Relative reliability of the auditory evoked potential and Bispectral Index for monitoring sedation level in surgical intensive care patients.

Sedation is an important adjunct therapy for patients in the intensive care unit. The objective of the present study was to observe correlation between an established subjective measure, the Ramsay Sedation Scale, and two objective tools for monitoring critically ill patients: the Bispectral Index (BIS) and auditory evoked potential. Ninety patients undergoing major surgery scheduled for postoperative mechanical ventilation and continuous sedation with propofol and fentanyl were selected. Electrodes for determining BIS and auditory evoked potential were placed on the foreheads of all patients according to manufacturer's specifications at least six hours after patients' arrival at the intensive care unit. Ramsay Sedation Scale, BIS, signal quality index, composite A-line autoregressive index (AAI) and electromyographic activities were recorded every five minutes for 30 minutes. BIS and AAI showed good correlation amongst readings (r(s)=0.697, P <0.01). Both were significantly influenced by electromyographic activities (BIS, r(s)=0.735, P <0.01; AAI, r(s)=0.856, P <0.01). Comparison of BIS and AAI revealed an acceptable correlation between electroencephalogram variables and the Ramsay Sedation Scale (BIS, tau=-0.689; AAI, tau=-0.621; P <0.01). In conclusion, the auditory evoked potential and BIS monitors revealed an acceptable correlation with the Ramsay Sedation Scale. However, the BIS and auditory evoked potential monitors do not perform adequately as a substitute in the assessment of sedated intensive care unit patients. These monitors could be used as part of an integrated approach for the evaluation of those patients especially when the subjective scales do not work well in the setting of neuromuscular blockade or may not be sufficiently sensitive to evaluate very deep sedation.

Differential roles of neuronal and endothelial nitric oxide synthases during carrageenan-induced inflammatory hyperalgesia.

The present study investigated the role of neuronal nitric oxide synthase (nNOS) in carrageenan-induced inflammatory pain by combining genomic and pharmacological strategies. Intrathecal injection of the nNOS inhibitor 7-nitroindazole dose-dependently inhibited carrageenan-induced thermal hyperalgesia in both early and late phases in wild-type mice. However in nNOS knockout mice, carrageenan-induced thermal hyperalgesia remained intact in the early phase but was reduced in the late phase. Spinal Ca2+ -dependent nitric oxide synthase (NOS) activity in nNOS knockout mice was significantly lower than that in wild-type mice. Following carrageenan injection, although the spinal Ca2+ -dependent NOS activity in both wild-type and knockout mice increased, the enzyme activity in nNOS knockout mice reached a level similar to that in wild-type mice. On the other hand, no significant difference in spinal Ca2+ -independent NOS activity was noted between wild-type and nNOS knockout mice before and after carrageenan injection. Furthermore, intrathecal administration of the endothelial NOS (eNOS) inhibitor L-N5-(1-iminoethyl)-ornithinein nNOS knockout mice inhibited the thermal hyperalgesia in both early and late phases, though this inhibitor had no effect in wild-type mice. Meanwhile, Western blot showed that eNOS expression in the spinal cord of nNOS knockout mice was up-regulated compared with wild-type mice; immunohistochemical staining showed that the spinal eNOS was mainly distributed in superficial laminae of the dorsal horn. Finally, double staining with confocal analysis showed that the enhanced spinal eNOS was expressed in astrocytes, but not in neurons. Our current results indicate that nNOS plays different roles in the two phases of carrageenan-induced inflammatory pain. In this model, enhanced spinal eNOS appears to compensate for the role of nNOS in nNOS knockout mice.

Evidence of neuronal excitatory amino acid carrier 1 expression in rat dorsal root ganglion neurons and their central terminals.

