Gian Paula Villamayor

Thea Ferina Vital

2C- PH

Comparative Pharmacokinetics of a Once-Daily Tramadol Extended-Release Tablet and an Immediate-
Release Reference Product Following Single-Dose and Multiple-Dose Administration
(A Critique Paper)


I. Citation
Ferreira, M., MBChB, Fradette, C. PhD, Karhu, D. Bsc, Potgieter, M. A., PhD, and Terblanche,
J. 2010. Comparative Pharmacokinetics of a Once-Daily Tramadol Extended-Release
Tablet and an Immediate-Release Reference Product Following Single-Dose and
Multiple-Dose Administration. Journal of Clinical Pharmacology, Vol. 50:544553.

II. Topic
A. The journal article is about the comparison about the Administration, Distribution,
Metabolism, and Excretion of a Once-Daily Tramadol Extended-Release Tablet from
an Immediate-Release Reference Product Following Single-Dose and Multiple-Dose
Administration. The major objective is to report the outcomes of 2 comparative
bioavailability studies that assessed the performance of Tramadol Contramid OAD
200-mg tablets following single-dose and multiple-dose administration. The minor
objective is to present the dissolution profiles of Tramadol immediate-release 50-
mg tablets and the 3 strengths of Tramadol Contramid OAD.
B. Tramadol is an atypical synthetic, centrally acting analgesic used in the management
of pain. Tramadol produces analgesia comparable to that of codeine, pentazocine,
dextropropoxyphene, or metamizole: however, the affinity of tramadol for micro-
opioid receptors is weak. Tramadol Once Daily was developed by Labopharm, Inc.
uses Contramid, a proprietary drug delivery technology that is based on chemically
cross-linked high amylose starch, to achieve controlled release. Gastric fluid
transform the surface of the tablet into a gel through which the drug diffuses at a
constant rate. Tramadol Extended Release includes more consistent pain control,
reduction in the occurrence of breakthrough pain, improved pain control at night,
and possibly improved quality of drug. In addition they have the potential to
improve patient compliance by simplifying the dosing regimen. Pharmacokinetics is
the administration, distribution, metabolism, and excretion of a drug in the body.
The definitions of the important concepts focused on by the author are clearly
stated.

A. Theory/Research Methods
A. The research was guided by the law of Pharmacokinetics. The said theoretical
perspective assisted in identifying the problem through comparing the effectivity of
Tramadol Extended-release plasma half-life levels versus Tramadol Immediate-
release plasma half-life levels.
B. The author conducted the research in compliance with the International Conference
on Harmonization good clinical practice guidelines and applicable local regulations,
as well as in accordance with the ethical principles of the Declaration of Helsinki.
Both studies had an open-label, randomized, 2-period, crossover design. Twenty-six
healthy adults were the subjects of the study. The maximum observed plasma
concentration (C
max
), the time required to reach C
max
(t
max
), and the concentration at
the end of the profile period (C
min
) of the drug given were also observed. The
pharmacokinetical variables (except t
max
) were analyzed with the uses of analysis of
variance (ANOVA). Meanwhile the bioequivalence was tested through the use of a
two 1-sided t test procedure.
C. The said methods were explained by the author in a specified manner without
deviating from the studys general idea.

B. Main Ideas
A. According to the research, the pharmacokinetics of an immediate-release Tramadol
was compared with that of a once-daily formulation of tramadol succeeding single-
dose and multiple-dose administration. By observing the variables, it was known
that the peak exposure of C
max
was lower on the extended-release Tramadol than of
the immediate-release formulation. Severe chronic low back pain was also reported
to happen frequently to the patients undergoing immediate-release intake. The
major argument of this study focuses on the greater efficiency of Tramadol
Extended-release versus Tramadol Immediate-release formulation.
B. The relative short plasma half-life of Tramadol Extended-release and the effectivity
of controlled-release Tramadol to induce a pain-killing outcome on the patient after
taking.
C. The ideas of this research were clearly and cohesively elaborated.

C. Conclusions
Tramadol Contramid OAD provides a rapid rise in plasma concentrations and an
equivalent daily systemic exposure as tramadol IR, with a reduction in peak plasma
concentrations. The pharmacokinetic profile is well suited for administration once daily and
provides an interesting option for the management of moderate to moderately severe chronic
pain requiring around-the-clock treatment. The pharmacokinetics of a once daily formulation of
tramadol following single-dose and multiple-dose administration was compared with that of an
immediate-release product in 2 separate studies.

In both studies, AUC parameters met bioequivalence criteria, whereas Cmax of
Tramadol Contramid OAD was lower than that of tramadol IR following a 200-mg daily dosage.
After single-dose administration, the mean tramadol concentration at 1 hour post dose was
within the range associated with analgesic efficacy, and the mean concentration remained
above this level for the remainder of the dosing interval. Steady state was attained within 48
hours following multiple-dose administration. Tramadol Contramid OAD provides a rapid rise in
plasma concentrations and an equivalent daily systemic exposure as tramadol IR, with a
reduction in peak plasma concentrations.

D. Reflection
A. The data obtained from the study did support the conclusion since the results were
synonymous to the conclusion formulated.
B. The results were not really thought provoking because it was already expected by
the researchers that Tramadol extended-release drug will give a more efficient
effect on the patients plasma peak exposure.
C. To improve this study, we suggest that the next research will focus more on
comparing the pharmacokinetics of a more particular modified-release Tramadol
versus another modified-release drug with a different feature. Through this, we can
know which kind of modified-release Tramadol will be the most effective and
efficient on the patients.
D. The most important thing I learned from this article is that the Immediate-release
Tramadol and Extended-release Tramadol may provide the same effect, however,
the controlled-release one (as well as for most drugs) will give a more efficient
outcome on the patient.