Buprenorphine via drinking water and combined oral-injection protocols for pain relief in mice

Buprenorphine is the opioid analgesic most commonly used in laboratory mice. However, to maintain therapeutically effective serum levels, repeated injections are required. To overcome negative aspects of restraint and injection, oral self-administration is a promising alternative but has been criticized to be unreliable. Here we analyze voluntary intake of buprenorphine via drinking water as well as drinking water/injection combinations for their reliability to achieve effective drug supply in C57BL/6j female mice. Mice were assigned to one of five groups: a) naive/no treatment (N); b) buprenorphine administration via drinking water for 24h (W); c) buprenorphine administration via two subcutaneous injections during light, and via drinking water during dark phase (IW2); d) buprenorphine administration via three subcutaneous injections during light phase and drinking water for 24h (IW3) ore) surgery plus buprenorphine administration via three subcutaneous injections during light phase and drinking water for 24 h (S). Drinking frequency, water and food intake, activity, body mass progression, blood serum concentrations of buprenorphine and behavioral pain indicators were determined. Water intake was not decreased due to buprenorphine treatment or surgery. Administration of buprenorphine resulted in a significant increase of home cage activity in IW3 animals and a decrease in body mass (n.s.). Food intake decreased significantly in IW2, IW3 and S, compared to nave mice (IW2: p = 0.001; IW3: p = 0.0253; S: p <= 0.0001). All treatment groups showed mean serum concentrations higher than the targeted value (>1 ng/ml) throughout dark phase. Nevertheless, sporadic drinking events and consequently highly variable individual serum concentrations during light phase suggest the use of a combination protocol (IW3: 24h water administration + injections every 4h during light phase), that proved to result in continuous therapeutic mean and individual serum concentrations and minimization of pain indicators after surgery (S). (C) 2016 Elsevier B.V. All rights reserved.