B. F. Esposito

Efficacy of Methylnaltrexone Versus Naloxone for Reversal of Morphine-induced Depression of Hypoxic Ventilatory Response

Methylnaltrexone (MNTX) is a quaternary derivative of naltrexone. It does not cross the blood-brain barrier and, thus, it reverses peripherally mediated effects of morphine without blocking its centrally located analgesic effects. The effects of MNTX on morphine-induced depression of hypoxic ventilatory response are unknown. We evaluated the efficacy of MNTX, compared with naloxone, in reversing this effect. On three sessions separated by a week, 10 healthy male volunteers received morphine, 0.125 mg/kg, as a bolus at 20 min after completing a control hypoxic ventilatory challenge. At 60 min, naloxone, 5 μg/kg, MNTX, 0.3 mg/kg, or placebo was administered in a randomized double-blind order. Four isocapnic hypoxic ventilatory challenges were conducted: 0 min (control), 40 min (postmorphine), and 80 and 120 min (postreversal) and the hypoxic respiratory responses were recorded. Morphine administration was associated with a significant depression in hypoxic responses: The slope of the response (L/min/Spo2) and the predicted ventilation at 80% O2 saturation (VE80) (L/min) decreased significantly in the three sessions (P < 0.05). Naloxone injection reversed the respiratory depression at 80 min (85% of the control value of the slope and 89% of VE80), whereas MNTX and placebo did not. At 120 min, the slope (69%) and VE80 (80%) after naloxone administration were not significantly different from control. MNTX slope (69%) was not statistically different from the control, whereas VE80 (70%) was still depressed (P < 0.05). Placebo slope and VE80, at 120 min, remained lower than the control (P < 0.05). These data show that MNTX is not as effective as naloxone for reversal of morphine-mediated depression of respiration during acute hypoxia.

A comparison of the cost-effectiveness of remifentanil versus fentanyl as an adjuvant to general anesthesia for outpatient gynecologic surgery.

The unique pharmacokinetic properties of remifentanil make it a potentially useful adjuvant during general anesthesia for ambulatory surgery. Fentanyl, inexpensive and easy to administer, is the most common opioid used for this purpose. As an adjuvant to general anesthesia for outpatient gynecologic surgery, we questioned if remifentanil was cost-effective as an alternative to fentanyl. Thirty-four patients undergoing gynecologic laparoscopy or hysteroscopy were prospectively and randomly assigned to a standard practice (n = 18) or a study (n = 16) group. Standard practice patients received fentanyl (3 &mgr;g/kg) before induction; study patients received remifentanil by continuous infusion (0.5 &mgr;g · kg · min−1 at induction, then 0.2 &mgr;g · kg · min−1). Sevoflurane was titrated to a Bispectral index value of 40–55. We investigated recovery profiles, patient and health care professional satisfaction, and drug costs. The incidence of rescue antiemetic treatment (2 of 16 vs 8 of 18;P = 0.013) and the nausea visual analog scale scores during second stage recovery (0.2 vs 0.6;P = 0.044) were more frequent in the study group. However, the incidence of intraoperative adverse events and other postoperative sequelae, recovery times, pain and nausea visual analog scale scores, opioid analgesic dosage requirements in the postanesthetic care unit, and satisfaction survey responses were similar between groups. Perioperative drug costs per patient were

A-3665, a new short-acting opioid: A comparison with alfentanil

17.72 more in the remifentanil (vs fentanyl) group. Implications As an opioid adjuvant to general anesthesia for outpatient gynecologic laparoscopy and hysteroscopy, the benefits of remifentanil did not offset its added cost as compared with fentanyl.

Effect of Slow Versus Fast Desaturation on Ventilatory Response to Hypoxia

A-3665 is a new short-acting synthetic opioid of the piperidine class. We conducted a double-blind, escalating dose comparison of A-3665 to alfentanil and placebo. Analgesic efficacy was assessed after the administration of A-3665 in increasing intravenous doses (0.25, 0.5, 1, 2, 4, 8, 16, 32, and 64 μg/kg) to nine groups of volunteers. At the lower doses (0.25, 0.5, 1, and 2 μg/kg), five volunteers were in each group; four received A-3665 and one received placebo in a double-blind manner. There were nine volunteers in each of the next three groups; four received A-3665 (4, 8, or 16 μg/kg), four received alfentanil (4,8, or 16 μg/kg), and one received placebo. At the 32 μg/kg and 64 μg/kg dose levels, five subjects each were to be enrolled (four to receive A-3665 and one to receive placebo); however, the study was terminated after two subjects in the 64 μg/kg group had significant respiratory depression. Both drugs caused potent analgesia, compared with placebo, with peak effect occurring 3 min after injection. There was no significant difference in analgesic potency of A-3665 and alfentanil as measured by tolerance to tibial pressure at 3 min. At the dose of 16 μg/kg, both drugs significantly increased pain tolerance to tibial pressure compared with placebo at 3 min, but alfentanil continued to display significant analgesic effect versus placebo and versus A-3665 at 6, 11, and 15 min after injection. A-3665 caused significant respiratory depression at doses of 32 μg/kg and 64 μg/kg, but alfentanil did not induce significant respiratory depression at the doses tested. A-3665 is a potent opioid analgesic that can be administered safely to humans. Over the dosage range tested, it appears equipotent to alfentanil but has a significantly shorter duration of action. It may also cause more respiratory depression and have a greater incidence of pruritus. (Anesth Analg 1993;76:812–6)

Naloxone-induced and spontaneous reversal of depressed ventilatory responses to hypoxia during and after continuous infusion of remifentanil or alfentanil.

The ventilatory response to progressive hypoxia was studied in 15 healthy adult males by employing two different rates of desaturation. In a slow hypoxic ramp, peripheral oxygen saturation was gradually reduced to 70% over 10-13 min, while in a fast ramp the saturation was reduced over 3-5 min. The ventilatory response to hypoxia was evaluated as the slope of the regression between oxygen desaturation and minute ventilation (l/min/%). There was no significant difference in the slope between the slow and fast ramps. The subjects were further divided into two subgroups; namely high and low responders, according to the value of their slopes. A slope of 0.6 l/min/% was considered the cut-off limit for this classification. In the group of high responders, the hypoxic ventilatory response was significantly higher with the slow ramp than with the fast ramp (p < 0.05). In the low responders, the response was significantly higher with the fast ramp (p < 0.05). We conclude that the hypoxic ventilatory responses are influenced by the rate of desaturation and they appear to be related to the individual sensitivity to hypoxia. These responses are reversed in the low compared with the high responders.