Skip to main content
SpringerLink
Log in

Tramadol SR Formulations

Pharmacokinetic Comparison of a Multiple-Units Dose (Capsule) versus a Single-Unit Dose (Tablet)

  • Original Research Article
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Introduction: Different oral sustained-release (SR) formulations of tramadol have been introduced in pain treatment in order to prolong the dosage interval to improve convenience for the patient. The objective of this study was to compare tramadol pharmacokinetics and intra- and intersubject variability after replicate single-dose administrations of a multiple-units SR formulation (capsule) and a single-unit formulation (tablet).

Methods: This was a randomised, single-dose, single-centre study with an open-label, four-period, two-sequence, two-formulation, replicate crossover design in healthy subjects under fed conditions. The main outcome measures were the intra- and intersubject variance of the area under the concentration-time curve from 0 to 12 hours (AUC12) and maximum concentration (Cmax), as well as the mean AUC12 and CPmax for tramadol. Study drugs were a tramadol SR multiple-units formulation (capsule) and a tramadol SR single-unit formulation (tablet), each containing tramadol hydrochloride 100mg. The time interval from 0 to 12 hours of AUC12 of the single-dose design corresponds to the recommended twice-daily dosage interval for both study drugs during long-term treatment.

Results: The two formulations were equivalent in the area under the curve (AUC∞: 2411 vs 2527 μg · h/L). However, capsules led to a lower Cmax (148.6 vs 183.2 μg/L), to a later time to reach Cmax (5.9 vs 4.9 hours), and to a longer half-value duration (13.4 vs 10.4 hours). In addition, intrasubject variability of AUC12 was significantly smaller for capsules than for tablets (p = 0.041). Capsules also produced smaller intra- and intersubject variability in plasma concentrations during the first 2.5 and 3.0 hours after administration, respectively (p < 0.05).

Conclusion: Although tramadol SR capsules and tramadol SR tablets led to an equivalent systemic exposure to the drug, capsules provided a smoother and more extended plasma profile. In addition, in the case of capsules, bioavailability was subjected to lower variability in terms of both rate and extent of absorption.

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

Table I
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Table II
Table III

Similar content being viewed by others

Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Scott L, Perry C. Tramadol: a review of its use in perioperative pain. Drugs 2000 Jul; 60(1): 139–76

    Article  PubMed  CAS  Google Scholar 

  2. Raffa RB, Nayak RK, Lia S, et al. The mechanism(s) of action and pharmacokinetics of tramadol hydrochloride. Rev Contemp Pharmacother 1995; 6: 485–97

    CAS  Google Scholar 

  3. Bamigbade TA, Langford RM. The clinical use of tramadol hydrochloride. Pain Rev 1998; 5: 155–82

    Article  CAS  Google Scholar 

  4. Shipton E. Tramadol: present and future. Anaesth Intensive Care 2000 Aug; 28(4): 363–74

    PubMed  CAS  Google Scholar 

  5. Lintz W, Barth H, Osterloh G, et al. Bioavailability of enteral tramadol formulations: 1st communication: capsules. Arzneimittel Forschung 1986; 36 (II) 8: 1278–83

    PubMed  CAS  Google Scholar 

  6. Raber M, Schulz HU, Schürer M, et al. Pharmacokinetic properties of tramadol sustained release capsules: 2nd communication: investigation on relative availability and food interaction. Arzneimittel Forschung 1999; 49 (II) 7: 588–93

    PubMed  CAS  Google Scholar 

  7. Raber M, Hoffman S, Junge K, et al. Analgesic efficacy and tolerability of tramadol 100mg sustained-release capsules in patients with moderate to severe chronic low back pain. Clin Drug Invest 1999 Jun; 17(6): 415–23

    Article  CAS  Google Scholar 

  8. Sorge J, Stadler T. Comparison of the analgesic efficacy and tolerability of tramadol 100mg sustained-release tablets and tramadol 50mg capsules for the treatment of chronic low back pain. Clin Drug Invest 1997 Sep; 14(3): 157–64