The expression and distribution of the neuronal glutamate transporter, excitatory amino acid carrier-1 (EAAC1), are demonstrated in the dorsal root ganglion neurons and their central terminals. Reverse transcriptase-polymerase chain reaction shows expression of EAAC1 mRNA in the dorsal root ganglion. Immunoblotting analysis further confirms existence of EAAC1 protein in this region. Immunocytochemistry reveals that approximately 46.6% of the dorsal root ganglion neurons are EAAC1-positive. Most EAAC1-positive neurons are small and around 250-750 microm2 in surface area, and some co-label with calcitonin gene-related peptide (CGRP) or isolectin IB4. In the spinal cord, EAAC-1 immunoreactive small dot- or patch-like structures are mainly localized in the superficial dorsal horn, and some are positive for CGRP or labeled by isolectin IB4. Unilateral dorsal rhizotomy experiments further show that EAAC1 immunoreactivity is less intense in superficial dorsal horn on the side ipsilateral to the dorsal rhizotomy than on the contralateral side. The results indicate the presence of EAAC1 in the dorsal root ganglion neurons and their central terminals. Our findings suggest that EAAC1 might play an important role in transmission and modulation of nociceptive information via the regulation of pre-synaptically released glutamate.

Knockdown of spinal cord postsynaptic density protein-95 prevents the development of morphine tolerance in rats.

The activation of spinal cord N-methyl-D-aspartate (NMDA) receptors and subsequent intracellular cascades play a pivotal role in the development of opioid tolerance. Postsynaptic density protein-95 (PSD-95), a molecular scaffolding protein, assembles a specific set of signaling proteins around NMDA receptors at neuronal synapses. The current study investigated the possible involvement of PSD-95 in the development of opioid tolerance. Opioid tolerance was induced by intrathecal injection of morphine sulfate (20 microg/10 microl) twice a day for 4 consecutive days. Co-administration of morphine twice daily and PSD-95 antisense oligodeoxynucleotide (50 microg/10 microl) once daily for 4 days not only markedly reduced the PSD-95 expression and its binding to NMDA receptors in spinal cord but also significantly prevented the development of morphine tolerance. In contrast, co-administration of morphine twice daily and PSD-95 missense oligodeoxynucleotide (50 microg/10 microl) once daily for 4 days did not produce these effects. The PSD-95 antisense oligodeoxynucleotide at the doses we used did not affect baseline response to noxious thermal stimulation or locomotor function. The present study indicates that the deficiency of spinal cord PSD-95 attenuates the development of opioid tolerance. These results suggest that PSD-95 might be involved in the central mechanisms of opioid tolerance and provide a possible new target for prevention of development of opioid tolerance.

Intact carrageenan-induced thermal hyperalgesia in mice lacking inducible nitric oxide synthase.

To date, the exact role of inducible nitric oxide synthase (iNOS) in inflammatory pain remains controversial. In the present study, we combined a pharmacological strategy (using a selective iNOS inhibitor) with a genomic strategy (using mice lacking the iNOS gene) to address the function of iNOS in the central mechanism of carrageenan-induced persistent inflammatory pain. In the wild type mice, intrathecal administration of L-N(6)-(1-iminoethyl)-lysine, a selective iNOS inhibitor, significantly inhibited thermal hyperalgesia in the late phase but not in the early phase of carrageenan inflammation. Moreover, iNOS mRNA expression in the lumbar enlargement segments of the spinal cord was dramatically induced at 24 h (late phase) after injection of carrageenan into a hind paw. Interestingly, targeted disruption of iNOS gene did not affect carrageenan-induced thermal hyperalgesia in either the early (2-6 h) or late phase. In the lumbar enlargement segments of iNOS knockout mice, nitric oxide synthase (NOS) enzyme activity remained at a similar level to that of the wild type mice at 24 h after carrageenan injection. We found that intrathecal administration of 7-nitroindazole (a selective neuronal NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (a selective endothelial NOS inhibitor), significantly reduced carrageenan-induced thermal hyperalgesia in both the early phase and the late phase in iNOS knockout mice. We also found that expression of neuronal NOS but not endothelial NOS in the lumbar enlargement segments was significantly increased in iNOS knockout mice compared with wild type mice at 24 h after carrageenan injection. Our results indicate that neuronal NOS might compensate for the function of iNOS in the late phase of carrageenan-induced inflammatory pain in iNOS knockout mice. This suggests that iNOS may be sufficient, but not essential, for the late phase of the carrageenan-induced thermal hyperalgesia.

Dexamethasone for preventing nausea and vomiting associated with epidural morphine: a dose-ranging study.

