Improvement of pain treatment after major abdominal surgery by intravenous S+-ketamine

The use of intraoperative racemic ketamine for pain prevention after abdominal surgery is controversial. We compared one preincisional i.v. injection of S(+)-ketamine with its preincisional and repeated intraoperative use in 45 patients undergoing surgery with epidural and general anesthesia. S(+)-ketamine is a new drug formulation that contains the more potent S(+)-stereoisomer of ketamine. Patients were randomized to receive placebo, 0.5 mg/kg preincisional S(+)ketamine, or 0.5 mg/kg preincisional and 0.2 mg/kg intraoperative S(+)-ketamine repeated at 20-min intervals. In the postoperative period, epidural ropivacaine (2 mg/mL; 0.12 mL.kg(-1).h(-1)) was infused for pain therapy. Patients who received repeated S(+)-ketamine reported smaller pain scores than those who received placebo after awakening and 3 and 6 h later (P < or = 0.05). Fewer patients with repeated S(+)-ketamine required additional analgesics than those with placebo (P < or = 0.05). Cumulative consumption of additional diclofenac and dextropropoxyphene at 24 h was less after single (P < 0.05) and repeated (P < 0.05) S(+)-ketamine versus placebo. After awakening, patients who received repeated S(+)-ketamine reported being in a better mood than those in the other groups (P < 0.05). No psychotomimetic side effects were noted. In conclusion, preincisional and repeated intraoperative small-dose S(+)-ketamine added to general and epidural anesthesia causes better postoperative pain relief than general and epidural anesthesia alone. IMPLICATIONS: After major visceral surgery, preincisional and repeated intraoperative small-dose S(+)-ketamine added to general and epidural anesthesia causes better postoperative pain relief than general and epidural anesthesia alone.     

Intraartikuläre Ketamingabe bei arthroskopischen Knieoperationen

BACKGROUND: Surgery of the knee can be very painful and sufficient postoperative pain treatment is often problematic. To optimize postoperative analgesia, application of local analgesics has been suggested. In the present study it was investigated whether intra-articular administration of ketamine reduces the level of pain after arthroscopic knee surgery. MATERIAL AND METHODS: A total of 68 patients undergoing arthroscopic knee surgery were randomized into 4 groups. At the end of surgery the following pharmaceuticals were administered: 10 ml 0.25% bupivacaine intra-articular (i.a.), 0.25 mg S-(+)-ketamine/kg body weight to 10 ml in 0.9% NaCl i.a., 0.25 mg S-(+)-ketamine/kg body weight intravenous (i.v.), and 10 ml 0.9% NaCl i.a. as placebo. Postoperative pain therapy was performed as i.v. patient controlled analgesia (PCA) with piritramide. Postoperative opioid consumption and pain intensity were assessed as the main criteria in the postoperative course. RESULTS: All 4 groups were comparable with respect to biometrical data. The scores of the visual analogue scale (VAS) showed a significantly (p<0.05) lower pain intensity in patients treated with ketamine i.a. or i.v. compared to the other groups. Shortly after surgery the highest reduction of pain was detected in the i.a. ketamine group compared to i.a. bupivacaine or placebo administration. The postoperative opioid consumption was always lowest in the i.a. ketamine group. A significant difference in piritramide consumption (p<0.05) was demonstrated in the first 20 min after operation in the i.a. ketamine group compared to the i.a. administration of placebo and bupivacaine. CONCLUSIONS: The i.a. application of ketamine after arthroscopic knee surgery leads to a significant decrease of postoperative analgesic demand and decreases patients' subjective level of pain compared to i.a. application of bupivacaine or placebo. Likewise, the i.v. application of ketamine is similarly effective but the effect is of shorter duration.     

Ketamine distribution described by a recirculatory pharmacokinetic model is not stereoselective

