Efficacy of Sub-Threshold Dorsal Root Ganglion (DRG) Stimulation Versus Sham in Established Responders: A Randomised, Double-Blind, Two-Period Crossover Trial
Phase: NA
Conditions: Neuropathic Pain, Complex Regional Pain Syndromes (CRPS), Causalgia, Chronic Pain, Low Back Pain, Pelvic Pain
Sponsor: Umeå University

Pedram Tabatabaei, MD, PhD 
Department of Neurosciences, Umeå University Hospital        
Efficacy of Sub Threshold Dorsal Root Ganglion (DRG) 
Stimulation versus Sham in Established Responders: A 
Randomised, Double Blind, Two Period Crossover Trial 
 
Single-centre study conducted at Umeå University Hospital, Sweden 
Document date: 2025-09-04 
 
 
 

 
1 
Innehållsförteckning 
Purpose and Aims ............................................................................................................................. 2 
Signiﬁcance .................................................................................................................................... 2 
Background & Rationale .................................................................................................................... 3 
Preliminary Results ........................................................................................................................... 4 
Objectives & Hypotheses ................................................................................................................... 4 
Study Design .................................................................................................................................... 4 
Participant Selection ......................................................................................................................... 5 
Inclusion Criteria ........................................................................................................................... 5 
Exclusion Criteria .......................................................................................................................... 5 
Interventions ................................................................................................................................. 5 
Randomisation & Blinding Procedures ................................................................................................ 5 
Study Schedule & Assessments ............................................................................................................ 6 
Outcome Measures ......................................................................................................................... 6 
Data Collection & Management .......................................................................................................... 6 
Statistical Analysis Plan ..................................................................................................................... 7 
Safety Monitoring ............................................................................................................................. 7 
Ethical Considerations ...................................................................................................................... 8 
Dissemination .................................................................................................................................. 8 
References ...................................................................................................................................... 9 
Appendix 1: Data report from our quality database for patients with DRG stimulation therapy ............ 11 
 
 
 
 
 
 
 
 

 
2 
Purpose and Aims 
DRG stimulation is today considered a standard therapy for several neuropathic pain 
conditions. Despite its widespread clinical use, a critical knowledge gap remains: the efficacy 
of DRG stimulation has never been validated against sham in a controlled trial. The only 
randomized controlled study conducted to date is an industry-sponsored comparison between 
DRG stimulation and spinal cord stimulation (SCS) (9), but no trial has directly tested DRG 
against placebo. 
Umeå University Hospital is internationally recognized as a leading center for DRG 
stimulation. Patients from across Sweden are referred to our department, making our clinic 
the de facto national referral center for this therapy. In practice, DRG therapy is centralized to 
our unit. The resulting high patient volumes, together with our long-standing expertise and 
comprehensive quality database, provide unique opportunities to fill this knowledge gap—
opportunities that no other center is currently positioned to offer. 
The purpose of this study is therefore to rigorously evaluate whether ongoing sub-threshold 
DRG stimulation provides genuine analgesic benefit beyond contextual or placebo effects. 
Sub-threshold programming is already the accepted standard within DRG stimulation, but the 
specific contribution of this approach remains to be clarified in a placebo-controlled setting. 
Addressing this knowledge gap will provide robust scientific evidence to support or refute the 
physiological efficacy of sub-threshold DRG stimulation. 
Our primary aim is to determine the impact of sub-threshold DRG stimulation on pain 
intensity in established responders, using a double-blind, crossover design. Secondary aims 
include assessing effects on sleep, mood, and activity, as well as evaluating the feasibility of 
maintaining blinding and capturing safety and tolerability data. 
 
