We have observed that spinal liposome administration in the rat resulted in in an allodynia evoked by light touch. We later determined that liposomes composed of D-isomer phospholipids were essentially non-toxic. This study examines the effects of alfentanil encapsulated in liposomes made from the natural L-isomer and synthetic D-isomer of dipalmitoyl phosphatidyl choline on antinoceiception, side effects, and algogenic behaviour. Both unilamellar and multilamellar liposomes were studied. Rats prepared with chronic intrathecal catheters received intrathecal injections of alfentanil (5 or 50 micrograms) in saline or encapsulated in liposomes composed of either L- or D-isomers of dipalmitoyl phosphatidyl choline (DPPC) in unilamellar or multilamellar liposome formulations. Antinociception was measured using the hot plate test (52.5 degrees). Side effects were measured by catalepsy, corneal responses, pinna response, righting reflex, and paw step. Allodynia was measured by lightly stroking the animal's back. Intrathecal alfentanil in saline or in the liposomes produced a dose-dependent increased latency in the hot plate response. Encapsulation of alfentanil in the liposomes produced a significant decrease in the loss of corneal, paw step and righting reflex and a slight decrease in catalepsy and loss of the pinna response. There was no significant difference between liposome preparations in preventing side effects. L-multilamellar-DPPC produced allodynia in 100% of the animals whereas significantly less allodynia was observed with the other preparations. This study indicates that liposomal preparations can significantly enhance the therapeutic ratio of a lipid soluble opioid after spinal delivery. However, the choice of lipids for the formulation of liposomes intended for spinal drug delivery must be considered since the L-isomer and larger lipid load of multilamellar liposomes have a direct spinal effect leading to alledynia. Previous studies have in fact shown that spinal lysolecithin can yield focal demyelination.