Search

Unlabelled: Adding a small dose of ketamine to opioids may increase the analgesic effect and prevent opioid-induced hyperalgesia and acute tolerance to opioids. In this randomized, double-blinded, placebo-controlled crossover study, we investigated the effect of remifentanil combined with small concentrations of ketamine on different experimental pain models. Pain detection thresholds to single and repeated IM electrical stimulation and to repeated transcutaneous electrical stimulation, pressure pain tolerance threshold, and sedative, respiratory, and cardiovascular side effects were assessed in 14 healthy volunteers. Saline, remifentanil alone, and remifentanil combined with ketamine at target plasma concentrations of 50 or 100 ng/mL were administered in four study sessions. The ketamine infusion was started after baseline testing at a constant target concentration. Remifentanil was started after testing with ketamine alone at an initial target concentration of 1 ng/mL and then increased to 2 ng/mL and decreased to 1 ng/mL. The last test series were started 10 min after discontinuation of remifentanil. Acute remifentanil-induced hyperalgesia and tolerance were detected only by the pressure pain test and were not suppressed by ketamine. Remifentanil alone induced significant analgesia with all pain tests. Ketamine further increased the remifentanil effect only on IM electrical pain. Remifentanil at a 2 ng/mL target concentration induced a slight respiratory depression that was antagonized by ketamine. We conclude that ketamine effects on opioid analgesia are pain-modality specific., Implications: Coadministration of ketamine and morphine for pain relief is still controversial. Our experimental pain study with volunteers showed that ketamine enhances opioid analgesia without increasing sedation and reduces respiratory depression. Opioid-induced hyperalgesia and tolerance were not affected by ketamine and depended on the type of nociceptive stimulus. This may explain the conflicting results on opioid tolerance in previous studies.

There is no objective measure of a complete pain perception; we can, however, measure different aspects of nociceptive processing and pain perception. Earlier, experimental pain models often only involved induction of cutaneous pain using a single stimulus modality. Recently new experimental models have been developed eliciting various modalities of deep and visceral pain which more closely resemble clinical pain conditions. It is imperative to use multi-modal and multi-structure pain induction and assessment techniques, because a simple model cannot describe the very complex and multi-factorial aspects of clinical pain. Furthermore, it is important to assess pain under normal and pathophysiological conditions. The importance of peripheral and central hyperexcitability for acute and chronic pain has been demonstrated in animals and, to some extent, in humans. However, in spite of our immense knowledge, we still do not know how to prevent and treat this hyperexcitability efficiently. Our understanding of nociceptive mechanisms involved in acute and chronic pain and the effects of anaesthetic drugs or combinations of drugs on these mechanisms in humans may also be expanded using human experimental models. This mechanism-based approach may help us to develop and test therapeutic regimes in patients with acute and chronic pain.

Background: The laser-Doppler skin vasomotor reflex (SVmR) caused by tetanic stimulation of the ulnar nerve may be a test that can predict the haemodynamic response to tracheal intubation. A decrease in pulse wave amplitude (pulse wave reflex, PWR) may be an alternative index of this response. We compared the abilities of PWR and SVmR to predict the haemodynamic response to tracheal intubation and studied how alfentanil, muscle relaxation, stimulation site and stimulation pattern affected the two reflexes., Methods: Anaesthesia was induced and maintained with 2% sevoflurane and 50% nitrous oxide in two groups of 10 ASA status 1 patients. Tetanic stimuli were applied to the flexor muscles of the forearm and the ulnar nerve before and after administration of vecuronium. The change in skin blood flow (laser-Doppler) and pulse wave amplitude (pulse oximetry) after a 5 and 10 s stimulation was measured on the opposite hand. If skin blood flow (laser-Doppler) decreased by more than 10%, a computer-controlled infusion of alfentanil was started and the target plasma concentration was increased in steps until this response was suppressed (< 10%). The trachea was intubated and arterial pressure and heart rate responses were recorded. Plasma alfentanil concentration was measured., Results: When PWR and SVmR were suppressed, the haemodynamic response to tracheal intubation was reduced in 100 and 53% of patients respectively. PWR and SVmR responses decreased with increasing plasma alfentanil concentration. The SVmR response to muscle stimulation was reduced by muscle relaxants. The pulse wave response to both muscle and neural stimulation was reduced by relaxants. The responses to 5 and 10 s stimulations were similar., Conclusion: An absent SVmR does not predict a blunted arterial pressure or heart rate response to tracheal intubation. The PWR may be a better predictor.