BACKGROUND: Differences in the pharmacokinetics of the enantiomers of ketamine have been reported. The authors sought to determine whether these differences extend to pulmonary uptake and peripheral tissue distribution and to test the hypothesis that tissue distribution of the stereoisomers differs because of carrier-mediated drug transport. METHODS: The dispositions of markers of intravascular space and blood flow (indocyanine green, ICG) and total body water and tissue perfusion (antipyrine) were determined along with S-(+)- and R-(-)-ketamine in five mongrel dogs. The dogs were studied while anesthetized with 2.0% halothane. Marker and drug dispositions were described by recirculatory pharmacokinetic models based on frequent early and less-frequent later arterial blood samples. These models characterize pulmonary uptake and the distribution of cardiac output into parallel peripheral circuits. RESULTS: Plasma elimination clearance of the S-(+)-ketamine enantiomer, 29.9 ml x min(-1) x kg(-1), was higher than that of the R-(-)-enantiomer, 22.2 ml x min(-1) x kg(-1). The apparent pulmonary tissue volumes of the ketamine S-(+) and R-(-)-enantiomers (0.31 l) did not differ and was approximately twice that of antipyrine (0.16 l). The peripheral tissue distribution volumes and clearances and the total volume of distribution (2.1 l/kg) were the same for both stereoisomers when elimination clearances were modeled from the rapidly equilibrating peripheral compartment. CONCLUSIONS: Although the elimination clearance of S-(+)-ketamine is 35% greater than that of the R-(-)-enantiomer, there is no difference in the apparent pulmonary tissue volume or peripheral tissue distribution between the stereoisomers, suggesting that physicochemical properties of ketamine other than stereoisomerism determine its perfusion-limited tissue distribution.     

Imaging human cerebral pain modulation by dose-dependent opioid analgesia: a positron emission tomography activation study using remifentanil

BACKGROUND: Previous imaging studies have demonstrated a number of cortical and subcortical brain structures to be activated during noxious stimulation and infusion of narcotic analgesics. This study used O-water and positron emission tomography to investigate dose-dependent effects of the short-acting mu-selective opioid agonist remifentanil on regional cerebral blood flow during experimentally induced painful heat stimulation in healthy male volunteers. METHODS: Positron emission tomography measurements were performed with injection of 7 mCi O-water during nonpainful heat and painful heat stimulation of the volar forearm. Three experimental conditions were used during both sensory stimuli: saline, 0.05 microg x kg x min remifentanil, and 0.15 microg x kg x min remifentanil. Cardiovascular and respiratory parameters were monitored noninvasively. Across the three conditions, dose-dependent effects of remifentanil on regional cerebral blood flow were analyzed on a pixel-wise basis using a statistical parametric mapping approach. RESULTS: During saline infusion, regional cerebral blood flow increased in response to noxious thermal stimulation in a number of brain regions as previously reported. There was a reduction in pain-related activations with increasing doses of remifentanil in the thalamus, insula, and anterior and posterior cingulate cortex. Increasing activation occurred in the cingulofrontal cortex (including the perigenual anterior cingulate cortex) and the periaqueductal gray. CONCLUSIONS: Remifentanil induced regional cerebral blood flow increases in the cingulofrontal cortex and periaqueductal gray during pain stimulation, indicating that mu-opioidergic activation modulates activity in pain inhibitory circuitries. This provides direct evidence that opioidergic analgesia is mediated by activation of established descending antinociceptive pathways.     

The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans

Background : Ketamine in sub-dissociative doses has been shown to have analgesic and phantom-Limb pain, where conventional treatment has often failed. Chronic ischemic pain due to lower extremity arteriosclerosis obliterans often responds poorly to analgesics, and the pain-generating mechanisms are not well understood.
Methods : Eight patients with rest pain in the lower extremity due to arteriosclerosis obliterans were given sub-dissociative doses of 0.15, 0.30, or 0.45 mg/kg racemic ketamine and morphine 10 mg as a 5-min infusion on four separate days in a cross-over, double-blind, randomised protocol. Plasma levels of (S)- and (R)-ketamine and their nor-metabolites were analysed with an enantioselective high-performance liquid chromatography (HPLC) method. Pain levels were evaluated with a visual analogue scale (VAS).
Results : Individual pain levels were highly variable during and after all the infusions but the pooled pain levels showed a dose-dependent analgesic effect of ketamine with a transient but complete pain relief in all patients at the highest dose (0.45 mg/ kg). Side-effects, mainly disturbed cognition and perception, were pronounced and dose-dependent. Morphine 10 mg had an analgesic peak at 20 min and 5/8 patients had complete pain relief. The remaining 3 patients also had high baseline pain scores, indicating a higher analgesic potency for the 0.30 and 0.45 mg/ kg ketamine doses than for morphine 10 mg.
Conclusion : We have demonstrated a potent dose-dependent analgesic effect of racemic ketamine in clinical ischemic pain. Due to a narrow therapeutic window, this analgesic effect is probably best utilised in combination with other analgesics.     

