Hydrogels have increasingly received considerable attention for local opioids delivery in order to sustained wound pain relief. However, burst release of drugs is a critical problem of hydrogels. To this aim, a local drug delivery system consisting of polycaprolactone (PCL) microspheres containing methadone hydrochloride/polyethylene glycol (PEG)-based hydrogels were developed to prolong drug release with potential utilization in pain treatment. Four different drug delivery systems, including methadone hydrochloride/PEG-(N 3 ) 4 -based hydrogel, methadone hydrochloride/PEG-(N 3 ) 2 -based hydrogel, methadone hydrochloride/PCL/PEG-(N 3 ) 4 , and methadone hydrochloride/PCL/PEG-(N 3 ) 2 composite hydrogels, were fabricated to investigate drug release profiles of these systems. The results showed that drug released can be controlled by both the double-barrier matrix (hydrogel/microsphere), and the crosslinking density of hydrogels. Therefore, methadone hydrochloride/PCL/PEG-(N 3 ) 2 composite hydrogel with high crosslinking density has great potential application in sustained release systems for wound pain relief.