Signiﬁcance 
The efficacy of DRG stimulation has never been validated in a sham-controlled trial, leaving 
a critical knowledge gap that this study seeks to address. Without placebo-controlled 
evidence, the true physiological contribution of DRG stimulation remains uncertain and 
current clinical guidelines are built on a limited scientific foundation. 
By conducting the first sham-controlled trial of DRG stimulation in this setting, we can 
generate definitive evidence on efficacy and safety, with findings likely to influence clinical 
practice and policy both nationally and internationally. The results will directly inform 
clinical guidelines, payer decisions, and programming strategies, and they will strengthen the 
scientific foundation of DRG stimulation as a safe, effective, and durable treatment for 
neuropathic pain. 
 

 
3 
Background & Rationale 
Neuropathic pain affects roughly 6–10 % of the adult population and is notoriously refractory 
to pharmacotherapy, leaving many patients with disabling pain, sleep disturbance and mood 
disorders. Aberrant ectopic firing in the dorsal root ganglion (DRG)—where primary afferent 
somata reside—has been identified as a key generator and amplifier of neuropathic signalling 
(1–5). Therapeutically targeting the DRG is therefore conceptually attractive: modulating 
neuronal activity at this choke-point can quell both peripheral hyperexcitability and 
downstream central sensitisation. 
Dorsal root ganglion stimulation (DRG-S) delivers biphasic electrical pulses via 
percutaneously placed leads anchored inside the intervertebral foramen. Unlike conventional 
spinal cord stimulation (SCS), in which lead migration and rostro-caudal current spread often 
blur coverage, each DRG occupies a stereotyped position and maps to a discrete dermatome. 
This anatomic precision translates into highly focal pain relief, fewer unwanted paraesthesias 
and reduced energy consumption (6,7). Over the past decade, DRGS has progressed from an 
experimental therapy to an established treatment for complex regional pain syndrome 
(CRPS), causalgia, postsurgical and post-traumatic pain, failed back surgery syndrome and 
chronic low-back pain (8–14). Contemporary consensus guidelines explicitly recommend 
sub-threshold programming as the default setting, citing improved patient comfort and 
comparable efficacy (6,7). Contemporary consensus recognises sub-threshold stimulation as 
an accepted and widely applied programming technique within DRG stimulation. 
While early systems relied on supra-threshold amplitudes that elicited paresthesia, modern 
programmers default to sub-threshold output because patients find the absence of tingling 
more acceptable and battery longevity improves without an apparent loss of efficacy 
(9,12,19). Animal data suggest that tonic sub-threshold fields preferentially depress 
spontaneous DRG firing, inhibit dorsal horn wide-dynamic-range neurons and normalize 
thalamocortical connectivity—all without recruiting large-diameter Aβ fibers thought to 
mediate paresthesia (19). Yet the true clinical contribution of these physiological effects is 
unknown because, to date, no double-blind, sham-controlled randomized trial has directly 
compared DRG-S with placebo. Existing evidence consists mainly of open-label cohorts or 
active-control designs (e.g., DRG-S versus SCS), which cannot disentangle treatment benefit 
from expectation, interaction or regression to the mean. To our knowledge, no previous 
double-blind, randomized, and sham-controlled trial has specifically investigated DRG 
stimulation, highlighting the novelty of the present design. 
The present study addresses this critical knowledge gap. By enrolling patients who have 
already demonstrated durable (> 3 months) and substantial (≥ 50 %) pain relief on DRG-S and 
randomizing them to short crossover periods of sub-threshold stimulation or sham, we can 
isolate the physiological effect of ongoing DRG-S while minimizing ethical concerns and 
placebo variability. A rigorous sham-controlled, crossover design will provide high internal 
validity and maximize power with a modest sample size. The resulting evidence will clarify 
whether sub-threshold DRG-S delivers genuine analgesia beyond contextual factors and will 
inform future guideline recommendations, payer decisions and programming algorithms. 
Testing in established responders is desirable to ensure safety, feasibility, and parameter 
optimization, and to confirm the capacity to maintain blinding. As a subsequent step 
following this trial, we plan to conduct a randomized, blinded study in de novo patients to 
validate efficacy in a primary implantation population. 

