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Clinical trials landscape

TL;DR — The trial landscape spans repurposed drugs, ion-channel targets, topical agents, cortical stimulation, SCS/DRG and rehabilitation. Registry status is not efficacy: completed trials may be unpublished, “unknown” often reflects stale verification, and recruiting studies can fail. Current examples include phenotype-stratified pregabalin/duloxetine (NCT06614322), closed-loop DBS (NCT04144972) and CIPN scrambler therapy (NCT06914557), all verified live on 2026-08-30.

Registry snapshot

NCT Population Intervention Status 2026-08-30
NCT06614322 Painful peripheral neuropathy QST + pregabalin/duloxetine Recruiting
NCT04144972 Refractory chronic pain Closed-loop DBS Recruiting
NCT06914557 CIPN Scrambler + usual care Recruiting
NCT06522685 CIPN Remote tDCS Not yet recruiting
NCT06010251 SCI pain tDCS + bodily illusion Recruiting
NCT05005026 SCI pain Virtual walking Recruiting

The snapshot is a monitoring sample, not an exhaustive trial census. Live ClinicalTrials.gov v2 records were re-queried on 2026-08-30; the table below adds enrollment and planned completion because “recruiting” alone says little about maturity.

NCT Brief intervention domain Status Enrollment Planned/actual completion
NCT04144972 Closed-loop DBS for refractory chronic pain Recruiting 12 2030-10-24
NCT04699734 Peripheral nerve block in painful diabetic polyneuropathy Recruiting 16 2026-12-31
NCT05005026 Virtual walking for SCI neuropathic pain Recruiting 250 2026-09
NCT06010251 tDCS plus multisensory body representation after SCI Recruiting 30 2026-10-20
NCT06522685 Remote motor-cortex tDCS and CIPN correlates Not yet recruiting 80 2029-06-30
NCT06614322 QST-stratified pregabalin/duloxetine (SPENDD) Recruiting 190 2028-06
NCT06834685 Photobiomodulation for CIPN pain Recruiting 70 2028-12
NCT06914557 Scrambler therapy plus duloxetine-based care Recruiting 50 2027-06-30

Enrollment is the registry's planned or actual count, not the analyzable denominator. Completion dates can move and should be re-queried before any claim that results are overdue.

Completed anchors

NCT00300222 tested capsaicin in PHN; NCT00407745 tested pregabalin in SCI pain; NCT03029884 tested closed-loop DBS. Completion does not establish positive results.

NCT Registry intervention/population Status on 2026-08-30 Enrollment Interpretation boundary
NCT00300222 NGX-4010/capsaicin for PHN Completed 400 Requires linked publication and prespecified outcome check
NCT00407745 Pregabalin for SCI neuropathic pain Completed 220 Registration does not show effect size or attrition
NCT00993070 Topical capsaicin in painful diabetic neuropathy Completed 33 Small phase 2 study; not the later 369-person pivotal RCT
NCT03029884 Closed-loop DBS for refractory neuropathic pain Completed 4 Feasibility scale; no comparative efficacy inference
NCT03176472 Ricolinostat in painful diabetic neuropathy Completed 282 Completion requires publication/results linkage
NCT06074562 LY3556050/mazisotine in diabetic neuropathic pain Completed 404 Registry status is neutral about success or failure

Painful diabetes

NCT06074562 tested mazisotine; NCT03176472 ricolinostat; NCT00993070 capsaicin; NCT04699734 remains recruiting for nerve block.

Painful-diabetes trials illustrate three development routes: reformulating established peripheral mechanisms (capsaicin), targeting novel molecular pathways (ricolinostat and LY3556050), and moving to procedures after pharmacologic failure. The successful 10-kHz SCS RCT enrolled 216 selected implant candidates and reported a 79% versus 5% six-month composite response, but used medical management rather than invasive sham (Petersen 2021, PMID 33818600). Novel-drug programs need target-engagement evidence because plausible ion-channel biology has repeatedly failed to translate into broad efficacy (Dickenson 2021, PMID 33899639).