UNLABELLED: We conducted a dose-ranging study of dexamethasone for preventing nausea and vomiting within the first 24 h after the administration of epidural morphine. Two hundred twenty-five women (n = 45 in each of the five groups) undergoing simple abdominal total hysterectomy under epidural anesthesia were enrolled in this randomized, double-blind, placebo-controlled study. When the incision closure was completed, patients received IV dexamethasone, 10 mg, 5 mg, or 2.5 mg; IV droperidol 1.25 mg; or saline 2 mL. All patients received epidural morphine 3 mg for postoperative analgesia. We found that patients who received dexamethasone 5 mg or 10 mg or droperidol 1.25 mg were significantly different from those who received saline alone in the following variables: the total incidence of nausea and vomiting, the incidence of more than four vomiting episodes, the number of patients requiring rescue antiemetics, the total number of patients with no vomiting and/or no antiemetic medication (P < 0.05 to P < 0.01). The differences among dexamethasone 10 mg and 5 mg and droperidol 1.25 mg were not significant. Dexamethasone 2.5 mg was ineffective. In conclusion, because dexamethasone 5 mg was as effective as 10 mg as an antiemetic, we recommend the smaller dose for preventing nausea and vomiting associated with epidural morphine. IMPLICATIONS: We conducted a dose-ranging study of dexamethasone for preventing nausea and vomiting within the first 24 h after the administration of epidural morphine. We found that dexamethasone 5 mg was as effective as 10 mg. We recommend the smaller dose for this purpose.

Pseudomonas cepacia induced septic shock after propofol--a case report.

We report a healthy young female who developed septic shock and multiple organ failure soon after receiving a cosmetic surgery for augmentation of breasts under general anesthesia. Blood cultures yielded the growth of pseudomonas cepacia. We describe the clinical course and investigate the causes of the septic shock. Contamination of propofol, the intravenous anesthetic agent, was suspected.

Pain relief after arthroscopic knee surgery: intravenous morphine, epidural morphine, and intra-articular morphine.

OBJECTIVE: The aim of this study was to compare the analgesic efficacy and side effects of intravenous (IV), epidural, and intra-articular (IA) morphine after arthroscopic knee surgery. DESIGN: Prospective, randomized, double-blind clinical investigation. SETTING: Medical center, university teaching hospital. PATIENTS: Inpatients with an American Society of Anesthesiologists physical status of I or II who were scheduled for elective arthroscopic knee surgery. INTERVENTIONS AND OUTCOME MEASURES: A total of 75 patients scheduled for arthroscopic knee surgery under epidural anesthesia were randomly divided into three groups (n = 25 in each group). At the end of surgery, patients in group 1 received 3 mg of IV morphine, patients in group 2 received 3 mg of epidural morphine, and patients in group 3 received 3 mg of IA morphine. Patients were then observed for 24 hours. During the observation period, the proportion of patients requiring rescue analgesia with intramuscular diclofenac in each group was calculated and the occurrence of morphine-related side effects was recorded. RESULTS: We found that patients who received IV morphine requested more rescue analgesia than those who received either epidural or IA morphine. The proportions of patients requiring rescue analgesia in the IV, epidural, and IA groups were 65%, 13%, and 9%, respectively (p < 0.01 in group 1 vs. group 2 and in group 1 vs. group 3). Epidural morphine was associated with higher incidences of nausea and vomiting, pruritus, and urinary retention than IA morphine (range, p < 0.05-0.01 in group 2 vs. group 3). CONCLUSIONS: Patients who received IA morphine consumed less rescue analgesia than those who received IV morphine. They also reported fewer side effects than those patients who received epidural morphine. Intra-articular morphine may be the method of choice for pain relief after arthroscopic knee surgery.

Surgical pain attenuates acute morphine tolerance in rats.

