Ultra-low dose naloxone restores the antinociceptive effect of morphine in pertussis toxin-treated rats by reversing the coupling of mu-opioid receptors from Gs-protein to coupling to Gi-protein.

Pertussis toxin (PTX) treatment results in ADP-ribosylation of Gi-protein and thus in disruption of mu-opioid receptor signal transduction and loss of the antinociceptive effect of morphine. We have previously demonstrated that pretreatment with ultra-low dose naloxone preserves the antinociceptive effect of morphine in PTX-treated rats. The present study further examined the effect of ultra-low dose naloxone on mu-opioid receptor signaling in PTX-treated rats and the underlying mechanism. Male Wistar rats implanted with an intrathecal catheter received an intrathecal injection of saline or PTX (1 microg in 5 microl of saline), then, 4 days later, were pretreated by intrathecal injection with either saline or ultra-low dose naloxone (15 ng in 5 microl of saline), followed, 30 min later, by saline or morphine (10 microg in 5 microl of saline). Four days after PTX injection, thermal hyperalgesia was observed, together with increased coupling of excitatory Gs-protein to mu-opioid receptors in the spinal cord. Ultra-low dose naloxone pretreatment preserved the antinociceptive effect of morphine, and this effect was completely blocked by the mu-opioid receptor antagonist CTOP, but not by the kappa-opioid receptor antagonist nor-BNI or the delta-opioid receptor antagonist naltrindole. Moreover, a co-immunoprecipitation study showed that ultra-low dose naloxone restored mu-opioid receptor/Gi-protein coupling and inhibited the PTX-induced mu-opioid receptor/Gs-protein coupling. In addition to the anti-neuroinflammatory effect and glutamate transporter modulation previously observed in PTX-treated rats, the re-establishment of mu-opioid receptor Gi/Go-protein coupling is involved in the restoration of the antinociceptive effect of morphine by ultra-low dose naloxone pretreatment by normalizing the balance between the excitatory and inhibitory signaling pathways. These results show that ultra-low dose naloxone preserves the antinociceptive effect of morphine, suppresses spinal neuroinflammation, and reduces PTX-elevated excitatory Gs-coupled opioid receptors in PTX-treated rats. We suggest that ultra-low dose naloxone might be clinically valuable in pain management.

Amitriptyline induces nuclear transcription factor-kappaB-dependent glutamate transporter upregulation in chronic morphine-infused rats.

We previously showed that intrathecal co-administration of amitriptyline with morphine upregulates the expression of the glial glutamate transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) and restores neuronal glutamate transporter excitatory amino acid carrier 1 (EAAC1) expression in chronically morphine-infused rats. The present study examined the role of nuclear transcription factor-kappaB (NF-kappaB) in the regulation of the expression of GLAST, GLT-1, and EAAC1 following long-term amitriptyline/morphine co-infusion. Male Wistar rats were implanted with two intrathecal catheters with or without a microdialysis probe; one of the catheters was used for continuous infusion of saline (control), morphine (15 microg/h), or morphine plus amitriptyline (both 15 microg/h) for 5 days, while the other was used for a single daily intrathecal injection of the NF-kappaB inhibitor Ro106-9920 (10 microl of 10 microM) for 5 days. We found that amitriptyline co-infusion restored the antinociceptive effect of morphine (4.5-fold right-shift in the morphine dose-response curve compared with a 65-fold right-shift in its absence) and this effect was inhibited by Ro106-9920 administration (48-fold right-shift). Moreover, amitriptyline/morphine co-infusion increased IkappaBalpha phosphorylation and the translocation of NF-kappaB p65 from the cytosol to the nucleus. Daily intrathecal injection of Ro106-9920 prevented the amitriptyline/morphine-induced NF-kappaB p65 translocation and reversed the amitriptyline/morphine-induced GLAST and GLT-1 upregulation and inhibited the restoration of EAAC1 expression. The Ro106-9920 injections abolished the inhibitory effect of amitriptyline on the morphine-evoked release of excitatory amino acids into the spinal cerebrospinal fluid (CSF) dialysates. In conclusion, amitriptyline/morphine co-infusion restores the antinociceptive effect of morphine and upregulates GLAST and GLT-1 expression and restores EAAC1 expression to baseline levels, thus reducing excitatory amino acid levels in the spinal CSF dialysates. The mechanism involves activation of the NF-kappaB pathway, but may also involve other pathways.

