Opioids and regulation of breathing

Abstract: A most important challenge even in modern medicine is effective treatment of pain. Respiratory depression is the most feared side effect of analgesic treatment in the clinical situation. The serious effect of opioid induced respiratory depression and our incomplete understanding of this phenomenon are reasons why clinicians continue to hesitate to prescribe opioid analgesics. It is well known that opioids depress minute ventilation, tidalvolume and respiratory rate and that the responsiveness to hypercarbia is diminished. The search for analgesics without serious side effects is an important target. In line with this, new molecules have been developed, including sameridine, a partial µ-opioid receptor agonist with local anesthetic properties, and frakefamide, a peripherally active µ-opioid receptor agonist. The general aim of these studies was to extensively examine if these drugs depress ventilation. In study I, we investigated the effects on resting ventilation of two doses of sameridine 0.15 mg/kg (S-Small) and 0.73 mg/kg (S-Large) in comparison with 0.10 mg/kg of morphine. Plasma was collected and analysed for sameridine and morphine. In study II, two doses of sameridine 0.15 mg/kg (S-Small) and 0.73 mg/kg (S-Large) were compared to 0.10 mg/kg of morphine and placebo was investigated after hypercarbic challenge. In study III, intrathecal sameridine and bupivacaine were compared at resting ventilation and at ventilatory challenges during hypercarbia and hypoxia. In studies IV and V frakefamide was investigated during resting ventilation (study IV) and after hypercarbic and hypoxic ventilatory challenges (study V) at steady state. The effect was compared with two clinical doses of morphine (M-low and M-high) and placebo. The subjects received in total 1.22 mg/kg FF, 0.44 mg/kg M-high and 0.11 mg/kg M-low. Sodium chloride 9 mg/ml was used as placebo. Blood was collected and plasma concentration analysed for frakefamide, morphine and its metabolites. All studies were performed in healthy volunteers breathing air through a transparent facemask. Minute ventilation (VE) and respiratory rate (RR) were measured by integration of the flow signal from a pneumotachograph. Flow (V), tidal volume (VT), and in-line end-tidal C02 (ETC02) were recorded on an ink-jet recorder and stored in a computer. Inspired and expired concentrations Of 02 were continuously recorded. The most important findings in this series were that the combined molecule with both local anesthetic and partial µ-opioid receptor agonist effects caused a depression of respiratory motor function while respiratory rate was unchanged. Intrathecal sameridine reduced the tidal volume response to C02 stimulation of breathing, wheras intrathecal bupivacaine allowed tidal volumes to increase during hypercarbia. Clinical doses of sameridine did not impair resting ventilation. It was demonstrated that drug design of opioid agonists with peripheral action is feasible and that frakefamide do not interfere with regulation of breathing.