Differential scanning calorimetry has been used to demonstrate that amethocaine base, when formulated as a percutaneous anaesthetic gel, undergoes a phase change at or below normal skin temperature. Under aqueous conditions the melting point of amethocaine was lowered by approx. 10°C. The influence of the phase change on drug release characteristics was investigated in respect of both gelled, saturated amethocaine solutions and formulations containing a reservoir of undissolved drug. Drug release from the formulation, and subsequent penetration of iipophilic barriers, was shown to proceed from the aqueous diffusion layer at the formulation/barrier membrane interface. A more rapid replenishment of the diffusion layer can be achieved after the phase change has occurred. Under these conditions the drug is present both in solution and as undissolved oil droplets, the latter having an enhanced dissolution rate compared to solid drug particles in suspension. Given the low solubility of amethocaine base, and therefore the comparatively low concentration gradient established across the diffusion layer, the proven percutaneous anaesthetic efficacy of amethocaine is largely related to its lipophilicity and anaesthetic potency. An overall scheme is proposed for the drug release characteristics of the amethocaine phase-change system.