CIPN

The field includes acupuncture (NCT04917796), neurofeedback (NCT02573766), photobiomodulation (NCT06834685) and scrambler therapy (NCT06914557).

Registry status on 2026-08-30 was active, not recruiting for neurofeedback (NCT02573766; enrollment 91) and electroacupuncture (NCT04917796; enrollment 255), while photobiomodulation and scrambler therapy were recruiting. This modality diversity reflects a thin established-treatment base: duloxetine's pivotal five-week trial found a 0.73-point mean advantage over placebo (95% CI 0.26–1.20), and ASCO judged benefit limited (Smith 2013, PMID 23549581); (Loprinzi 2020, PMID 32663120).

CIPN trials should stratify or prespecify chemotherapy class, cumulative exposure, time since treatment and painful versus painless neuropathy. Pooling taxane, platinum, vinca-alkaloid and proteasome-inhibitor injury can dilute a mechanism-specific signal (Seretny 2014, PMID 25261162).

Failure patterns

Small samples, etiologic pooling, enriched withdrawal, short follow-up, mean-only outcomes and missing publication weaken inference (Sauzet 2013, PMID 23042476).

Sauzet and colleagues found neuropathic-pain RCT quality and reporting uneven, with short durations and variable diagnostic rigor (Sauzet 2013, PMID 23042476). Enriched-enrollment randomized-withdrawal designs can improve assay sensitivity but estimate maintenance among initial tolerators/responders, not effectiveness in all treatment-naïve patients. Crossover designs improve efficiency for stable pain but require adequate washout and are vulnerable to period and carryover effects.

Design Strength Bias/estimand risk Minimum report
Parallel placebo-controlled Clear randomized contrast Placebo response and attrition Allocation, masking, responder thresholds and all randomized participants
Active-comparator Direct clinical choice Noninferiority margin and open-label bias Margin justification and both ITT/per-protocol analyses
Crossover Within-person efficiency Carryover, period effects, selective completion Washout, sequence, period estimate and first-period sensitivity
Enriched withdrawal Detects maintenance in initial responders Excludes nonresponders/intolerant participants Enrichment losses and restricted estimand
Device versus usual care Pragmatic treatment-package effect No invasive sham; expectation and crossover Failed trials, implantation denominator and procedural harms
Phenotype-stratified Tests treatment heterogeneity Low interaction power; multiplicity Prespecified phenotype and interaction CI

Design priorities

Use confirmed grading, report ≥30%/≥50% responders, function and harms, prespecify phenotype interactions, and follow devices for revision/explant.

“Clinically important” should not be assigned from a universal one-point rule. Across 66 chronic-pain studies/31,254 patients, median absolute minimal important change was 23/100 (IQR 12–39) and relative change 34% (IQR 22–45), with heterogeneity I²=99% and 96%; baseline pain explained much absolute-threshold variation (Olsen 2018, PMID 29793007). Trials should therefore report continuous change, cumulative responder curves, ≥30% and ≥50% response, and patient global change.

Harms require the same denominator discipline as efficacy. Drug trials should report adverse-event withdrawals and dose exposure; topical trials application pain and sensory change; implants failed trials, infection, revision and explant; and stimulation studies headache, seizure and discontinuation. A statistically significant pain mean without functional or harm context is not a complete net-benefit estimate (Edwards 2023, PMID 36198371).

Mechanism trials

Candidate channel biology is strong, but past modulators show why target engagement and phenotype enrichment are essential (Dickenson 2021, PMID 33899639).

Oxcarbazepine provided 0.7/10 more pain relief than placebo (95% CI 0.4–1.4) and showed a phenotype interaction of 0.7 (95% CI 0.01–1.4); NNT for ≥50% relief was 3.9 in the irritable versus 13 in the non-irritable nociceptor phenotype (Demant 2014, PMID 25139589). That result motivated precision designs but was not a universal validation of QST guidance.

