Peripheral Analgesic Effects of Ketamine in Acute Inflammatory Pain

Background: This study examined the analgesic effect of local ketamine infiltration, compared with placebo and systemic ketamine, in a human model of inflammatory pain.

Methods: Inflammatory pain was induced by a burn (at 47 [degree sign]C for 7 min; wound size, 2.5 x 5 cm) on the calf in 15 volunteers on 3 separate days with 7-day intervals. They received either (1) subcutaneous infiltration with ketamine in the burn area (local treatment) and contralateral placebo injections, or (2) subcutaneous ketamine contralateral to the burn (systemic treatment) and placebo in the burn area, or (3) placebo on both sides. The study was double-blinded and the order of the treatments was randomized. Hyperalgesia to mechanical and heat stimuli was examined by von Frey hairs and contact thermodes (3.75 and 12.5 cm2), and pain was rated using a visual analog scale (0-100).

Results: The burns produced significant hyperalgesia. Local ketamine infiltration reduced pain during the burn injury compared with systemic treatment and placebo (P 相似文献   

氯胺酮超前镇痛对腹腔镜胆囊切除术后疼痛的临床观察

目的 探讨氯胺酮在腹腔镜胆囊切除术后的超前镇痛作用. 方法将2006年7～8月,40例择期腹腔镜胆囊切除术按随机数字表法分为2组（每组20例）：氯胺酮组和对照组.对术后1、2、4、6、12 h及术后1、2、3 d切口痛及非切口痛分别进行VAS镇痛评分和术后镇静评分,记录术后不良反应及术后止痛药的需求情况. 结果 术后非切口痛及切口痛,氯胺酮组VAS评分较对照组显著降低（F=22.805, P=0.000;F=18.109, P=0.000）.术后恶心、呕吐发生率氯胺酮组（55%）和对照组（60%）相比无明显差异（P=1.000）;术后需要止痛药氯胺酮组3例,对照组9例,2组无统计学差异（P=0.082）. 结论在腹腔镜胆囊切除手术前应用氯胺酮能减轻术后疼痛,具有超前镇痛作用,但不能降低术后恶心、呕吐发生率.     

Oral Ketamine and Transdermal Nitroglycerin as Analgesic Adjuvants to Oral Morphine Therapy for Cancer Pain Management

Background: Guidelines for cancer pain management include nonsteroidal antiinflammatory drugs with opioids administered in a time-contingent manner. This study was designed to evaluate the role of oral ketamine or transdermal nitroglycerin polymer, a nitric oxide donor, as coadjuvants to oral morphine in cancer pain therapy.

Methods: After institutional approval and informed patient consent were obtained, 60 patients with cancer pain were randomized to one of four groups (n = 15) and studied prospectively to evaluate analgesia and any adverse effects. A visual analog scale that consisted of a 10-cm line with 0 representing "no pain at all" and 10 representing "the worst possible pain" was introduced. All patients were regularly taking oral amitriptyline 50 mg at bedtime. The morphine regimen was adjusted individually to a maximal oral dose of 80-90 mg/day to keep the visual analog scale score less than 4. When patients reported pain (visual analog scale of 4 or more), despite taking 80-90 mg oral morphine daily, the test drug was added as follows: the control group (CG) received an additional 20 mg oral morphine (10 mg at 12-h intervals); the nitroglycerin group (NG) received a 5-mg nitroglycerin patch daily; the ketamine group (KG) received 0.5 mg/kg oral ketamine at 12-h intervals; and the dipyrone group (DG) received 500 mg oral dipyrone at 6-h intervals. Patients were free to manipulate their daily morphine consumption when the test drug was introduced to keep their visual analog scale score less than 4.