Pre-medication with intravenous clonidine suppresses fentanyl-induced cough.

BACKGROUND: A reflex cough is often observed after an intravenous bolus of fentanyl. This study was conducted to determine whether pre-treatment with intravenous clonidine could effectively attenuate fentanyl-induced cough. METHODS: Three hundred ASA I-II patients, aged between 18 and 80 years, undergoing various elective surgeries, were enrolled in this study. All patients were randomly assigned to one of two groups treated with intravenous clonidine 2 microg/kg (clonidine group) or the same volume of normal saline (control group). Intravenous fentanyl (2 microg/kg in 2 s) was injected 2 min after the clonidine or normal saline injection. Changes in the hemodynamics, auditory evoked potentials (AEPs) and Observer Assessment of Alertness/Sedation (OAA/S) rating scale were recorded before and 2 min after the clonidine or normal saline injection and 1 min after the fentanyl injection. The number of coughs 1 min after the fentanyl injection was also recorded. RESULTS: Patients in the clonidine group showed a significantly lower incidence of cough than those in the control group (17.3% vs. 38.7%, respectively; P < 0.01). The blood pressure was lower in the clonidine group than in the control group. There were no significant differences in AEP or OAA/S rating scale. CONCLUSIONS: Pre-treatment with intravenous clonidine (2 microg/kg) suppressed the reflex cough induced by fentanyl, with mild hemodynamic changes. Therefore, intravenous clonidine may be a clinically useful method of suppressing fentanyl-induced cough.

Epidural fentanyl speeds the onset of sensory block during epidural lidocaine anesthesia.

BACKGROUND AND OBJECTIVES: Shortening the onset time of sensory block is a practical goal to improve the quality of epidural anesthesia. The addition of fentanyl to a local anesthetic solution is widely used during epidural anesthesia. This randomized double-blind study examined the onset time of sensory block during epidural lidocaine anesthesia with and without added fentanyl to the epidural solution. METHODS: Thirty-six young male patients undergoing knee arthroscopy were randomly allocated into 3 groups of 12 patients each: epidural fentanyl (EF, epidural administration of 17 mL of 2% lidocaine plus 100 microg fentanyl and followed by intravenous (IV) injection of 2 mL of normal saline); IV fentanyl (IF, epidural administration of 17 mL of 2% lidocaine plus 2 mL of normal saline and followed by IV injection of 100 microg of fentanyl); and control (C, epidural administration of 17 mL of 2% lidocaine plus 2 mL of normal saline and followed by IV injection of 2 mL of normal saline). The sensory block was assessed by pinprick method. The hemodynamic changes, postepidural shivering, and side effects of epidural fentanyl were also recorded. RESULTS: There was no difference in the distribution of age, weight, and height among the 3 groups. The onset time of sensory block up to T(10) dermatome was significantly more rapid in the EF group (8.3 +/- 3.7 minutes) than that of the IF group (13.1 +/- 4.2 minutes, P <.05) or C group (14.2 +/- 5.4 minutes, P <.05). The upper level of sensory block was also significantly higher in the EF group. Although the incidence of shivering was lower in the EF group, this did not reach statistical significance. Postepidural arterial blood pressures and heart rates were no different among the 3 groups. No nausea, vomiting, pruritus, respiratory depression, urinary retention, or hypotension were observed in any patients. CONCLUSION: Epidural injection of the mixture of 100 microg fentanyl and 2% lidocaine solution accelerated the onset of sensory block during epidural lidocaine anesthesia without increased side effects.

