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Introduction: We explored in mice, the analgesic, tolerance, dependency, and rewarding effects of systemic acetaminophen (APAP). Methods: Studies employed adult mice (C57Bl6). (1) Intraplantar formalin flinching + post formalin allodynia. Mice were given intraperitoneal APAP in a DMSO (5%)/Tween 80 (5%) or a water-based formulation before formalin flinching on day 1 and tactile thresholds assessed before and after APAP at day 12. (2) Paw incision. At 24 hours and 8 days after hind paw incision in male mice, effects of intraperitoneal APAP on tactile allodynia were assessed. (3) Repeated delivery. Mice received daily (4 days) analgesic doses of APAP or vehicle and tested upon formalin flinching on day 5. (4) Conditioned place preference. For 3 consecutive days, vehicle was given in the morning in either of 2 chambers and in each afternoon, an analgesic dose of morphine or APAP in the other chamber. On days 5 and 10, animals were allowed to select a "preferred" chamber. Results: Formalin in male mice resulted in biphasic flinching and an enduring postformalin tactile allodynia. Acetaminophen dose dependently decreased phase 2 flinching, and reversed allodynia was observed postflinching. At a comparable APAP dose, female mice showed similarly reduced phase 2 flinching. Incision allodynia was transiently reversed by APAP. Repeated APAP delivery showed no loss of effect after sequential injections or signs of withdrawal. Morphine, but not APAP or vehicle, resulted in robust place preference. Conclusions: APAP decreased flinching and allodynia observed following formalin and paw incision and an absence of tolerance, dependence, or rewarding properties.
RESUMO
Chloroprocaine is a short-acting local anaesthetic with a rapid onset of action and an anaesthesia duration up to 60 min. In this pivotal study success rates, onset and remission of motor and sensory block and safety of chloroprocaine 2% was compared to ropivacaine 0.75% for short-duration distal upper limb surgery with successful block rates as primary outcome. The study was designed as a prospective, randomised, multi-centre, active-controlled, double-blind, parallel-group, non-inferiority study, performed in 4 European hospitals with 211 patients scheduled for short duration distal upper limb surgery under axillary plexus block anaesthesia. Patients received either ultrasound guided axillary block with 20 ml chloroprocaine 2%, or with 20 ml ropivacaine 0.75%. Successful block was defined as block without any supplementation in the first 45 min calculated from the time of readiness for surgery. 90.8% patients achieved a successful block with chloroprocaine 2% and 92.9% patients with Ropivacaine 0.75%, thus non-inferiority was demonstrated (10% non inferiority margin; 95% CI - 0.097, 0.039; p = 0.02). Time to onset of block was not significantly different between the groups. Median time to motor and sensory block regression was significantly shorter as was time to home discharge (164 [155-170] min for chloroprocaine versus 380 [209-450] for the ropivacaine group, p < 0.001). For short-duration surgical procedures, the short-acting Chloroprocaine 2% may be used, with success rates non-inferior to ropivacaine and a favourable safety profile.Trial registration: The trial was registered at Clinicaltrials.gov with registration number NCT02385097 (March 11th, 2015) and European Clinical Trial Database with the EudraCT number 2014-002519-40 (July 7th, 2015, Austria-BASG).