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Because only limited and controversial data exist concerning the respiratory effects of clonidine in humans, the authors evaluated the respiratory effects of clonidine alone and in combination with morphine, in 12 healthy adult males. Subjects received clonidine (0.3-0.4 mg orally), morphine (0.21 mg/kg intramuscularly), or the same doses of the two drugs combined, at three separate sessions in a randomized fashion. The study was balanced for all possible sequences of drug administration. Blood pressure, heart rate, hemoglobin oxygen saturation via finger pulse oximetry, and ventilatory and occlusion pressure responses to CO2 were obtained before and 20, 40, 60, 90, 120, 180, 240, 300, and 360 min after administration of drug or drug combination. Systolic blood pressure decreased significantly only in the clonidine and clonidine plus morphine groups (P less than 0.05). Hemoglobin oxygen saturation decreased by a statistically significant (P less than 0.05), though clinically minor, degree only in the morphine or morphine plus clonidine groups. Clonidine alone did not depress the slope of either the ventilatory or the occlusion pressure response to CO2. In addition, clonidine did not significantly worsen morphine-induced depression of the slope of the ventilatory and occlusion pressure responses in the drug combination group. Both the ventilatory and occlusion pressure responses to CO2 were shifted to the right in all three drug groups (P less than 0.05) but were shifted to a significantly lesser degree by clonidine alone than by morphine and morphine plus clonidine. In healthy young adult males, clonidine alone produces little respiratory depression and does not significantly potentiate morphine-induced respiratory depression.

More than 80 deaths have occurred after the use of midazolam (Versed), often in combination with opioids, to sedate patients undergoing various medical and surgical procedures. We investigated the respiratory effects of midazolam (0.05 mg.kg-1) and fentanyl (2.0 micrograms.kg-1) in volunteers. The incidence of hypoxemia (oxyhemoglobin saturation less than 90%) and apnea (no spontaneous respiratory effort for 15 s) and the ventilatory response to carbon dioxide were evaluated. Midazolam alone produced no significant respiratory effects. Fentanyl alone produced hypoxemia in half of the subjects and significant depression of the ventilatory response to CO2, but did not produce apnea. Midazolam and fentanyl in combination significantly increased the incidence of hypoxemia (11 of 12 subjects) and apnea (6 of 12 subjects), but did not depress the ventilatory response to CO2 more than did fentanyl alone. Adverse reactions linked to midazolam and reported to the Department of Health and Human Services highlight apnea- and hypoxia-related problems as among the most frequent adverse reactions. Seventy-eight per cent of the deaths associated with midazolam were respiratory in nature, and in 57% an opioid had also been administered. All but three of the deaths associated with the use of midazolam occurred in patients unattended by anesthesia personnel. We conclude that combining midazolam with fentanyl or other opioids produces a potent drug interaction that places patients at a high risk for hypoxemia and apnea. Adequate precautions, including monitoring of patient oxygenation with pulse oximetry, the administration of supplemental oxygen, and the availability of persons skilled in airway management are recommended when benzodiazepines are administered in combination with opioids.

The authors evaluated the effect of transdermal scopolamine on the incidence of postoperative nausea, retching, and vomiting after outpatient laparoscopy in a double-blind, placebo-controlled study. A Band-Aid-like patch containing either scopolamine or placebo was placed behind the ear the night before surgery. Anesthesia was induced with fentanyl (0.5-2 micrograms/kg iv), thiopental (3-5 mg/kg iv), and succinylcholine (1-1.5 mg/kg iv) and maintained with isoflurane (0.2-2%) and nitrous oxide (60%) in oxygen. Scopolamine-treated patients had less nausea, retching, and vomiting compared with placebo-treated patients (P = 0.0029). Severe nausea and/or vomiting was present in 62% of the placebo group but only 37% of those getting the scopolamine patch. Repeated episodes of retching and vomiting were also less frequent in the scopolamine group compared with the placebo group (23% vs. 41%; P = 0.0213) as was the need for additional antiemetic therapy (13% vs. 32%; P = 0.0013). Patients in the scopolamine group were also discharged from the hospital sooner (4 +/- 1.3 vs. 4.5 +/- 1.5 h; P = 0.0487). Side effects were more frequent among those patients treated with the scopolamine patch (91% vs. 45%; P less than 0.05) but were not troublesome. The authors conclude that transdermal scopolamine is a safe and effective antiemetic for outpatients undergoing laparoscopy.