Results: The groups were similar with respect to demographic data and visual analog scale pain scores before treatment. The visual analog scale scores after the test drug was introduced were similar among the groups. The daily consumption of oral morphine was as follows: on day 15: CG = DG = NG (P > 0.05), CG > KG (P = 0.036); on day 20: CG > NG = KG (P < 0.02) (CG > KG, P < 0.005; CG > NG, P < 0.02), DG > KG (P < 0.05); on day 30: CG = DG > KG = NG (P < 0.05). Patients in the CG and DG groups reported somnolence, but patients in the NG and KG groups did not.     

疼痛治疗专辑实验与临床研究氯胺酮、可乐定和羟丁酸钠合用的镇痛效应

用小鼠热板法和扭体法研究氯胺酮、可乐定、羟丁酸钠单用及合用的镇痛效应。结果表明，这三种药物单用均有一定镇痛作用；两药合用时镇痛作用增强；三药合用则镇痛作用更强     

Analgesic Mechanisms of Ketamine in the Presence and Absence of Peripheral Inflammation

Background: The studies on the mechanisms of ketamine antinociception have led to conflicting results. In this study, the authors investigated the contribution of supraspinal monoaminergic descending inhibitory system to ketamine analgesia for acute nociception and inflammation-induced hyperalgesia.

Methods: Male Sprague-Dawley rats were used. The paw withdrawal latencies to radiant heat stimuli were measured to assess the thermal nociceptive threshold. The analgesic effects of intrathecal or intraperitoneal ketamine were examined in the rats that received unilateral intraplantar carrageenan and in those that were untreated. In addition, it was examined whether pretreatment with intrathecal yohimbine or methysergide inhibited the analgesic effects of ketamine. Using an intrathecal microdialysis method, noradrenaline and 5-hydroxytryptamine concentrations in lumbar cerebrospinal fluid were measured after intraperitoneal ketamine in both saline- and carrageenan-treated rats.

Results: In the untreated rats, intraperitoneal but not intrathecal ketamine produced antinociceptive effects in a dose-dependent manner. Pretreatment with intrathecal yohimbine or methysergide inhibited these antinociceptive effects. Intraplantar carrageenan significantly reduced paw withdrawal latencies on the injected paw but not on the contralateral paw. Both intraperitoneal and intrathecal ketamine reversed the shortened paw withdrawal latencies on the injected side in a dose-dependent manner without any effects on the contralateral side. Neither yohimbine nor methysergide inhibited these antihyperalgesic effects. In analyses of monoamines, the magnitude of increase in monoamines after intraperitoneal ketamine was significantly smaller in the carrageenan-treated rats than in the saline-treated rats.     

Analgesic Effect of Low-dose Intrathecal Morphine after Spinal Fusion in Children

Background: This study was designed to assess the postoperative analgesic effect of low-dose intrathecal morphine after scoliosis surgery in children.

Methods: Thirty children, 9-19 yr of age, scheduled for spinal fusion, were randomly allocated into three groups to receive a single dose of 0 (saline injection), 2, or 5 [mu]g/kg intrathecal morphine. After surgery, a patient-controlled analgesia device (PCA) provided free access to additional intravenous morphine. Children were monitored for 24 h in the postanesthesia care unit.

Results: The three groups were similar for age, weight, duration of surgery, and time to extubation. The time to first PCA demand was dose-dependently delayed by intrathecal morphine. The first 24 h of PCA morphine consumption was 49 +/- 17, 19 +/- 10, and 12 +/- 12 mg (mean +/- SD) in the saline, 2 [mu]g/kg morphine, and 5 [mu]g/kg morphine groups, respectively. Pain scores at rest were significantly lower over the whole study period after 2 and 5 [mu]g/kg intrathecal morphine than after saline, but there was no difference between intrathecal doses. Pain scores while coughing and the incidence of side effects were similar in the three groups.     

Preemptive Analgesia by Intravenous Low-dose Ketamine and Epidural Morphine in Gastrectomy: A Randomized Double-blind Study

Background: Morphine and ketamine may prevent central sensitization during surgery and result in preemptive analgesia. The reliability of preemptive analgesia, however, is controversial.

