Skip to main content
SpringerLink
Log in

Impact of environmental and genetic factors on codeine analgesia

  • Originals
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Summary

The polymorphic cytochrome P-450 DB1 (P-450 IID6) is responsible for the O-demethylation of codeine to morphine by human liver microsomes. The influence of P-450 DB1 variable activity on the bioactivation of codeine in vivo to morphine and on its analgesic effect was investigated in phenotyped healthy volunteers — 7 extensive [EM] and 1 poor [PM] metabolizer of debrisoquine. After pretreatment with oral placebo or quinidine sulphate 50 mg, codeine phosphate 100 mg or placebo were administered orally according to a double-blind randomized crossover design.

In EM subjects the plasma morphine Cmax was 17.9 nmol/l, whereas virtually no morphine was detectable after quinidine pretreatment (1.5 nmol/l), and in the PM subject (0.60 nmol/l). In EM codeine significantly increased subjective (VAS) and objective (R-III reflex) pain thresholds in response to selective transcutaneous nerve stimulation, whereas no significant analgesia was detected after placebo, or after codeine with quinidine pretreatment, or in the PM. In PM of genetic origin, or due to environmental alteration of the phenotypic expression (i.e. drug interaction), codeine is not activated into morphine and is an inefficient analgesic.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Sanfilipo G (1948) Contributo sperimentale all'ipotesi della smetilazione della codeina nell'organismo. — I) Influenza della dose sull'assuafazione alla codeina. Boll Soc Ital Biol Sper 24: 723–726

    Google Scholar 

  2. Butz RF, Jones EC, Welch RAM et al. (1983) Pharmacokinetics and O-dealkylation of morphine-3-alkyl ethers in the rat. A radio-immunoassay study. Drug Metabol Dispos 11: 481–488

    Google Scholar 

  3. Findlay JWA, Fowle ASE, Butz RF et al. (1986) Comparative disposition of codeine and pholcodine in man after single oral doses. Br J Clin Pharmacol 22: 61–71

    Google Scholar 

  4. Cohen R (1961) The pharmacology of pholcodine. Bull Narcotics 13: 19–36

    Google Scholar 

  5. Dahlström B, Paalzow L (1976) Pharmacokinetics and analgesia of codeine and its metabolite morphine. In: Opiates and endogenous opioid peptides. Ed Elsevier/North-Holland. Biomedical Press, Amsterdam, pp 395–398

    Google Scholar 

  6. Pert CB, Snyder SH (1973) Properties of opiates-receptor binding in the rat brain. Proc Nat Acad Sci USA 8: 2243–2247

    Google Scholar 

  7. Quinding H, Anderson P, Bondesson U et al. (1986) Plasma concentrations of codeine and its metabolite, morphine, after single and repeated oral administration. Eur J Clin Pharmacol 30: 673–677

    Google Scholar 

  8. Rogers JF, Findlay JWA, Hull JH et al. (1982) Codeine disposition in smoker and non smoker. Clin Pharmacol Ther 32: 218–227

    Google Scholar 

  9. Donnerer J, Cardinale G, Coffey C et al. (1987) Chemical Characterization and regulation of endogenous morphine and codeine in rat. J Pharmacol Exp Ther 242: 583–587

    Google Scholar 

  10. Quinding H, Oikarinen V, Sane J et al. (1984) Analgesic efficacy after single and repeated doses of codeine and acetaminophen. J Clin Pharmacol 24: 27–34

    Google Scholar 

  11. Honig S, Murray KA (1984) An appraisal of codeine as an analgesic: Single-dose analysis. J Clin Pharmacol 24: 96–102

    Google Scholar 

  12. Brunelle RL, George RE, Sunshine A et al. (1988) Analgesic effect of picenadol, codeine, and placebo in patients with postoperative pain. Clin Pharmacol Ther 43: 663–667

    Google Scholar 

  13. World Health Organization (1986) Cancer pain relief. WHO Monograph Geneva 19, 54.

  14. Stjernswärd J (1988) WHO cancer pain relief programme. Cancer Surv 7: 195–208

    Google Scholar 

  15. Foley KM (1985) The treatment of cancer pain. N Engl J Med 313: 84–95

    Google Scholar 

  16. Findlay JWA, Jones EC, Butz RF et al. (1978) Plasma codeine and morphine concentrations after therapeutic oral doses of codeine-containing analgesics. Clin Pharmacol Ther 24: 60–68

    Google Scholar 

  17. Dayer P, Desmeules J, Leemann T et al. (1988) Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation. Biochem Biophys Res Commun (1988) 152: 411–416

