Reversal of opioid-induced bladder dysfunction by intravenous naloxone and methylnaltrexone.

Peripheral mechanisms may be involved in opioid actions on the urinary bladder. This double-blind study investigated whether opioid inhibition of bladder function is reversed by methylnaltrexone, a peripheral opioid antagonist. Thirteen healthy male volunteers received an intravenous (i.v.) infusion of remifentanil, 0.15 mcg/kg/min, then a single i.v. dose of study medication (methylnaltrexone 0.3 mg/kg, naloxone 0.01 mg/kg, or saline). Urodynamics were measured with indwelling bladder and rectal catheters, and pupil size was assessed with infrared pupillometry. Remifentanil decreased detrusor pressure in 21/25 sessions and caused complete urinary retention in 18/25. Voiding was possible in 7/7, 5/12, and 0/6 sessions after naloxone, methylnaltrexone, and saline, respectively (P=0.0013). Remifentanil caused marked miosis that was reversed by naloxone, but not methylnaltrexone or placebo (P<0.0001). The pupil data confirm that methylnaltrexone did not reverse central opioid effects. Reversal of urinary retention by methylnaltrexone indicates that peripheral mechanisms may play a role in opioid-induced bladder dysfunction.

Ondansetron is effective in decreasing postoperative nausea and vomiting.

The efficacy of ondansetron, a selective 5-HT3 receptor antagonist, in preventing postoperative nausea and vomiting in surgical patients was studied. Fifty women were randomized in a double-blind manner to receive either two 8 mg doses of intravenous ondansetron or two doses of placebo vehicle: the first given just before general anesthesia induction and the second 8 hours later. During the first 24 postoperative hours, the number of emetic episodes was recorded and the subjects rated their nausea on a scale from 0 to 10. Ondansetron-treated subjects had fewer emetic episodes (p less than 0.001) and lower subjective nausea scores (p less than 0.001). The number of complete responders (no emetic episodes and no rescue therapy) was 1 of 24 (4%) and 15 of 26 (58%) in the placebo and ondansetron groups, respectively (p less than 0.001). Ondansetron is clearly more effective than placebo in the prophylaxis of postoperative nausea and vomiting. The adverse event profile for ondansetron was similar to that of placebo.

Histamine antagonists and d-tubocurarine-induced hypotension in cardiac surgical patients.

Hemodynamic effects and histamine release by bolus injection of 0.35 mg/kg of d-tubocurarine were studied in 24 patients. H1- and H2-histamine antagonists or placebo were given before dosing with d-tubocurarine in a randomized double-blind fashion to four groups: group 1--placebo; group 2--cimetidine, 4 mg/kg, plus placebo; group 3--chlorpheniramine, 0.1 mg/kg, plus placebo; and group 4--cimetidine plus chlorpheniramine. Histamine release occurred in most patients, the highest level 2 minutes after d-tubocurarine dosing. Group 1 had a moderate negative correlation between plasma histamine change and systemic vascular resistance (r = 0.58; P less than 0.05) not present in group 4. Prior dosing with antagonists partially prevented the fall in systemic vascular resistance. These data demonstrate that the hemodynamic changes associated with d-tubocurarine dosing are only partially explained by histamine release. Thus prior dosing with H1- and H2-antagonists provides only partial protection.

Temperature gradients and rewarming time during hypothermic cardiopulmonary bypass with and without pulsatile flow.

Pulsatile perfusion during cardiopulmonary bypass (CPB) has been reported to have a number of beneficial effects, including attenuation of hormonal stress responses and improved organ blood flow and function. To determine the effect of pulsatile perfusion on temperature gradients and the time required for cooling and rewarming during CPB, we studied 21 patients scheduled for elective coronary artery operations. The patients were divided into two comparable groups: Group 1 (N = 11) had standard nonpulsatile perfusion, while in Group 2 (N = 10), a pulsatile pump was used. Rectal and esophageal temperatures were monitored, as were deltoid muscle temperatures and upper arm and finger skin temperatures in the same extremity. Ambient temperature, bypass flow and pressure, and bypass time were similar in both groups. Time required to cool to the lowest esophageal temperature was virtually identical for both groups (Group 1, 17 +/- 3 min; Group 2, 17.6 +/- 5 min), as was rewarming time (Group 1, 26.8 +/- 11 min; Group 2, 27.2 +/- 6 min). There were no significant differences in temperature measurements between groups except briefly during rewarming when finger skin temperature rose more rapidly in Group 1 (p less than 0.05). Temperature changes following CPB were the same for both groups, with rectal and esophageal temperatures showing an inverse relationships. These data demonstrate that pulsatile flow does not substantially alter rewarming time or temperature gradients during hypothermic CPB.