Facilitation of fiberoptic nasotracheal intubation by simultaneous direct laryngoscopy in anesthetized patients.

Two cases of unexpected difficult intubation during induction of general anesthesia were reported. The first case, a 68-year-old male was scheduled for coronary artery bypass surgery. The second case, a 94-year-old male with senile dementia was arranged for exploratory laparotomy. Anesthesia was induced with diazepam 10 mg, fentanyl 30 micrograms/kg, and pancuronium 8 mg in the first case while in the second case fentanyl 100 micrograms, lidocaine 80 mg, thiopental 200 mg and succinylcholine 80 mg were used. In these two cases oral tracheal intubation with laryngoscope was unsuccessful. Assisted ventilation could be maintained via a face mask. With the help of direct laryngoscopy, fiberoptic bronchoscope-aided nasotracheal intubation was successfully achieved.

Rhabdomyolysis after a long-term thoracic surgery in right decubitus position.

We report a rare case who developed rhabdomyolysis associated with the use of the right decubitus position for 10 h during thoracotomy with lobectomy. It appears that an increasing of the compartment pressure may induce reperfusion injury of the ischemic muscle by prolonged compression of the gluteal and flank muscles against the operation table. Early recognition and aggressive treatment with intravenous fluid and diuresis may prevent the development of acute renal failure. Adequate prevention in high-risk patients, early diagnosis and aggressive treatment are the keys to a successful recovery.

Intrathecal administration of excitatory amino acid receptor antagonists or nitric oxide synthase inhibitor reduced autotomy behavior in rats.

UNLABELLED: Peripheral nerve injury may produce neuropathic pain. At the spinal cord level, excitatory amino acid receptors play a role in nociceptive signal modulation. N-methyl-D-aspartate (NMDA) receptor activation initiates the NO-cGMP pathway and further modulates nociceptive signal. Using the autotomy model, we examined the effect of an NMDA and a non-NMDA receptor antagonist, and nitric oxide synthase inhibitor in the treatment of autotomy behavior in rats. A right-side brachial plexus (C5-T1) transection was performed in all rats. In the treatment groups, MK-801, 1-(4-chlorobenzoyl)-piperazine-2,3-dicarboxylic acid (a non-NMDA antagonist), and L-NG-nitro arginine methyl ester (L-NAME) were infused intrathecally via an osmotic pump for 7 days at doses of 10, 4, and 400 microg/h, respectively. Saline was infused to control animals. Autotomy behavior was observed daily for 8 wk. The incidence of autotomy was 85% in the control group. MK-801, the non-NMDA antagonist, and L-NAME reduced the autotomy incidence to 10%, 20%, and 10% (P < 0.0001), respectively. All treatments delayed the onset of the autotomy behavior from 15+/-4.5 days in the control group to 52+/-3.8, 43+/-5.6, and 54+/-2.9 (P < 0.001) days in the treatment groups, respectively. The average autotomy scores were also attenuated significantly by these treatments. We conclude that the excitatory amino acid receptors and their intracellular signal messenger NO play a role in deafferentation behavior development. Inhibition of this signaling pathway may be of use for neuropathic pain relief. IMPLICATIONS: The excitatory amino acid receptors and their intracellular signal messenger NO play a role in deafferentation behavior development. Inhibition of this signaling pathway may be of use for neuropathic pain relief.

The prevalence and severity of cancer pain: a study of newly-diagnosed cancer patients in Taiwan.

