D-Amphetamine Accelerates Recovery of Consciousness and Respiratory Drive After High-Dose Fentanyl in Rats

Abstract

In the United States, fentanyl causes approximately 60,000 drug overdose deaths each year. Fentanyl is also frequently administered as an analgesic in the perioperative setting, where respiratory depression remains a common clinical problem. Naloxone is an efficacious opioid antagonist, but it possesses a short half-life and undesirable side effects. This study was conducted to test the hypothesis that d-amphetamine ameliorates respiratory depression and hastens the return of consciousness following high-dose fentanyl. Behavioral endpoints (first head movement, two paws down, and return of righting), arterial blood gas analysis and local field potential recordings from the prefrontal cortex were conducted in adult rats after intravenous administration of of fentanyl (55 µg/kg) at a dose sufficient to induce loss of righting and respiratory depression, followed by intravenous d-amphetamine (3 mg/kg) or saline (vehicle). D-amphetamine accelerated the time to return of righting by 36.6% compared to saline controls. D-amphetamine also hastened recovery of arterial pH, and the partial pressure of CO2, O2 and sO2 compared to controls, with statistically significant differences in pH after 5 min and 15 min. Local field potential recordings from the prefrontal cortex showed that within 5 min of d-amphetamine administration, the elevated broadband power <20 Hz produced by fentanyl had returned to awake baseline levels, consistent with the return of consciousness. Overall, d-amphetamine attenuated respiratory acidosis, increased arterial oxygenation, and accelerated the return of consciousness in the setting of fentanyl intoxication. This suggests that d-amphetamine may be a useful adjunct or alternative to opioid receptor antagonists such as naloxone.

Sodium alginate and naloxone loaded macrophage-derived nanovesicles for the treatment of spinal cord injury

“…In the drug delivery system, NAL played a significant role in inflammation and apoptosis as a drug. However, the short half-life of NAL influenced the therapeutic effect severely [36] . As endogenous drug carrier materials, MVs can prolong the circulatory time of NAL in vivo and improve drug bioavailability.…”

D-Amphetamine Rapidly Reverses Dexmedetomidine-Induced Unconsciousness in Rats

“…In addition to reversal of propofol and sevoflurane anesthesia ( Kenny et al, 2015 ), we recently reported that d-amphetamine accelerates recovery from respiratory depression and unconsciousness induced by fentanyl ( Moody et al, 2020 ). These findings suggest that d-amphetamine may be clinically useful to reverse the effects of multiple anesthetics and sedatives that have distinct mechanisms of action.…”

“…Male and female rats ( n = 8 each) were used for behavioral experiments, and six additional male rats were implanted with skull screws and intracranial electrodes for neural recordings. Sample sizes were based on those we have used previously in similar rodent studies ( Kenny et al, 2015 ; Moody et al, 2020 ). A minimum of 3 days of rest was provided between experiments.…”

Amphetamine Promotes Cortical Up State in Part Via Dopamine Receptors

“…The state-dependence of D -amphetamine’s effect may have important clinical implications. Studies suggest that psychostimulants, including D -amphetamine and methylphenidate, accelerate emergence from general anesthesia ( Solt et al, 2011 ; Chemali et al, 2012 ; Kenny et al, 2015 ; Moody et al, 2020 ). The state-dependence of D -amphetamine’s effect predicts that these agents are less effective in reversing anesthesia when the level of anesthesia is relatively deep.…”