Methods: Gastrectomy patients were given preemptive analgesia consisting of epidural morphine, intravenous low-dose ketamine, and combinations of these in a randomized, double-blind manner. Postsurgical pain intensity was rated by a visual analog scale, a categoric pain evaluation, and cumulative morphine consumption.

Results: Preemptive analgesia by epidural morphine and by intravenous low-dose ketamine were significantly effective but not definitive. With epidural morphine, a significant reduction in visual analog scale scores at rest was observed at 24 and 48 h, and morphine consumption was significantly lower at 6 and 12 h, compared with control values. With intravenous ketamine, visual analog scale scores at rest and morphine consumption were significantly lower at 6, 12, 24, and 48 h than those in control subjects. The combination of epidural morphine and intravenous ketamine provided definitive preemptive analgesia: Visual analog scale scores at rest and morphine consumption were significantly the lowest at 6, 12, 24, and 48 h, and the visual analog scale score during movement and the categoric pain score also were significantly the lowest among the groups.     

Comparison of Five Experimental Pain Tests to Measure Analgesic Effects of Alfentanil

Background: Several experimental pain models have been used to measure opioid effects in humans. The aim of the current study was to compare the qualities of five frequently used experimental pain tests to measure opioid effects.

Methods: The increase of electrical, heat, and pressure pain tolerance and the decrease of ice-water and ischemic pain perception was determined at baseline and at four different plasma concentrations of alfentanil (n = 7) administered as target controlled infusion or placebo (n = 7). A linear mixed-effects modeling (NONMEM) was performed to detect drug, placebo, and time effect as well as interindividual and intraindividual variation of effect.

Results: Only the electrical, ice-water, and pressure pain tests are sensitive to assess a concentration-response curve of alfentanil. At a plasma alfentanil concentration of 100 ng/ml, the increase in pain tolerance compared with baseline was 42.0% for electrical pain, 22.2% for pressure pain, and 21.7% for ice-water pain. The slope of the linear concentration-response curve had an interindividual coefficient of variation of 58.3% in electrical pain, 35.6% in pressure pain, and 60.0% in ice-water pain. The residual error including intraindividual variation at an alfentanil concentration of 100 ng/ml was 19.4% for electrical pain, 6.1% for pressure pain, and 13.0% for ice-water pain. Electrical pain was affected by a significant placebo effect, and pressure pain was affected by a significant time effect.     

An Investigation to Dissociate the Analgesic and Anesthetic Properties of Ketamine Using Functional Magnetic Resonance Imaging

Background: Anatomic sites within the brain, which activate in response to noxious stimuli, can be identified with the use of functional magnetic resonance imaging. The aim of this study was to determine whether the analgesic effects of ketamine could be imaged.

Methods: Ketamine was administered to eight healthy volunteers with use of a target-controlled infusion to three predicted plasma concentrations: 0 (saline), 50 (subanalgesic), and 200 ng/ml (analgesic, subanesthetic). Volunteers received noxious thermal stimuli and auditory stimuli and performed a motor task within a 3-T human brain imaging magnet. Activation of brain regions in response to noxious and auditory stimuli and during the motor task was compared with behavioral measures.

Results: The analgesic subanesthetic dose of ketamine significantly reduced the pain scores, and this matched a decrease in activity within brain regions that activate in response to noxious stimuli, in particular, the insular cortex and thalamus. A different pattern of activation was observed in response to an auditory task. In comparison, smaller behavioral and imaging changes were found for the motor paradigm. The lower dose of ketamine gave similar but smaller nonsignificant effects.     