Cancer pain is a relatively neglected public health issue in Taiwan. To characterize the nature of this problem, interviews were conducted on newly diagnosed cancer patients admitted to the Tri-Service General Hospital during a period of 18 months. Data were collected on the prevalence and severity of cancer pain, its treatment, and impact on patients in the week before the interview. Correlates of prevalence and severity of cancer pain were also examined. The final analysis included 296 patients who had no history of recent surgery. Most of the patients (69%) were interviewed within 14 days of their definitive diagnosis of cancer. Thirty-eight percent (N = 113) of the patients had cancer-related pain. Of these 113 patients, 65% had "significant worst pain" (worst pain level at or above five on a ten-point scale) and 31% had "significant average pain" (average pain level at or above five most of the time); 69% received no pain medication at all or inadequate medication (not "by the ladder"), and 23% had pain medication that was not administered at a fixed interval (not "by the clock"). Multivariate analyses showed that cancer pain was more prevalent in non-Mainlanders, those with a lower level of insurance, those with a history of excellent pain tolerance, those with poor Eastern Cooperative Oncology Group (ECOG) performance status, and those with distant metastases. Patients who were at greater risk of "significant worst pain" were those with regional or distant metastases, those in whom an inadequate analgesic medication had been prescribed (not "by the ladder"), and those who had received an appropriate analgesic medication but no fixed schedule dosing ("by the ladder" but not "by the clock"). Patients who were at greater risk of "significant average pain" were those not undergoing any resection of the tumor lesion and those who received an appropriate drug but no fixed schedule dosing ("by the ladder" but not "by the clock").

Pre-emptive analgesia with ketamine, morphine and epidural lidocaine prior to total knee replacement.

PURPOSE: Pre-emptive analgesia can improve postoperative pain management. The purpose of this study was to examine the effectiveness of ketamine as a pre-emptive analgesic as previous studies have shown the involvement of N-methyl-D-Aspartate (NMDA) receptor in neuroplasticity. METHODS: Forty-five ASA 1-2 patients, undergoing unilateral total knee replacement were studied. In the study groups, epidural lidocaine was used as the primary anaesthestic. Patients received ketamine + morphine epidurally 30 min either before (group EB) or after skin incision (group EA). Group G patients received general anaesthesia and ketamine + morphine were given 30 min after skin incision via an epidural catheter used for postoperative pain control. Epidural morphine and ketamine in lidocaine was given to all patients at the end of surgery and every 12 hr for three days for analgesia supplemented with PCA morphine. The time until first PCA trigger, morphine consumption, pain scores, satisfaction scores, and morphine related side effects were recorded at 6, 12, 24, 48 and 72 hr after surgery. RESULTS: Epidural ketamine plus morphine with lidocaine before surgical incision produced better pain relief and patient satisfaction than when given after incision. A longer time to PCA and decreased morphine consumption were observed in group EB than in group G. In group EA, epidural anaesthesia also produced some pre-emptive analgesic effect compared with general anaesthesia shown by decreased morphine consumption. CONCLUSIONS: Administration of ketamine plus morphine with epidural lidocaine anesthesia before surgery provided improved postoperative analgesia compared with general anaesthesia alone or when analgesics were given after skin incision.

Patient barriers to cancer pain management: from the viewpoint of the cancer patients receiving analgesics in a teaching hospital of Taiwan.

BACKGROUND: The purpose of this study was to investigate the barriers to receiving analgesics for cancer pain in Taiwanese patients. METHODS: The sample consisted of 128 hospitalized patients. All of the subjects were receiving analgesics. Three questionnaires entitled "Barriers Questionnaire-Taiwan Form (BQT)", "Brief Pain Inventory Short Form", and "Pain Management Index (PMI)" were used in this study. Data were analyzed using Student's t-test and Pearson correlation. RESULTS: The results showed that most of BQT subscales including disease progression, time interval, tolerance, injection, addiction, fatalism and side effects were approaching toward the moderate or high end of the scale. 42.1% (n = 54) of the patients had negative PMI scores indicating that they were using less than adequate analgesics for pain. There was a significant difference between those who had adequate medication and those who did not, in terms of disease progression score and the total BQT score. CONCLUSIONS: Overall the result revealed that pain management in these cancer patients was inadequate. Misconceptions on the part of patients still exist. Educational intervention could be an effective means for overcoming such barriers in Taiwanese patients who received analgesics for cancer pain.

