Methods and Findings in Experimental and Clinical Pharmacology
Vol. 26, Suppl. A, 2004
ISSN 0379-0355
Copyright 2004 Prous Science, S.A.
CCC: 0379-0355/2004
http://www.prous.com

Paracetamol-Tramadol Combination

L.M. Torres Morera

Departamento de Anestesiología y Reanimación, y Unidad del Dolor, Hospital Universitario Puerta del Mar, Cádiz, Spain

Pain causes a marked deterioration of quality of life. Therefore, it is necessary to continue developing innovative options that facilitate the treatment of pain without increasing side effects and that promote compliance with the prescription.

The studies that have been published, including a meta-analysis, confirm the analgesic superiority of the combination of paracetamol and tramadol (Zaldiar^®) over either component used separately, without increasing adverse effects. Formulations containing analgesic combinations are an effective means for treating pain and have proven their usefulness, including in elderly patients and other patient groups who cannot be treated with NSAIDs, including the new COX-2 inhibitors (1, 2).

Zaldiar^® enables symptomatic treatment of moderate to severe, acute and chronic pain, with a very high efficacy/ adverse effects ratio. As a result, it shows a high level of effectiveness in the treatment of pain and, in moderate to severe pain, it enables the dose of tramadol to be reduced for an equivalent level of analgesia, thereby reducing the opioid side effects induced by tramadol.

It is obvious that the combination of low doses of opioids, which would not be effective by themselves, with a non-opiate analgesic provides an effective, safe analgesic compound and refutes previous beliefs that the combinations did not have additive effects or that any such effect would be outweighed by an increase in side effects. These arguments are no longer tenable in the light of the evidence available (1). Neither is it tenable to argue that fixed analgesic combinations are more expensive and, therefore, it is better to administer each one separately. In fact, many patients, particularly elderly patients (a steadily growing population group), are already taking large quantities of medicines every day. This polypharmacy is a considerable barrier to prescription compliance and, consequently, should be minimized. One of the options for doing this is a careful combination of drugs that enables the number of pills taken each day to be reduced, without decreasing efficacy or increasing side effects. In view of this, together with other authors and clinicians specialized in the treatment of pain, we consider Zaldiar^® to be a compound offering a high intrinsic value in the treatment of pain.

Zaldiar^® is the first medicinal product that combines the analgesic properties of tramadol and the analgesic and antipyretic properties of paracetamol.

The therapeutic advantages of this new, original product are backed by the results of its extensive pharmacological and clinical development, which has been carried out in accordance with the European Medicines Agency's Fixed Combination Products Guidelines and the FDA's guidelines on the clinical research of analgesics.

The pharmacological development of Zaldiar^® has been carried out with:

• Experimental models of the analgesic combination's synergy of action
• Pharmacokinetic studies of the analgesic combination
• Phase II and III clinical trials of the combination's efficacy and safety, including a total of 6,519 patients

The contributions and advantages of the analgesic combination Zaldiar^® are conclusive according to the best scientific evidence available:

• A preclinical study showed the synergistic analgesic effect of tramadol and paracetamol, and enabled an optimal dose ratio between these two active ingredients to be determined, with fixed doses of 37.5 mg of tramadol and 325 mg of paracetamol per tablet.
• The overall analgesic activity of Zaldiar^® is based on three different mechanisms of analgesic action: the dual analgesic effect of tramadol (opioid and monoaminergic effect) and the specific analgesic effect of paracetamol (probable effect on the nociceptive threshold).
• In order to define the analgesic efficacy of the tramadol/ paracetamol combination, a population-based pharmacokinetic/pharmacodynamic model was established using data from 1,652 patients. It was concluded that the onset of action of Zaldiar^® appears in less than half the time of tramadol, and the duration of the effect is 66% longer than tramadol and 15% longer than paracetamol. The pharmacokinetics of Zaldiar^® shows no modification of either active ingredient's pharmacokinetic parameters. Neither does concurrent administration affect either active ingredient's peak plasma concentration. To summarize, the pharmacokinetic profiles of tramadol and paracetamol are complementary and compatible and there are no undesirable interactions when the two analgesics are given together in single or repeated-dose regimens.
• Pursuant to the recommendations of the CPMP, the clinical trials show that the pain relief and decrease in pain intensity achieved with Zaldiar^® are significantly greater than when tramadol and paracetamol are given alone.
• The comparative analysis of the two meta-analyses described previously in this document have established that the analgesic effect of the combination of tramadol 75 mg and paracetamol 650 mg is superior to that of a 100 mg dose of tramadol, and equivalent to that of a 150 mg dose of tramadol. Thus, 2 tablets of Zaldiar^® have an efficacy equivalent to 3 50-mg capsules of tramadol. The comparative analysis of the meta-analyses shows that the safety of use observed (tolerability) with 2 tablets of Zaldiar^® is better overall than that observed with 2 and 3 50-mg capsules of tramadol, particularly as regards dizziness and, above all, drowsiness.
• In the multiple-dose studies, particular emphasis was placed on dose flexibility, with the patient determining his or her own requirements each day. This treatment flexibility and individualization was rendered easier by the low doses of each component proposed for the combination in Zaldiar^®. In the open-label study, with study periods up to 24 months, the score for maximum pain relief remained constant and was not associated with the development of tolerance. The average dose used in this 24-month study was 31% less than the dose determined in the long-term studies of tramadol, with the resulting decrease in adverse effects.
• In the double-blind study of the Zaldiar^® combination versus tramadol 50 mg in multiple doses for the treatment of lower back pain (not included in the registration dossier), there were no significant differences in pain reduction. However, the daily dose of tramadol given in the Zaldiar^® combination was lower: 165 mg tramadol/1430 mg paracetamol versus 214 mg tramadol given alone. The combination caused significantly less adverse reactions than tramadol alone, particularly the typical adverse reactions of the opioids (constipation, nausea, drowsiness, dizziness, vomiting), with the resulting improvement in the benefit/risk ratio.

To summarize, Zaldiar^® provides all of the expected benefits of an analgesic combination in terms of speed of action, duration of action, efficacy, reduction of opioid dose, and reduction of adverse reactions, offering a high level of effectiveness in the treatment of moderate to severe pain, with a very high efficacy/adverse effect ratio.

It is obvious that the combination of low doses of opioids, which would not be effective by themselves, with a non-opiate analgesic provides an effective, safe analgesic compound. Many patients, particularly elderly patients (a steadily growing population group), are already taking large quantities of medicines every day. This polypharmacy is a considerable barrier to prescription compliance and, consequently, should be minimized. One of the options for doing this is a careful combination of drugs that enables the number of pills taken each day to be reduced, without decreasing efficacy or increasing side effects.

REFERENCES

1. Edwards, J.E., Phil, D., McQuay, H.J. et al. Combination analgesic efficacy: Individual patient data meta-analysis of single-dose oral tramadol plus acetaminophen in acute postoperative pain. J Pain and Symptom Management 2002, 23(2): 121-30.

2. McQuay, H., Moore, R.A. Oral tramadol versus placebo, codeine, and combination analgesics. An evidence-based resource for pain. Oxford University Press 1998.

Methods and Findings in Experimental and Clinical Pharmacology Vol. 26, Suppl. A, 2004
ISSN 0379-0355 Copyright 2004 Prous Science, S.A. CCC: 0379-0355/2004 http://www.prous.com