A later lacosamide trial closed early with 63 randomized participants. The phenotype interaction CI crossed no effect (0.41, 95% CI −1.2 to 2.0); overall mean pain did not differ, although responder NNTs were 4.0 (95% CI 2.3–16.1) for ≥30% and 5.0 (95% CI 2.8–24.5) for ≥50% relief (Carmland 2024, PMID 37565715). The contrast is an explicit unresolved replication problem, not evidence that phenotyping is useless.

Translation

Registry-to-publication linkage and results reporting are core evidence-quality outcomes, not administrative details.

For each completed record, curation should reconcile registered primary outcome, time point, enrollment, analysis population and adverse events with the publication. A title-level match is insufficient: outcome switching, delayed publication and unreported negative secondary outcomes can distort the apparent landscape. Active records should be revisited after their completion date rather than labeled “failed” when a planned date passes.

Evidence interpretation map

The table makes the evidence role and inferential boundary explicit; it is not a replacement for the full reports.

PMID Year Evidence role What it cannot establish alone
23042476 2013 Empirical audit of neuropathic-pain RCT quality Current registry status or efficacy of a modality
29793007 2018 Quantifies instability of chronic-pain MCID A single universal responder threshold
25139589 2014 Positive phenotype-by-oxcarbazepine interaction Replicable class-wide precision rule
37565715 2024 Lacosamide phenotype-stratified replication attempt Definitive absence of a small interaction after early closure
33818600 2021 Large device-versus-medical-care PDN RCT Invasive-sham-specific effect
36198371 2023 Precision-pain development recommendations Validation of any one candidate biomarker

Explicit controversies

  1. Phenotype enrichment: signal or unstable subgroup? Oxcarbazepine produced a nominally significant interaction (Demant 2014, PMID 25139589); lacosamide did not reproduce prediction and was underpowered after early closure (Carmland 2024, PMID 37565715). SPENDD (NCT06614322) is therefore testing an unresolved strategy, not implementing a validated test.
  2. Implanted-device sham requirements. Large treatment-package effects in PDN (Petersen 2021, PMID 33818600) coexist with very-low-certainty placebo-controlled chronic-pain evidence (O'Connell 2021, PMID 34854473). Ethical and technical sham constraints remain central to interpretation.
  3. Mean pain versus responder outcomes. Lacosamide showed no overall primary mean effect but favorable responder NNTs (Carmland 2024, PMID 37565715). Multiplicity, distribution shape and prespecification determine whether that is a meaningful signal or chance secondary finding.
  4. Completed versus known. NCT03029884 is completed with enrollment four, while NCT06074562 is completed with enrollment 404; neither status alone reveals direction, publication completeness or clinical importance. Registry completion must remain evidence-neutral.

Minimum reporting controls

Domain Required report
Case definition Possible, probable or definite neuropathic pain
Etiology Lesion/disease and diagnostic evidence
Distribution Focal, length-dependent, dermatomal, at-level or below-level
Baseline phenotype Negative and positive sensory signs
Comparator Placebo/sham, active care or natural history
Exposure Dose, duration, adherence and co-interventions
Benefit Mean change plus ≥30% and ≥50% responders where applicable
Function Sleep, mobility, participation and patient global change
Harm Adverse events, withdrawals and serious events
Durability Follow-up after treatment and attrition
Subgroups Prespecified interaction test, not within-group significance
Missingness Denominator and imputation method

Reporting cautions

  • Do not infer lesion presence from a symptom descriptor.
  • Do not convert a group-average association into an individual diagnostic rule.
  • Do not treat statistical significance as clinically important benefit.
  • Do not compare NNTs without checking outcome threshold, duration and population.
  • Do not interpret an inactive or completed registry record as proof of efficacy.
  • Do not merge painful and painless neuropathy outcomes.
  • Do not omit adverse-event withdrawals from responder interpretation.
  • Do not call a post hoc subgroup predictive without an interaction test.
  • Do not generalize a focal peripheral result to central neuropathic pain.
  • State when evidence is short-term, indirect or restricted to a selected cohort.

Open questions

  • Will SPENDD validate QST-guided selection?
  • Can closed-loop systems outperform open-loop stimulation?
  • Which CIPN modality survives sham control?
  • How many completed trials remain unpublished?

References

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