To address the different types of pain different classes of medications, mainly non-steroidal anti-inflammatory drugs and narcotics (opioids), are used. The alleviation or treatment of moderate to severe pain states, in particular, commonly invokes the use of opioids. Unfortunately, their chronic administration induces various undesirable side effects, such as for example physical dependence and tolerance. One strategy to overcome these major side effects and to prolong the antinociceptive efficiency of the applied drugs involve the design of peptide-based hydrogels as delivery systems for the controlled-release of painkillers. To overcome the need of repeated high dose administration, hydrogels have been reported as suitable controlled drug-delivery systems. More specifically, peptide hydrogels loaded with active ingredients can liquefy during injection, followed by quick hydrogel reformation once injected. These systems present several advantages such as the protection of the drug against the enzymatic degradation by encapsulation in the hydrogel network, while maintaining the therapeutic plasma drug concentration over a long period via diffusion from the hydrogel or by degradation of the network.[1,2] Consequently, lower dosage and frequency of administration are possible and result in an improvement of the drug efficacy while reducing the risk of side effects. Here, a new family of short, tunable and amphipathic hexapeptide hydrogel-forming peptides was designed. In order to study their eventual therapeutic potential, the hydrogels have been used for entrapment and sustained release of opioid drugs. The in vitro drug release properties and hydrogel toxicity were, for instance, determined. Based on the best physicochemical, mechanical, and noncytotoxic properties, selected hydrogels were investigated for in vivo release of opioids. Opioid administration (both morphine-type compounds and potent peptide ligands) by subcutaneous injection and subsequent testing in the tail-flick assay (acute pain model), showed sustained antinociceptive effects over longer periods of time (up to 96 hours), as compared to drug injections in saline solutions (<3 hours).