Effect of systemic N-methyl-D-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia in humans

Ketamine reduces nociception by binding noncompetitively to the N- methyl-D-aspartate (NMDA) receptor, activation of which increases spinal hypersensitivity. We studied 19 healthy, unmedicated male volunteers, aged 20-31 yr. Burn injuries were produced on the medial surface of the dominant calf with a 25 x 50 mm rectangular thermode. On 3 separate days, at least 1 week apart, subjects received a bolus of either ketamine 0.15 mg kg-1, ketamine 0.30 mg kg-1 or placebo, delivered by a mechanical infusion pump over 15 min. The bolus was followed by continuous infusion of ketamine 0.15 mg kg-1 h-1, ketamine 0.30 mg kg-1 h-1 or placebo, respectively, for 135 min. Ketamine reduced the magnitude of both primary and secondary hyperalgesia, and also pain evoked by prolonged noxious heat stimulation, in a dose- dependent manner. In contrast, ketamine did not alter phasic heat pain perception (perception of transient, painful, thermal stimuli) in undamaged skin. The analgesic effects of ketamine in the burn injury model are in agreement with results from experimental studies, and can be distinguished from those of local anaesthetics and opioids. Side effects caused by continuous infusion of ketamine 0.15 and 0.30 mg kg-1 h-1 were frequent but clinically acceptable.      

S(+)-ketamine as an analgesic adjunct reduces opioid consumption after cardiac surgery

There are no studies evaluating S(+)-ketamine for pain management after sternotomy. In this prospective, randomized, double-blind, placebo-controlled clinical trial, we evaluated the efficacy and feasibility of S(+)-ketamine as an adjunctive analgesic after cardiac surgery. Ninety patients scheduled for elective coronary artery bypass grafting (CABG) were randomized to receive either a 75 microg/kg bolus of S(+)-ketamine followed by a continuous infusion of 1.25 microg . kg(-1) . min(-1) for 48 h (n = 44) or placebo (normal saline bolus and infusion) (n = 46). From the time of tracheal extubation, patients could access an opioid (oxycodone) via a patient-controlled analgesia device, and the cumulative oxycodone doses were measured over 48 h. Pain was evaluated on a visual analog scale three times daily. The quality of recovery, patient satisfaction with pain management, and adverse effects were recorded. The cumulative oxycodone consumption during the first 48 postoperative hours was less in the S(+)-ketamine group (103 +/- 44 mg) than in the placebo group (125 +/- 45 mg; mean difference, 22 mg; 95% confidence interval for the difference, 3-40 mg; P = 0.023). Pain scores did not differ between the groups at rest (P = 0.17) or during a deep breath (P = 0.23). Patient satisfaction was superior in S(+)-ketamine-treated patients: 26 (60%) of 44 in the S(+)-ketamine group compared with 16 (35%) of 46 in the placebo group were very satisfied with the analgesic management (P = 0.032). Nausea and vomiting were the most common adverse events, with similar frequencies in both groups. Four patients in the S(+)-ketamine group developed transient hallucinations during the infusion, versus none in the placebo group. In conclusion, small-dose S(+)-ketamine decreased opioid consumption in CABG patients during the first 48 h after surgery.     

Perioperative small-dose S(+)-ketamine has no incremental beneficial effects on postoperative pain when standard-practice opioid infusions are used

Several studies report that when small-dose racemic ketamine, an N-methyl-D-aspartate receptor antagonist, is administered perioperatively, opioid consumption is reduced postoperatively. S(+)-ketamine has a higher affinity for the N-methyl-D-aspartate receptor and less-serious side effects than racemic ketamine. Thirty patients scheduled for elective arthroscopic anterior cruciate ligament repair were enrolled in this randomized, double-blinded clinical trial designed to determine the preemptive effect of S(+)-ketamine on postoperative analgesia requirements in a setting of clinically relevant perioperative analgesia. Total IV anesthesia was induced and maintained with remifentanil (0.125-1.0 microg x kg(-1) x min(-1)) and a propofol target-controlled infusion (target 2-4 microg/mL). The Ketamine group received a bolus of 0.5 mg/kg S(+)-ketamine before incision, followed by a continuing infusion of 2 microg x kg(-1) x min(-1) until 2 h after emergence from anesthesia. The Control group received NaCl in the same sequence. After IV morphine provided pain relief down to < or =3 on a visual analog scale scored from 0 to 10, patients were connected to a patient-controlled analgesia device. There were no significant differences between the two groups in terms of total morphine consumption or VAS scores, either at rest or with movement. In our study, S(+)-ketamine did not contribute to postoperative pain reduction, possibly because of the clinically routine perioperative opioid analgesia. IMPLICATIONS: Small-dose S(+)-ketamine had no positive effect on postoperative analgesia when administered perioperatively for elective arthroscopic anterior cruciate ligament repair. Unlike investigations of the racemic mixture of ketamine, our study methods included timely standard-practice perioperative opioid analgesia, which seems to make supplemental analgesia unnecessary.     

