Epidural administration of drugs is becoming more common in the treatment of severe forms of pain. To improve present therapies, a long-acting single-dose gel injection would be beneficial. The present study investigated the use of three different polymers as additives in injectable poloxamer gel in controlling the drug release. The release of lidocaine.HCl and ibuprofen.NA from 25% poloxamer (PO) gel and poloxamer gel with hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (CMC), or dextran (DE) was studied in vitro. Cellulose additives significantly prolonged ibuprofen release, whereas additives were found to have a slight release-increasing effect on lidocaine as compared with the PO gel. The structural differences of the gels, more than the macroviscosity, seem to regulate the release of drugs. The drug permeation-prolonging effect of the respective gels, along with the control solutions, was evaluated in vitro using porcine dura mater membrane. The compact gel depot acted as the rate-limiting step, and significantly prolonged the dural permeation of both drugs in comparison with control solutions. The difference in the drug release and permeation-reducing effects of the gels demonstrated the possibility for interactions between dural membrane and the gel. The findings are promising for further experimental in vivo animal testing of these injectable poloxamer-based gels.