ANTINOCICEPTION AND SIDE-EFFECTS OF LIPOSOME-ENCAPSULATED ALFENTANIL AFTER SPINAL DELIVERY IN RATS

We investigated the spinal antinociceptive and supraspinally mediated side effects of intrathecal (IT) alfentanil after delivery in saline o r when encapsulated in Liposomes of different Lipid constituencies in rats. Rats prepared with chronic IT catheters received IT injections o f alfentanil (1, 3, 10, 30, or 50 mu g) prepared in either saline or i n one of three liposome formulations (dipalmitoyl phosphatidyl choline [DPPC], DPPC containing 20% by weight of dipalmitoyl phosphatidyl gly cerol [DPPC-DPPG], or DPPC containing 20 weight percent of cholesterol [DPPC-CHOL]). Antinociception was measured by hot-plate (HP) test (52 .5 degrees C). In separate groups of halothane-anesthetized rats, plas ma alfentanil concentrations were measured (2-120 min) after 50 mu g I T alfentanil given in either saline or Liposomes. Antinociception was measured by tail withdrawal upon its immersion in water 52.5 degrees C . Supraspinal side effects of the drug were tested by measuring catale psy and the eye blink evoked by touching the cornea. IT alfentanil in saline produced a dose-dependent increase in the HP response latency a nd this effect was accompanied by a similar dose-dependent increase in the incidence of catalepsy and blockade of corneal responses, indicat ing a rapid supraspinal redistribution. The HP dose-response curve for IT alfentanil delivered in liposomes was shifted slightly to the righ t, as compared to saline vehicle, but liposome encapsulation totally a bolished the side effects that were otherwise observed at the highest IT alfentanil dose. The delivery of alfentanil in DPPC-DPPG and DPPC-C HOL liposomes, in comparison to saline, resulted in a significant dela y in peak plasma levels, diminished early rostral redistribution of al fentanil, and higher spinal cord levels of alfentanil even at 2 h afte r administration. Unexpectedly, in control liposomes (without alfentan il), a prominent allodynia (pain behavior evoked by light touch) was o bserved with all three formulations. The study indicates that liposoma l preparations can significantly enhance the therapeutic ratio of a li pid soluble opioid after spinal delivery. The initial findings of allo dynia associated with the Liposomes, however, suggest the need for sys tematic studies on the behavioral and tissue toxicology of these drugs .