Skip to main content
SpringerLink
Log in

Pharmacokinetic-pharmacodynamic modeling of the effects of clonidine on pain threshold, blood pressure, and salivary flow

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

Summary

Although clonidine analgesia appears to be mediated by the same central α2-adrenoceptors that mediate its hypotensive effect, it is short-lasting when compared to the fall in blood pressure. This has been investigated by combined pharmacokinetic-pharmacodynamic analysis in 10 healthy volunteers who received (double-blind and crossover) clonidine 200 μg orally + placebo i.v. and clonidine orally + naloxone i.v. (2.8 mg/5 h). Analgesia was assessed by measuring the subjective (VAS) and objective (RIII) pain thresholds after transcutaneous electrical stimulations of the sural nerve; the mean arterial blood pressure (MAP), salivary flow (SF), and plasma clonidine concentrations were also monitored. A combined pharmacokinetic (first order absorption — 1 compartment) — pharmacodynamic (linear) model, including a hypothetical effect compartment with and without tolerance, were fitted to the data.

Clonidine and clonidine + naloxone increased subjective and objective pain thresholds for 4 h. The concentration-effect plot for MAP showed distinct hysteresis. The t1/2s for effect compartment equilibration were 29 and 42 min for clonidine + naloxone and clonidine. The concentration-effect curves for RIII had the same shape as MAP but the starting hysteresis suddenly collapsed, suggesting acute tolerance. The best fit was obtained with a model where the linear relationship between concentration in the effect compartment and analgesia changed acutely after the third hour.

The short-lived analgesia was probably related to an acute change in pain sensitivity induced by food, suggesting that it is not mediated solely by the α2-adrenoceptors responsible for hypotension.

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. Paalzow L (1974) Analgesia produced by clonidine in mice and rats. J Pharm Pharmacol 26: 361–363

    Google Scholar 

  2. Paalzow G, Paalzow L (1976) Clonidine anti-nociceptive activity, Effects of drugs influencing central monoaminergic and cholinergic mechanism in the rat. Naunyn-Schmiedberger's Arch Pharmacol 292: 119–126

    Google Scholar 

  3. Luttinger D, Ferrari R, Perrone MH, Haubrich DR (1984) Pharmacological analysis of alpha-2 adrenergic mechanisms in nociception and ataxia. J Pharmacol Exp Ther 232: 883–889

    Google Scholar 

  4. Yaksh TL (1985) Pharmacology of spinal adrenergic system which modulate spinal nociceptive processing. Pharmacol Biochem Behav 22: 845–858

    Google Scholar 

  5. Yaksh TL, Reddy SVR (1981) Studies in the primate on the analgesic effects asociated with intrathecal actions of opiates, alpha-adrenergic agonists and baclofen. Anesthesiology 54: 451–467

    Google Scholar 

  6. Gordh T, Tamsen A (1983) A study on the analgesic effect of clonidine in man. Act Anaesthesiol Scand [Suppl] 87: 72

    Google Scholar 

  7. Tan YM, Croese J (1986) Clonidine and diabetic patients with leg pains. Ann Intern Med 105: 633–634

    Google Scholar 

  8. Tamsen A, Gordh T (1984) Epidural clonidine produces analgesia. Lancet II: 231–232

    Google Scholar 

  9. Coombs DW, Saunders RL, Fratkin JD, Jensen LE, Murphy CA (1986) Continuous intrathecal hydromorphone and clonidine for intractable cancer pain. J Neurosurg 64: 890–894

    Google Scholar 

  10. Max MB, Schafer SC, Culnane M, Dubner R, Gracely RH (1988) Association of pain relief with drug side effects in postherpetic neuralgia, a single-dose study of clonidine, codeine, ibuprofen, and placebo. Clin Pharm Ther 43: 363–371

    Google Scholar 

  11. Petros AJ, Bowen Wright RM (1987) Epidural and oral clonidine in domiciliary control of deafferentation pain. Lancet I: 1034

    Google Scholar 

  12. Glynn CJ, Jamous MA, Teddy PJ, Lloyd JW (1986) Role of spinal noradrenergic system in transmission of pain in patients with spinal cord injury. Lancet II: 1249–1250

    Google Scholar 

  13. Porchet HC, Piletta P, Dayer P (1990) Objective assessment of clonidine analgesia in man and influence of naloxone. Life Sci 46: 991–998

    Google Scholar 

  14. Solomon RE, Brody MJ, Gebhart GF (1989) Pharmacological characterization of alpha adrenoceptors involved in the antinociceptive and cardiovascular effects of intrathecally administered clonidine. J Pharmacol Exp Ther 251: 27–38