 
4 
 
Preliminary Results 
Umeå University Hospital is internationally recognized as one of the leading centers in the 
world for DRG stimulation. Over the past decade, our department has established a 
comprehensive quality database with structured, prospective data collection, including 
patient-reported outcome measures (PROMs), patient-reported experience measures 
(PREMs), detailed device and implant information, and systematic adverse event reporting. 
This database currently includes more than 100 patients with active DRG therapy, 
representing what is likely the largest clinical cohort worldwide. The longest follow-ups now 
exceed five years (Appendix 1: Data report from our quality database). Analyses of these data 
indicate that DRG stimulation is a safe and effective treatment for a broad spectrum of 
neuropathic pain conditions, with consistent and long-lasting analgesic effects. Our findings 
further suggest that treatment durability extends beyond pain reduction, positively influencing 
function, mood, and quality of life. Importantly, a comprehensive retrospective analysis of 
these data is being finalized and will be published during the second half of 2025, further 
underscoring the robustness and maturity of our clinical experience. 
This extensive real-world experience and infrastructure provide a unique foundation for the 
proposed trial, ensuring feasibility, robust recruitment, and reliable follow-up. Moreover, our 
track record demonstrates both the scientific and clinical capability of our team to conduct a 
sham-controlled study of this scope with high internal validity. 
 
Objectives & Hypotheses 
• 
Primary Objective – To compare mean daily pain intensity during five days of 
sub-threshold DRG stimulation versus sham. 
• 
Secondary Objectives – To compare sleep quality, mood, and daily activity between 
conditions; to assess safety and tolerability; to explore within-subject carry-over 
effects. 
• 
Primary Hypothesis – Sub-threshold DRG stimulation will reduce mean Numeric 
Rating Scale (NRS, 0–10) pain scores compared with sham. 
 
Study Design 
• 
Randomized, double-blind, two-period crossover. 
• 
Two treatment arms of 5 days each, separated by a 24 h wash-out. 
• 
Order of conditions (Active → Sham or Sham → Active) allocated 1:1 using 
computer-generated random blocks. 
• 
Participant, treating clinician, and outcome assessors blinded. 
 

 
5 
Participant Selection 
Inclusion Criteria 
1. Adults (≥ 18 y) with an implanted DRG stimulator for a chronic neuropathic pain 
condition (not necessarily focal). 
2. ≥ 50 % pain reduction sustained for ≥ 3 months on standard (supra-threshold) therapy. 
3. Stable analgesic regimen ≥ 4 weeks. 
4. Ability to comply with diary completion and study visits. 
Exclusion Criteria 
1. Active infection or wound complication at implant site. 
2. Significant psychiatric comorbidity (e.g. uncontrolled depression, psychosis). 
3. Planned surgery, stimulation adjustments, or medication changes within 2 weeks prior 
to enrolment or at any time during the study period. 
4. Pregnancy or breastfeeding. 
5. Occurrence of any adverse event during the study that meets the predefined 
withdrawal criteria (see Safety Monitoring); such participants are withdrawn 
immediately and not re-randomized. 
Interventions 
• 
Active Sub-Threshold Stimulation – Device amplitude individually titrated to 80 % of 
perception threshold (no paresthesia felt), frequency and pulse-width unchanged from 
clinical settings. 
• 
Sham – Stimulator switched off. Device interrogation logs masked from participants 
and outcome staff. 
 