Nociceptive stimuli, such as formalin-induced pain and adjuvant-induced arthritis, attenuate tolerance to morphine antinociception. In this study, we have explored the effect of upper and lower abdominal surgical pain on the prevention of acute tolerance to morphine antinociception in Sprague-Dawley rats. Group I received lower abdominal surgery (LAS) and i.v. morphine infusion; group II received LAS and i.v. saline infusion; group III received upper abdominal surgery (UAS) and i.v. morphine infusion; group IV received UAS and i.v. saline infusion; group V received i.v. morphine infusion; and group VI received i.v. saline infusion. The antinociceptive effects of morphine were measured by an infrared thermal tail flick test. We also measured plasma concentrations of morphine in rats receiving morphine infusions with or without surgical treatment. We found that acute tolerance to morphine antinociception developed after 2 h following i.v. infusion of morphine alone. However, both UAS and LAS significantly slowed the rate of development of acute tolerance to morphine. The area under the time-response curves (AUC) of groups I and III were mean 34,556 (SD 5607) and 32,548 (9783), respectively, which were significantly different from that of group V (18,759 (8225)) (P < 0.01). Also, there were no significant differences between groups I and III. There were no significant differences between groups for plasma morphine concentrations during the 8-h study (e.g. groups I, III and V: 179.9 (22.6), 182.7 (14.4) and 170.9 (15.8) ng ml-1 at 8 h, respectively) and we suggest that the appearance of acute morphine tolerance after morphine infusion is not pharmacokinetic in nature.

Pain on injection of propofol: the mitigating influence of metoclopramide using different techniques.

BACKGROUND: Metoclopramide administered intravenously (i.v.) immediately before injection of propofol, after mixing with propofol, or after a rubber tourniquet for 1 min before propofol injection will reduce pain induced by propofol injection. In this study, these three different techniques in reducing propofol injection pain with metoclopramide were compared with lidocaine or saline to evaluate the most effective method in reducing propofol injection pain. METHODS: In a randomized, semi-double-blind treatment, 175 patients were included into this study. Patients in group A were pretreated with metoclopramide 10 mg i.v. before propofol (2 mg/kg) induction. Patients in group B were induced with a mixture of propofol and metoclopramide. Patients in group C were pretreated with metoclopramide i.v. with a rubber tourniquet on the arm for 1 min followed by propofol administration. Groups D and E were identical to group C except for the replacement of pretreatment with either lidocaine (40 mg) or saline, respectively. RESULTS: Groups A, C and D (with active pain prophylaxis) showed a significantly less incidence of pain than the saline control group (E) as propofol was injected. There was no significance difference between metoclopramide and lidocaine in reducing propofol injection pain using a tourniquet technique. The intensity of the propofol injection pain (verbal pain score) was stronger with saline as compared with the other groups. CONCLUSIONS: We conclude that i.v. retention of metoclopramide with tourniquet is as good as lidocaine and may be a useful alternative for reducing pain on propofol injection.

Determination of tramadol by capillary gas chromatography with flame ionization detection. Application to human and rabbit pharmacokinetic studies.

A rapid, sensitive, precise and accurate capillary gas chromatographic assay with flame ionization detection was developed for the determination of tramadol in human, rabbit, pig and dog plasma. It is comprised of only a one-step extraction procedure with dichloromethane at pH 11.15 and gas chromatography on a capillary column. The recoveries of tramadol and meperidine (internal standard) were greater than 88%. Calibration graphs were linear over the concentration range 12.5-10,000 ng/ml with a coefficient of variation, both within-day and between-day, of less than 10% at any level. The limit of detection was 8 ng/ml of plasma based on signal-to-noise ratio of 3. Six other clinically used analgesics were investigated to check for potential interferences and their analytical conditions. The specificity of this assay was checked with two major metabolites of tramadol (M1: O-demethyltramadol; M2: N-demethyltramadol). Tramadol in plasma did not decompose significantly at -20 degrees C for 56 days. Pharmacokinetic application with intravenous tramadol in humans and rabbits revealed that tramadol followed a two-compartment open model with one distribution phase and one elimination phase. The distribution and elimination half-lives in humans were 1.02 and 141.9 min. The distribution and elimination half-lives in rabbits were 7.31 and 63.2 min, respectively.

Comparison of PCA nalbuphine and morphine in Chinese gynecologic patients.