    Google Scholar 

  18. Schmid B, Bircher J, Preissig R et al. (1985) Polymorphic dextrometorphan metabolism. Cosegregation of oxidative O-demethylation with debrisoquine hydroxylation. Clin Pharmacol Ther 38: 618–624

    Google Scholar 

  19. Dayer P, Leemann T, Striberni R (1989) Dextromethorphan O-demethylation in liver microsomes as a prototype reaction to monitor cytochrome P-450 dbl activity. Clin Pharmacol Ther 45: 34–40

    Google Scholar 

  20. Matejczyck RJ, Kosinski JA (1985) Determination of cross-reactant drugs with a new radioimmunoassay procedure. J Forens Sci 30: 667–680

    Google Scholar 

  21. Bathien N (1971) Réflexes spinaux chez l'homme et niveaux d'attention. EEG Clin Neurophysiol 30: 32–37

    Google Scholar 

  22. Willer JC, Bathien N (1977) Comparative study of perceived pain and nociceptive flexion reflex in man. Pain 3: 69–80

    Google Scholar 

  23. Hill AV (1910) The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curve. J Physiol (Lond) 40: iv-vii

    Google Scholar 

  24. Otton SV, Inaba T, Kalow W (1984) Competitive inhibition of sparteine oxidation in human liver by β-adrenoceptor antagonists and other cardiovascular drugs. Life Sci 34: 73–80

    Google Scholar 

  25. Dayer P, Kronbach T, Eichelbaum M et al (1987) Enzymatic basis of the debrisoquine/sparteine type genetic polymorphism of drug oxidation-characterisation of bufuralol l'-hydroxylation in liver microsomes of in vivo phenotyped carriers of the genetic deficiency. Biochem Pharmacol 36: 4145–4152

    Google Scholar 

  26. Leemann T, Dayer P, Meyer UA (1986) Single-dose quinidine treatment inhibits metoprolol oxidation in extensive metabolizers. Eur J Clin Pharmacol 29: 739–741

    Google Scholar 

  27. Chen ZR, Somogyi AA, Bochner F (1988) Polymorphic O-demethylation of codeine. Lancet II: 914–915

    Google Scholar 

  28. Yue QY, Svensson JO, Alm C et al. (1989) Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation. Br J Clin Pharmacol 28: 639–645

    Google Scholar 

  29. Mortimer Ö, Persson K, Ladona MG et al. (1990) Polymorphic formation of morphine from codeine in poor and extensive metabolizers of dextromethorphan: Relationship to the presence of immunoidentified cytochrome P-450IID1. Clin Pharmacol Ther 47: 27–35

    Google Scholar 

  30. Ventafrida Y, Tamburini M, Caraceni A et al. (1987) A validation study of the WHO method for cancer pain relief. Cancer 59: 850–856

    Google Scholar 

  31. Osborne R, Joel S, Trew D, Slevin M (1988) Analgesic activity of morphine-6-glucuronide. Lancet II: 828

    Google Scholar 

  32. Nordberg G, Borg L, Hedner T et al. (1985) CSF and plasma pharmacokinetics of intramuscular morphine. Eur J Clin Pharmacol 27: 677–681

    Google Scholar 

  33. Cardinale GJ, Donnerer J, Finck AD et al. (1987) Morphine and codeine are endogenous components of human cerebrospinal fluid. Life Sci 40 (3): 301–306

    Google Scholar 

  34. Kodeira H, Spector S (1988) Transformation of thebaine to oripavine, codeine, and morphine by rat liver, kidney, and brain microsomes. Proc Natl Acad Sci (USA) 85: 1267–1271

    Google Scholar 

  35. Oldendorf WH, Hyman S, Braun L et al. (1972) Blood-brain barrier: penetration of morphine, codeine, heroin, and methadone after carotid injection. Science 178: 984–986

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacology and Pain Clinic, Geneva University Hospital, Switzerland

    J. Desmeules, M.-P. Gascon & P. Dayer

  2. Division of Clinical Neurophysiology, Geneva University Hospital, Switzerland

    M. Magistris

Authors
  1. J. Desmeules
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M.-P. Gascon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. Dayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Magistris
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Desmeules, J., Gascon, MP., Dayer, P. et al. Impact of environmental and genetic factors on codeine analgesia. Eur J Clin Pharmacol 41, 23–26 (1991). https://doi.org/10.1007/BF00280101

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00280101

Key words

Search

Navigation