    Google Scholar 

  15. Reddy SVR, Yaksh TL (1980) Spinal nordrenergic terminal system mediates antinociception. Brain Res 189: 391–401

    Google Scholar 

  16. Dollery CT, Davies DS, Draffan GH, Dargie MB, Dean CR, Reid JL, Clare RA, Murray S (1976) Clinical pharmacology and pharmacokinetics of clonidine. Clin Pharm Ther 19: 11–17

    Google Scholar 

  17. Farina PR, Homon CA, Chow CT, Keirns JJ, Zavorskas PA, Esber HJ (1985) Radioimmunoassay for clonidine in human plasma and urine using a solid phase second antibody separation. Ther Drug Monitor 7: 344–350

    Google Scholar 

  18. Sheiner LB, Stansky DR, Vozeh S, Miller RD, Ham J (1979) Simultaneous modelling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther 25: 358–371

    Google Scholar 

  19. Porchet HC, Benowitz NL, Sheiner LB (1988) Pharmacodynamic model of tolerance: Application to nicotine. J Pharmacol Exp Ther 244: 231–236

    Google Scholar 

  20. Schwartz G (1978) Estimating the dimension of a model. Ann Stat 6: 461–464

    Google Scholar 

  21. Holford N (1987) MKMODEL an extended least squares modeling system, version 3.34

  22. Davies DS, Wing MH, Reid DM, Neill E, Tippett P, Dollery CT (1977) Pharmacokinetics and concentration-effect relationships of intravenous and oral clonidine. Clin Pharmacol Ther 21: 593–601

    Google Scholar 

  23. Langer SZ, Duval N, Massingham R (1985) Pharmacologic and therapeutic significance of α-adrenoceptor subtypes. J Cardiovasc Pharmacol 7 [Suppl 8]: 1–8

    Google Scholar 

  24. Warren JB, Dollery CT, Sciberras D, Goldberg M (1990) Assessment of MK-467, a peripheral α2-adrenoceptor antagonist using intravenous clonidine. Br J Clin Pharmacol 29: 306P

  25. Montastruc P, Berlan M, Montastruc JL (1989) Effects of yohimbine on submaxillary salivation in dogs. Br J Pharmacol 98: 101–104

    Google Scholar 

  26. Schmitt H, Le Douarec JC, Petillot N (1974) Antinociceptive effects of some α-sympathomimetic agents. Neuropharmacol 13: 289–294

    Google Scholar 

  27. Castro MI, Eisenach JC (1989) Pharmacokinetics and dynamics of intravenous, intrathecal, and epidural clonidine in sheep. Anesthesiology 71: 418–425

    Google Scholar 

  28. Piletta P, Porchet HC, Dayer P (1991) Distinct central nervous system involvement of paracetamol and salicylate. In: Proceedings of the VIth World Congress on Pain, Eds: Bond MR, Charlton JE, Woolf CJ. Elsevier, pp 181–184

  29. Raz I, Hasdai D, Seltzer Z, Melmed RN (1988) Effect of hyperglycemia on pain perception and on efficacy of morphine analgesia in rats. Diabetes 37: 1253–1259

    Google Scholar 

  30. Lux F, Brase DA, Dewey WI (1988) Antagonism of antinociception in mice by glucose and fructose: comparison of subcutaneous and intrathecal morphine. Eur J Pharmacol 146: 337–340

    Google Scholar 

  31. Lee JH, Cox DJ, Mook DG, McCarty RC (1989) Effect of hyperglycemia on pain threshold in alloxan-diabetic rats. Pain 40: 105–107

    Google Scholar 

  32. Schoenbaum GM, Martin RJ, Roane DS (1990) Discontinuation of sustained sucrose-feeding aggravates morphine withdrawal. Brain Res Bull 24: 565–568

    Google Scholar 

  33. Morley GK, Mooradian AD, Levine AS, Morley JE (1984) Mechanism of pain in diabetic peripheral neuropathy: effect of glucose on pain perception in humans. Am J Med 77: 79–82

    Google Scholar 

Download references

Author information

Authors and Affiliations

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

    H. C. Porchet, P. Piletta & P. Dayer

Authors
  1. H. C. Porchet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Piletta
    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

Rights and permissions

Reprints and permissions

About this article

Cite this article

Porchet, H.C., Piletta, P. & Dayer, P. Pharmacokinetic-pharmacodynamic modeling of the effects of clonidine on pain threshold, blood pressure, and salivary flow. Eur J Clin Pharmacol 42, 655–661 (1992). https://doi.org/10.1007/BF00265932

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00265932

Key words

Search

Navigation