Randomisation & Blinding Procedures 
Randomization is generated automatically within the Patientkollen® patient-management 
platform using concealed permuted blocks (1:1 allocation) and stored entirely inside the 
single-site environment at Umeå University Hospital; no files are exported outside the 
platform. 
To maintain blinding: After each treatment period, participants will be asked whether they 
experienced any paresthesia during the preceding stimulation phase, in order to assess 
whether the study was genuinely blinded. We will not ask participants to identify whether 
they believe the period involved sham or active stimulation, as such judgements could be 
influenced by perceived analgesic benefit. Prior to study initiation, a pre-trial acute detection 
test will be performed in 10 participants: each will undergo 10 randomized one-minute 
sessions (stimulator ON at 80% perception threshold or OFF), and after each session indicate 
whether or not paresthesia was perceived. This will ensure the feasibility of maintaining 
blinding in the main trial. The programming nurse makes all parameter changes while the 
participant’s handheld programmer is hidden from view. 

 
6 
• 
After programming, the handheld unit is locked with a unique access code known only 
to the nurse and stored in the electronic Trial Master File (eTMF). 
• 
In a documented emergency (e.g. device-related adverse event or intolerable pain), the 
code may be disclosed by an investigator uninvolved in outcome assessment. 
Disclosure automatically withdraws the participant from the study; the reason is 
logged in the eTMF. 
Unblinding procedure: Once the final participant completes Day 10, Patientkollen runs 
automated integrity checks (range, consistency, missing-value rules) and locks the dataset. 
The platform then executes predefined statistical scripts comparing sequence labels A and B 
without human intervention. After the automated analysis is complete, the research team 
convenes, and the programming nurse activates the “reveal” function in Patientkollen to link 
each label to its actual treatment order. The validated dataset, analysis outputs, and audit trail 
then become accessible to the full study group. 
 
Study Schedule & Assessments 
Study Day 
 
Activity 
−7 to −1 
Screening, informed consent, baseline questionnaires, recording perception 
threshold. 
0 
Randomization; begin first 24 h wash-out (device OFF). 
 
1-5 
Period 1 treatment (Active or Sham) + twice-daily electronic diary. 
 
5 
24 h wash-out (device OFF). 
 
6-10 
Period 2 treatment + diaries. 
 
10 
End-of-study visit, adverse event review, exit interview 
 
Outcome Measures 
Category 
Measure 
 
Time-Points 
Primary 
Average NRS pain (0–10) across 5 treatment days 
 
Daily AM & PM 
Secondary 
Sleep quality (5-point PGIC)* 
 
Daily AM 
 
Mood (5-point PGIC)* 
 
Daily PM 
 
Daily activity (5-point PGIC)* 
 
Daily PM 
 
Adverse events 
 
Continuous 
Exploratory Device usage logs, rescue medication use 
 
Daily 
 
Data Collection & Management 
All study data remain entirely inside Patientkollen®’s two mirrored on-premises physical 
servers located in secure Swedish data centres—no exports, downloads, or external copies are 
made during the trial. The analysis workspace is hosted within this mirrored infrastructure 
under read-only permissions. 
• 
Randomization module – generates concealed allocation; visible only to the 
programming nurse. 

 
7 
• 
eConsent – digital Participant Information Sheet and Bank-ID e-signature; signed 
PDFs stored in-platform. 
• 
eDiary – questionnaires (pain, sleep, mood, activity) are scheduled at 09:00 and 20:00 
daily; SMS and e-mail prompts are sent, followed by an automated reminder after 1 h 
if still incomplete. 
o Missing > 2 consecutive diaries triggers an investigator alert. 
• 
Real-time dashboards – colour-coded indicators flag missing entries and SAE alerts 
for investigators and the DSMB. 
• 
Locked analysis workspace – pre-specified statistical scripts execute within 
Patientkollen on read-only copies of the dataset; a complete audit trail is archived. 
• 
Comprehensive audit logging – every action by patients and study personnel (e.g., 
diary entry, parameter change, data review) is time-stamped and written to an 
immutable audit log within Patientkollen. 
All data are encrypted at rest and in transit on the mirrored servers, which operate under ISO 
27001-compliant security policies with role-based access control. 
 
