Prolongation of local pain insensitivity by anesthetic lidocaine loaded pH-TW20 Gly niosomes: effects on nociception in murine models of pain

Current drugs treating neuropathic pain fail in up to 40-50% of the patients, because they have limited efficacy and are associated with dose related unwanted adverse effects [1]. One of the most extensively studied agents for neuropathic pain in animals and humans is lidocaine, a local anesthetic with a short duration of action [2]. The great interest in lidocaine delivery systems is increased in the last years. The final purpose is to prolong the effective time of lidocaine and to reduce the frequency of administration. Particularly, pH-sensitive molecules to niosome formulation represents an effective and promising delivery strategy [3]. pH-sensitive nonionic surfactant vesicles (niosomes) by polysorbate-20 derivatized by glycine (added as pH sensitive agent), were developed to deliver Lidocaine (LID). Lidocaine (5%) were chosen into niosome (N[LID]) (TW20-GLY LIDO 5%) [3]. Experiments to assess the in vivo efficacy of lidocaine loaded pH-TW20 GLY niosomes were carried out in murine models to evaluate the potential advantages of stimuli responsive nanocarriers, loaded with lidocaine in pain treatments. The data related to these tests and obtained from lidocaine loaded pH-TW20 Gly niosomes were compared with those obtained from free lidocaine, in order to highlight the overlap with the data. The following models of pain were used: formalin test, zymosan-induced hyperalgesia, Tail flick test and sciatic nerve ligation inducing neuropathic allodynia and hyperalgesia. The subcutaneous administration of N[LID] in the dorsal surface of mice paw 10 min or 180 min before formalin in a volume of 40 μL/paw and 1h after zymosan A in a same volume was able to reduce the response to nociceptive stimuli in the formalin test and hyperalgesia induced by zymosan. The already high effects of free lidocaine were improved in terms of higher duration of its action over time. The results obtained by Tail flick test confirmed that N[LID] has a longer analgesic effect than free lidocaine, especially in terms of longer duration of action. Experience to date suggests that 40 μL/paw s.c. administration of N[LID] significantly reduced allodynia and hyperalgesia produced by sciatic nerve ligation. Niosome represents an effective and promising delivery strategy, which may greatly increase the utility of niosomes as a targeted delivery vehicle, which is degraded only in the target area, where the drug will be released and accumulated. In our opinion, N[LID] should be developed as a new potential drug in the treatment of pain in humans. _____________________________________ 1. Y.B. Martin, G. Herradón, L. Ezquerra, Curr Pharm Des., 2011, 17, 434. 2. C.P.N. Watson, Progress in Pain Research and Management, 2001, 21, 215. 3. F. Rinaldi, E. Del Favero, V. Rondelli, S. Pieretti, A. Bogni, J. Ponti, F. Rossi, L. Di Marzio, D. Paolino, J Enzyme Inhib Med Chem., 2017, 32, 538