[Removal of femoral interlocking nail-induced pulmonary embolism under spinal anesthesia--a case report].

Most of the lower limb surgeries are done under spinal anesthesia. This 21 year-old male had undergone open reduction with interlocking nail for his right femoral fracture and was scheduled for removal of interlocking nail. Spinal anesthesia was performed and a sensory block up to T8 level was achieved. During removing of the nail, the patient complained of chest pain, dyspnea and headache. Consequently, tachycardia and hypotension were observed. Then he coughed up pink frothy sputum. Ephedrine 5 mg was given to raise his blood pressure. About 3 min later, he recovered from the hypotension. Arterial blood gas analysis showed hypoxemia and hypercapnia. After endotracheal intubation, he was sent to surgical intensive care unit. In surgical intensive care unit, fat globules in urine, anemia and thrombocytopenia were noted. Chest roentgenogram showed patchy pulmonary infiltrates in the left lower lobe. A pulmonary artery catheter was inserted for pulmonary measurement, which read pulmonary artery pressure 45/28 mmHg, wedge pressure 14 mmHg, and cardiac output was 5-34 L/min. Supportive treatment which included steroid therapy, and O2 therapy with positive end-expiratory pressure was initiated under the impression of pulmonary embolism. The course in surgical ICU was uneventful and he left there three days later and was discharged on the fifth hospitalization day.

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.

Erratic passage and anchorage of a right subclavian catheter caused by preoccupancy of an indwelling right jugular venous catheter--a case report.

We report a case of central venous catheter (CVC) malposition. Through subclavian approach the CVC tip was intended to anchor in the superior cava, but it turned out to be in the right internal jugular vein as revealed by chest X-ray. The cause of malposition was perhaps the preoccupancy of the jugular venous CVC which interferred with a normal advancement. Although the malposition of the catheter might not produce any immediate problem, later complication might occur. Thus, removal of a problematic catheter and recatheterization was indicated.

Spinal actions of nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the signs and symptoms of inflammation. They originated from man's early use of willow bark in the treatment of rheumatism. Although these drugs have been developed because of their effects on arthritis, their substantial analgesic and antipyretic actions have led to their widespread application. The NSAIDs are classified on the basis of their chemical structure under the category of acidic and nonacidic agents. The anti-inflammatory, analgesic and antipyretic effects of NSAIDs are attributable to their suppression of prostaglandin synthesis activity through cyclooxygenase inhibition. Regarding the analgesic effects of NSAIDs, initially, the peripheral mechanism was proposed. It has been assumed that the effects result from inhibition of the synthesis of prostaglandins in the peripheral inflamed tissue because prostaglandin may sensitize the peripheral nociceptors to the effects of other mediators released from the inflamed tissue. However, the central mechanism, acting within supraspinal or spinal level, was also suggested recently. Their exact sites and modes of action within the spinal cord are poorly defined, and even controversial. There are two main hypotheses to elucidate this issue. One is that the spinal analgesic actions are associated with prostaglandins synthesis, because of the excitatory effect of prostaglandins in the spinal cord and the other is dissociated from prostaglandins synthesis, and their effect may be related to their ability to affect the spinal nociceptive, processing cellularly or intracellularly. However, both mechanisms are probably linked. In conclusion, although the real mechanisms of the spinal analgesic actions of NSAIDs remain unclear, further basic and clinical studies should be made. In this way, we may hopefully provide more opportunities for effective pain management.

Effects of NMDA receptor antagonists on inhibition of morphine tolerance in rats: binding at mu-opioid receptors.

