Antinociception and Side Effects of Liposome-Encapsulated Alfentanil After Spinal Delivery in Rats

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Abstract
We investigated the spinal antinociceptive and supraspinally mediated side effects of intrathecal (IT) alfentanil after delivery in saline or when encapsulated in liposomes of different lipid constituencies in rats. Rats prepared with chronic IT catheters received IT injections of alfentanil (1, 3, 10, 30, or 50 /μg) prepared in either saline or in one of three liposome formulations (dipalmitoyl phosphatidyl choline [DPPC], DPPC containing 20% by weight of dipalmitoyl phosphatidyl glycerol [DPPC-DPPG], or DPPC containing 20 weight percent of cholesterol [DPPC-CHOL]). Antinociception was measured by hot-plate (HP) test (52.5°C). In separate groups of halothane-anesthetized rats, plasma alfentanil concentrations were measured (2–120 min) after 50 jug IT alfentanil given in either saline or liposomes. Antinociception was measured by tail withdrawal upon its immersion in water 52.5°C. Supraspinal side effects of the drug were tested by measuring catalepsy and the eye blink evoked by touching the cornea. IT alfentanil in saline produced a dose-dependent increase in the HP response latency and this effect was accompanied by a similar dose-dependent increase in the incidence of catalepsy and blockade of corneal responses, indicating a rapid supraspinal redistribution. The HP dose-response curve for IT alfentanil delivered in liposomes was shifted slightly to the right, as compared to saline vehicle, but liposome encapsulation totally abolished the side effects that were otherwise observed at the highest IT alfentanil dose. The delivery of alfentanil in DPPC-DPPG and DPPC-CHOL liposomes, in comparison to saline, resulted in a significant delay in peak plasma levels, diminished early rostral redistribution of alfentanil, and higher spinal cord levels of alfentanil even at 2 h after administration. Unexpectedly, in control liposomes (without alfentanil), a prominent allodynia (pain behavior evoked by light touch) was observed with all three formulations. The study indicates that liposomal preparations can significantly enhance the therapeutic ratio of a lipid soluble opioid after spinal delivery. The initial findings of allodynia associated with the liposomes, however, suggest the need for systematic studies on the behavioral and tissue toxicology of these drugs.

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