We present a case of a probably unnecessary Caesarean section due to misinterpretation of the cardiotocography (CTG) trace during general anaesthesia. A 27-yr-old patient in her 30th week of an uneventful, normal first pregnancy presented with a deep venous thrombosis in the pelvic region. She was to undergo an emergency thrombectomy under general anaesthesia. During the operation, the CTG showed a lack of beat-to-beat heart rate variation (silent pattern CTG) with normal fetal heart rate. This silent CTG pattern was probably a result of the effect of general anaesthesia on the fetus. The CTG pattern was interpreted as indicating fetal distress, and an emergency Caesarean section was performed after the thrombectomy. The infant was apnoeic and had to be resuscitated and admitted to the neonatal intensive care unit. The pH at delivery was 7.23 and the baby was extubated 2 days later. Mother and child recovered without short-term sequelae. In the absence of alternative explanations, reduced fetal beat-to-beat variability with a normal baseline heart rate during general anaesthesia is probably normal.

In experimental studies, drug-induced analgesia is usually assessed by cutaneous stimulation. If analgesics act differently on cutaneous and deep nociception, the results of these studies may not be entirely applicable to clinical pain involving deep structures. We tested the hypothesis that opioids have different abilities to inhibit cutaneous and muscular pain. Either the opioid remifentanil or placebo was infused in 12 healthy volunteers in a cross-over fashion. Repeated electrical stimulation (five impulses at 2 Hz) was applied to both skin and muscle. Pain thresholds were recorded. Remifentanil caused a higher increase in the muscular pain thresholds than in the cutaneous pain thresholds (P = 0.035). We conclude that opioids inhibit muscular pain more strongly than cutaneous pain in humans.

It is neurophysiologically and neurobiologically verified that the central nociceptive system can undergo changes and become hyperexcitable. Hyperexcitability involves wind-up (exaggerated responses) of dorsal horn neurones which in humans can be studied (temporal summation) by electrophysiological and psychophysical reactions to repeated nociceptive stimuli. Temporal summation occurs if repeated stimuli evoke increasing pain reactions. Human experimental models are adequate to investigate basic aspects and pharmacological modulation of summation and to bridge the gap between basic and clinical sciences facilitating the transfer of knowledge from basic science into the clinic. Human experimental investigations have confirmed animal studies that show that central summation is a potent mechanism in both normal and pathophysiological (hyperexcitable) conditions. Central summation should be considered as a target for the development of new centrally acting analgesics, for designing management regimens to treat intractable pain, and as a possible way of inhibiting surgically-induced afferent barrage from reaching brain centres (subconscious pain) during anaesthesia.

Background: The hemodynamic effects of isoflurane have been studied extensively. However, most data are obtained from volunteers or patients in the absence of surgical stimulation. The hemodynamic responses to various stimulation patterns of different intensity have not been evaluated., Methods: In 26 patients, the ability of isoflurane to suppress motor and hemodynamic reactions in response to noxious stimulations of variable degree (trapezius squeeze, tetanic stimulation, laryngoscopy, skin incision, and laryngoscopy plus intubation) was evaluated by measuring arterial blood pressure and heart rate before and after stimulation., Results: At concentrations that inhibited motor response to these stimuli in 50% of all patients, systolic blood pressure increased by 9 (trapezius squeeze), 15 (tetanic stimulation), 23 (laryngoscopy), 35 (skin incision) and 49 (intubation) mmHg, and heart rate by 5 (trapezius squeeze), 15 (tetanic stimulation), 17 (laryngoscopy), 36 (skin incision), and 36 (intubation) min-1 compared to the prestimulation values. An analysis using multiple regression showed that blood pressure response was influenced most by the type of stimulation followed by the concomitantly occurring motor reaction, the anesthesia time, and least by the isoflurane concentration per se. A high isoflurane concentration had no influence on the magnitude of blood pressure or heart rate increase to stimulation, but it decreased the prestimulation blood pressure and slightly increased the prestimulation heart rate. Heart rate responses were less consistent than those of blood pressure., Conclusions: Isoflurane used as a sole agent is unable to suppress hemodynamic reactions (blood pressure and heart rate) to painful stimuli. A "normal" blood pressure following stimulation can be achieved only if prestimulation blood pressure is depressed to levels that may be clinically unacceptable. The lack of motor response is not an accurate predictor of the ability of an agent to depress hemodynamic reaction.