High-Dose Morphine and Methadone in Cancer Patients

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Abstract
Several clinical studies have shown oral morphine and methadone to be effective in the treatment of intractable pain in patients with malignant disease. Recent pharmacokinetic studies have confirmed the rationale for regular administration of oral morphine and methadone but have revealed marked interindividual differences in the kinetics and metabolism which must be considered when titrating the oral dose according to the individual patient’s need. Oral absorption of morphine in patients with malignant diseases is rapid, with peak plasma concentrations occurring at 20 to 90 minutes. Predose steady-state concentrations bear a constant relationship to dose, but vary considerably between individuals. The oral bioavailability is approximately 40% with marked patient-to-patient variations as a result of differences in presystemic elimination. The reported values for the volume of distribution range from 1.0 to 4.7 L/kg. Plasma protein binding is about 30%. The elimination half-life varies between 0.7 and 7.8 hours. Plasma clearance is approximately 19 ml/min/kg (5 to 34 ml/min/kg) and mostly accounted for by metabolic clearance. Studies in a few patients with malignant diseases treated regularly with daily doses of oral morphine ranging from 20 to 750mg indicate a linear relationship between the dose and trough concentration of morphine. Long term treatment with 10- to 20-fold increase of the oral dose over a period of 6 to 8 months does not seem to change the kinetics of oral morphine. The plasma concentrations of the main metabolite, morphine-3-glucuronide (M3G), exceed those of the parent drug by approximately 10-fold after intravenous administration and by 20-fold after oral administration. The relationship between the area under the plasma concentration-time curve (AUC) of morphine and the AUC of morphine-3-glucuronide remains constant during the development of tolerance upon long term treatment with increasing doses. Renal disease causes a significant increase in the mean plasma concentrations of morphine for 15 minutes after its administration, while mean values of terminal half-life and total body clearance are within the normal range. However, the glucuronidated polar metabolite morphine-3-glucuronide rises rapidly to high concentrations which persist for several days. Chronic liver disease causes an increase in the bioavailability of oral morphine but no, or only a slight reduction in the intravenous clearance. The elimination half-life and volume of distribution are within the normal range. In the elderly, there is a reduction in the volume of distribution and the total plasma clearance, while the elimination phase is shorter compared with younger patients. Increased sensitivity has been reported in the elderly, in patients with liver disease, and patients with renal dysfunction. Consequently cautious dosing is needed in these groups of patients. The initial dose of oral morphine is mainly determined by the patient’s previous medication. Most opiate-naive patients experience pain relief with initial oral doses of morphine of 5 to 30mg every 4 to 6 hours. The dose and/or the dose interval are adjusted according to therapeutic response evaluated at steady-state, i.e. after 4 to 5 half-lives. Continuous re-evaluation of the dosage regimen is necessary during long term treatment. Dose adjustments are recommended to be in the order of 25 to 30% of the previous dose. When switching from oral to parenteral therapy the morphine dose should be reduced by 75% and thereafter adjusted according to the individual patient’s needs. The pharmacokinetics of oral methadone have, almost exclusively, been studied in former opiate addicts. Single-dose studies have shown methadone to be equivalent to morphine in both its potency and duration of analgesia while during repeated dosing, as a consequence of its kinetics, the duration of action will increase beyond 4 to 6 hours. Methadone is rapidly absorbed from the gastrointestinal tract and has a high oral bioavailability of about 90%. The peak plasma concentrations after administration of tablets occurred at 1 to 5 hours. The volume of distribution is approximately 4 L/kg and the plasma clearance is about 95 ml/min (5.7 L/h). The protein binding is 60 to 90% and α1-acid glycoprotein is the main binding protein and hence the determinant of the free fraction in plasma. Lower free fractions of methadone have been shown in cancer patients compared with healthy volunteers. Plasma methadone concentrations decline in a biexponential manner with an elimination half-life of 15 to 60 hours. Biotransformation as well as renal and faecal excretion are important determinants of the disposition of methadone. Studies, although non-conclusive, have indicated decreased steady-state plasma concentrations during methadone maintenance treatment. Similar to morphine, there are marked interindividual differences in the kinetics of methadone which must be taken into account in the clinical use of the drug. Although the long elimination half-life of methadone is an obvious advantage, it is difficult to titrate the minimum effective safe dose for the individual patient. In order to shorten the time to reach an analgesic effect, a loading dose regimen with dosage intervals of 4 to 6 hours has been suggested during the first 2 days of therapy. The dosage interval should thereafter be increased to 8 or 24 hours. When switching from oral to parenteral therapy, the methadone dose should be reduced by 50% and thereafter if necessary further dose adjustment can be performed according to the individual patient’s need.