Pain Attenuation through Mindfulness is Associated with Decreased Cognitive Control and Increased Sensory Processing in the Brain

Pain can be modulated by several cognitive techniques, typically involving increased cognitive control and decreased sensory processing. Recently, it has been demonstrated that pain can also be attenuated by mindfulness. Here, we investigate the underlying brain mechanisms by which the state of mindfulness reduces pain. Mindfulness practitioners and controls received unpleasant electric stimuli in the functional magnetic resonance imaging scanner during a mindfulness and a control condition. Mindfulness practitioners, but not controls, were able to reduce pain unpleasantness by 22% and anticipatory anxiety by 29% during a mindful state. In the brain, this reduction was associated with decreased activation in the lateral prefrontal cortex and increased activation in the right posterior insula during stimulation and increased rostral anterior cingulate cortex activation during the anticipation of pain. These findings reveal a unique mechanism of pain modulation, comprising increased sensory processing and decreased cognitive control, and are in sharp contrast to established pain modulation mechanisms.     

Inner experience of pain: imagination of pain while viewing images showing painful events forms subjective pain representation in human brain

Pain is an unpleasant sensation, and at the same time, it is always subjective and affective. Ten healthy subjects viewed 3 counterbalanced blocks of images from the International Affective Picture System: images showing painful events and those evoking emotions of fear and rest. They were instructed to imagine pain in their own body while viewing each image showing a painful event (the imagination of pain). Using functional magnetic resonance imaging, we compared cerebral hemodynamic responses during the imagination of pain with those to emotions of fear and rest. The results show that the imagination of pain is associated with increased activity in several brain regions involved in the pain-related neural network, notably the anterior cingulate cortex (ACC), right anterior insula, cerebellum, posterior parietal cortex, and secondary somatosensory cortex region, whereas increased activity in the ACC and amygdala is associated with the viewing of images evoking fear. Our results indicate that the imagination of pain even without physical injury engages the cortical representations of the pain-related neural network more specifically than emotions of fear and rest; it also engages the common representation (i.e., in ACC) between the imagination of pain and the emotion of fear.     

Treatment of neuropathic cancer pain with continuous intrathecal administration of S +-ketamine

The effective treatment of patients suffering from neuropathic cancer pain remains a clinical challenge. When patients experience either insufficient analgesia or problematic side-effects after opioid administration, intrathecal administration of morphine and other medications such as bupivacaine and clonidine may offer significant advantages. Additionally, ketamine, a non-competitive N-methyl-D-Aspartate-receptor antagonist is able to alter pain perception at the spinal level. Because of the potential neurotoxicity after neuraxial use of racemic ketamine, intrathecal administration of the preservative-free active compound, S (+)-ketamine may be a valuable alternative. In this paper, we present a patient with severe neuropathic cancer pain successfully treated by continuous intrathecal infusion of morphine, bupivacaine, clonidine and S (+)-ketamine. Moreover, quality of life measurements before and 3 weeks after the start of spinal treatment revealed an improvement in pain relief and a higher overall quality of life. No clinical signs of neurologic deficit were observed during spinal treatment with S (+)-ketamine. However, the continuous intrathecal administration of S (+)-ketamine should be considered as the last resort because there are no preclinical safety data with relevant concentrations on intrathecal use of S (+)-ketamine.     

