Endogenous opioid peptides have been aligned with a diverse array of effects. Their activity is not only attributable to action the three main opioid receptors, mu (MOR), delta (DOR), and kappa (KOR) opioid receptors but their impacts appear to extend to activities at sodium channels, cytokine receptors (Finley et al., 2008), calcium channels and non-specific and partially undefined pharmacological effects inconsistent with G-protein coupled opioid receptor activity. Of the family of opioid peptides beta-endorphin (BE 1-31) is one of the most prominent and is the prototypical endogenous peptide for the MOR class of opioid receptors and is found within the CNS and the immune system (Cabot et al., 1997). BE 1-31 is derived from pro-opiomelanocortin (POMC) in the cytosol of cell bodies. BE has been shown to possess peripheral and central analgesic activity (Van Den Burg et al., 2001), producing a morphine-like effect by inhibiting the signals of C- and Aδ-fiber activation (Duggan and Fleetwood-Walker, 1993). In addition, BE 1-31 is a non-selective endogenous peptide with the highest affinities for MOR and DOR (Binder et al., 2004), suggesting that the endogenous system is not modulated by specific and selective opioid agonists in isolation. This concept touches on a new theme evolving in novel therapeutic strategies in the pain field, i.e. the targeting of multiple channels with either one non-selective ligand or a combination of selective ligands to produce effects that are either synergistic or, at a minimum, differential in terms of side effects. This could seemingly point to a multitude of combinations of drugs of both G-protein receptor targeting ligands or extend to those targeting other receptor classes including sodium channels (Su et al., 2002), potassium channels (Welch and Dunlow, 1993) and calcium channels (Smart et al., 1995). The scope of the possible therapeutic targets is immense and, potentially of even greater complexity, is the dose determination for such combinations. Perhaps the answer in part lies in the endogenous opioid system, which is, in essence, the system designed to mediate noxious stimuli as well as interact with the immune system in disease (Figure ​(Figure11). Figure 1 Biotransformation of beta-endorphin 1–31 within inflamed tissue and fragment actions. Immune cells containing beta-endorphin migrate to inflamed tissue in a site directed manner. Beta-endorphin is released within the inflammatory mileu and biotransformed ...