Pharmacokinetics of an implanted osmotic pump delivering sufentanil for the treatment of chronic pain

• Published in: Anesthesiology (Philadelphia) Vol. 99; no. 4; pp. 929 - 937
• Main Authors: FISHER, Dennis M, KELLETT, Norma, LENHARDT, Rainer
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott 01-10-2003
• Subjects: Adult; Analgesics; Biological and medical sciences; Chronic Disease; Drug Delivery Systems - instrumentation; Drug Delivery Systems - methods; Female; Humans; Infusion Pumps, Implantable; Male; Medical sciences; Neuropharmacology; Osmosis; Pain - blood; Pain - drug therapy; Pharmacology. Drug treatments; Sufentanil - administration & dosage; Sufentanil - blood; Sufentanil - pharmacokinetics; Human; Delivery system; Healthy subject; Opiates; Bioavailability; Narcotic analgesic; Absorption; Implanted; Perfusion; Subcutaneous administration; Pharmacokinetics; Osmotic pump; Sufentanil
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/00000542-200310000-00028

A matchstick-sized implanted osmotic pump (Chronogesic) that delivers sufentanil subcutaneously for more than 90 days is being developed to treat chronic pain. This study evaluates pharmacokinetic characteristics related to the absorption of sufentanil using a prototype 60-day system.
Twelve opioid-naive volunteers were given naltrexone to prevent opioid effects. Sufentanil, 60 microg, was infused intravenously over 6 h, then 48 h later, the pump was implanted subcutaneously in the upper arm under local anesthesia. Pumps were removed 9 days later. In six volunteers, fever (1.6-3.3 degrees C) was induced with interleukin-2. Plasma was sampled and population pharmacokinetic modeling was performed to estimate in vivo release rate and absorption half-life. Bioavailability was calculated by comparing in vivo to in vitro release rates. The impact of perturbations in release rate on sufentanil plasma concentration (Cp) was simulated.
Fever had no systematic effect on Cp. Release rate estimated in vivo was similar to that measured in vitro; bioavailability did not differ from 100%. Absorption half-life was 16.2 h. Simulation demonstrated that supplemental release of sufentanil from the implant (as might occur with local heating) increases Cp an average of 2.5-2.8% per hours supplemental dose.
An implantable osmotic pump delivered sufentanil in vivo at the rate predicted from in vitro experiments. The rate at which sufentanil was absorbed from the subcutaneous space (half-life > 16 h) was markedly slower than reported with subcutaneous or intramuscular administration of large volumes of dilute opioids; this slow absorption dampens potential changes in Cp if release rate is perturbed.