The clinical usefulness of agonist-antagonist analgesics in acute pain.

The opioid agonist-antagonists are a heterogeneous group of compounds capable of providing analgesia sufficient to treat moderate to severe acute pain. Pentazocine, butorphanol and nalbuphine produce subjective effects which are quite different from those of morphine. Lack of mood elevation and occasional dysphoria may contribute to a lower level of patient acceptance, but all of these analgesics are significantly safer than the pure agonists. Doses in the therapeutic range are unlikely to produce dangerous levels of respiratory depression in most patients. Other opioid side-effects such as nausea, constipation and biliary spasm appear to be less frequent as well. The mu partial agonist buprenorphine shares many of the safety advantages of the older drugs, and its subjective effects appear more morphine-like. It is not clear whether mu partial agonists have real clinical advantages over kappa-type analgesics. All of these drugs are opioid antagonists and are able to precipitate abstinence in individuals with significant prior exposure to opiates. Neither absolute potency nor the ratio of agonist to antagonist effect are predictors of therapeutic usefulness. There is now an enormous amount of clinical experience with the agonist-antagonists. In many, but not all, clinical situations they are acceptable alternatives to the morphine-like drugs.

Sufentanil citrate: a new opioid analgesic for use in anesthesia.

Sufentanil citrate is a potent analogue of fentanyl that has been evaluated primarily for use in opioid anesthesia. It is a pure mu receptor agonist and produces the typical spectrum of opioid effects. The major side effects are truncal rigidity and prolonged respiratory depression. In doses of 4-30 micrograms/kg sufentanil produces hypnosis and suppresses most hemodynamic and hormonal responses to surgery without producing significant cardiovascular depression. In this respect sufentanil and fentanyl have clear advantages over morphine, meperidine and potent inhalation anesthetics. Compared to fentanyl, sufentanil has a more rapid onset and shorter duration of action. The relatively high concentration of commercially available sufentanil injection will make it much more convenient for its intended application than fentanyl injection. This new agent will be used primarily for open-heart surgery and major operations in patients with severe cardiovascular compromise.

The tumescent technique: the effect of high tissue pressure and dilute epinephrine on absorption of lidocaine.

Injection of lidocaine into the subcutaneous tissues by the tumescent technique results in a delayed absorption of the local anesthetic and has allowed clinicians to exceed the maximum recommended dose of lidocaine without reported complications. However, little knowledge exists about the mechanisms that permit such high doses of lidocaine to be used safely with this technique. The presence of low concentration epinephrine and the increased tissue pressure resulting from the tumescent injection have both been implicated as important factors, but neither has been studied in patients whose results were not altered by the variability of the suction procedure. The purpose of this work was to determine the effect of tissue pressure during tumescent injection and presence of low concentration epinephrine on the absorption of lidocaine from subcutaneous tissues in human volunteers. Twenty healthy female human volunteers were randomized into four study groups. After body fat measurements, all subjects received an injection of 7 mg/kg of lidocaine into the subcutaneous tissues of both lateral thighs. The injected solution consisted of 0.1% lidocaine and 12.5 meq/liter sodium bicarbonate in normal saline with or without 1:1,000,000 epinephrine. Tissue pressure was recorded during injection using a specially designed double-barreled needle. The time required for injection was also recorded. Subjects in group 1 received lidocaine with epinephrine injected by a high-pressure technique. Group 2 subjects received lidocaine with epinephrine injected by a low-pressure technique. Group 3 subjects received lidocaine without epinephrine injected under high pressure. Group 4 subjects received lidocaine without epinephrine injected under low pressure. Following injection, sequential blood samples were drawn over a 14-hour period, and plasma lidocaine concentrations were determined by gas chromatography. No suction lipectomy was performed. Maximum tissue pressure during injection was 339 +/- 63 mmHg and 27 +/- 9 mmHg using high- and low-pressure techniques, respectively. Addition of 1:1,000,000 epinephrine, regardless of the pressure of injected fluid, significantly delayed the time to peak plasma concentration by over 7 hours. There was no significant difference in the peak plasma concentration of lidocaine among the four groups. Peak plasma concentrations greater than 1 mcg/ml were seen in 11 subjects. Epinephrine (1:1,000,000) significantly delays the absorption of lidocaine administered by the tumescent technique. High pressure generated in the subcutaneous tissues during injection of the solution does not affect lidocaine absorption. The delay in absorption may allow time for some lidocaine to be removed from the tissues by suction lipectomy. In addition, the slow rise to peak lidocaine concentration in the epinephrine groups may allow the development of systemic tolerance to high lidocaine plasma levels.

