Nitrous oxide analgesia: reversal by naloxone and development of tolerance

The objective of this study was to characterize further the nature of nitrous oxide analgesia and to establish if tolerance to nitrous oxide occurs. Methods for studying the analgesic action of a gas are described. In mice, nitrous oxide is analgesic in the phenylquinone and acetic acid abdominal constriction tests. Aspirin and very high doses of alcohol are also active in these tests; however, only nitrous oxide-induced analgesia is antagonized by narcotic antagonists. These data indicate the mechanism of action of nitrous oxide analgesia differs from that of the other two drugs. Nitrous oxide produced a dose-related analgesic response in rats (ED50, 67%) as measured by the tail-flick method. Naloxone, 5 to 30 mg/kg, also antagonized nitrous oxide analgesia in rats. Lower doses of the antagonist were not effective. Tolerance developed to the effects of nitrous oxide in both rats and mice after prolonged exposure. These data lend support to the hypothesis that nitrous oxide and opiates have a significant pharmacologic resemblance and may ultimately produce similar molecular events in the brain leading to the relief of pain.     

Latex allergy in the operating room: case report and a brief review of the literature

OBJECTIVE: To study whether the use of analgesic treatment in labour is influenced by ethnicity. DESIGN: A cross-sectional study of hospital patients. Setting; the two municipal hospitals, Ullev?l and Aker, in Oslo, Norway. Subjects; a total of 137 obstetrical patients, 67 Pakistani women and 70 Norwegian women. Main outcome measure; use of analgesics in labour. RESULTS: 30% of the Pakistani and 9% of the Norwegian women received no analgesia in labour. Pethidine injection was the preferred analgesic administered to Pakistani women. Women of Pakistani origin received epidural infusion or nitrous oxide and oxygen gas less frequently than Norwegian women. They also received fewer combinations of other analgesic methods. When adjusted for the mothers' age, parity and duration of delivery, Pakistani origin was the only significant predictor for receiving no analgesia in labour. CONCLUSION: Women of Pakistani origin were more than three times as likely not to receive analgesia in labour as Norwegian women. The health services offered to Pakistani women in labour were different from those offered to Norwegian women. These results indicate that women of Pakistani origin may be offered insufficient obstetrical analgesia, or that Norwegian women received unnecessary pain relief in labour.     

Subjective, psychomotor, cognitive, and analgesic effects of subanesthetic concentrations of sevoflurane and nitrous oxide

BACKGROUND: Sevoflurane is a volatile general anesthetic that differs in chemical nature from the gaseous anesthetic nitrous oxide. In a controlled laboratory setting, the authors characterized the subjective, psychomotor, and analgesic effects of sevoflurane and nitrous oxide at two equal minimum alveolar subanesthetic concentrations. METHODS: A crossover design was used to test the effects of two end-tidal concentrations of sevoflurane (0.3% and 0.60%), two end-tidal concentrations of nitrous oxide (15% and 30%) that were equal in minimum alveolar concentration to that of sevoflurane, and placebo (100% oxygen) in 12 healthy volunteers. The volunteers inhaled one of these concentrations of sevoflurane, nitrous oxide, or placebo for 35 min. Dependent measures included subjective, psychomotor, and physiologic effects, and pain ratings measured during a cold-water test. RESULTS: Sevoflurane produced a greater degree of amnesia, psychomotor impairment, and drowsiness than did equal minimum alveolar concentrations of nitrous oxide. Recovery from sevoflurane and nitrous oxide effects was rapid. Nitrous oxide but not sevoflurane had analgesic effects. CONCLUSIONS: Sevoflurane and nitrous oxide produced different profiles of subjective, behavioral, and cognitive effects, with sevoflurane, in general, producing an overall greater magnitude of effect. The differences in effects between sevoflurane and nitrous oxide are consistent with the differences in their chemical nature and putative mechanisms of action.     

Dependence of dopamine calibration factors on media Ca2+ and Mg2+ at carbon-fiber microelectrodes used with fast-scan cyclic voltammetry

We give a brief history and development of the use of analgesic nitrous oxide in various clinical situations, emphasizing the very important difference between analgesic and anesthetic concentrations of the gas. We give evidence for the opioid nature of analgesic nitrous oxide and the probable role that these opioid properties play in its clinical effects. Its uniqueness among the opioids arises from its ability to safely stimulate both mu and kappa opioid receptors thereby modulating these systems, which are at times antagonistic to each other. These opposing systems appear to be particularly important during addictive withdrawal. We also discuss the possible relationship existing between nitric and nitrous oxide.     