The effects of ketamine and its enantiomers on the morphine- or dexmedetomidine-induced antinociception after intrathecal administration in rats

BACKGROUND: The spinal administration of some N-methyl-d-aspartate receptor antagonists results in antinociception and potentiates the effects of opioids and alpha2-adrenoceptor agonists, but ketamine and its enantiomers have not been examined. The present study investigated the interactions of racemic ketamine, R(-)-ketamine and S(+)-ketamine with morphine and with dexmedetomidine. METHODS: Intrathecal catheters were implanted into male Wistar rats. Three days later, the acute nociceptive sensitivity was assessed using the tail-flick test. Analgesic latencies were converted to the percentage maximum possible effect. The dose that yielded 50% of the maximum possible effect (ED50) and dose-response and time-course curves were determined for the ketamines (30-300 microg), morphine (0.1-3.0 microg), dexmedetomidine (0.3-10.0 microg), and mixtures of two doses of ketamines (30 or 100 microg) with different doses of morphine or dexmedetomidine for fixed-dose analysis. RESULTS: Neither racemic ketamine nor its enantiomers alone had a significant effect on the tail-flick test, with the exception of the highest dose of racemic ketamine, which caused motor impairment. Morphine and dexmedetomidine each produced dose-dependent antinociception, with ED50 of 1.7 microg (95% confidence interval: 1.04-2.32) and 4. 85 microg (3.96-5.79), respectively. A low dose (30 microg) of racemic ketamine or its enantiomers did not influence the ED50 of morphine significantly. Coadministration of 100 microg racemic ketamine or S(+)-ketamine, but not R(-)-ketamine, significantly enhanced and prolonged the antinociceptive effect of morphine. Both doses of racemic ketamine or its isomers significantly decreased the ED50 value for dexmedetomidine, although the higher dose of racemic or S(+)-ketamine had the highest potency. One-hundred micrograms of racemic ketamine or S(+)-ketamine also prolonged the effects of dexmedetomidine. CONCLUSIONS: These data indicate that racemic ketamine and S(+)-ketamine, but not R(-)-ketamine, exhibit similar effectiveness in potentiating the antinociceptive effects of both morphine and dexmedetomidine.     

Modulation of NMDA receptor function by ketamine and magnesium: Part I

N-methyl-D-aspartate (NMDA) receptors are important components of pain processing. Ketamine and Mg2+ block NMDA receptors and might therefore be useful analgesics, and combinations of Mg2+ and ketamine provide more effective analgesia. We investigated their interactions at NMDA receptors. Xenopus oocytes, expressing NR1/NR2A or NR1/NR2B glutamate receptors, were studied. The effects of Mg2+, racemic ketamine and its isomers, and the combination of Mg2+ and S(+)-ketamine on NMDA signaling were determined. Mg2+ and ketamine alone inhibited NMDA receptors noncompetitively (half-maximal inhibitory effect concentration: Mg2+ 4.2 +/- 1.2 x 10(-)(4) M at NR1/NR2A and 6.3 +/- 2.4 x 10(-)(4) M at NR1/NR2B; racemic ketamine 13.6 +/- 8.5 x 10(-)(6) M at NR1/NR2A and 17.6 +/- 7.2 x 10(-)(6) M at NR1/NR2B; S(+)-ketamine 4.1 +/- 2.5 x 10(-)(6) at NR1/NR2A and 3.0 +/- 0.3 at NR1/NR2B; R(-)-ketamine 24.4 +/- 4.1 x 10(-)(6) M at NR1/NR2A and 26.0 +/- 2.4 x 10(-)(6) M at NR1/NR2B). The combined application of Mg2+ and ketamine decreased the half-maximal inhibitory effect concentration >90% at both receptors. Isobolographic analysis demonstrated super-additive interactions. Ketamine and Mg2+ inhibit responses of recombinantly expressed NR1/NR2A and NR1/NR2B glutamate receptors, and combinations of the compounds act in a super-additive manner. These findings may explain, in part, why combinations of ketamine and Mg2+ are more effective analgesics than either compound alone. IMPLICATIONS: Ketamine and Mg2+ inhibit functioning of recombinantly expressed NR1/NR2A and NR1/NR2B glutamate receptors, and combinations of the compounds act in a super-additive manner. These findings may explain, in part, why combinations of ketamine and Mg2+ are more effective analgesics than either compound alone.     

