The perioperative administration of systemic small-dose lidocaine reduces pain during surgery associated with the development of pronounced central hyperalgesia, presumably by affecting mechanoinsensitive nociceptors, because these have been linked to the induction of central sensitization and were shown to be particularly sensitive to small-dose lidocaine.

Numerous animal studies suggest that acute and chronic exposure to opioids can be associated with the development of hyperalgesia, i.e. an increased sensitivity to noxious stimuli. Hyperalgesia has been documented during withdrawal and on occasion while animals were still exposed to opioids. A pivotal role in the genesis of opioid-associated hyperalgesia has been attributed to a pain facilitating system involving the N-methyl-D-aspartate (NMDA)-receptor. In humans little direct evidence documents opioid-associated hyperalgesia, albeit observational data suggest that such hyperalgesia may be relevant in a clinical context. This study used a double blind, randomized, crossover and placebo-controlled design to test in opioid-naïve, healthy human volunteers whether hyperalgesia would develop within 30 min of stopping a 90-min infusion with the mu-opioid agonist remifentanil, and whether co-administration of the NMDA-receptor antagonist S-ketamine would prevent such hyperalgesia. We found that a skin area with pre-existing mechanical hyperalgesia was significantly enlarged after stopping the remifentanil infusion. However, the pain response to heat assessed in regular skin was not different before and after the infusion of remifentanil. Co-administration of the NMDA-receptor antagonist S-ketamine abolished observed enlargement of the hyperalgesic skin area. This study provides direct evidence in humans that short-term administration of an opioid can enhance hyperalgesia as observed during withdrawal and points to a potential role of the NMDA-receptor system in mediating such a hyperalgesic response. This study also points to a differential susceptibility of different pain modalities for the expression of hyperalgesia associated with opioid administration.

Opioid-induced postinfusion hyperalgesia could be abolished by S-ketamine, suggesting an N-methyl-d-aspartate-receptor mechanism. In contrast, elevated pain ratings after infusion were not reduced by ketamine but were alleviated by the alpha(2)-receptor agonist clonidine. The results of this study suggest different mechanisms of opioid-induced postinfusion antianalgesia and secondary hyperalgesia.

BackgroundNormalization of plasma fibrinogen levels may be associated with satisfactory haemostasis and reduced bleeding. The aim of this retrospective study was to assess fibrinogen recovery parameters after administration of fibrinogen concentrate (Haemocomplettan® P) to patients with diffuse bleeding in cardiovascular surgery. Data on transfusion and patient outcomes were also collected.MethodsPatient characteristic and clinical data were obtained from patient records. Results of the thromboelastometry (FIBTEM®) and of the standard coagulation tests, including plasma fibrinogen level, measured before surgery, before and after haemostatic therapy, and on the following day, were retrieved from laboratory records.ResultsThirty-nine patients receiving fibrinogen concentrate for diffuse bleeding requiring haemostatic therapy after cardiopulmonary bypass were identified. The mean fibrinogen concentrate dose administered was 6.5 g. The mean fibrinogen level increased from 1.9 to 3.6 g litre−1 (mean increment of 0.28 g litre−1 per gram of concentrate administered); maximum clot firmness increased from 10 to 21 mm. The mean fibrinogen increase was 2.29 (sd 0.7) mg dl−1 per mg kg−1 bodyweight of concentrate administered. Thirty-five patients received no transfusion of fresh-frozen plasma (FFP) or platelet concentrate after receiving fibrinogen concentrate; the remaining four patients received platelet concentrate intraoperatively. Eleven patients received platelets, FFP, or both during the first postoperative day. No venous thromboses, arterial ischaemic events, or deaths were registered during hospitalization.ConclusionsIn this retrospective study, fibrinogen concentrate was effective in increasing plasma fibrinogen level, and contributed to the correction of bleeding after cardiovascular surgery.

Diminished synaptic inhibition in the spinal dorsal horn is a major contributor to chronic pain. Pathways, which reduce synaptic inhibition in inflammatory and neuropathic pain states, have been identified, but central hyperalgesia and diminished dorsal horn synaptic inhibition also occur in the absence of inflammation or neuropathy, solely triggered by intense nociceptive (C–fiber) input to the spinal dorsal horn. We found that endocannabinoids produced upon strong nociceptive stimulation activated CB1 receptors on inhibitory dorsal horn neurons to reduce the synaptic release of GABA and glycine and thus rendered nociceptive neurons excitable by non-painful stimuli. Spinal endocannabinoids and CB1 receptors on inhibitory dorsal horn interneurons act as mediators of heterosynaptic pain sensitization and play an unexpected role in dorsal horn pain controlling circuits.