Effects of anesthetics on somatosensory evoked potentials by median nerve stimulation in human--analyses after single administration in volunteers

In the present study, effects of midazolam, thiopental sodium, propofol, and nitrous oxide upon SEP in a clinically used dose were investigated on 24 male volunteers. In addition, antagonistic actions of flumazenil and naloxone against effects of midazolam and nitrous oxide, respectively, on SEP were studied. Midazolam had no effect on latencies of N 20 and P 25, but increased latency of P 45 and attenuated P 100 amplitude. Flumazenil reversed these effects of midazolam of P 45 latency and P 100 amplitude to their control values. While thiopental sodium and propofol suppressed P 100 amplitude, they had no effect on N 20, P 25, P 45 latencies. Nitrous oxide elongated latencies of N 20, P 25, P 45 and decreased P 100 amplitude. Naloxone reversed the effects of nitrous oxide on N 20 and P 25 latencies without affecting increased P 45 latency and attenuated P 100 amplitude. These results suggest that midazolam might have an analgesic action of suppressing cortical sensory neurons, whereas thiopental sodium and propofol have no effect on neurons in the primary sensory cortex. The finding that naloxone antagonized the increased latencies of N 20 and P 25 by nitrous oxide could be explained by the analgesic action of nitrous oxide that could be mediated by opioid receptors. The results also indicate that electrical activities of the cortical neurons in the associated area are more susceptible to psychotropic agents than those in the primary sensory cortex. The effects of anesthetics on SEP appear to reflect their characteristics of functioning mechanisms on cortical neurons. Analysis of SEP is, therefore, useful for the assessment of the mechanism and the acting site of anesthetics in the sensory cortex.     

The effect of clonidine on intra-operative requirements of fentanyl during combined epidural/general anaesthesia

The study evaluates the analgesic effects of epidural clonidine in patients undergoing abdominal hysterectomy under combined epidural/general anaesthesia. Forty ASA 1-2 patients were divided into two groups who received epidurally either clonidine 300 micrograms (group 1) or placebo (group 2). Anaesthesia was maintained with oxygen/nitrous oxide, a midazolam infusion, vecuronium, and boluses of fentanyl 100 micrograms administered as needed to maintain cardiovascular stability. The mean (SD) intraoperative fentanyl requirements were 2.05 (0.18) and 3.66 (0.3) micrograms.kg-1.h-1 for groups 1 and 2 respectively (p < 0.001). Patients in Group 1 had a lower heart rate after tracheal intubation and surgical incision (p < 0.02). In the recovery room, pain intensity was lower in group 1 (p < 0.003) and the mean (SD) time until analgesia request was increased from 48.5 (8.4) min in group 2 to 235.7 (33.2) min in group 1 (p < 0.001). Our results demonstrate that epidural clonidine produces decreased fentanyl requirements, improved cardiovascular stability, reduced pain intensity and effective postoperative analgesia in the recovery room.     

Identification of the receptor subtype involved in the analgesic effect of neurotensin

The neuropeptide neurotensin (NT) elicits hypothermic and naloxone-insensitive analgesic responses after brain injection. Recent pharmacological evidence obtained with NT agonists and antagonists suggests that these effects are mediated by a receptor distinct from the initially cloned high-affinity NT receptor (NTR1). The recent cloning of a second NT receptor (NTR2) prompted us to evaluate its role in NT-induced analgesia. Intracerebroventricular injections in mice of two different antisense oligodeoxynucleotides from the NTR2 markedly decreased NTR2 mRNA and protein and reduced NT-induced analgesia. This effect was specific, because NTR1 levels were unaffected, and sense or scramble oligodeoxynucleotides had no effect. Structure-activity studies revealed a close correlation between the analgesic potency of NT analogs and their affinity for the NTR2 and disclosed potent and selective agonists of this receptor. These data confirm that NTR1 is involved in the NT-elicited turning behavior and demonstrate that the NTR2 mediates NT-induced analgesia.     

Sevoflurane anaesthesia for a patient with adult polyglucosan body disease

PURPOSE: Adult polyglucosan body disease (APBD) is a rare neurological disorder of unknown cause characterized by four manifestations: upper motor neuron signs, peripheral neuropathy with motor and sensory loss, urinary incontinence, and dementia. The purpose of this report is to present a patient with APBD anaesthetized successfully with sevoflurane and nitrous oxide. CLINICAL FEATURE: A 51-yr-old man with APBD was scheduled for haemorrhoidectomy. Paraesthesia, dysaesthesia, distal muscular atrophy and fasciculation were recognized in the extremities. Dementia, bulbar paralysis and respiratory insufficiency were basent. Anaesthesia was induced with inhalation of sevoflurane and nitrous oxide, and the trachea was intubated without the use of muscle relaxants. Maintenance of anaesthesia was performed with sevoflurane (inspired concentration: 1.5-2.5%) and nitrous oxide (50%). Emergence from anaesthesia and the postoperative course were uneventful, and no exacerbation of neurological signs and symptoms was recognized. No postoperative analgesia was required. CONCLUSION: General anaesthesia and tracheal intubation with sevoflurane and nitrous oxide provided safe anaesthesia for a patient with APBD.     