BACKGROUND: The aim of this study was to evaluate the efficacy and side effects of PCA nalbuphine (intravenous) versus morphine on postoperative pain in Chinese gynecologic patients. METHODS: Sixty women undergoing abdominal hysterectomy or myomectomy under spinal anesthesia were enrolled into the investigation. Patients were randomly divided into 2 groups (n = 30 each). Group 1 received intravenous nalbuphine using PCA device for the management of postoperative pain, whereas group 2 received PCA morphine for the same purpose. During the first 48 hours postoperatively, we collected the following data: analgesic doses, pain scores, vital signs, nausea, vomiting, pruritus and dizziness. RESULTS: The results showed that despite different treatments, pain scores on day 1 and day 2 postoperatively were low and were not significantly different between groups. Meanwhile, the cumulative consumption of PCA nalbuphine (32 +/- 10 mg) and PCA morphine (30 +/- 9 mg) was similar. Both treatments showed only minor side effects and the incidence of each side effect was not significant between groups. CONCLUSIONS: Both PCA nalbuphine and morphine are effective in the treatment of postoperative pain in Chinese gynecologic patients undergoing hysterectomy or myomectomy after spinal anesthesia and the potency of nalbuphine is similar to that of morphine.

Intraarticular triamcinolone acetonide for pain control after arthroscopic knee surgery.

UNLABELLED: Intraarticular corticosteroids provide valuable local therapy for chronic joint pain caused by inflammatory joint diseases. In this inpatient study, we evaluated the effect of intraarticular triamcinolone acetonide on acute pain after arthroscopic knee surgery. Sixty patients who underwent arthroscopic knee surgery under spinal anesthesia were enrolled into this double-blind, randomized trial. At the end of surgery, Group 1 (n = 30) received intraarticular triamcinolone acetonide 10 mg in isotonic saline 20 mL, and Group 2 (n = 30) received intraarticular isotonic saline 20 mL. After surgery, pain was assessed by using a visual analog scale. The time to first analgesic request (IV morphine) was recorded, and the proportion of patients requiring rescue analgesia was calculated. The results demonstrated that patients in Group 1 had lower pain scores than those in Group 2 from 6 to 24 h postoperatively (P < 0.05 to P < 0.01). From 6 h to 24 h, no patient in Group 1, compared with 53% of patients in Group 2, requested rescue analgesia (P < 0.001). We conclude that intraarticular triamcinolone acetonide provides a valuable local therapy of acute joint pain after arthroscopic knee surgery. IMPLICATIONS: The value of intraarticular triamcinolone acetonide in the management of pain after arthroscopic knee surgery has been evaluated. Patients who received intraarticular triamcinolone acetonide 10 mg at the end of surgery had lower pain scores and used less systemic analgesia than the saline control group. These data are important to the clinical use of this new therapy.

Manipulation of epidural catheter that has migrated restores adequate postoperative analgesia--a case report.

The use of epidural anesthesia and analgesia is ordinary in patients undergoing total knee replacement (TKR). As many as 23% of epidural anesthetics may not provide satisfactory analgesia for women in labor. A similar condition is encountered following the operation of TKR. We reported a case in whom the in-place epidural catheter which functioned well for surgical anesthesia previously migrated to an intervertebral foramen postoperatively and led to failure of providing post-operative analgesia. With deliberate manipulation we succeeded in restoring its function and analgesia showed up again.

Determination of morphine by high-performance liquid chromatography with electrochemical detection: application to human and rabbit pharmacokinetic studies.

A rapid, sensitive, precise and accurate high-performance liquid chromatographic assay with coulometric electrochemical detection was developed for the determination of morphine in human, rabbit, pig and dog plasma. It includes a one-step extraction procedure with hexane-isoamyl alcohol (1:1, v/v) at pH 8.9 (adjusted with phosphoric acid) and reversed-phase liquid chromatography on a microPorasil column. The mobile phase was composed of 5 mM sodium acetate buffer (pH 3.75)-acetonitrile (25:75, v/v). A flow-rate of 1.2 ml/min at 20 degrees C was used. The working potentials for the electrochemical detector were +0.20 V for detector cell 1, +0.55 V for detector cell 2 and +0.75 V for the guard cell. The limit of detection of morphine was 100 pg/ml of plasma. Repeatability, precision and accuracy were also determined concomitantly. The calibration graphs were linear in the concentration range 0.25-250 ng/ml with correlation coefficients of 0.998+/-0.01 and with a minimum intercept of 0.05+/-0.08. The precision in plasma was acceptable, with coefficients of variation less than 11%. The absolute recoveries of morphine and nalbuphine (internal standard) were between 86 and 89% and independent of morphine concentration. Pharmacokinetics after oral morphine [MST Continus (morphine sulphate tablets) 30 mg, Bard Pharmaceutical, Cambridge, UK] in humans revealed a one-compartment first-order absorption model with one absorption phase and one elimination phase. The absorption and elimination half-lives were 2.46 and 1.80 h, respectively. Pharmacokinetics after intravenous morphine (3 mg/kg) in rabbits showed a linear two-compartment open model with one distribution phase and one elimination phase. The distribution and elimination half-lives were 0.5 and 33.8 h, respectively.

