Polypharmacology, or the associations between two or more drugs producing biological effects on two or more different sites of action could represent a possible therapeutic approach for the clinical management of acute and chronic pain. The multitude and complexity of neuronal mechanisms that contribute to pain transmission provide several possible targets for pharmacological intervention. Thus, multitarget ligands possessing opioid-opioid or non-opioid-opioid mechanisms of action are potential drug candidates for pain relief. In this perspective, the past medicinal chemistry paradigm “one-target, one-disease” has been reconsidered and converted into “one-molecule, multiple targets”. Multitarget ligands in comparison with cocktail drugs, besides an improved analgesic effect, display a more predictable pharmacokinetic and pharmacodynamic profile coupled to a less incidence of side-effects. Thus, they ameliorate patient compliance and decrease the risk of drug-drug interactions. In our previous review multitarget ligands with an opioid-opioid mechanism of action were described. Here, we deal with multitarget ligands with opioid-non opioid mechanism of action as potential drug candidates for the management of different pain states.