Anesthetic drug interaction: an overview.

Modern anesthetic techniques involve combinations of intravenous (i.v.) and inhaled anesthetic drugs that may produce synergistic (supraadditive), additive, or antagonistic interactions. Synergistic interaction is most likely to occur when two or more drugs produce similar effects by different mechanisms. All of the tested combinations of opioids and i.v. sedative-hypnotics have been shown to produce synergistic hypnotic effects, and the majority of these interactions are predictable and useful in daily practice. Opioids, benzodiazepines, lidocaine, and alpha-2 agonists can all reduce the requirements for volatile anesthetics, but only the opioids and the alpha-2 agonists produce this effect at clinically acceptable concentrations. The usefulness of a drug interaction depends on whether it produces greater efficacy or reduced toxicity. Surprisingly, these outcomes have only been specifically measured for a handful of common drug combinations.

Perioperative drug interactions.

The various classes of IV and inhalation anesthetics all appear to potentiate one another. Many of these interactions are clinically useful in outpatient anesthesia, and many are quite predictable. True synergy is most likely to occur when two drugs produce similar actions by slightly different mechanisms. These principles are particularly well demonstrated by the interactions of hypnotic drugs at the locus ceruleus. It is possible that the reduced anesthetic requirements seen in some disease states may involve similar mechanisms.

A randomized, double-blind, dose-response study of ondansetron in the prevention of postoperative nausea and vomiting.

STUDY OBJECTIVE: To determine the dose-response relationship of ondansetron in preventing postoperative nausea and vomiting (PONV) in women undergoing elective surgery. DESIGN: Prospective, randomized, double-blind study. SETTING: University-affiliated hospital. PATIENTS: 175 women aged 18 to 80 years scheduled for elective surgery. INTERVENTIONS: One of six doses of ondansetron (0.5 mg, 1 mg, 2 mg, 4 mg, 8 mg, 16 mg) or placebo was given prior to the induction of general anesthesia with propofol. Maintenance was with nitrous oxide, isoflurane, opioid, and muscle relaxant. MEASUREMENTS AND MAIN RESULTS: The study period began when the patient emerged from anesthesia. Nausea scores were recorded on a 0 to 10 scale at multiple time points during the 24-hour study period. Patient satisfaction via a visual analog scale (VAS) was determined at 1 and 24 hours after awakening. Rescue medication was given for severe nausea, three emetic episodes within 15 minutes, or if requested by the patient. The primary efficacy variable was the need for rescue antiemetic therapy. The dose-response curve (by logistic regression) of the percentage of patients not rescued versus dose indicated an ED50 of 0.54 mg (95% confidence interval 0.03-1.05 mg). Fewer patients required rescue in the 4 mg dose group compared with lower doses. However, the difference reached significance only in comparison with the 0.5 mg dose group. Survival analysis of the need for rescue, and nausea score versus time curves, also both suggested the superiority of the 4 mg dose compared with lower doses. In addition, there was a highly significant correlation between the lack of need for rescue and satisfaction with anesthesia at 24 hours after emergence. CONCLUSION: The recommended dose of ondansetron for PONV prophylaxis in women remains 4 mg.

A randomized, double-blind pilot study examining the use of intravenous ondansetron in the prevention of postoperative nausea and vomiting in female inpatients.

STUDY OBJECTIVE: To compare the efficacy and safety profiles of intravenous (IV) ondansetron (two 8 mg doses 8 hours apart) and a placebo when used in the prevention of postoperative nausea and emesis (vomiting or retching). DESIGN: Randomized, double-blind, placebo-controlled, parallel, multicenter pilot study. SETTING: Four university hospitals in the United States. PATIENTS: Two hundred seven women scheduled to undergo inpatient surgical procedures during general anesthesia. INTERVENTIONS: Patients were randomized to receive, in a double-blind fashion, either two 8 mg doses of IV ondansetron or a placebo. The first study drug dose was administered before induction of anesthesia; the second dose was given 8 hours later. Each study drug dose was admixed with normal saline to 20 ml and administered IV over 2 to 5 minutes. Vital signs were monitored immediately before and 1 minute after completion of the study drug infusion. MEASUREMENTS AND MAIN RESULTS: For the 24-hour period following operation, 60% of the patients who received ondansetron and 26% of the patients who received the placebo were emesis-free (p < 0.001). Subanalyses based on patients' previous history of general anesthesia indicated that ondansetron was superior to the placebo in preventing emesis regardless of history [66% vs. 33% in patients who had never had general anesthesia or had had no nausea or emesis following previous anesthesia (p = 0.001) and 50% vs. 17% in patients who had nausea or emesis following previous anesthesia (p = 0.005)]. Ondansetron also was superior to the placebo for the prevention of nausea over the 24-hour study period regardless of anesthesia history. Ondansetron was generally well tolerated. The adverse event, vital sign, and clinical laboratory test profiles were similar to those for the placebo. No patient who received ondansetron had untoward changes in central nervous system function, including sedation. CONCLUSIONS: Prophylactic IV ondansetron appears to be safe and causes a significant reduction in the frequency and severity of postoperative nausea and emesis.