关节内注射镇痛混合剂在全髋关节置换术后的应用

目的评价全髋关节置换术后关节内鸡尾酒式镇痛混合剂注射的镇痛效果和安全性。方法将80例行单侧全髋关节置换术的骨关节炎患者进行随机分配：试验组行关节内鸡尾酒式镇痛混合剂（包括吗啡、布比卡因、复方倍他米松、肾上腺素）注射,对照组予以生理盐水做对照。所有患者术后48 h均接受吗啡自控式静脉镇痛泵镇痛,比较两组患者术后髋关节静息和活动视觉模拟疼痛评分、麻醉剂使用情况、主动直腿抬高时间、屈曲到90°时间、活动度以及并发症。结果采用关节内鸡尾酒式镇痛混合剂注射后,可以显著减少术后0~36 h各时间段和总的麻醉剂使用量,并推迟术后第一次使用麻醉剂的时间。在术后视觉模拟评分的比较上,静息痛在术后第6、10、24、36 h关节内试验组疼痛评分显著小于对照组,活动痛在术后24、36 h试验组疼痛评分显著小于对照组。患者在可以行主动直腿抬高的时间、髋关节主动活动达90°时间以及术后15 d髋关节活动度的比较上,试验组均优于对照组。在术后伤口愈合、感染发生率、血压、心率、皮疹、呼吸抑制和尿潴留的监测上,两组间均无统计学意义,恶心、呕吐发生率试验组小于对照组。结论关节内鸡尾酒式镇痛混合剂注射有助于减少术后麻醉镇痛剂使用量,减轻术后早期疼痛,有助于患者的早期康复,且没有明显的副作用。     

Respiratory, Analgesic and Endocrine Responses to an Enkephalin Analogue in Normal Man

In a controlled study, the effect of a new enkephalin analogue (FW 34–569, Sandoz) on respiratory function (ventilatory response to CO₂), pain threshold (hot plate technique), and plasma cortisol, prolactin, growth hormone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) was investigated in six normal subjects. One milligram of enkephalin, but not 0.5 mg, resulted in a significantly decreased ventilatory response to CO₂, although mean values were not significantly different from saline control values (0.05 < P< 0.1). Neither 0.5 mg nor 1.0 mg enkephalin influenced pain threshold, but both doses stimulated growth hormone and prolactin release and inhibited the release of cortisol and LH, while FSH remained unchanged.     

Analgesic, Respiratory and Endocrine Responses in Normal Man to THIP, a GABA-Agonist

In a controlled study, the effects of THIP (a synthetic gamma-aminobutyric-acid-agonist) on respiratory function (ventilatory response to Co₂), first detection of stimulation (electrical stimulation of a tooth), pain threshold, magnitude of maximal tolerated pain stimulation, and plasma cortisol, prolactin and glucose were investigated in six normal men. Intramuscular injection of THIP in dosages of both 10 mg and 20 mg increased the magnitude of stimulus before first detection, and the pain threshold as well as the maximal tolerance of pain stimulation. THIP did not lead to changes in respiratory function, or in plasma cortisol, prolactin or glucose, suggesting an analgesic action independent of opiate receptors.     

High-and Low-dose Regimens of Cyclosporin in Renal Transplantation: Immunosuppressive Efficacy and Side-effects

The immunosuppressive effectiveness and nephrotoxic side-effectsof either high-dose cyclosporin (CsA) (16 mg/kg per day) orlow-dose (9mg/kg per day) in combination with azathioprine (Aza)(1 mg/kg per day) were studied in 80 renal transplant patientswho also received low-dose corticosteroids. At 3 months, patientswho received high-dose CsA were randomly assigned to eithercontinuation of CsA or conversion to Aza, whereas in the triple-therapygroup either CsA or Aza was discontinued. No differences inpatient (97.5%) or graft survival (90%–92.5%) were foundat 1 year. There were no differences in the incidence of primarynon-functioning kidneys. The incidence of acute rejection episodeswas 45% in the high-dose CsA group and 55% in the group treatedwith low CsA doses together with Aza (not significant). At 3months the mean creatinine clearance was 60±4ml/min (mean±SEM)in the high-dose group (mean cumulative CsA dose 0.96 g/kg)compared with 55±3 ml/min in the low-dose group (meancumulative CsA dose 0.60 g/kg). At 1 year no differences inthe degree of proteinuria or the incidence of hypertension wasfound between the different groups. The best mean creatinineclearance at 1 year (77±5 ml/min) was found in patientswho received high doses of CsA for 3 months followed by conversion.     

