Pharmacokinetics and pharmacodynamics of twenty-four-hourly Kapanol compared to twelve-hourly MS Contin in the treatment of severe cancer pain

Abstract

Twenty-four patients with severe pain related to cancer completed a randomised, double-blind, double-dummy, crossover study examining morphine pharmacokinetics and pharmacodynamics when the same 24-h morphine dose was administered using two modified release oral morphine formulations; either one dose of Kapanol (a new sustained release polymer coated pellet formulation administered in capsule form, Glaxo Wellcome group of companies) per 24 h, or MS Contin (Purdue Frederick Company, Connecticut, USA) administered at 12-h intervals. The morphine dose was optimised for each patient using an immediate release morphine solution in the lead-in period to provide the most favourable balance between pain relief and side-effects. Patients were then randomly allocated to receive their 24-h morphine dose as either Kapanol or MS Contin in period 1. Patients recorded daily measures of pain relief and morphine related side-effects (morphine pharmacodynamics) in a diary. Patients were admitted to the Pain Management Unit on the morning of day 7 (+/- 1 day) and frequent blood samples were collected for 24 h following the 10:00 h dose to fully characterise the pharmacokinetic profile for morphine and its metabolites at steady state. Morphine pharmacodynamics and the amount and timing of rescue medication (dextromoramide) were also recorded during this time. Period 2, which commenced at 10:00 h on day 8, was identical to period 1 except the modified release formulations were changed. The pharmacokinetic profile of Kapanol exhibited a significantly higher Cmin (minimum plasma morphine concentration), less fluctuation in plasma morphine concentration throughout the dosing interval, a longer Tmax (time associated with the maximum morphine concentration) and a greater time that the plasma morphine concentration was > or = 75% of Cmax (an index of the control the formulation exerts over the morphine release rate) compared to that of MS Contin. Some of these pharmacokinetic differences (e.g., Cmin and fluctuation in plasma morphine concentration) were surprising given that the dosing interval for Kapanol (24 h) was double that of MS Contin (12 h). There was no significant difference between the Kapanol and MS Contin treatment phases in any of the pharmacodynamic parameters, morphine related side-effects, the percentage of patients taking rescue medication as well as the amount or time to the first dose of rescue analgesia on day 7 in periods 1 and 2, patient or investigator assessments of global efficacy at the end of periods 1 and 2, or patient treatment preference at the end of the study. Once a day Kapanol provided the same degree of pain relief and morphine related side-effects as 12-h MS Contin.

Morphine and alternative opioids in cancer pain: the EAPC recommendations

“…Peak plasma concentrations usually occur within the first hour after oral administration (Hoskin et al, 1989), with a reasonably rapid onset of analgesia which then lasts for about 4 hours. In contrast modified release morphine formulations produce a delayed peak plasma concentration after 2-6 hours (Hoskin et al, 1989;Gourlay et al, 1997), the peak is attenuated (Hoskin et al, 1989), and analgesia lasts for 12 or 24 hours (Hanks, 1990;Gourlay et al, 1997). This means that with modified release morphine it is more difficult to rapidly assess the adequacy of analgesia and to adjust the dose during the dose-finding period.…”

“…Increasing the frequency of administration may adversely affect compliance and convenience for the patient. Increasing the dose allows a 4-hourly or 12-or 24-hourly regimen to be achieved without producing troublesome adverse effects associated with the increase in peak blood concentrations (Hanks, 1990;Gourlay et al, 1997). A few patients receiving 12-hourly formulations do not seem to achieve a 12 hour duration of analgesia and require administration every 8 hours.…”

“…Several once-a-day formulations of morphine have also been developed. There are significant differences between some in their pharmacokinetic profiles (Gourlay et al, 1997) but there is no evidence that this is reflected in clinically significant differences in patients: they appear to be equivalent in efficacy and in the duration of effect.8. If patients are unable to take morphine orally the preferred alternative route is subcutaneous.…”

Controlled-release morphine tablets in patients with chronic cancer pain

“…Other delayed-release morphine preparations appear to have a lower degree of fluctuation of plasma morphine concentrations. [33][34][35][36][37] The therapeutic consequences of these differences in fluctuation are not fully understood.…”

Morphin und andere Opioide in der Tumorschmerztherapie

“…Zusätzlich schwanken die Schmerzintensitäten, sodass die Dosis für jeden Patienten bis zum gewünsch-ten Effekt titriert werden muss, und die Anfangsdosis durch die vorherige analgetische Therapie bestimmt wird. Patienten, die von einer Dauermedikation mit einem Opioid der WHO-Stufe 2 (in Kombination mit einem Nichtopioid) umgestellt werden, beginnen in der Regel mit 10 …”