Relative contribution of low-density lipoprotein receptor and lipoprotein lipase gene mutations to angiographically assessed coronary artery disease among French Canadians

A possible future clinical application of NMDA receptor antagonists is the control of the development of opiate analgesic tolerance. Therefore, the ability of NMDA receptor antagonists to modify the acute analgesic effects of opiates becomes increasingly important. The present study sought to evaluate the analgesic potency of combined administration of morphine (5-20 mg/kg) and a competitive NMDA receptor antagonist D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid; 0.3-5.6 mg/kg) in the tail-flick and tail-pinch tests with rats. It was found that D-CPPene significantly increased the duration of morphine analgesia, but there was hardly any evidence for potentiation of morphine analgesia shortly after morphine administration. This effect could only in part be attributed to the D-CPPene-induced disruption of the development of 'learned hyperresponsiveness' (i.e., acquisition of decreased latencies to escape from repeated exposures to noxious stimulation). In addition, the plasma concentration of morphine was not affected by concurrent treatment with D-CPPene.     

Kinetic properties and stereospecificity of the monomeric dUTPase from herpes simplex virus type 1

The heptadecapeptide orphanin FQ or nociceptin (OFQ/N), the endogenous ligand for the orphan opioid receptor, has a complex pharmacology in mice, eliciting either an anti-opioid/hyperalgesic action or analgesia depending upon the dose and testing paradigm. Unlike mice, orphanin FQ/nociceptin fails to elicit hyperalgesia in the rat following intracerebroventricular injection. Both OFQ/N and a truncated version, OFQ/N(1-11), produce a robust analgesic response. OFQ/N analgesia is readily antagonized by the opioid antagonists naloxone or diprenorphine, despite their very poor affinity for the cloned orphan opioid receptor. Antisense studies revealed that probes targeting the second and third coding exon of the orphan clone significantly attenuate OFQ/N analgesia, while the exon 1 probe was inactive. These results indicate that OFQ/N elicits a naloxone-sensitive analgesia in rats similar to that previously reported in mice.     

The role of growth factors, cytokines, and vasoactive compounds in obstructive nephropathy

The pre-emptive analgesia concept suggests that pre-administration of analgesics may enhance the efficacy of these drugs. This review has selected the data from the literature according to two types of methodological criteria: Sackett's criteria, and those specific of pre-emptive analgesia studies. Infiltration, spinal and peripheral nerve blocks using local anaesthetic drugs do not seem to produce pre-emptive analgesia. The few positive results have limited clinical significance. The results concerning opioids are contradictory and the clinical significance is limited. Preoperative oral administration of non steroidal anti-inflammatory drugs (NSAIDs) offers no benefit. Intravenous pre-administration has a limited advantage, but enhances perioperative bleeding. Ketamine, an NMDA receptor antagonist, may have some pre-emptive analgesic properties according to the few studies available. In conclusion, pre-administration of analgesic drugs represents the usual strategy for the anaesthesiologist (spinal or peripheral block, infiltration, opioids). In other cases (NSAIDs, ketamine), pre-administration represents a change in usual practice. This is not justified for NSAIDs; NMDA receptor antagonists may offer an interesting research area. Data concerning pre-emptive analgesia for chronic pain syndrome such as phantom limb pain are quite limited.     

