Two Studies on Reversal of Opioid-induced Respiratory Depression by BK-channel Blocker GAL021 in Human Volunteers

• Published in: Anesthesiology (Philadelphia) Vol. 121; no. 3; pp. 459 - 468
• Main Authors: ROOZEKRANS, Margot, VAN DER SCHRIER, Rutger, OKKERSE, Pieter, HAY, Justin, McLEOD, James F, DAHAN, Albert
• Format: Conference Proceeding Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.09.2014
• Subjects: Adolescent; Adult; Alfentanil - adverse effects; Alfentanil - therapeutic use; Analgesia; Analgesics, Opioid - adverse effects; Anesthesia; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Cross-Over Studies; Double-Blind Method; Doxapram - therapeutic use; Healthy Volunteers; Hemodynamics - drug effects; Humans; Large-Conductance Calcium-Activated Potassium Channels - antagonists & inhibitors; Male; Medical sciences; Middle Aged; Potassium Channel Blockers - therapeutic use; Respiratory Insufficiency - chemically induced; Respiratory Insufficiency - drug therapy; Triazines - therapeutic use; Human; Anesthesia; Ionic channel; Respiratory depression; Volunteer
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/ALN.0000000000000367

Opioid-induced respiratory depression is potentially lethal. GAL021 is a calcium-activated potassium (BKCa) channel blocker that causes reversal of opioid-induced respiratory depression in animals due to a stimulatory effect on ventilation at the carotid bodies. To assess in humans whether GAL021 stimulates breathing in established opioid-induced respiratory depression and to evaluate its safety, a proof-of-concept double-blind randomized controlled crossover study on isohypercapnic ventilation (study 1) and subsequent double-blind exploratory study on poikilocapnic ventilation and nonrespiratory end points (study 2) was performed. In study 1, intravenous low- and high-dose GAL021 and placebo were administrated on top of low- and high-dose alfentanil-induced respiratory depression in 12 healthy male volunteers on two separate occasions. In study 2, the effect of GAL021/placebo on poikilocapnic ventilation, analgesia, and sedation were explored in eight male volunteers. Data are mean difference between GAL021 and placebo (95% CI). Study 1: Under isohypercapnic conditions, a separation between GAL021 and placebo on minute ventilation was observed by 6.1 (3.6 to 8.6) l/min (P < 0.01) and 3.6 (1.5 to 5.7) l/min (P < 0.01) at low-dose alfentanil plus high-dose GAL021 and high-dose-alfentanil plus high-dose GAL021, respectively. Study 2: Similar observations were made on poikilocapnic ventilation and arterial pCO2. GAL021 had no effect on alfentanil-induced sedation, antinociception and no safety issues or hemodynamic effects became apparent. GAL021 produces respiratory stimulatory effects during opioid-induced respiratory depression with containment of opioid-analgesia and without any further increase of sedation. Further studies are needed to confirm these preliminary data.