The current study investigated the pharmacokinetic profile of a newly developed biodegradable subcutaneous tramadol implant and shed some light on neurochemical changes. Ribbons of polycaprolactone polymer were loaded with tramadol HCl in two quantities (T350, T650) and implanted in back skin of rats. Plasma tramadol levels were monitored for 45 days and pharmacokinetic parameters were evaluated in addition to analgesic activity. Cortical oxidative stress indicators, orexin, and serotonin levels were determined. The CB-1 receptor and PPAR-α receptor protein levels were assayed.

Both T350 and T650 loaded ribbons attained a sustained release profile for 45 days. T650 implants achieved higher bioavailability than T350. However, the analgesic efficacy of tramadol started once it was implanted and decreased along time indicating accelerated tolerance. Oxidative biomarkers were of normal range. The ventrolateral periaqueductal gray (vlPAG) analgesic pathway involving orexin, endocannabinoid, and serotonin was found to be affected in relation to developing tolerance. Induced cortical 5-HT and orexin-A and decreased level of DA after implanting T350 and T650 were observed. PPAR-α and CB-1R were of elevated abundance in cortex after T650 implants. However, pharmacodynamics reported a sensitizing effect related to vlPAG pathway. The implant achieved long stable release profile but of diminished analgesic activity.