    Article  CAS  Google Scholar 

  9. Hummel T, Roscher S, Pauli E, et al. Assessment of analgesia in man: tramadol controlled release vs tramadol standard formulation. Eur J Clin Pharmacol 1996; 51: 31–8

    Article  PubMed  CAS  Google Scholar 

  10. Benchgaard H, Nielsen GH. Controlled-release multiple-unit and single unit doses: a literature review. Drug Dev Ind Pharm 1978; 4(1): 53–67

    Article  Google Scholar 

  11. Guidance for industry. Statistical approaches to establishing bioequivalence. US Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER), 2001 Jan, Rockville, MD

  12. Chow SC, Liu JP. Design and analysis of bioavailability and bioequivalence studies. New York: Marcel Dekker Inc, 1992: 253–88

    Google Scholar 

  13. Holm S. A simple sequentially rejective multiple test procedure. Scan J Statist 1979; 6: 65–70

    Google Scholar 

  14. Note for guidance on modified release oral and transdermal dosage forms: section II (pharmacokinetic and clinical evaluation), EAMEA. CPMP/EWP/280/96. London: 1999 Jul 28

  15. Comparison of the release rate profiles of tramadol SR capsules with tramadol SR tablets. Company internal report; 2004 Jul (Data on file, VIATRIS)

  16. Petrone D, Kamin M, Olson W. Slowing the titration rate of tramadol HCl reduces the incidence of discontinuation due to nausea and/or vomiting: a double-blind randomized trial. J Clin Pharm Ther 1999; 24: 115–23

    Article  PubMed  CAS  Google Scholar 

  17. Ruoff G. Slowing the initial titration rate of tramadol improves tolerability. Pharmacotherapy 1999; 19(1): 88–93

    Article  PubMed  CAS  Google Scholar 

  18. Bechgaard H, Benzon A. Critical factors influencing gastrointestinal absorption: what is the role of pellets? Acta Pharm Technol 1982; 28(2): 149–56

    CAS  Google Scholar 

  19. Fara JW. Physiological limitations: gastric emptying and transit of dosage forms. In: Prescott LF, Nimmo WS, editors. Rate control in drug therapy. Edinburgh: Churchill Livingstone, 1985: 144–50

    Google Scholar 

  20. Davis SS, Hardy JG, Fara JW. Transit of pharmaceutical dosage forms through the small intestine. Gut 1986; 27: 886–92

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The principal investigator of this study was Katharina Erb, MD, Frankfurt am Main, Germany. The study was supported by ASTA Medica AG, Frankfurt am Main, Germany (predecessor of VIATRIS GmbH & Co. KG, Bad Homburg, Germany).

The authors thank Dr Diana A. Taylor, Medical Information, VIATRIS GmbH & Co. KG, for editing this article.

Author information

Authors and Affiliations

  1. Scientific Affairs Clinical Research, VIATRIS GmbH & Co. KG, Benzstrasse 1, 61352, Bad Homburg, Germany

    Peter J. Cnota (MD) & Joachim Maus

  2. Biostatistics and Data Management, VIATRIS GmbH & Co. KG, Bad Homburg, Germany

    Horst Nowak

  3. VIATRIS Pharmaceuticals, Madrid, Spain

    Ignacio Tagarro

  4. clinphase — Clinical Pharmacology Services, Hanau, Germany

    Katharina Erb

  5. LAFAA Laboratory for Contract Research in Clinical Pharmacology and Biopharmaceutical Analytics GmbH, Bad Schwartau, Germany

    Michael Schürer & Hans-Ulrich Schulz

Authors
  1. Peter J. Cnota
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Horst Nowak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ignacio Tagarro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Katharina Erb
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Schürer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hans-Ulrich Schulz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Joachim Maus
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter J. Cnota.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cnota, P.J., Nowak, H., Tagarro, I. et al. Tramadol SR Formulations. Clin. Drug Investig. 25, 435–443 (2005). https://doi.org/10.2165/00044011-200525070-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00044011-200525070-00002

Keywords

Search

Navigation