The preemptive effect of pre-incisional bupivacaine infiltration on postoperative analgesia following lower abdominal surgery under epidural anesthesia.

BACKGROUND: In attempts to reduce central sensitization after tissue injury, the concept of preemptive analgesia has evolved. The aim of the present study was to evaluate the preemptive effect of pre-incisional infiltration of the surgical area with bupivacaine on pain following lower abdominal surgery under epidural anesthesia. METHODS: Sixty female patients scheduled for lower abdominal surgery under epidural anesthesia with bupivacaine were randomly divided into two Groups (n = 30, each). Five minutes before surgical incision, patients in Group 1 received subcutaneous infiltration of the proposed surgical area with 30 ml of 0.125% bupivacaine (with 1/200,000 epinephrine), while those in Group 2 received 30 ml of isotonic saline (with 1/200,000 epinephrine) infiltration. Postoperatively, pain was assessed for 48 h by a visual analogue scale of pain at rest, during cough and by cumulative morphine doses (self-administered by patient-controlled analgesia). RESULTS: The pain score at rest was significantly lower in Group 1 than in Group 2 from the 6th h to the 24th h postoperatively. The cough-associated pain score was lower in Group 1 than in Group 2 from the 6th h to the 28th h postoperatively. Furthermore, Group 1 consumed less morphine than did Group 2 from the 6th h to the 24th h postoperatively. CONCLUSIONS: The results indicate that pre-incisional infiltration of surgical area with bupivacaine markedly decreases the intensity of pain following lower abdominal surgery under epidural anesthesia.

The analgesic effect of PCA buprenorphine in Taiwan's gynecologic patients.

BACKGROUND: The aim of this study was to evaluate the analgesic effect of PCA buprenorphine (intravenous) on postoperative pain in gynecologic patients of Taiwan and the potency ratio of buprenorphine versus morphine, a commonly used potent analgesic. METHODS: Fifty women undergoing abdominal total hysterectomy under spinal anesthesia were enrolled into the investigation. Patients were randomly divided into 2 groups (n = 25 each). Group 1 received intravenous buprenorphine using PCA device for the management of postoperative pain, whereas Group 2 received PCA morphine for the same purpose. During the first 48 hours postoperatively, we collected the following data: demand and delivery of analgesics, pain scores, vital signs, nausea, vomiting and pruritus. RESULTS: Despite different treatments, we found that pain scores on day 1 and day 2 postoperatively were low and were not significantly different between groups. Also, times of demand for delivery of PCA medication were not significantly different between groups. The cumulative consumption of buprenorphine and morphine within 48 h were 1.5 +/- 0.6 mg and 36 +/- 7 mg, respectively. The potency ratio between buprenorphine and morphine was 24:1. Both treatments showed only minor side effects. CONCLUSIONS: We found that PCA buprenorphine (intravenous) could be effective in the treatment of postoperative pain in the gynecologic patients in Taiwan and the potency ratio of buprenorphine versus morphine appeared to be 24:1.

[Cellular mechanism of opioid tolerance].

