• Analgesic Drugs
• Anesthesiology Clinical Trials
• Pain Management
• Acute & Chronic

• Analgesic Drugs
• Anesthesiology Clinical Trials
• Pain Management
• Acute & Chronic
• Anesthesiology

A pharmacokinetic/pharmacodynamic (PK/PD) modeling study on the effect of the BK channel blocker GAL021 found that it produced rapid reversal of opioid–induced respiratory depression (OIRD) in a population of healthy male volunteers [Roozekrans M et al. Anesthesiology. 2014].

GAL021—calcium–activated potassium with a stimulatory effect on ventilation at the carotid bodies—reversed OIRD in healthy volunteers without an effect on sedation, analgesia, or hemodynamics [Cotton J. Anesthesiology. 2014]. Margot Roozekrans, MD, Leiden University Medical Center, Leiden, The Netherlands, presented results of the study.

The research assessed whether GAL21 stimulates breathing in OIRD and evaluated its safety in a proof–of–concept, double–blind crossover study on isohypercapnic ventilation (study 1) and a subsequent double–blind exploratory study on poikilocapnic ventilation and nonrespiratory end points (study 2).

Twelve volunteers were randomized to GAL021 or placebo in the controlled crossover study. Respiratory measurements were obtained under isohypercapnic conditions. The researchers administered intravenous low– and high–dose GAL021 or placebo on top of low–and high–dose alfentanil–induced respiratory depression. Arterial plasma was collected for measurement of GAL021 and alfentanil concentrations.

Data were analyzed with a population PK/PD model in NONMEM in 2 steps. First, the alfentanil and GAL021 PK data were characterized. Next, the PK models were used as inputs of the sigmoid E_MAX PD model, in which GAL021 was assumed to increase ventilation in a multiplicative fashion so that the degree of reversal depended on the degree of respiratory depression.

The alfentanil concentration causing 50% respiratory depression was 26.3 ± 3.8 ng/mL (estimate ± SE); the alfentanil blood–effect site equilibration half–life was 1.0 ± 0.5 minutes. At a plasma concentration of 1 μg/mL, GAL021 reversed the OIRD by 37%; at the maximum dose, it reversed ventilation by 53%. For GAL021, the blood–effect site equilibration half–life was not significantly different from zero.

GAL02 produced rapid reversal of OIRD in the volunteers. The rapid onset of effect supports the findings in animals that GAL021 stimulates respiration at a site close to the vascular bed—namely, the peripheral chemo–receptors of the carotid bodies. In the future, studies should assess whether more complete reversal is possible at varying levels of OIRD.

Anesthesiologists routinely administer drugs that compromise a patient's ability to breathe, and dealing with the consequences can be a challenge [Cotton J. Anesthesiology. 2014]. Current clinical practice is to treat OIRD with such drugs as the opioid antagonist naloxone, which reverses OIRD as well as analgesia and sometimes has other deleterious side effects [Dahan A et al. Anesthesiology. 2010; van Dorp E et al. Expert Opin Drug Saf. 2007]. Doxapram is another widely used drug that was developed in the 1960s.

High–risk powerful opioids such as oxycodone, methadone, propofol, and fentanyl are commonly used by anesthesiologists to manage perioperative and postoperative pain. Less–than–complete relief often takes place due to the fear of OIRD.

The therapeutic drug GAL021 offers an alternative to naloxone that promises to restore breathing and reduce morbidity and mortality from OIRD without compromising pain relief or increasing sedation.

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