Butorphanol in perspective.

Butorphanol tartrate is a highly effective opioid agonist-antagonist analgesic with qualitative as well as quantitative differences from the pure agonists. These differences are thought to be due to interaction with a distinct subset of opioid receptors. Although it relieves severe pain, the drug does not usually elevate mood, and it may occasionally cause dysphoria. Counterbalancing its disadvantages is a wealth of clinical experience with the drug showing an impressive record of safety. Butorphanol produces limited respiratory depression and smooth muscle spasm, and both effects are reversible with naloxone. The most prominent side effect is sedation, a property that is generally quite useful in the perioperative period. Butorphanol is a weak morphine antagonist, so it may interact with agonists like morphine or fentanyl. The chief advantages of this agent are its low toxicity and very low potential for abuse.

Central nervous system symptoms after intravenous lignocaine: dose-response during pregnancy.

There is continuing controversy over what dose of what drug should be used to identify an accidental intravascular or subarachnoid catheter placement in obstetric epidural anaesthesia. The purpose of this randomized, double-blind study was to evaluate the dose-effect relationship for the production of central nervous system (CNS) symptoms by intravenous lignocaine. Sixty first-trimester, pregnant patients divided into groups of 10 received saline or one of five doses of lignocaine (0.39, 0.5, 0.63, 0.79, and 1.0 mg kg-1) i.v. An ED95 of 1.12 mg kg-1 was calculated to produce reliable CNS symptoms when injected intravascularly. Lignocaine is an effective and reliable marker for intravenous injection in pregnant women.

Comparison of the sedative effects of butorphanol and midazolam.

Although kappa opioid agonists and certain agonist-antagonists are known to be sedating, this effect has not been well characterized in a drug-naive population. We compared the sedative properties of intravenous butorphanol with those of midazolam or the combination in 126 healthy preoperative patients. Subjects were randomly assigned to receive one of nine treatments in a double-blind fashion: 7.1, 22.5, or 71.4 micrograms/kg butorphanol; 4.3, 13.6, or 42.9 micrograms/kg midazolam; or 3.6 + 2.2, 11.3 + 6.8, or 35.7 + 21.5 micrograms/kg butorphanol and midazolam in combination. Eight visual analogue scales (VAS) were completed by the subject and an observer. The subject then performed two psychomotor tests (the Trieger dot test and the Halstead trail-making test) and was shown two playing cards in order to assess memory. The test drug was administered, and 5 min later the evaluations were repeated and two more cards were shown. On the following day the subjects were asked to recall the names of the playing cards. Butorphanol, midazolam, and their combination produced dose-related changes in VAS scores that were significant and qualitatively similar: subjects became sleepy, less nervous, weak, and less clear-thinking. There was no significant euphoria or dysphoria. The sedative and depressant effects on respiratory rate of the high-dose combination were significantly greater than those predicted by simple additivity: 14 of 14 subjects receiving the high dose of the butorphanol/midazolam combination had lid droop and marked sedation, and 2 of 14 subjects had respiratory rates of less than 4 breaths per min. All three drug treatments caused significant, dose-dependent impairment of psychomotor function.(ABSTRACT TRUNCATED AT 250 WORDS)

The opioid system and temperature regulation.

