Rediscovery of old drugs: the forgotten case of dermorphin for postoperative pain and palliation

Jan M Keppel Hesselink,1,2 Michael E Schatman3,4 1Department of Health, University of Witten/Herdecke, Witten, Germany; 2Institute for Neuropathic Pain, Bosch en Duin, the Netherlands; 3Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA; 4Research and Network Development, Boston Pain Care, Waltham, MA, USA Abstract: The repurposing of old drugs for new indications is becoming more accepted as a cost-efficient solution for complicated health problems. However, older drugs are often forgotten when they are not repositioned. This analysis makes a case for re-exploration of dermorphin for intrathecal use in postoperative pain and in a palliative context, with the goal of re-establishing this compound. Dermorphin was isolated from the skin of an Amazonian frog, characterized and identified as a bioactive heptapeptide by Vittorio Erspamer’s research group in the early 1980s. It was traditionally called “Kambo” or “Sapo” by Amazon tribes and was used to improve their physical and psychic skills as hunters. Its structure is rather enigmatic, containing a D-amino acid, and its pharmacological activity in a number of assays was found to be quite impressive and superior to morphine. Moreover, it has been established as more selective and potent with long-lasting analgesia compared to morphine after intracerebroventricular administration in animal models. In 1985, the first clinical trial results of a randomized, placebo-controlled study in postoperative pain were reported, and dermorphin administered via the intrathecal route was again impressively superior over the placebo and the reference compound morphine. This milestone study was apparently minimally read by clinicians, as the study has never been referenced; only 15 pharmacological and review papers after 1985 mentioned the results, with not one being a clinical paper. The interest in dermorphin decreased after 1985, and the compound was never again introduced in the clinical setting. Considering the enormous pressure to find superior acting opioids, this is quite puzzling. We suggest new clinical studies to further evaluate the safety and efficacy of dermorphin, especially administered via the intrathecal route in postoperative pain or for palliative use in terminal patients. Keywords: Kambo, Sapo, peptides, postoperative, analgesia, palliative, pain