Respiratory depression is a leading cause of death from overdose of some classes of abused drugs but can also arise during medically supervised procedures such as perisurgical anaesthesia. Fentanyl, a µ-opioid agonist which is approximately 100 times more potent than morphine, is widely used to treat acute, postoperative, and chronic pain. Activation of opiate receptors can, however, lead to significant respiratory depression in a subset (10-15%) of patients. This has commonly been reversed by administration of a µ-opioid antagonist such as naloxone, albeit with the undesirable effect of blocking pain relief.
Writing in the journal Anesthesiology, researchers at the University of Alberta have now described the use of an Ampakine compound, CX717, for treating fentanyl-induced respiratory depression without interfering with analgesia. Ampakines bind allosterically to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors and are undergoing clinical trials as potential treatments for cognitive disorders and as enhancers of memory and attentiveness. AMPA receptors mediate fast synaptic transmission in the CNS and play a central role in maintaining respiratory rhythm. In the present study, pre-administration of CX717 to rats was found to markedly attenuate fentanyl-induced respiratory depression and post-administration of CX717 rescued the animals from a lethal dose of fentanyl. The effective doses of CX717 were within the range considered to be safe from clinical study data (ca 10mg/kg bid) and, importantly, did not reverse the analgesia, suggesting that co-administration of Ampakines with fentanyl could improve pain management in a variety of clinical settings.
Older people, those with a history of sleep apnea, obese individuals and those with a history of chronic obstructive pulmonary disease are particularly at risk for fentanyl-induced respiratory depression during surgery. In a small Phase IIa study in alfentanil-induced respiratory depression, a single dose of 1500mg of CX717 achieved statistical significance over placebo on the primary endpoint measure of spontaneous basal respiration without affecting analgesia.
Another ampakine compound, CX546, has previously been shown to reverse respiratory distress in rats treated with fentanyl or the barbiturate, phenobarbitol, without compromising the analgesic effect.