Continuous intrathecal infusion of hydromorphone: safety in the sheep model and clinical implications.
OBJECTIVE
To determine the safety of hydromorphone delivered by continuous intrathecal infusion via implanted delivery systems in sheep.


METHODS
Sheep implanted with intrathecal infusion systems were randomly assigned to receive either 1.5, 3, or 6 mg/day hydromorphone HCl or saline control (3 sheep/dose level) at a fixed infusion rate of 1.92 mL/day for 28-31 days. Infusions were initiated approximately 5 days after surgical implantation of the delivery systems (pumps and intrathecal catheters), and investigators were blinded to doses administered. An additional group of sheep (N=3) received hydromorphone (open label) at a dose of 12 mg/day. All animals were examined daily during drug infusion for changes in behavior and neurologic function. Cerebrospinal fluid was analyzed for protein, cytology, and hydromorphone concentration in samples collected prior to and at the end of drug infusion. The spinal cord with the catheter in situ was removed en bloc and fixed in formalin for microscopic analysis.


RESULTS
All sheep receiving intrathecal hydromorphone exhibited gaiting deficits and biting behavior over the caudal lumbar area above the infusion site. Animals treated with 12 mg/day were sedate and lethargic, and exhibited repeated biting behavior over the caudal lumbar area during the study. No lesions were noted in any animal upon gross evaluation of the spinal cord. Microscopic changes were comparable between hydromorphone- and saline-treated animals with one exception. Mild inflammation 5 cm cranial to the catheter tip was present in two of three sheep receiving 12 mg/day and in one of three sheep receiving 1.5 mg/day. Mild chronic inflammation hydromorphone in the vicinity of the catheter was also presented in saline-treated animals.


CONCLUSIONS
Hydromorphone was not associated with inflammatory mass formation in the sheep model. Further studies are necessary to determine whether hydromorphone is a safer alternative to morphine for continuous intrathecal infusion for the treatment of chronic pain.
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Mary J
MJ
Johansen
William C
WC
Satterfield
Wallace B
WB
Baze
Keith R
KR
Hildebrand
Tamara Lee
TL
Gradert
Samuel J
SJ
Hassenbusch
D000818:Animals; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D004091:Hydromorphone / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood / Q000737:chemistry; D015918:Infusion Pumps, Implantable; D007278:Injections, Spinal; D008159:Lumbar Vertebrae; D008297:Male; D023421:Models, Animal; D012756:Sheep / Q000097:blood*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology
D004091:Hydromorphone