Epidural electrical stimulation of the cervical spinal cord opposes opioid-induced respiratory depression.

Opioid overdose suppresses brainstem respiratory circuits, causes apnoea and may result in death. Epidural electrical stimulation (EES) at the cervical spinal cord facilitated motor activity in rodents and humans, and we hypothesized that EES of the cervical spinal cord could antagonize opioid-induced respiratory depression in humans. Eighteen patients requiring surgical access to the dorsal surface of the spinal cord between C2 and C7 received EES or sham stimulation for up to 90 s at 5 or 30 Hz during complete (OFF-State) or partial suppression (ON-State) of respiration induced by remifentanil. During the ON-State, 30 Hz EES at C4 and 5 Hz EES at C3/4 increased tidal volume and decreased the end-tidal carbon dioxide level compared to pre-stimulation control levels. EES of 5 Hz at C5 and C7 increased respiratory frequency compared to pre-stimulation control levels. In the OFF-State, 30 Hz cervical EES at C3/4 terminated apnoea and induced rhythmic breathing. In cadaveric tissue obtained from a brain bank, more neurons expressed both the neurokinin 1 receptor (NK1R) and somatostatin (SST) in the cervical spinal levels responsive to EES (C3/4, C6 and C7) compared to a region non-responsive to EES (C2). Thus, the capacity of cervical EES to oppose opioid depression of respiration may be mediated by NK1R+/SST+ neurons in the dorsal cervical spinal cord. This study provides proof of principle that cervical EES may provide a novel therapeutic approach to augment respiratory activity when the neural function of the central respiratory circuits is compromised by opioids or other pathological conditions. KEY POINTS: Epidural electrical stimulation (EES) using an implanted spinal cord stimulator (SCS) is an FDA-approved method to manage chronic pain. We tested the hypothesis that cervical EES facilitates respiration during administration of opioids in 18 human subjects who were treated with low-dose remifentanil that suppressed respiration (ON-State) or high-dose remifentanil that completely inhibited breathing (OFF-State) during the course of cervical surgery. Dorsal cervical EES of the spinal cord augmented the respiratory tidal volume or increased the respiratory frequency, and the response to EES varied as a function of the stimulation frequency (5 or 30 Hz) and the cervical level stimulated (C2-C7). Short, continuous cervical EES restored a cyclic breathing pattern (eupnoea) in the OFF-State, suggesting that cervical EES reversed the opioid-induced respiratory depression. These findings add to our understanding of respiratory pattern modulation and suggest a novel mechanism to oppose the respiratory depression caused by opioids.

Postpartum Respiratory Depression.

Postpartum respiratory depression is a complex, multifactorial issue that encompasses a patient's baseline preexisting conditions, certain pregnancy-specific conditions or complications, as well as the iatrogenic element of various medications given in the peripartum period. In this review, we discuss many of these factors including obesity, sleep-disordered breathing, chronic lung disease, neuromuscular disorders, opioids, preeclampsia, peripartum cardiomyopathy, postpartum hemorrhage, amniotic fluid embolism, sepsis, acute respiratory distress syndrome (ARDS), and medications such as analgesics, sedatives, anesthetics, and magnesium. Current recommendations for screening, treatment, and prevention are also discussed.

Novel Oral Nanoparticle Formulation of Sustained Release Naloxone with Mild Withdrawal Symptoms in Mice.

Chronic use of opioids can lead to tolerance, dependence, abuse, and addiction. This in turn can result in dose escalation and opioid overdose. Opioid overdose can be fatal due to severe opioid-induced respiratory depression (OIRD). Naloxone, a nonspecific antagonist of the mu-opioid receptors, is used for the reversal of OIRD. However, one of the major challenges of using naloxone is its short elimination half-life, which is significantly shorter compared to many opioid analgesics. Thus, renarcotization and rapid return to full respiratory depression might occur, specifically in individuals who have taken large doses or long-acting opioid formulations. Additionally, because of the very low oral bioavailability of naloxone, an oral formulation is not currently available. This study examines in mice a novel oral formulation of naloxone based on polymer nanoparticles (NP-naloxone). A single dose of 1 or 5 mg/kg NP-naloxone was highly effective at inhibiting the activating effects of repeated administration of 10 mg/kg morphine for at least up to 24 h. Onset of action was approximately 5 min. Reversal of morphine-induced locomotion was already detected within 1 min and a full effect of returning to baseline activity levels was observed within 5 min. Importantly, at 1 mg/kg, NP-naloxone precipitated very minimal withdrawal behaviors. At the 5 mg/kg dose, NP-naloxone precipitated approximately 40% of the jumping withdrawal behaviors of injectable naloxone. Thus, this study demonstrates that orally administered naloxone based on polymer nanoparticles has high potential to be developed to circumvent OIRD and withdrawal symptoms.