Statistical Analysis Plan 
• 
Sample Size – Assuming within-subject SD = 1.5 NRS points, minimally important 
difference = 1 point, α = 0.05, power = 0.90, two-sided paired test → 24 completers 
needed (calculated with G*Power). To accommodate 15 % attrition, target 
enrolment = 28. 
• 
Primary Analysis – Paired t-test (or Wilcoxon signed-rank if non-normal) comparing 
mean NRS pain across days 3–5 between Active and Sham periods. If a period is 
aborted due to high pain, the last recorded score will be carried forward for the 
remaining days. Treatment order and carry-over tested via mixed-effects model with 
fixed effects for treatment, period, and sequence. 
• 
Secondary Outcomes – Similar within-subject comparisons; Bonferroni correction 
applied. 
• 
Missing Data – Multiple imputation if > 5 % diary fields missing. 
 
Safety Monitoring 
All adverse events (AEs) occurring between screening and study exit lead to the immediate 
withdrawal of the participant from the trial. If the AE is judged related to either the DRG 
stimulation or the sham condition, it is captured in the study database with these mandatory 
details: (i) AE type and MedDRA term, (ii) date/time of onset, (iii) action taken (e.g., device 
OFF, medical treatment), and (iv) final outcome/resolution. 
The event report is recorded in Patientkollen within 24 h via the SAE portal and automatically 
forwarded to the Data Safety Monitoring Board (DSMB) for review at its next meeting. 
Intraperiod stopping rule: If any diary entry records (i) an NRS pain score > 8 or (ii) an 
increase ≥ 4 points versus Baseline Day 0, the current treatment period is halted. The 

 
8 
participant immediately enters the 24 h wash-out and then crosses to the alternate arm. The 
episode is logged as an AE (device insufficient efficacy) and triggers a real-time alert to the 
DSMB. 
 
Ethical Considerations 
The study complies with the Declaration of Helsinki, ISO 14155 Good Clinical Practice, and 
Swedish regulations for medical-device research. Ethical approval has been obtained for this 
study from the Swedish Ethical Review Authority (Etikprövningsmyndigheten), DNR 2025-
04065-01. It will be prospectively registered on the public registry ClinicalTrials.gov 
(identifier to be obtained) prior to enrolment of the first participant. All participants provide 
written informed e-consent via Patientkollen. Risks are minimal and relate mainly to 
temporary cessation of therapeutic stimulation. 
 
Dissemination 
Results will be submitted to peer-reviewed journals and presented at pain and 
neuromodulation conferences. De-identified data and statistical code will be made available 
via an open repository (OSF) within 12 months of publication. 
 
 

