Animal data suggest that the antidepressant and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor modulator tianeptine is able to prevent opioid-induced respiratory depression. The hypothesis was that oral or intravenous tianeptine can effectively prevent or counteract opioid-induced respiratory depression in humans.


Healthy male and female volunteers participated in two studies that had a randomized, double blind, placebo-controlled, crossover design. First, oral tianeptine (37.5-, 50-, and 100-mg doses with 8 subjects) pretreatment followed by induction of alfentanil-induced respiratory depression (alfentanil target concentration, 100 ng/ml) was tested. Primary endpoint was ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg (V̇E55). Next, the ability of four subsequent and increasing infusions of intravenous tianeptine (target tianeptine plasma concentrations 400, 1,000, 1,500, and 2,000 ng/ml, each given over 15 min) to counteract remifentanil-induced respiratory depression was determined in 15 volunteers. Ventilation was measured at isohypercpania (baseline ventilation 20 ± 2 l/min). The primary endpoint was minute ventilation during the 60 min of tianeptine versus placebo infusion.


Alfentanil reduced V̇E55 to 13.7 (95% CI, 8.6 to 18.8) l/min after placebo pretreatment and to 17.9 (10.2 to 25.7) l/min after 50-mg tianeptine pretreatment (mean difference between treatments 4.2 (–11.5 to 3.0) l/min, P = 0.070). Intravenous tianeptine in the measured concentration range of 500 to 2,000 ng/ml did not stimulate ventilation but instead worsened remifentanil-induced respiratory depression: tianeptine, 9.6 ± 0.8 l/min versus placebo 15.0 ± 0.9 l/min; mean difference, 5.3 l/min; 95% CI, 2.5 to 8.2 l/min; P = 0.001, after 1 h of treatment.


Neither oral nor intravenous tianeptine were respiratory stimulants. Intravenous tianeptine over the concentration range of 500 to 2000 ng/ml worsened respiratory depression induced by remifentanil.

Editor’s Perspective
What We Already Know about This Topic
  • Tianeptine is an atypical antidepressant and cognitive enhancer that can be administered orally or intravenously
  • Tianeptine may cause respiratory stimulation during opioid-induced respiratory depression by enhancing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated transmission and reducing glutamatergic transmission at N-methyl-d-aspartate receptors
  • However, tianeptine also acts as a µ-opioid receptor agonist, which may reduce its respiratory stimulatory capabilities
What This Article Tells Us That Is New
  • The hypothesis that tianeptine is able to cause effective reversal of opioid-induced respiratory depression was tested in 15 male and female subjects in a double-blind, randomized, placebo-controlled crossover study by determining the effect of tianeptine at four increasing target plasma concentrations on remifentanil-induced respiratory depression at isohypercapnia
  • Over the plasma tianeptine concentration range tested (500 to 2,000 ng/ml), it did not produce respiratory stimulation during remifentanil-induced respiratory depression but instead worsened respiratory depression with a further decline in ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg by 5 l/min