Magnesium Increases Morphine Analgesic Effect in Different Experimental Models of Pain

Background: An excess of excitatory pathway activation via N-methyl-d-aspartate (NMDA) receptors has been described in neuropathic pain that responds poorly to morphine. However, in this situation, several published data sets show that coadministration of NMDA receptor antagonists restores the efficacy of opioids. Considering that magnesium behaves like an NMDA receptor antagonist, we investigated the effect of the combination of magnesium and morphine in experimental models of chronic and tonic pain.

Methods: Mechanical hyperalgesia was assessed with the paw-pressure test in mononeuropathic (chronic constrictive injury model) and diabetic rats. Behavioral reactions were scored in a model of inflammation induced by formalin. The animals were assigned to one of three groups according to the intraperitoneal pretreatment: magnesium (30 mg/kg x 3), magnesium (30 mg/kg), and saline. Before testing, morphine was injected intravenously in mononeuropathic (0.3 mg/kg) and diabetic rats (1 mg/kg) and by the subcutaneous route in rats with the formalin test (1.5 mg/kg).

Results: Magnesium alone induced a significant antihyperalgesic effect in mononeuropathic and diabetic rats after a cumulative dose of 90 mg/kg. Furthermore, it significantly increased morphine analgesia, regardless of the loading dose used (30 or 90 mg/kg) in the two models of neuropathic pain. In the formalin test, magnesium alone did not have a significant effect. However, in combination with morphine, it revealed the analgesic effect of this opiate.     

Differential Effect of Ketamine and Lidocaine on Spontaneous and Mechanical Evoked Pain in Patients with Nerve Injury Pain

Background: The mechanisms underlying neuropathic pain are incompletely understood. Targeting specific molecular mechanisms in the pain signaling system may assist in understanding key features in neuropathic pains such as allodynia. This study examined the effect of systemically administered ketamine, an N-methyl-d-aspartate receptor antagonist and lidocaine, a sodium channel blocker, on spontaneous pain, brush-evoked pain, and pinprick-evoked pain in patients with nerve injury pain.

Methods: Twenty patients participated in two randomized, double-blinded, placebo-controlled, crossover experiments in which they, on four different days, received a 30-minute intravenous infusion of ketamine (0.24 mg/kg), lidocaine (5 mg/kg), or saline. Ongoing pain, pain evoked by brush and repetitive pinprick stimuli, and acetone was measured before, during, and after infusion.

Results: Ketamine significantly reduced ongoing pain and evoked pain to brush and pinprick, whereas lidocaine only reduced evoked pain to repetitive pinprick stimuli. In individual patients, there was no correlation between the pain-relieving effect of lidocaine and ketamine on ongoing or mechanically evoked pains.     

Prediction of Postoperative Pain by Preoperative Nociceptive Responses to Heat Stimulation

Background: Despite major advances in the understanding of the neurobiologic mechanisms of pain, the wide variation in acute pain experience has not been well explained. Therefore, the authors investigated the potential of a preoperatively induced heat injury to predict subsequent postoperative pain ratings in patients undergoing knee surgery.

Methods: Twenty patients were studied. The burn injury was induced 6 days before surgery with a contact thermode (12.5 cm2, 47[degrees]C for 7 min). The sensory testing, before and 1 h after the injury, included pain score during induction of the burn, secondary hyperalgesia area, thermal and mechanical pain perception, and pain thresholds. Postoperative analgesia consisted of ibuprofen and acetaminophen. Pain ratings (visual analog scale) at rest and during limb movement were followed for 10 days after surgery.

Results: The burn injury was associated with development of significant hyperalgesia. There was a significant correlation between preoperative pain ratings during the burn injury and early (0-2 days, area under the curve) and late (3-10 days, area under the curve) postoperative dynamic pain ratings during limb movement.