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

Ruyi Huang^{1

2

3}, Jason Worrell^{1

2}, Eric Garner¹, Stephanie Wang^{1

2}, Tali Homsey^{1

2}, Bo Xu^{1

2}, Erika L Galer^{1

2

4}, Yan Zhou^{1

2}, Sherwin Tavakol⁵, Meelod Daneshvar⁶, Timothy Le^{1

2}, Harry V Vinters^{7

8}, Noriko Salamon⁹, David L McArthur¹, Marc R Nuwer¹⁰, Irene Wu¹¹, James C Leiter¹², Daniel C Lu^{1

2

3

8}

Affiliations

¹ Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
² Neuromotor Recovery and Rehabilitation Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
³ Interdepartmental Program in Neuroscience, University of California, Los Angeles, CA, USA.
⁴ Molecular, Cellular, Integrated Physiology Program, University of California, Los Angeles, CA, USA.
⁵ Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ University of California Fresno, Department of Surgery, Fresno, CA, USA.
⁷ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁸ Brain Research Institute, University of California, Los Angeles, CA, USA.
⁹ Department of Radiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
¹⁰ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
¹¹ Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
¹² Department of Molecular and Systems Biology, Geisel School of Medicine, Lebanon, NH, USA.

PMID: 35639046
DOI: 10.1113/JP282664

Free article

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

Ruyi Huang et al. J Physiol. 2022 Jun.

Free article

. 2022 Jun;600(12):2973-2999.

doi: 10.1113/JP282664. Epub 2022 May 31.

Authors

Affiliations

¹ Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
² Neuromotor Recovery and Rehabilitation Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
³ Interdepartmental Program in Neuroscience, University of California, Los Angeles, CA, USA.
⁴ Molecular, Cellular, Integrated Physiology Program, University of California, Los Angeles, CA, USA.
⁵ Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ University of California Fresno, Department of Surgery, Fresno, CA, USA.
⁷ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁸ Brain Research Institute, University of California, Los Angeles, CA, USA.
⁹ Department of Radiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
¹⁰ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
¹¹ Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
¹² Department of Molecular and Systems Biology, Geisel School of Medicine, Lebanon, NH, USA.

PMID: 35639046
DOI: 10.1113/JP282664

Abstract

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.

Keywords: epidural electrical stimulation (EES); intraoperative neuromodulation; opioid-induced respiratory depression (OIRD); respiratory pattern modulation.

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Comment in

A shock to the system: neurostimulation therapy for opioid-induced respiratory depression.
O'Halloran KD. O'Halloran KD. J Physiol. 2022 Jun;600(12):2833-2834. doi: 10.1113/JP283272. Epub 2022 May 31. J Physiol. 2022. PMID: 35544711 Free PMC article. No abstract available.
Electroceuticals and respiratory recovery: is there a place for electrical spinal stimulation in opioid-induced respiratory depression?
Sunshine MD. Sunshine MD. J Physiol. 2022 Jun;600(12):2829-2830. doi: 10.1113/JP283182. Epub 2022 May 31. J Physiol. 2022. PMID: 35574706 No abstract available.

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1. Bezdudnaya, T., Lane, M. A., & Marchenko, V. (2018). Paced breathing and phrenic nerve responses evoked by epidural stimulation following complete high cervical spinal cord injury in rats. Journal of Applied Physiology, 125(3), 687-696.
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Epidural electrical stimulation of the cervical spinal cord opposes opioid-induced respiratory depression

Affiliations

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

Authors

Affiliations

Abstract

Comment in

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous