Two studies on reversal of opioid-induced respiratory depression by BK-channel blocker GAL021 in human volunteers.

Abstract

BACKGROUND:

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.

METHODS:

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).

RESULTS:

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.

CONCLUSION:

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.

• Authors: Margot Roozekrans, Rutger van der Schrier, Pieter Okkerse, Justin Hay, James F McLeod, Albert Dahan
• Journal: Anesthesiology (Anesthesiology) Vol. 121 Issue 3 Pg. 459-68 (Sep 2014) ISSN: 1528-1175 [Electronic] United States
• PMID: 25222672 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics, Opioid
• Large-Conductance Calcium-Activated Potassium Channels
• Potassium Channel Blockers
• Triazines
• Alfentanil
• GAL021
• Doxapram

Topics

• Adolescent
• Adult
• Alfentanil (adverse effects, therapeutic use)
• Analgesia
• Analgesics, Opioid (adverse effects)
• Cross-Over Studies
• Double-Blind Method
• Doxapram (therapeutic use)
• Healthy Volunteers
• Hemodynamics (drug effects)
• Humans
• Large-Conductance Calcium-Activated Potassium Channels (antagonists & inhibitors)
• Male
• Middle Aged
• Potassium Channel Blockers (therapeutic use)
• Respiratory Insufficiency (chemically induced, drug therapy)
• Triazines (therapeutic use)