Safety Assessment of Encapsulated Morphine Delivered Epidurally in a Sustained-Release Multivesicular Liposome Preparation in Dogs

Abstract

We have shown that the epidural (EPI) delivery of morphine encapsulated in multivesicular liposomes (DepoFoam drug delivery system) produces a sustained clearance of morphine and a prolonged analgesia. We have sought to subsequently determine the likelihood of deleterious effects on local tissue of repetitive epidural injections of this encapsulated morphine preparation (C0401). Beagle dogs were prepared according to protocol approved by the Institutional Animal Care and Use Committee under volatile general anesthesia with chronic lumbar EPI catheters and subcutaneous injection ports. Male and female dogs (three groups) received a total of 4 EPI injections at 8-day intervals of 3 mL of C0401 (10 mg/mL morphine) (N = 6), DepoFoam vehicle (N = 6), or 0.9% sodium chloride (N = 6). Following EPI-C0401, but not saline or DepoFoam vehicle, there were transient (< 72 hr) decreases in food consumption, arousal, hindlimb muscle tone, and body temperature. Heart rate was unaltered, but there were modest decreases in blood pressure and respiratory rate, which persisted for 24-72 hr after C0401. No persistent changes in sensory/motor function, body weight, or stool/urine production were observed. Cerebrospinal fluid, blood chemistry, and urinalysis performed at surgery and on the day of sacrifice (24 hr after the last dose) were within normal ranges. Gross pathology at necropsy was unremarkable. Spinal histopathology findings were judged to be minimal (e.g., modest pericatheter inflammation and fibrosis) and present in all dogs. However, a statistical trend in the rank order of pathology scores was noted (Saline < DepoFoam vehicle < C0401). Repeated EPI injection of C0401 at the maximum dose that could be administered (30 mg) resulted in moderate, transient behavioral and physiological effects after each injection, consistent with morphine administration, and a modest effect on cord histopathology. This level of pathology is reflected in the lack of change observed in cerebrospinal fluid and lack of neurological findings. These results suggest that C0401 is without significant pathological effects at this dose after repeated epidural delivery in dogs.

Development of a canine nociceptive thermal escape model

“…The animal's arousal status following drug administration was considered an important component of the model. This was quantified at each observation time on a −3 to +3 score of profound sedation (−3) to normal (0) to profound agitation (+3) in increments of 0.5 as previously described (Yaksh et al, 2000).…”

Advances in opioid therapy and formulations

“…These microscopic particles remain within the epidural space, releasing morphine slowly for up to 48 h. The lipid component of the formulation is nontoxic and biodegradable [36]. No serious histopathologic, neurologic, or physiologic consequences have been observed in dogs following the repeated epidural administration of this formulation [37]. Ordinarily, epidural analgesia requires placement of an epidural catheter for continuous infusion or repeated epidural injection, exposing the patient to additional risks and discomfort [38].…”

Liposomal Drug Delivery for Postoperative Pain Management

“…17 After drug release and disintegration of the MVL particle, the lipids can be safely broken down by standard catabolic pathways. 18,26 The MVL is applicable to either local or systemic delivery and can be administered by a variety of nonvascular routes of injection, such as subcutaneous, intramuscular, intraperitoneal, epidural, intrathecal, intraventricular, intra-articular, subconjunctival, and intravitreal, depending on its target of action. 17,21 On subcutaneous or intramuscular injection, depending on the drug, the pharmacokinetics of the MVL therapeutic may exhibit a monophasic or biphasic profile.…”

“…23,26 Morphine is then absorbed through the meninges into the intrathecal space and systemically, 23,30 and the MVL lipids are cleared from the epidural space and metabolized/biodegraded safely. 26,31 In rats after intrathecal administration of 14 C-labeled extendedrelease MVL, the label was cleared within 2 to 3 weeks with expiration as 14 CO 2 ; a small amount was recovered from the central nervous system or the peripheral tissues. 26,31 Histologic changes caused by the epidural administration of extendedrelease MVL morphine sulfate have been assessed in dogs.…”

“…26,31 In rats after intrathecal administration of 14 C-labeled extendedrelease MVL, the label was cleared within 2 to 3 weeks with expiration as 14 CO 2 ; a small amount was recovered from the central nervous system or the peripheral tissues. 26,31 Histologic changes caused by the epidural administration of extendedrelease MVL morphine sulfate have been assessed in dogs. Although a mild local inflammatory reaction was observed at the pericatheter site, a similar mild localized reaction was also observed with an epidural injection of conventional morphine sulfate alone or the MVL carrier.…”