Past studies have shown antagonists of excitatory amino acid receptors, both N-methyl-D-aspartate (NMDA) and non-NMDA, to produce an antinociceptive effect in vitro and in vivo. Additionally, NMDA receptor antagonists have been demonstrated to prevent morphine tolerance. We had found that one NMDA receptor antagonist, ketamine, potentiates morphine's analgesic effect in post-operative patients. Our latest experiment was performed to examine the modulatory effect of competitive and non-competitive NMDA receptor antagonists on morphine antinociception and tolerance. A PE10 catheter was intrathecally (i.t.) implanted in male Sprague-Dawley rats for drug administration. The antinociceptive effect of morphine, D-(-)-2-amino-5-phosphonovaleric acid (D-AP5) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate (MK-801) was measured using the hot-water tail immersion test. Neither competitive nor non-competitive NMDA receptor antagonists had an antinociceptive effect by themselves, but they did potentiate the antinociceptive effect of morphine. Both D-AP5 (AD50 = 0.18 micrograms) and MK-801 (AD50 = 0.57 micrograms) shifted the antinociceptive dose-response curve of morphine (AD50 = 4.2 micrograms) to the left. Both D-AP5 (4 micrograms/h) and MK-801 (10 micrograms/h) when co-administered with i.t. morphine infusions (10 micrograms/h) also inhibited the development of tolerance. In [3H][D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin ([3H]DAMGO) binding assays, MK-801 (Bmax = 32.90 +/- 3.33 fmol/mg) treatment prevented the down-regulation of mu-opioid receptor high-affinity sites induced by continuous morphine infusions alone (Bmax = 13.97 +/- 1.47 fmol/mg). D-AP5 (Bmax = 20.78 +/- 3.36 fmol/mg) did not prevent the reduction of mu-opioid receptor high-affinity sites. However, high-affinity sites in rats treated with D-AP5 and morphine displayed a higher affinity (KD = 0.45 +/- 0.09 nM) than those of control animals (KD = 0.95 +/- 0.08 nM). Results of this study indicate that competitive as well as non-competitive NMDA receptor antagonists enhance morphine's antinociceptive effect, and prevent the development of morphine tolerance. Thus, in our opinion, there opens a new frontier in clinical pain management, especially for those patients who require long-term opioid treatment for pain relief.

Clinical applications of excitatory amino acid antagonists in pain management.

Pain is an important indicator of stress particularly after surgical operation. It is not only a physical and mental suffering but also a main factor for postoperative complications. Relieving of postoperative pain is perquisite for improving outcome and shortening hospital stay. Opioids are still the mainstream for pain relief in common practice. However, opioids are also accompanied by many side effects which limit their usefulness. Therefore, methods to avoid the narcotic-associated side effects are still being searched. Excitatory amino acid receptor antagonists, particularly the NMDA receptor, have been demonstrated to produce satisfactory analgesic effect under certain conditions. This article is an introductory overview of some possible applications of the excitatory amino acid receptor antagonists in future clinical pain management.

Analgesic effect of intra-articular morphine after arthroscopic knee surgery in Chinese patients.

BACKGROUND: Small or systematically inactive doses of morphine administered into the knee joint during intra-articular surgery can elicit potent and long-lasting postoperative analgesia. The reports studied in USA, Spain, UK, Germany, Ireland, etc. showed that intra-articular morphine 0.5-5 mg could produce a significant analgesic effect with an onset time of 0-6 h after administration and a duration of 24-48 h. However, there were no available data about the Chinese people; therefore, this study was designed to collect the data regarding this subject. METHODS: Forty patients undergoing arthroscopic knee surgery under spinal anesthesia were randomly divided into two groups. At the end of surgery, group 1 received intra-articular morphine sulfate 1 mg in normal saline 10 ml, while group 2 received intra-articular 0.5% bupivacaine 10 ml for postoperative pain relief. RESULTS: The results showed that all pain scores were lower in morphine group than in bupivacaine group from 6 to 24 h after surgery. Supplemental analgesic consumption was significantly greater in the bupivacaine group than in the morphine group from 6 to 24 h postoperatively. These results were quite similar with those presented in other races. CONCLUSIONS: We concluded that intra-articular morphine 1 mg in Chinese patients could provide an effective and long-lasting analgesic effect, which was quite similar with the result presented in other races.