A randomised, controlled study of peri-operative low dose s(+)-ketamine in combination with postoperative patient-controlled s(+)-ketamine and morphine after radical prostatectomy

In a randomised, double-blind prospective study we compared the effects on postoperative pain and analgesic consumption of intra-operative s(+)-ketamine (100 microg.kg-1 bolus and a continuous infusion of 2 microg.kg-1.min-1) followed by postoperative patient-controlled analgesia with morphine (1 mg per bolus) plus s(+)-ketamine (0.5 mg per bolus), or intra-operative saline followed by postoperative patient-controlled analgesia morphine (1 mg per bolus) alone. A total of 28 male patients undergoing radical prostatectomy were studied. Morphine consumption, pain scores, pressure algometry and adverse effects were recorded for 48 h after surgery. Cumulative morphine consumption was significantly lower in the ketamine/morphine group (47.9 +/- 26.2 mg) than in the saline/morphine group (73.4 +/- 34.8 mg; p = 0.049). Pain scores at rest were significantly lower in the ketamine/morphine group across the 48-h study period (p = 0.01). No significant differences were found in pressure algometry measurements or the occurrence of adverse effects.     

S(+)-ketamine increases muscle sympathetic activity and maintains the neural response to hypotensive challenges in humans

BACKGROUND: S(+)-Ketamine is reported to exert twofold greater analgesic and hypnotic effects but a shorter recovery time in comparison with racemic ketamine, indicating possible differential effects of stereoisomers. However, cardiovascular regulation during S(+)-ketamine anesthesia has not been studied. Muscle sympathetic activity (MSA) may be an indicator of the underlying alterations of sympathetic outflow. Whether S(+)-ketamine decreases MSA in a similar manner as the racemate is not known. Thus, the authors tested the hypothesis that S(+)-ketamine changes MSA and the muscle sympathetic response to a hypotensive challenge. METHODS: Muscle sympathetic activity was recorded by microneurography in the peroneal nerve of six healthy participants before and during anesthesia with S(+)-ketamine (670 microg/kg intravenously followed by 15 microg x kg(-1) x min(-1)). Catecholamine and ketamine plasma concentrations, heart rate, and arterial blood pressure were also determined. MSA responses to a hypotensive challenge were assessed by injection of sodium nitroprusside (2-10 microg/kg) before and during S(+)-ketamine anesthesia. In the final step, increased arterial pressure observed during anesthesia with S(+)-ketamine was adjusted to preanesthetic values by sodium nitroprusside infusion (1-6 microg x kg(-1) x min(-1)). RESULTS: Anesthesia with S(+)-ketamine (ketamine plasma concentration 713 +/- 295 microg/l) significantly increased MSA burst frequency (mean +/- SD; 18 +/- 6 to 35 +/- 11 bursts/min) and burst incidence (32 +/- 10 to 48 +/- 15 bursts/100 heartbeats) and was associated with a doubling of norepinephrine plasma concentration (from 159 +/- 52 to 373 +/- 136 pg/ml) parallel to the increase in MSA. Heart rate and arterial blood pressure also significantly increased. When increased arterial pressure during S(+)-ketamine was decreased to awake values with sodium nitroprusside, MSA increased further (to 53 +/- 24 bursts/min and 60 +/- 20 bursts/100 heartbeats, respectively). The MSA increase in response to the hypotensive challenge was fully maintained during anesthesia with S(+)-ketamine. CONCLUSIONS: S(+)-Ketamine increases efferent sympathetic outflow to muscle. Despite increased MSA and arterial pressure during S(+)-ketamine anesthesia, the increase in MSA in response to arterial hypotension is maintained.     

Caudal additives for postoperative pain management in children: S(+)-ketamine and neostigmine

BACKGROUND: The aim of the present pilot study was to compare the analgesic efficacy of S(+)-ketamine either alone or in combination with neostigmine for caudal blockade in pediatric surgery. METHODS: A total of 40 children were randomly assigned to receive after induction of general anesthesia either caudal S(+)-ketamine 1 mg.kg(-1) (group K, n = 20) or caudal S (+)-ketamine 0.5 mg.kg(-1) plus neostigmine 10 microg.kg(-1) (group KN, n = 20). Anesthesia was maintained with sevoflurane and a laryngeal mask airway (LMA), no additional analgesics were administered. Postoperative pain and sedation were assessed by the Children's Hospital of Eastern Ontario Pain Score and Ramsay scale for 24 h. RESULTS: No statistical difference in duration of analgesia and sedation was found. Mean duration of postoperative analgesia was 18 +/- 9.4 h in group K and 21.8 +/- 6.7 h in group KN. There was a significantly higher incidence of postoperative vomiting after administration of caudal ketamine with neostigmine (30% group KN Vs 0% group K; P < 0.05). CONCLUSIONS: This pilot study demonstrates equianalgesic effects on postoperative pain relief in children with both caudal S(+)-ketamine 1 mg.kg(-1) and caudal S(+)-ketamine 0.5 mg.kg(-1) plus neostigmine 10 microg.kg(-1). Further studies are required to confirm adoption of caudal neostigmine into routine clinical practice.     