Effects of xenon on hemodynamic responses to skin incision in humans

BACKGROUND: The authors evaluated the hemodynamic suppressive effects of xenon in combination with sevoflurane at skin incision in patients undergoing surgery. METHODS: Forty patients were assigned randomly to receive one of the following four anesthetics: 1.3 minimum alveolar concentration (MAC) sevoflurane, 0.7 MAC xenon with 0.6 MAC sevoflurane, 1 MAC xenon with 0.3 MAC sevoflurane, or 0.7 MAC nitrous oxide with 0.6 MAC sevoflurane (n = 10 each group). Systolic blood pressure and heart rate were measured before anesthesia, before incision, and approximately 1 min after incision. RESULTS: The changes in hemodynamic variables in response to incision were less with sevoflurane in combination with xenon and nitrous oxide than with sevoflurane alone. Changes in heart rate (in beats/min) were 19+/-11 (+/- SD) for sevoflurane alone, 11+/-6 for 0.7 MAC xenon-sevoflurane, 4+/-4 for 1 MAC xenon-sevoflurane, and 8+/-7 for nitrous oxide-sevoflurane. Changes in systolic blood pressure were 35+/-18 mmHg for sevoflurane alone, 18+/-8 mmHg for 0.7 MAC xenon-sevoflurane, 16+/-7 mmHg for 1 MAC xenon-sevoflurane, and 14+/-10 mmHg for nitrous oxide-sevoflurane. CONCLUSIONS: Xenon and nitrous oxide in combination with sevoflurane can reduce hemodynamic responses to skin incision compared with sevoflurane alone. One probable explanation may be that xenon has analgesic properties similar to those of nitrous oxide, although the exact mechanism is yet to be determined.     

I'd rather have a baby than root canal, or how to treat the fearful patient

I have tried to enumerate the ways that can be used to communicate with the apprehensive patient in order to dispel the myths and allay the fears of root canal therapy. The categories discussed were communication, local anesthesia, nitrous oxide analgesia, pre-visit sedation and i.v. sedation. Some or all of these disciplines can be used depending on the situation.     

A case of acquired petrous cholesteatoma associated with insidious middle ear infection treated by staging the surgical procedures

STUDY OBJECTIVE: To compare the efficacy of preincision wound infiltration with bupivacaine to wound infiltration at the end of the operation. DESIGN: A prospective, randomized, double-blind study. SETTING: University medical center. PATIENTS: 56 ASA status I and II women scheduled for abdominal hysterectomy were randomly assigned to one of three treatment groups. INTERVENTIONS: Group 1 (control) received no local anesthetic infiltration. Group 2 received subcutaneous infiltration with 40 ml of bupivacaine 0.5% (pH 6.9) 15 minutes prior to incision. Group 3 received wound infiltration with a similar solution at the end of surgery. Anesthesia was induced with thiopental 3.0 mg/kg i.v., droperidol 50 micrograms/kg i.v., and sufentanil 0.5 microgram/kg i.v. and maintained with nitrous oxide 67% in oxygen and sufentanil 0.1 microgram/kg IV boluses as required. Postoperative pain was treated with morphine via a patient-controlled analgesia delivery system for 24 hours, followed by oral hydrocodone for 3 days. MEASUREMENTS AND MAIN RESULTS: The opioid consumption was recorded for 4 days postoperatively. Pain scores were measured at 4 to 8-hour intervals using 100 mm visual analog scales. There was no difference in either the opioid analgesic requirements or the pain scores between the three study groups. CONCLUSIONS: Wound infiltration, either preincision or postincision, had no clinically significant effect on the pain scores or analgesic requirements following abdominal hysterectomy.     

VDAC/porin is present in sarcoplasmic reticulum from skeletal muscle

Direct intraspinal injection of the catecholamines epinephrine and norepinephrine, and the alpha-adrenergic agents dexmedetomidine and clonidine, produced a dose-dependent elevation of pain thresholds in the Northern grass frog, Rana pipiens. Significant analgesic effects were noted for at least 4 h. The analgesic effect of intraspinal dexmedetomidine or epinephrine was blocked by systemic pretreatment with the alpha 2-adrenoceptor antagonists, yohimbine and atipamezole, but not with the alpha 1-adrenoceptor antagonist, prazosin. Dose-response analyses showed that dexmedetomidine, epinephrine, norepinephrine had similar analgesic potencies, but clonidine was significantly less potent. Analgesia was observed without accompanying motor or sedative effects. These results suggest that alpha 2-adrenoceptor mechanisms which mediate analgesia may have evolved early in vertebrate evolution and that descending epinephrine-containing fibers in the amphibian nervous system may be the source of endogenous catecholamines regulating nociceptive sensitivity in the amphibian spinal cord.     

Pain and dissociation in the cold pressor test: A study of hypnotic analgesia with "hidden reports" through automatic key pressing and automatic talking.

