Gj. Lesser et al., IN-VITRO AND IN-VIVO STUDIES OF SUBCUTANEOUS HYDROMORPHONE IMPLANTS DESIGNED FOR THE TREATMENT OF CANCER PAIN, Pain, 65(2-3), 1996, pp. 265-272
Unrelieved cancer pain remains a significant problem worldwide. Patien
ts receive inadequate analgesia for a variety of complex and multifact
orial reasons. Limited availability of opioids secondary to concerns a
bout potential diversion of these medications for illicit use and poor
compliance with oral regimens are significant factors in many countri
es. This study was designed to develop and test an implantable opioid
delivery device capable of releasing a potent opioid subcutaneously at
a continuous rate for 4 weeks. A low temperature solvent casting tech
nique was used to formulate ethylene vinyl acetate (EVA) copolymer dis
ks containing 50% hydromorphone by weight. The release characteristics
of disks of different height and diameter, coated and uncoated, and w
ith and without a central uncoated channel were studied, The effect of
temperature and pH were also evaluated, In vitro assessments were con
ducted in phosphate buffer using UV spectrophotometry, In vivo studies
employed New Zealand White Rabbits and a radioimmunoassay. Plasma lev
els following hydromorphone delivery by polymer, osmotic pump, and int
ravenous administration were compared. In vitro, uncoated EVA polymer
disks measuring 1.05 cm in diameter and 0.27 cm in height released an
initial large burst of hydromorphone. Coating the disks with 100-200 m
u M of poly(methyl-methacrylate) prevented drug egress from the polyme
r. A central uncoated channel measuring 1.25 mm in diameter in an othe
rwise coated polymer virtually eliminated the initial burst of drug re
lease and provided near zero-order hydromorphone release at an average
rate of 164 mu g per hour for 4 weeks. Doubling the height of the pol
ymer approximately doubled the release rate while doubling the diamete
r of the polymer extended the duration of drug release to over 8 weeks
. In rabbits, stable plasma hydromorphone concentrations (23-37 ng/ml)
were sustained for 4 weeks following implantation of 2 polymers with
an uncoated central channel. No initial burst of hydromorphone release
was noted. Increasing the number of polymers produced sustained and p
redictable increases in plasma hydromorphone concentrations, Plasma le
vels were similar with subcutaneous hydromorphone delivered by polymer
and osmotic pump and much less variable than with intravenous bolus h
ydromorphone. A uniquely configured implantable drug delivery device h
as been developed using materials which are approved for human use, It
safely and reproducibly releases hydromorphone for weeks in vitro and
in vivo without an initial burst of drug release. Varying the thickne
ss, diameter, and number of implants provides flexibility in the relea
se rate and duration of release. This implantable opioid delivery devi
ce could provide a sustained subcutaneous infusion of hydromorphone to
patients with cancer pain in developed and developing nations without
pumps, catheters, or extensive outpatient support services, In additi
on, it should improve compliance and reduce concern regarding illicit
diversion of opioids.