Opioid plasma concentrations during a switch from transdermal fentanyl to methadone

Opioid switching is often used to improve the opioid response in patients with cancer experiencing poor analgesia or adverse effects. When switching between drugs with delayed effect because of pharmacokinetics or type of delivery, concerns exist about the correct timing of introducing the second drug after stopping the previous one. The aim of this study was to assess plasmatic changes of fentanyl and methadone underlying the clinical events occurring during opioid switching. Eighteen patients with cancer receiving transdermal fentanyl with uncontrolled pain and/or moderate to severe opioid adverse effects, were switched to oral methadone using an initial fixed ratio of 1:20. Fentanyl patches were removed and the first of three daily doses of methadone was started concurrently. Blood samples were obtained at intervals after removing the fentanyl patch, and at 5-hour intervals for the first 25 hours. The intensity of pain and the adverse effects were assessed before switching, the day after, and then daily up to dose stabilization. A successful switch was considered when the intensity of pain and distress score decreased at least of 33% of the basal value recorded before the switch, within a reasonable period of time. Complete blood samples were obtained in 16 patients. Methadone plasma concentration increased from 2 to 245 ng/mL, and fentanyl plasma concentration decreased from 15 to 8 ng/mL, 25 hours after. A successful switch was determined the day after in 7 patients, while 4 patients did not respond favorably (effective switching, 63%). Five patients were considered too terminal for an appropriate evaluation. No differences in plasma concentration pattern of the two opioids were found between patients considered responders and nonresponders. Conversion ratios between opioids at time of stabilization did not significantly change in comparison with the initial conversion ratio chosen. Starting methadone soon after removing fentanyl patches results in a rapid increase of methadone concentration, while the half-life of transdermal fentanyl is reached after 25 hours. As a result, the rapid achievement of a clinical effect is obtained avoiding distressing therapeutic holes in patients with a clinical condition, mainly characterized by poor pain control and severe adverse effects, requiring an immediate intervention.