To test whether pain blocked by hypnotic analgesia may still be perceived at some level, 20 highly hypnotizable undergraduates participated in an experiment involving cold pressor pain in the normal condition and in hypnotically suggested analgesia. 3 reports were obtained reflecting felt pain within the hypnotic analgesia condition: the usual verbal report on a numerical scale, a manual report by "automatic key pressing," and a retrospective verbal report through "automatic talking." 9 Ss who were amnesic for both keypressing and automatic talking reported more pain in the automatic (hidden) reports than in their usual verbal reports. 8 of these 9, following release of amnesia, had a clear perception of 2 levels of awareness of the pain: the usual hypnotic experience of pain attenuated by analgesia suggestions, and a knowledge at another level of a more severe pain. In no case, however, did an S give a retrospective report of normal suffering at this "hidden" level. The hypnotically analgesic S may have reported no pain verbally because he was amnesic for it; when amnesia was removed he recalled the sensory pain, but without a suffering component, because suffering apparently did not occur. (24 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Early endoscopic realignment as primary therapy for complete posterior urethral disruptions

Circadian changes in the interactions between L-NG-nitroarginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, and morphine-induced antinociception were investigated by the mouse hot-plate test. Both the basal pain sensitivity and morphine-induced analgesia undergo significant 24 h variations. L-NAME (40 mg/kg, i.p.) alone did not show any antinociceptive activity, but potentiated morphine-induced analgesia when combined with morphine at all injection times. In terms of percentage absolute potentiation (%AP), L-NAME dramatically augmented the analgesic effect of morphine in the late dark period at 19 hours after lights on (HALO). It is concluded that nitric oxide (NO) is involved in the modulation of the analgesic effect of morphine; thus, the L-NAME and morphine combination might be beneficial in alleviating pain.     

Opiate antagonists and long-term analgesic reaction induced by inescapable shock in rats.

Five experiments with 240 male albino rats examined the influence of opiate antagonists (naltrexone; 1–24 mg/kg, ip) on both the short-term analgesic reaction resulting 30 min after exposure to inescapable shock and the long-term analgesic reaction resulting after reexposure to shock 24 hrs after inescapable shock exposure. Exp I showed that the long-term analgesic reaction could be reduced by administration of naltrexone prior to exposure to inescapable tail shock. Exp II showed that the reduction in the long-term analgesic reaction produced by naltrexone was dose-dependent. Exp III showed that the long-term analgesic reaction could also be reduced by administration of naltrexone prior to reexposure to shock. Exp IV showed that the long-term analgesic reaction could be reduced by administration of a large dose of naloxone prior to reexposure to shock. Exp V showed that the short-term analgesic reaction was reduced by naltrexone administered prior to inescapable shock. Implications for the biochemical substrates of both learned helplessness and stress-induced analgesia are discussed. (56 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Potential of succinylcholine-induced neuromuscular blockade by nitrous oxide

To evaluate the potentiating effect of nitrous oxide on the succinylcholine (SCh)-induced neuromuscular blockade, 0.16, 0.20, 0.25 or 0.31 mg.kg-1 of Sch was given during thiamylal-fentanyl anesthesia with or without nitrous oxide, and the evoked electromyograph of hypothenar muscles was measured. ED50 and ED95 in the group receiving nitrous oxide were 0.187 and 0.301 mg.kg-1, and 0.218 and 0.389 mg.kg-1 in the group not receiving nitrous oxide respectively. In the presence of nitrous oxide, the dose-response curve (DRC) was shifted to the left significantly (P < 0.01). By the multiple regression analysis, the degree of the neuromuscular blockade was shown to be affected by dose and nitrous oxide. It was demonstrated that nitrous oxide decreased electromyographically measured SCh requirements by 16.1%. In addition, the dose-effect relationship for SCh-induced neuromuscular blockade varied widely, and gender did not affect the degree of block.     

The effects of idazoxan combined with 30% nitrous oxide on the jaw-opening reflex in the rat

In rats, the jaw-opening reflex is elicited by activation of a nociceptive receptor by the electric stimulation of the tooth pulp. This study was undertaken to assess the effects of 30% nitrous oxide and 30% nitrous oxide with idazoxan, an alpha 2-adrenergic antagonist, on this reflex. Each rat received electric stimulation for the jaw-opening reflex at 3, 5, 7, 10, 15, and 20 min after both the start of inhalation and the withdrawal of 100% oxygen or 30% nitrous oxide in oxygen. Idazoxan, 400 micrograms/ kg, was administered intravenously at the start of the inhalation period. Amplitudes significantly decreased during inhalation of nitrous oxide, but they returned gradually to control levels after cessation of nitrous oxide inhalation. In the cases of 100% oxygen, 100% oxygen with idazoxan, and 30% nitrous oxide in oxygen with idazoxan, amplitudes did not change from controls during and after 30% nitrous oxide inhalation. The latency remained unchanged irrespective of the treatment. Since in rats the degree of inhibition by 30% nitrous oxide in oxygen is partially diminished by administration of idazoxan, we conclude that nitrous oxide affects an alpha 2-adrenergic receptor in the central nervous system.