Fentanyl–trazodone–paracetamol triple drug combination: Multimodal analgesia in a mouse model of visceral pain

Synergistic Interaction Between Fentanyl and a Tramadol:Paracetamol Combination on the Inhibition of Nociception in Mice

“…The Institutional Committee on Animal Use and Care, in accordance with the International Association for the Study of Pain guidelines on ethical standards for investigation in animals, approved the protocol. As previously described, FEN and PRC induced a dose-dependent inhibition of writhes with similar efficacy (100%) and the following ED 50 's: FEN = 0.021 ± 0.003, PRC = 109.3 ± 2.5 mg/kg (6). Similarly, TRM also dose-dependently inhibited acetic acid-induced nociception (TRM = 3.18 ± 0.27 mg/kg).…”

“…Subsequently, our aim consisted of performing a multimodal analgesic paradigm, in which the three drugs were combined. It is noteworthy that we recently demonstrated that FEN and PRC interact in a synergic manner on the inhibition of acetic acid-induced nociception in mice (6), and similarly FEN and TRM have been shown to induce synergic antinociceptive effects in the writhing test (14), validating the clinical strategy of using opioidopioid combinations in the management of pain, usually in patients in which opioid tolerance appears (2). On the basis of these results, we expected supra-additive antinociceptive effects when combining the three drugs, and effectively FEN:TRM:PRC displayed a potent synergistic interaction on the inhibition of acetic acid-mediated nociception.…”

“…Briefly, male Swiss CD1 mice (20 -25 g) housed under controlled standard conditions (12-h dark/light cycle, 22°C temperature and 66% humidity) were injected with one or a mixture of the following drugs: FEN (KernPharma, Barcelona, Spain); TRM (Grünenthal, Madrid, Spain); PRC (Bristol-Myers Squibb, Madrid, Spain); naloxone (Sigma-Aldrich, St. Louis, MO, USA); naltrindole and nor-binaltorphimine (nor-BNI) (Tocris Bioscience, Bristol, UK) subcutaneously 30 min before testing. Then, mice were injected intraperitoneally with an acetic acid solution (0.6% v/v, 10 ml/kg) and placed in a clear plexiglass cylinder to observe after 5 min the number of writhes (a single writhe is defined as a contraction of the abdominal wall together with the twisting of the trunk and hind limbs extension) in a 5-min period (6). The Institutional Committee on Animal Use and Care, in accordance with the International Association for the Study of Pain guidelines on ethical standards for investigation in animals, approved the protocol.…”

Side effects of pain and analgesia in animal experimentation

“…Thus, the side effect profile of all drugs has to be analyzed carefully. For rodents, several effective multimodal analgesia protocols have been described, with examples including tramadol-carprofen 69 or fentanyltrazodone-paracetamol 70 .…”

Analgesic effect and pharmacological mechanism of fentanyl and butorphanol in a rat model of incisional pain

“…Accumulating evidence and documents have indicated that single-drug therapy with fentanyl or butorphanol, as well as combination therapy with other opioid analgesics, was widely used in the treatment of moderate to severe cancer pain and acute and chronic pain [23][24][25]. Nevertheless, the effects on opium receptors may differ from different opioid analgesics, and the effective dosage of opioid analgesics and its underlying mechanism were still incompletely illustrated.…”