Nitric Oxide Donor Sodium Nitroprusside Reduces Racemic Ketamine-But Not Esketamine-Induced Pain Relief.

Albert Dahan; Simone C Jansen; Rutger van der Schrier; Elise Sarton; David Dadiomov; Monique van Velzen; Erik Olofsen; Marieke Niesters

doi:10.1021/acsptsci.4c00133

Nitric Oxide Donor Sodium Nitroprusside Reduces Racemic Ketamine-But Not Esketamine-Induced Pain Relief.

Albert Dahan, Simone C Jansen, Rutger van der Schrier, Elise Sarton, David Dadiomov, Monique van Velzen, Erik Olofsen, Marieke Niesters

ACS Pharmacology & Translational Science July 12, 2024 DOI: 10.1021/acsptsci.4c00133 (opens in new tab)

Read Full Text

Relevant Not relevant

Study at a glance

AI-extracted from the abstract

Characteristics	Randomized double-blind placebo-controlled trial Peer reviewed
Sample size	17
Population	Healthy volunteers
Interventions	Sodium nitroprusside Racemic ketamine Esketamine
Dose	0.5 μg.kg-1.min-1 SNP; racemic ketamine total dose 140 mg; esketamine 70 mg
Duration	3-hour infusion
Topics	Esketamine Ketamine
Keywords	Ketamine research Pain medication Blood pressure drugs Pharmacology Drug interactions
Citations	8
Key findings	Sodium nitroprusside had no effect on S-ketamine potency but abolished the R-ketamine analgesic effect.

Abstract

The anesthetic, analgesic and antidepressant drug ketamine produces dissociation with symptoms of psychosis and anxiety, an effect attributed to neuronal nitric oxide depletion following N-methyl-d-aspartate blockade. There is evidence that dissociation induced by racemic ketamine, containing both ketamine enantiomers (S- and R-ketamine) but not esketamine (the S-isomer) is inhibited by nitric oxide (NO) donor sodium nitroprusside (SNP). We tested whether a similar intervention would reduce racemic and esketamine-induced analgesia in a randomized double-blind placebo-controlled trial. Seventeen healthy volunteers were treated with 0.5 μg.kg-1.min-1 SNP or placebo during a 3-h infusion of escalating doses of racemic ketamine (total dose 140 mg) or esketamine (70 mg). Pain pressure threshold (PPT) and arterial blood samples for measurement of S- and R-ketamine and their metabolites, S- and R-norketamine, were obtained. The data were analyzed with a population pharmacokinetic-pharmacodynamic model that incorporated the measured S- and R- ketamine and S- and R-norketamine isomers as input and PPT as output to the model. The potency of the 2 formulations in increasing PPT from baseline by 100% was 0.47 ± 0.12 (median ± standard error of the estimate) nmol/mL for esketamine and 0.62 ± 0.19 nmol/mL for racemic ketamine, reflecting the 52 ± 27% lower analgesic potency of R-ketamine versus S-ketamine. Modeling showed that SNP had no effect on S-ketamine potency but abolished the R-ketamine analgesic effect. Similar observations were made for S- and R-norketamine. Since SNP had no effect on S-ketamine analgesia, we conclude that SNP interacts on R-ketamine nociceptive pathways, possibly similar to its effects on R-ketamine activated dissociation pathways.

Comparable studies

Other randomized controlled trials on esketamine, most cited first.

Study	Year	Design	Participants
Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study Adults with moderate to severe nonpsychotic depression and a history of nonresponse to...	2019	Phase 3, double-blind, active-controlled, multicenter randomized controlled trial	n = 227
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression Adults with treatment-resistant depression who achieved stable remission or stable...	2019	Phase 3, multicenter, double-blind, randomized withdrawal study	n = 297
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression Adults with DSM-IV-TR diagnosis of major depressive disorder and history of inadequate...	2017	Phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study	n = 67
Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study Depressed patients at imminent risk for suicide	2018	Randomized controlled trial	n = 68
Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) Adults with moderate-to-severe depression and nonresponse to at least two...	2019	Randomized controlled trial	n = 346

Citations in the library

Cited by 1

Meta-correlation of the effect of ketamine and psilocybin induced subjective effects on therapeutic outcome. npj Mental Health Research October 6, 2024

Cites 16

and 11 more in the library