Dissociable brain activation responses to 5-Hz electrical pain stimulation: a high-field functional magnetic resonance imaging study

BACKGROUND: To elucidate neural correlates associated with processing of tonic aching pain, the authors used high-field (3-T) functional magnetic resonance imaging with a blocked parametric study design and characterized regional brain responses to electrical stimulation according to stimulus intensity-response functions. METHODS: Pain was induced in six male volunteers using a 5-Hz electrical stimulus applied to the right index finger. Scanning sequences involved different levels of stimulation corresponding to tingling sensation (P1), mild pain (P2), or high pain (P3). Common effects across subjects were sought using a conjunction analyses approach, as implemented in statistical parametric mapping (SPM-99). RESULTS: The contralateral posterior/mid insula and contralateral primary somatosensory cortex were most associated with encoding stimulus intensity because they showed a positive linear relation between blood oxygenation level-dependent signal responses and increasing stimulation intensity (P1 < P2 < P3). The contralateral secondary somatosensory cortex demonstrated a response function most consistent with a role in pain intensity encoding because it had no significant response during the innocuous condition (P1) but proportionally increased activity with increasingly painful stimulus intensities (0 < P2 < P3). Finally, a portion of the anterior cingulate cortex (area 24) and supplementary motor area 6 demonstrated a high pain-specific response (P3). CONCLUSIONS: The use of response function modeling, conjunction analysis, and high-field imaging reveals dissociable regional responses to a tonic aching electrical pain. Most specifically, the primary somatosensory cortex and insula seem to encode stimulus intensity information, whereas the secondary somatosensory cortex encodes pain intensity information. The cingulate findings are consistent with its proposed role in processing affective-motivational aspects of pain.     

Klinischer Stellenwert des S-(+)-Ketamin

Among anaesthetic drugs, ketamine occupies a special position. Biochemically, ketamine is a racemate consisting of equal shares of two optical enantiomers. Pharmacological investigations show differences between those enantiomers in both qualitative and quantitative properties. Furthermore, clinical superiority of S-(+)-ketamine has been described in different therapeutic studies with regard to anaesthetic potency, the extent of analgesia, effects and side effects during and after the operation, and undiserable psychological dysfunction. On a neuropharmacological basis, the clinical superiority of S-(+)-ketamine is due to its effect on NMDA receptors in central nervous tissue, opioid receptors on both central and peripheral levels, and noradrenergic, dopaminergic, and serotoninergic mechanisms. The main problems associated with the ketamine racemate in clinical use are desirable psychological dysfunction and a prolonged period of arousal. There are grounds for the assumption that the use of S-(+)-ketamine will minimise those problems without reducing anaesthetic potency or restricting the advantages of ketamine anaesthesia.     

Representations of pleasant and painful touch in the human orbitofrontal and cingulate cortices

The cortical areas that represent affectively positive and negative aspects of touch were investigated using functional magnetic resonance imaging (fMRI) by comparing activations produced by pleasant touch, painful touch produced by a stylus, and neutral touch, to the left hand. It was found that regions of the orbitofrontal cortex were activated more by pleasant touch and by painful stimuli than by neutral touch and that different areas of the orbitofrontal cortex were activated by the pleasant and painful touches. The orbitofrontal cortex activation was related to the affective aspects of the touch, in that the somatosensory cortex (SI) was less activated by the pleasant and painful stimuli than by the neutral stimuli. This dissociation was highly significant for both the pleasant touch (P < 0.006) and for the painful stimulus (P < 0.02). Further, it was found that a rostral part of the anterior cingulate cortex was activated by the pleasant stimulus and that a more posterior and dorsal part was activated by the painful stimulus. Regions of the somatosensory cortex, including SI and part of SII in the mid-insula, were activated more by the neutral touch than by the pleasant and painful stimuli. Part of the posterior insula was activated only in the pain condition and different parts of the brainstem, including the central grey, were activated in the pain, pleasant and neutral touch conditions. The results provide evidence that different areas of the human orbitofrontal cortex are involved in representing both pleasant touch and pain, and that dissociable parts of the cingulate cortex are involved in representing pleasant touch and pain.