A novel molecule with peripheral opioid properties: the effects on hypercarbic and hypoxic ventilation at steady-state compared with morphine and placebo.

Frakefamide (FF), is a new peripherally acting mu-opioid receptor agonist. The aim of this double-blind, randomized, double-dummy, four-way, crossover study was to investigate FF effects on hypercarbic and hypoxic ventilation at steady-state after a 6-h infusion. We compared the effect with 2 clinical doses of morphine (M-small and M-large) and placebo in 12 healthy men. The subjects received 1.22 mg/kg of FF, 0.44 mg/kg of M-large, and 0.11 mg/kg of M-small. Sodium chloride 9 mg/mL was used as placebo. Ventilation was studied by pneumotachography and in-line capnography. There were no ventilatory effects caused by FF or placebo. As expected, large doses of morphine influenced both hypercarbic and hypoxic ventilatory responses. We conclude that there were no signs of central respiratory depression caused by FF after 6 h of constant infusion, which supports a peripheral action of the compound. However, morphine caused a dose-dependent central depression during the hypercarbic ventilatory response and a mild depression of hypoxic ventilatory response.

A novel molecule (frakefamide) with peripheral opioid properties: the effects on resting ventilation compared with morphine and placebo.

In animal models frakefamide (FF) is a potent analgesic that acts as a peripheral active mu-selective receptor agonist. In this double-blind, randomized, double dummy four-way crossover study in 12 healthy male subjects, we investigated the effects on resting ventilation of FF and 2 dose levels of morphine compared with placebo. Each drug was infused for 6 h. The subjects received 1.22 mg/kg FF, 0.43 mg/kg morphine (M-large), and 0.11 mg/kg morphine (M-small). Sodium chloride 9 mg/mL was used as placebo. Ventilation was measured by pneumotachography and inline capnography. Blood was collected and plasma concentrations of FF and morphine and its metabolites were analyzed. Within 15 min after administration of FF all subjects complained of a transient myalgia, which disappeared within 30 min. At target measurement (335 min), there were no differences in tidal volume among the groups. Respiratory rates were, however, slower in the two M-groups (P < 0.05 in M-small and P < 0.001 in M-large) compared with FF and placebo. Minute volume was significantly less in the M-large group compared with the FF (P < 0.01) and placebo (P < 0.01) groups. This difference was reflected by an elevated ETco(2) in the M-large group (P < 0.01). We conclude that, during resting ventilation, FF, unlike morphine, did not cause central respiratory depression. This suggests that FF has only peripheral mu-opioid agonist activity in humans.

Hypercarbic and hypoxic ventilatory responses after intrathecal administration of bupivacaine and sameridine.

Sameridine is a new compound with both local anesthetic and opioid properties (partial micro -opioid receptor agonist). It was intended for intrathecal administration to provide anesthesia for surgery and extended postoperative analgesia. In this double-blinded pharmacodynamic study with a two-parallel-group design, we investigated, during a 24-h period, the effects of intrathecal sameridine and bupivacaine on ventilation at rest and at ventilatory challenges during hypercarbia and hypoxia. Twenty-four healthy volunteers received either 25 mg of sameridine or 15 mg of bupivacaine intrathecally. Ventilation was measured by pneumotachography and in-line capnography. Sedation was rated by a visual analog scale. Segmental spread and development of motor and sensory block were similar in both groups. There was a decrease in tidal volume 2.5 to 6 h after injection in the bupivacaine group. This was seen only at 4 h in the sameridine group. There were no other major ventilatory differences between sameridine and bupivacaine during resting ventilation. Hypercarbic (tidal volume, mean inspiratory flow) and hypoxic (mean inspiratory flow) ventilatory responses were slightly decreased in the sameridine group, but not in the bupivacaine group. We conclude that intrathecal administration of sameridine or bupivacaine in healthy volunteers produces similar, minor effects on ventilatory responses over a 24-h observation period.