a review based on the experience in Norway. Drug Alcohol Depend 47:125–135

    Article  CAS  PubMed  Google Scholar 

  28. Gjerde H, Christophersen AS, Skuterud B, Klemetsen K, Morland J (1990) Screening for drugs in forensic blood samples using EMIT urine assays. Forensic Sci Int 44:179–185

    CAS  PubMed  Google Scholar 

  29. Schuberth J, Schuberth J (1989) Gas chromatographic–mass spectrometric determination of morphine, codeine and 6-monoacetylmorphine in blood extracted by solid phase. J Chromatogr 490:444–449

    Article  CAS  PubMed  Google Scholar 

  30. Gjerde H, Fongen U, Gundersen H, Christophersen AS (1991) Evaluation of a method for simultaneous quantification of codeine, ethylmorphine and morphine in blood. Forensic Sci Int 51:105–110

    CAS  PubMed  Google Scholar 

  31. Rowland T (1995) Absorption and disposition kinetics, 3rd edn. Lippincott Williams & Wilkins, PA, pp 11–34

  32. Kuitunen T (1994) Drug and ethanol effects on the clinical test for drunkenness: single doses of ethanol, hypnotic drugs and antidepressant drugs. Pharmacol Toxicol 75:91–98

    CAS  PubMed  Google Scholar 

  33. Zacny JP (1995) A review of the effects of opioids on psychomotor and cognitive functioning in humans. Exp Clin Psycopharmacol 3:432–466

    Article  CAS  Google Scholar 

  34. Mørland J (2000) Driving under the influence of non alcohol drugs. Forensic Sci Rev 12:79–105

    Google Scholar 

  35. Drummer O (1994) Drugs in drivers killed in Australian road traffic accidents. Report no. 0594, Melbourne, Australia. Victoria Institute of Forensic Pathology

  36. Kay DC, Gorodetzky CW, Martin WR (1967) Comparative effects of codeine and morphine in man. J Pharmacol Exp Ther 156:101–106

    CAS  PubMed  Google Scholar 

  37. Poulsen L, Riishede L, Brosen K, Clemensen S, Sindrup SH (1998) Codeine in post-operative pain. Study of the influence of sparteine phenotype and serum concentrations of morphine and morphine-6-glucuronide. Eur J Clin Pharmacol 54:451–454

    Article  CAS  PubMed  Google Scholar 

  38. Vree TB, van Dongen RT, Koopman-Kimenai PM (2000) Codeine analgesia is due to codeine-6-glucuronide, not morphine. Int J Clin Pract 54:395–398

    CAS  PubMed  Google Scholar 

  39. Kerr B, Hill H, Coda B, Calogero M, Chapman CR, Hunt E, Buffington V, Mackie A (1991) Concentration-related effects of morphine on cognition and motor control in human subjects. Neuropsychopharmacology 5:157–166

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. National Institute of Forensic Toxicology, PO Box 495 Sentrum, 0105 , Oslo, Norway

    Liliana Bachs & Jørg Mørland

  2. Norwegian Institute of Public Health, Oslo, Norway

    Svetlana Skurtveit

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  1. Liliana Bachs
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  2. Svetlana Skurtveit
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  3. Jørg Mørland
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Correspondence to Liliana Bachs.

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Bachs, L., Skurtveit, S. & Mørland, J. Codeine and clinical impairment in samples in which morphine is not detected. Eur J Clin Pharmacol 58, 785–789 (2003). https://doi.org/10.1007/s00228-003-0561-y

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  • DOI: https://doi.org/10.1007/s00228-003-0561-y

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