Opioids relieve painful stimuli by interacting with the opioid receptor subtypes, mu, delta, and kappa, in brain regions and spinal cord. Tolerance reduces medication effectiveness and causes a right-hand shift in the dose-response curve. The mechanisms involved in the development of opioid tolerance remain not clear. Following long-term opioid treatment, either a decrease or increase in opioid receptors was demonstrated, depending on the types or subtypes of receptors and the central areas to which they are distributed. Opioid receptors, like most other hormone and neurotransmitter receptors, have been shown to mediate their effects through guanine nucleotide binding protein (G protein). Studies regarding chronic treatment with opioid agonists suggest that the uncoupling of the opioid receptors from their corresponding G protein may play an important role in opioid tolerance. The NMDA (N-methyl-D-aspartate) receptors have also been demonstrated involving not only in nociception and pain processing but also in the development of opioid tolerance. The sustained potentiation of NMDA receptor-mediated responses may be provided through activation of PKC (protein kinase C). Furthermore, NMDA receptor-mediated intracellular translocation and activation of PKC may be a critical step in the development of opioid tolerance. The NMDA receptors can also induce the synthesis of NO (nitric oxide) through the activation of NOS (NO synthase). NOS inhibitors were also shown to prevent the development of opioid tolerance, therefore, NO was suggested to play a role in opioid tolerance development. Although much evidence indicates the reasons of opioid tolerance, it is still worth further investigation to explore the mechanisms of multiplicity of opioid receptors and complexity of intracellular biochemical events.

Ketamine potentiates analgesic effect of morphine in postoperative epidural pain control.

BACKGROUND AND OBJECTIVES: Ketamine is currently the only N-methyl-D-aspartate receptor channel blocker in clinical use. This study evaluated the analgesic efficacy of epidurally coadministered ketamine and morphine in postoperative pain control. METHODS: The patient population consisted of ASA class I and II patients undergoing major joint replacement. Epidural lidocaine was used as the primary anesthesia for the surgery. In phase I of the study, either ketamine (10-30 mg) or morphine (0.5-2 mg) was administered via epidural catheter immediately after surgery. This was done to evaluate the dose-response effect of these drugs when used for postoperative pain relief, and the results were applied to phase II of the study, in which all patients received ketamine pretreatment (total 30 mg) with each dose of lidocaine administered before and during surgery. Forty patients were randomly divided into four groups, each of which received one of three different pain control regimens mixed with 10 ml of saline: group B received 10 mg ketamine, group C 2 mg morphine, and group D 10 mg ketamine plus 0.5 mg morphine while the control group A received 10 mL of saline with no additive. The intensity of pain expressed by patients, as well as the number of intramuscular meperidine (1 mg/kg) injections administered and any side effects that may have occurred, were recorded. RESULTS: Ketamine produced no significant pain relief. A 2-mg morphine dose did produce significant analgesia but was accompanied by a high incidence of side effects. Co-administration of subanalgesic doses of ketamine, 10 mg and morphine, 0.5 mg, however, also produced a strong analgesic effect. CONCLUSIONS: Ketamine, although not itself an epidural analgesic agent, potentiates the analgesic effect of morphine, especially when administered as a pretreatment. The resulting lowered dosage of epidural morphine needed for postoperative pain relief reduces, in turn, the incidence of side effects. Pretreatment of patients with ketamine epidurally, followed by injections of combined morphine and ketamine could be a promising new analgesic regimen.

Epidural coadministration of ketamine, morphine and bupivacaine attenuates post-herpetic neuralgia--a case report.

The N-methyl-D-aspartate (NMDA) receptor system plays an important role in nociceptive signal modulation in the central nerve system. There is considerable evidence that NMDA receptor antagonists can abolish hypersensitivity of nociceptors in animal models. In this case report, we described a patient who suffered post-herpetic neuralgia with severe pain, allodynia, and hyperesthesia over right side T2 to T8 dermatomes. Treatment with conventional doses of non-steroid anti-inflammatory drug (NSAID), antidepressant, anticonvulsant and benzodiazepine failed to provide satisfactory pain relief. With the patient's consent, we administered subanalgesic doses of ketamine (10 mg), morphine (1 mg), and 6 ml bupivacaine (0.1%) through the thoracic epidural route. After the treatment, hyperalgesia and allodynia improved dramatically, and the receptive field also reduced. After four weeks' treatment, satisfactory pain relief was achieved with conventional analgesics treatment. The combination of relatively low doses of morphine, ketamine and bupivacaine epidurally provides effective pain relief in this case. The result strongly suggests a synergy from this combination that warrants a formal study of the dose-response relationship involved in this treatment and the mechanism by which this effect is achieved. This regimen provides a promising treatment for the neuropathic pain with limited side effects.