Multicentre, prospective, double-blind, randomised controlled clinical trial comparing different non-opioid analgesic combinations with morphine for postoperative analgesia: the OCTOPUS study

BACKGROUND: Head-to-head comparisons of combinations of more than one non-opioid analgesic (NOA) with morphine alone, for postoperative analgesia, are lacking. The objective of this multicentre, randomised, double-blind controlled trial was to compare the morphine-sparing effects of different combinations of three NOAs-paracetamol (P), nefopam (N), and ketoprofen (K)-for postoperative analgesia. METHODS: Patients from 10 hospitals were randomised to one of eight groups: control (C) received saline as placebo, P, N, K, PN, PK, NK, and PNK. Treatments were given intravenously four times a day during the first 48 h after surgery, and morphine patient-controlled analgesia was used as rescue analgesia. The outcome measures were morphine consumption, pain scores, and morphine-related side-effects evaluated 24 and 48 h after surgery. RESULTS: Two hundred and thirty-seven patients undergoing a major surgical procedure were included between July 2013 and November 2016. Despite a failure to reach a calculated sample size, 24 h morphine consumption [median (inter-quartile range)] was significantly reduced in the PNK group [5 (1-11) mg] compared with either the C group [27 (11-42) mg; P<0.05] or the N group [21 (12-29) mg; P<0.05]. Results were similar 48 h after surgery. Patients experienced less pain in the PNK group compared with the C, N, and P groups. No difference was observed in the incidence of morphine-related side-effects. CONCLUSIONS: Combining three NOAs with morphine allows a significant morphine sparing for 48 h after surgery associated with superior analgesia the first 24 h when compared with morphine alone. CLINICAL TRIAL REGISTRATION: EudraCT: 2012-004219-30; NCT01882530

Effect of the vinyl-globin interactions on the temperature-dependent broadening of the Soret spectra: A study with horse myoglobin and Scapharca dimeric hemoglobin reconstituted with unnatural 2,4-heme derivatives

The temperature dependence of the Soret absorption spectra has been measured over the range 80 to 300 K on deoxygenated and carbonmonoxy horse heart myoglobin and Scapharca inaequivalvis dimeric hemoglobin reconstituted with proto- or with meso- and deutero-heme, in which the vinyl groups have been replaced with ethyl groups or hydrogen atoms, respectively, In the meso- and deutero-derivatives of both proteins the linewidth of the absorption spectra is narrower and less sensitive to thermal broadening effects than in the proto-derivatives. Moreover, the broadening effects are larger in the deoxygenated proteins with respect to the liganded adducts. The quantitative analysis of these effects shows that the change in linewidth is due to a marked decrease in the extent of coupling between the heme vibronic transitions and the protein low-frequency motions. The relevance of the vinyl groups in the dynamics of the heme-globin interaction is highlighted by this experimental approach which shows that the protein is capable of transmitting structural information to the heme by coupling the ensemble of the low-frequency modes to the stereochemistry of the vinyl itself. This mechanism, which entails adjustment of the equilibrium between vinyl torsional conformers, represents an additional pathway for the control of the heme reactivity in addition to the iron-histidine link. (C) 1997 Academic Press