title: Selective antagonism of opioid-induced ventilatory depression by an ampakine molecule in humans without loss of opioid analgesia.
abstract: Ventilatory depression is a significant risk associated with the use of opioids. We assessed whether opioid-induced ventilatory depression can be selectively antagonized by an ampakine without reduction of analgesia. In 16 healthy men, after a single oral dose of 1,500 mg of the ampakine CX717, a target concentration of 100 ng/ml alfentanil decreased the respiratory frequency by only 2.9 +/- 33.4% as compared with 25.6 +/- 27.9% during placebo coadministration (P < 0.01).Blood oxygenation and the ventilatory response to hypercapnic challenge also showed significantly smaller decreases with CX717 than with placebo. In contrast, CX717 did not affect alfentanil-induced analgesia in either electrical or heat-based experimental models of pain. Both ventilatory depression and analgesia were reversed with 1.6 mg of naloxone. These results support the use of ampakines as selective antidotes in humans to counter opioid-induced ventilatory depression without affecting opioid-mediated analgesia.
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: B G
authors.initials: BG
authors.lastname: Oertel
authors.forename: L
authors.initials: L
authors.lastname: Felden
authors.forename: P V
authors.initials: PV
authors.lastname: Tran
authors.forename: M H
authors.initials: MH
authors.lastname: Bradshaw
authors.forename: M S
authors.initials: MS
authors.lastname: Angst
authors.forename: H
authors.initials: H
authors.lastname: Schmidt
authors.forename: S
authors.initials: S
authors.lastname: Johnson
authors.forename: J J
authors.initials: JJ
authors.lastname: Greer
authors.forename: G
authors.initials: G
authors.lastname: Geisslinger
authors.forename: M A
authors.initials: MA
authors.lastname: Varney
authors.forename: J
authors.initials: J
authors.lastname: Lötsch
mesh_terms: D000284:Administration, Oral; D000328:Adult; D015760:Alfentanil / Q000009:adverse effects* / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000009:adverse effects* / Q000494:pharmacology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D006935:Hypercapnia / Q000503:physiopathology; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010100:Oxygen / Q000097:blood; D010146:Pain / Q000188:drug therapy*; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000517:prevention & control*; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; C542518:CX717; D007555:Isoxazoles; D009292:Narcotic Antagonists; D015760:Alfentanil; D009270:Naloxone; D010100:Oxygen