Respiratory effects of thyrotropin-releasing hormone and its analogue taltirelin on opioid-induced respiratory depression

Ladha

Journal of Applied Physiology

et al. 2022

Taltirelin is a stable, brain-penetrating thyrotropin-releasing hormone (TRH) analog with minimal endocrine activity and potential respiratory stimulant properties. Taltirelin's receptor target shows high differential expression at the hypoglossal motor nucleus, and local taltirelin microperfusion into the hypoglossal motor nucleus causes sustained tongue motor activation compared to the transient activating effects of TRH itself. Here we performed a randomized, within-subject, repeated measures design over six separate study days (separated by at least 72 hrs) in chronically instrumented male (n=10) and female (n=9) rats to identify effects on sleep and breathing. Vehicle controls or taltirelin (0.1 and 1 mg/kg), with and without trazodone (30 mg/kg) were administered by intraperitoneal injection. Trazodone was included due to clinical interest in the context of sleep apnea pharmacotherapy as it can suppress arousal without compromising pharyngeal muscle activity. Systemically administered taltirelin (1 but not 0.1 mg/kg) increased tonic and within-breath phasic tonic muscle activity compared to vehicle controls (P < 0.007), with little or no changes in diaphragm amplitude or respiratory rate. Taltirelin also suppressed non-rapid eye movement (non-REM) sleep and increased wakefulness (P <0.037). Other indices of taltirelin-induced central nervous system arousal included increased trapezius muscle tone in non-REM sleep and decreased total electroencephalogram power and delta (0.5-4 Hz) power (P < 0.046). These effects were especially apparent in non-REM sleep and not prevented by trazodone. These pre-clinical findings identify taltirelin as a stable upper airway-preferring respiratory stimulant with arousal properties, traits that have potential favorable relevance to some respiratory disorders but not others.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Thyrotropin-releasing hormone analog as a stable upper airway-preferring respiratory stimulant with arousal properties

Ladha

Journal of Applied Physiology

et al. 2022

“…Many of the synthetic opioids can produce significant muscle rigidity (the wooden cage syndrome) and/or vocal cord closure impairing gas exchange due to a sharp reduction in tidal volume. [56][57][58][59][60] In case of opioid-induced muscle rigidity and/or vocal cord closure, the respiratory stimulant might not work or might worsen the clinical condition of the patient. 58 This is another reason why the combination of a nonopioid respiratory stimulant with naloxone is favorable, as the opioid antagonist is able to reduce muscle rigidity.…”

Section: Naloxone Alternatives: Agnostic Respiratory Stimulantsmentioning

confidence: 99%

Opioid Overdose: Limitations in Naloxone Reversal of Respiratory Depression and Prevention of Cardiac Arrest

Lemmen

Florian

et al. 2023

Anesthesiology

Self Cite

Opioids are effective analgesics, but they can have harmful adverse effects, such as addiction and potentially fatal respiratory depression. Naloxone is currently the only available treatment for reversing the negative effects of opioids, including respiratory depression. However, the effectiveness of naloxone, particularly after an opioid overdose, varies depending on the pharmacokinetics and the pharmacodynamics of the opioid that was overdosed. Long-acting opioids, and those with a high affinity at the µ-opioid receptor and/or slow receptor dissociation kinetics, are particularly resistant to the effects of naloxone. In this review, we will examine the pharmacology of naloxone and its safety and limitations in reversing opioid-induced respiratory depression under different circumstances, including its ability to prevent cardiac arrest.

Pharmacology Res & Perspec

“…Cotton’s group further studied the effect of 1 mg/kg intravenous taltirelin, 1 ml/kg intramuscular saline and 30 μg/kg intravenous dexmedetomidine on gastrocnemius EMG activity in awake, restrained rats following 10 μg/kg intravenous sufentanil administration 66 . Sufentanil increased EMG activity that was subsequently reduced by the α 2 ‐adrenergic receptor agonist dexmedetomidine but not by taltirelin.…”

Section: Ability Of Trh To Reverse Opioid‐induced Respiratory Depressionmentioning

confidence: 99%

“…To investigate the effect of higher doses, we performed an exploratory study in six healthy male and female volunteers, 66 the volunteers received a continuous infusion of remifentanil (target plasma concentration 1.2 ng/mL) such that isohypercapnic ventilation was reduced by 45%–50%. When ventilation had reached a steady state, dose escalating intravenous TRH infusions were given.…”

Section: Ability Of Trh To Reverse Opioid‐induced Respiratory Depressionmentioning

confidence: 99%

Are thyrotropin‐releasing hormone (TRH) and analog taltirelin viable reversal agents of opioid‐induced respiratory depression?

Algera

Cotten

Velzen

et al. 2022

Self Cite

Opioid‐induced respiratory depression (OIRD) is a potentially life‐threatening complication of opioid consumption. Apart from naloxone, an opioid antagonist that has various disadvantages, a possible reversal strategy is treatment of OIRD with the hypothalamic hormone and neuromodulator thyrotropin‐releasing hormone (TRH). In this review, we performed a search in electronic databases and retrieved 52 papers on the effect of TRH and TRH‐analogs on respiration and their efficacy in the reversal of OIRD in awake and anesthetized mammals, including humans. Animal studies show that TRH and its analog taltirelin stimulate breathing via an effect at the preBötzinger complex, an important respiratory rhythm generator within the brainstem respiratory network. An additional respiratory excitatory effect may be related to TRH’s analeptic effect. In awake and anesthetized rodents, TRH and taltirelin improved morphine‐ and sufentanil‐induced respiratory depression, by causing rapid shallow breathing. This pattern of breathing increases the work of breathing, dead space ventilation, atelectasis, and hypoxia. In awake and anesthetized humans, a continuous infusion of intravenous TRH with doses up to 8 mg, did not reverse sufentanil‐ or remifentanil‐induced respiratory depression. This is related to poor penetration of TRH into the brain compartment but also other causes are discussed. No human data on taltirelin are available. In conclusion, data from animals and human indicate that TRH is not a viable reversal agent of OIRD in awake or anesthetized humans. Further human studies on the efficacy and safety of TRH’s more potent and longer lasting analog taltirelin are needed as this agent seems to be a more promising reversal drug.