 
9 
References 
1. Chakravarthy K, Fishman MA, Zuidema X, Hunter CW, Levy R. Mechanism of 
Action in Burst Spinal Cord Stimulation: Review and Recent Advances. Pain Med. 
2019;20(Suppl 1):S13-S22. 
2. Devor M. Ectopic discharge in Aβ afferents as a source of neuropathic pain. Exp Brain 
Res. 2009;196:115-128. 
3. Kajander KC, Wakisaka S, Bennett GJ. Spontaneous discharge originates in the dorsal 
root ganglion at the onset of a painful peripheral neuropathy in the rat. Neurosci Lett. 
1992;138:225-228. 
4. Esposito MF, Malayil R, Hanes M, Deer T. Unique Characteristics of the Dorsal Root 
Ganglion as a Target for Neuromodulation. Pain Med. 2019;20(Suppl 1):S23-S30. 
5. Michaelis M, Blenk KH, Janig W, Vogel C. Development of spontaneous activity and 
mechanosensitivity in axotomized afferent nerve fibers during the first hours after 
nerve transection in rats. J Neurophysiol. 1995;74:1020-1027. 
6. Deer TR, Pope JE, Lamer TJ, Grider JS, Provenzano D, Lubenow TR, et al. The 
Neuromodulation Appropriateness Consensus Committee on Best Practices for Dorsal 
Root Ganglion Stimulation. Neuromodulation. 2019;22:1-35. 
7. Chapman KB, Sayed D, Lamer T, Hunter C, Weisbein J, Patel KV, et al. Best 
Practices for Dorsal Root Ganglion Stimulation for Chronic Pain: Guidelines from the 
American Society of Pain and Neuroscience. J Pain Res. 2023;16:839-879. 
8. Huygen F, Kallewaard JW, Nijhuis H, Liem L, Vesper J, Fahey ME, et al. 
Effectiveness and Safety of Dorsal Root Ganglion Stimulation for the Treatment of 
Chronic Pain: A Pooled Analysis. Neuromodulation. 2020;23:213-221. 
9. Deer TR, Levy RM, Kramer J, Poree L, Amirdelfan K, Grigsby E, et al. Dorsal root 
ganglion stimulation yielded higher treatment success rate for complex regional pain 
syndrome and causalgia at 3 and 12 months: a randomized comparative trial. Pain. 
2017;158:669-681. 
10. Deer T, Pope J, Hunter C, Falowski S, Kapural L, Kramer J, et al. Safety Analysis of 
Dorsal Root Ganglion Stimulation in the Treatment of Chronic Pain. 
Neuromodulation. 2020;23:239-244. 
11. Mekhail N, Deer TR, Poree L, Staats PS, Burton AW, Connolly AT, et al. Cost-
Effectiveness of Dorsal Root Ganglion Stimulation or Spinal Cord Stimulation for 
Complex Regional Pain Syndrome. Neuromodulation. 2020. 
12. Deer TR, Hunter CW, Mehta P, Sayed D, Grider JS, Lamer TJ, et al. A Systematic 
Literature Review of Dorsal Root Ganglion Neurostimulation for the Treatment of 
Pain. Pain Med. 2020;21:1581-1589. 
13. Chapman KB, Groenen PS, Patel KV, Vissers KC, van Helmond N. T12 Dorsal Root 
Ganglion Stimulation to Treat Chronic Low Back Pain: A Case Series. 
Neuromodulation. 2020;23:203-212. 
14. Tabatabaei P, Salomonsson J, Kakas P, Eriksson M. Bilateral T12 Dorsal Root 
Ganglion Stimulation for the Treatment of Low Back Pain With 20-Hz and 4-Hz 
Stimulation, a Retrospective Study. Neuromodulation. 2024;27:141-150. 
15. Huygen F, Liem L, Cusack W, Kramer J. Stimulation of the L2-L3 Dorsal Root 
Ganglia Induces Effective Pain Relief in the Low Back. Pain Pract. 2018;18:205-213. 
16. Kallewaard JW, Nijhuis H, Huygen F, Wille F, Zuidema X, van de Minkelis J, et al. 
Prospective Cohort Analysis of DRG Stimulation for Failed Back Surgery Syndrome 
Pain Following Lumbar Discectomy. Pain Pract. 2019;19:204-210. 

 
10 
17. Chapman KB, Spiegel MA, van Helmond N, Patel KV, Yang A, Yousef TA, et al. 
Dorsal Root Ganglion Stimulation as a Salvage Therapy Following Failed Spinal Cord 
Stimulation. Neuromodulation. 2022;25:1024-1032. 
18. Tabatabaei P, Kakas P, Bredemo L, Salomonsson J. Low-frequency dorsal root 
stimulation is effective for various pain etiologies and pain locations. Pain Pract. 
2024;24:997-1004. 
19. Ting JE, Hooper CA, Dalrymple AN, Weber DJ. Tonic Stimulation of Dorsal Root 
Ganglion Results in Progressive Decline in Recruitment of Aα/β-Fibers in Rats. 
Neuromodulation. 2024;27:1347-1359. 
 
 

 
11 
Appendix 1: Data report from our quality database for patients with 
DRG stimulation therapy