The magnitude and duration of analgesia and respiratory depression induced by fentanyl (1.0, 2.0, and 4.0 micrograms/kg) and sufentanil (0.1, 0.2, and 0.4 microgram/kg) after intravenous administration over 30 s were measured in 30 healthy young adult male volunteers divided into three groups and studied in a double-blind, randomized fashion. Each volunteer received one dose of fentanyl or sufentanil and no sooner than 48 h later, the corresponding equipotent dose of the other opioid. End-tidal CO2 and ventilatory and occlusion pressure responses to CO2 rebreathing were used to measure drug-induced respiratory effects. Analgesic effects were assessed by changes in the pain threshold to electric shock applied to the forearm. Plasma levels of fentanyl and sufentanil were measured by radioimmunoassay. Testing and sampling intervals were 5, 30, 60, 90, 120, 240, 300, and 360 min after drug administration. The magnitude and duration of depression of the ventilatory and occlusion pressure response were significantly less with sufentanil compared with fentanyl, irrespective of dose. Ventilatory and occlusion pressure responses returned to control values by 30 and 30 min, respectively, after sufentanil and by 240 and 120 min, respectively, after fentanyl. Statistically significant elevations of the pain threshold were, however, greater and longer lasting after sufentanil compared with fentanyl. Pain threshold returned to control values 180 min after sufentanil but only 90 min after fentanyl. These results suggest that sufentanil may provide better patient comfort with less respiratory depression than does fentanyl.

The authors determined whether fentanyl incorporated into a candy lollipop, oral transmucosal fentanyl citrate (OTFC), would cross mucosal tissues of the mouth in sufficient quantities during and after dissolution to produce sedation and/or analgesia. Associated respiratory and circulatory changes, side effects, and plasma concentrations of fentanyl were also measured. The evaluations were done in 28 adult volunteers who received fentanyl citrate in doses of 5, 4, 2, 1, and 0.5 mg in OTFC and rapidly sucked the lollipops (N = 20) or allowed them to passively dissolve (N = 8). Rapid consumption of OTFC resulted in more rapid onset of a pleasant feeling (first subjective sensation) but not more rapid onset of objective sedation or analgesia than passive dissolution. There was a significant correlation between dose of OTFC and magnitude of sedation (P less than 0.001, Spearman rank correlation = -0.82). Higher doses of OTFC produced greater and longer lasting analgesia and respiratory depression and a higher incidence of nausea and vomiting than lower doses, but pruritus (33%-87%) was not related to the dose of OTFC. Heart rate and arterial blood pressures were not changed by any dose of OTFC. The data indicate that low doses of OTFC (0.5 and 1 mg, equivalent to 5-20 micrograms.kg-1 of fentanyl citrate) produce analgesia and sedation with minimal side effects and little respiratory depression in adult volunteers and deserve further evaluation in patients.

The authors compared naloxone and nalbuphine as antagonists of opioid-induced respiratory depression to determine the relative efficacies and safety of the two agents. In a double-blind, randomized fashion, 90 anesthetized patients received a mean dose of 25 micrograms/kg fentanyl during surgery. Inadequate spontaneous respirations at the end of anesthesia were treated with either naloxone 0.08 mg or nalbuphine 2.5 mg IV every 2 min while heart rate (HR), systolic and diastolic blood pressures (SBP, DBP), respiratory rate (RR), and tidal volume (TV) were measured at 2-min intervals. Arterial blood samples for analysis of PaCO2, PaO2, and pH were drawn when spontaneous ventilation resumed, and 30 and 60 min later. Narcotic antagonism and respiration were deemed adequate when TV was greater than or equal to 4 ml/kg and RR greater than or equal to 8 breaths/min. Heart rate, SBP, DBP, TV and RR were recorded, as were the occurrence of renarcotization (RR less than 8) and analgesic requirements every 5 min during the recovery room stay. Sixty of 90 patients required narcotic antagonism at the end of surgery. No patient required more than three doses (0.24 mg) of naloxone or four doses (10 mg) of nalbuphine. Both antagonists produced similar and moderate increases in SBP and HR while restoring adequate spontaneous ventilation. There were no significant differences in TV, RR, or arterial blood gases (ABGS) between the two groups after narcotic reversal.(ABSTRACT TRUNCATED AT 250 WORDS)