Opioid drugs and endogenous opioid peptides exert profound effects on body temperature. The particular effect seen is dependent on species, ambient temperature, degree of restraint imposed on the subject, route of drug administration, and a number of other factors. A major determinant is the opioid receptor type with which the agonist forms a complex. Evidence is accumulating that opioid ligands and opioid receptors play a functional role in thermoregulation, even though the opioid system may not be tonically active. Although further studies are needed to fully define the role and the mechanisms involved, as well as the generality of the role in a variety of species, a reasonable working hypothesis is that mu receptors in the rat and the mouse are involved in responses that result in heat gain, while K receptor activation results in opposite responses. To a large extent, the mu receptors in the rat appear to be located primarily in the brain, while the K receptors are outside the brain and perhaps even outside of the central nervous system. At present there is no evidence of involvement of delta receptors in thermoregulation. A fuller understanding of the opioid system and its role in thermoregulation will have broad clinical implications, as well as provide insights into interactions among the several neurotransmitter systems involved in thermoregulatory control of body temperature.

Effect of hypothermic hemodilutional cardiopulmonary bypass on plasma sufentanil and catecholamine concentrations in humans.

The effect of hypothermic hemodilutional cardiopulmonary bypass (CPB) on plasma sufentanil and catecholamine concentrations was studied in four groups of ten patients each, receiving four different doses of sufentanil. Samples for measurement of sufentanil were obtained before CPB, at 15, 30, and 45 minutes of CPB, during rewarming, immediately after and 15, 60, and 240 minutes after CPB. In addition, in groups III and IV, which received the highest dose of sufentanil, blood samples were also obtained for measurement of plasma levels of epinephrine and norepinephrine. Sufentanil concentration decreased in all groups with the start of CPB (group I, 2.92 +/- 0.2 to 2.04 +/- 0.2; group II, 3.30 +/- 0.3 to 1.51 +/- 0.2; group III, 7.08 +/- 0.7 to 3.45 +/- 0.3; group IV, 10.33 +/- 0.5 to 4.59 +/- 0.5 ng/ml). No further decreases occurred during CPB but increases occurred with rewarming. The first measurement after CPB approached the concentration before CPB (group I, 2.82 +/- 0.3; group II, 2.56 +/- 0.5; group III, 4.42 +/- 0.4; group IV, 6.10 +/- 0.4 ng/ml). Norepinephrine concentrations demonstrated a wide variability with no significant changes. Epinephrine levels increased significantly during rewarming in both groups (group III, 141 +/- 23 to 279 +/- 79 pg/ml; P less than 0.05; group IV, 105 +/- 24 to 267 +/- 68 pg/ml, P less than 0.05). The stability of plasma sufentanil concentrations during CPB suggest that no measurable metabolism or excretion occurred. The increase with rewarming and after CPB suggest significant sequestration.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of histamine in the hypotensive action of d-tubocurarine in humans.

The administration of d-tubocurarine (dTc) to animals and humans has been reported to produce hypotension. Experiments in animals suggest that the hypotension is a result of both ganglionic blockade and histamine release. In order to determine the role of histamine release in dTc-induced hypotension in humans, the authors developed a sensitive radioenzymatic assay for plasma histamine and measured plasma histamine following dTc administration (0.25-0.75 mg/kg) to 21 surgical patients. While neither fentanyl (3 microgram/kg) nor thiopental (6 mg/kg) produced a significant change in plasma histamine, dTc caused a dose-dependent increase in plasma [dose dTc vs. log (plasma histamine), r = 0.62 P less than 0.003]. The log (plasma histamine) correlated with the dTc-induced hypotension (r= 0.61, P less than 0.005). The data suggest that histamine release is an important factor in the hypotension accompanying dTc administration in humans.

Opiates and thermoregulation in mice. I. Agonists.

These studies were undertaken to determine the effects of morphine and other opiate and opioid agonists on body temperature in the mouse. Mice were lightly restrained, and rectal temperatures were monitored after injection of opiate analgesics at each of three ambient temperatures. The drugs tested were pure agonists representing eight different chemical classes. At 20 degrees C, morphine, hydromorphone, levorphanol, oxymorphone, methadone, etonitazene, fentanyl, etorphine and meperidine produced hyperthermia in low doses and hypothermia as the doses were raised. Codeine produced only hypothermia at 20 degrees C in the doses studied. At 25 degrees C, the hypothermic responses were greatly reduced in magnitude, and most drugs produced biphasic or only hyperthermic responses. At 30 degrees C, dose-related hyperthermia was the usual response with the exception of meperidine which produced only hypothermia, although a temperature increase was observed after anileridine, a closely related phenylpiperidine. There is good correlation between the relative potencies of the agonists with respect to their hypothermic effects in mice and their relative potencies as analgesics in mice. The temperature effects of morphine are complex but appear to be characteristic of opiate agonists as a class. The magnitude and the direction of the temperature responses to opiates are dose-dependent and profoundly influenced by the environmental temperature.