Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Apr 10;50(4):345-351.
doi: 10.1136/rapm-2024-105346.

First evidence of a biomarker-based dose-response relationship in chronic pain using physiological closed-loop spinal cord stimulation

Leah Muller  1 , Jason Pope  2 , Paul Verrills  3 , Erika Petersen  4 , Jan Willem Kallewaard  5 , Ian Gould  6 , Dean M Karantonis  6
Affiliations

First evidence of a biomarker-based dose-response relationship in chronic pain using physiological closed-loop spinal cord stimulation

Leah Muller et al. Reg Anesth Pain Med. .

Abstract

Background and objectives: In spinal cord stimulation (SCS) therapy, electricity is the medication delivered to the spinal cord for pain relief. In contrast to conventional medication where dose is determined by desired therapeutic plasma concentration, there is lack of equivalent means of determining dose delivery in SCS. In open-loop (OL) SCS, due to the dynamic nature of the epidural space, the activating electric field delivered is inconsistent at the level of the dorsal columns. Recent Food and Drug Administration guidance suggests accurate and consistent therapy delivered using physiologic closed-loop control (PCLC) devices can minimize underdosage or overdosage and enhance medical care. PCLC-based evoked compound action potential (ECAP)-controlled technology provides the ability to prescribe a precise stimulation dose unique to each patient, continuously measure neural activation, and objectively inform SCS therapy optimization.

Methods: Neurophysiological indicator metrics of therapy dose, usage above neural activation threshold, and accuracy of SCS therapy were assessed for relationship with pain reduction in over 600 SCS patients.

Results: Significant relationships between objective metrics and pain relief across the patient population are shown, including first evidence for a dose-response relationship in SCS.

Conclusions: Higher dose, more time over ECAP threshold, and higher accuracy are associated with better outcomes across patients. There is potential to optimize individual patient outcomes based on unique objective measurable electrophysiological inputs.

Keywords: chronic pain; neuromodulation; spinal cord stimulation.

PubMed Disclaimer

Conflict of interest statement

Competing interests: JP reports research and consulting fees from Saluda Medical during the conduct of the study; consultancy for Abbott, Medtronic, Saluda Medical, Flowonix, SpineThera, Vertos, Vertiflex, SPR Therapeutics, Tersera, Aurora, Spark, Ethos, Biotronik, Mainstay, WISE, Boston Scientific, and Thermaquil outside the submitted work; has received grant and research support from: Abbott, Flowonix, Aurora, Painteq, Ethos, Muse, Boston Scientific, SPR Therapeutics, Mainstay, Vertos, AIS, and Thermaquil outside the submitted work; and is a shareholder of Vertos, SPR Therapeutics, Painteq, Aurora, Spark, Celeri Health, Neural Integrative Solutions, Pacific Research Institute, Thermaquil, and Anesthetic Gas Reclamation. EP has received research support from Mainstay, Medtronic, Neuros Medical, Nevro Corporation, ReNeuron, SPR, and Saluda Medical outside the submitted work, as well as personal fees from Abbott Neuromodulation, Biotronik, Medtronic Neuromodulation, Nalu, Neuros Medical, Nevro, Presidio Medical, Saluda Medical, and Vertos outside the submitted work. She holds stock options from SynerFuse and neuro42. PV is a consultant at Saluda Medical, NaluMedical, Abbott, and Biotronik. JWK is on the advisory board for Abbott Laboratories, Nevro Corporation, Saluda Medical, Medtronic and Boston Scientific. LM, IG and DMK are employed by Saluda Medical. There are no other relationships that might lead to a conflict of interest in the current study.

Figures

Figure 1
Figure 1. Activation plot (AP) (left) and matching out-of-clinic histogram (right) data for two example visits. (A) A typical AP with usage above evoked compound action potential (ECAP) threshold, corresponding to a dose ratio >1 and (B) an example with dose ratio <1. Gray dots and bars in AP represent data means and SD per current. Orange curve overlaid on gray dots indicates the best-fit line for the AP. The green dashed line indicates the ECAP threshold. The blue solid line indicates the median ECAP amplitude. The corresponding dose ratio and percent usage over ECAP threshold are written above the plots.
Figure 2
Figure 2. Trends in objective neural indicator metrics individually, expressed as metric groupings by percent difference from the median maximal analgesic effect (MAE) percent pain reduction (79%, 80%, and 82% left to right). (A) Usage is positively associated with percent pain reduction. Number of patients in each grouping, left to right: 42, 48, 79, 380. (B) Dose ratio is positively associated with percent pain reduction. Number of patients in each grouping, left to right: 95, 121, 188, 138. (C) Dose accuracy is positively associated with percent pain reduction within the population of patients whose median dose is greater than threshold. Number of patients in each grouping, left to right: 23, 51, 189, 220. Bar heights represent median values. Black bars show SE. Lower subplots show the percentage of patients included in each grouping. ECAP, evoked compound action potential.
Figure 3
Figure 3. Scatter plots with associated distribution plots of usage over threshold, dose ratio, and dose accuracy. ECAP, evoked compound action potential.
Figure 4
Figure 4. Case studies from real patients with changing pain scores over time. Reported pain relief text is red if <50%, green if ≥50%. The circles in the Neural Metrics section are colored gray if they correspond to pain relief below median, green otherwise. A dose accuracy of ±0 µV relays the error with posture change is equal or less than that of the recording environment at baseline. ECAP, evoked compound action potential.
See this image and copyright information in PMC

References

    1. Wall PD, Sweet WH. Temporary abolition of pain in man. Science. 1967;155:108–9. doi: 10.1126/science.155.3758.108. - DOI - PubMed
    1. Shealy CN, Mortimer JT, Reswick JB. Electrical inhibition of pain by stimulation of the dorsal columns: preliminary clinical report. Anesth Analg. 1967;46:489–91. - PubMed
    1. Oakley JC, Prager JP. Spinal cord stimulation: mechanisms of action. Spine (Phila Pa 1976) 2002;27:2574–83. doi: 10.1097/00007632-200211150-00034. - DOI - PubMed
    1. Pope JE, Deer TR, Falowski S, et al. Multicenter retrospective study of Neurostimulation with exit of therapy by Explant: Neurostimulation Therapy Explant Analysis. Neuromodulation Technol Neural Interface. 2017;20:543–52. doi: 10.1111/ner.12634. - DOI - PubMed
    1. Chakravarthy K, Reddy R, Al-Kaisy A, et al. A call to action toward optimizing the electrical dose received by neural targets in spinal cord stimulation therapy for neuropathic pain. J Pain Res. 2021;14:2767–76. doi: 10.2147/JPR.S323372. - DOI - PMC - PubMed

Publication types

LinkOut - more resources