Dataset Information

Efficacy of different spinal cord stimulation paradigms for the treatment of chronic neuropathic pain (PARS-trial): study protocol for a double-blinded, randomized, and placebo-controlled crossover trial.

ABSTRACT:

Background

Spinal cord stimulation (SCS) is an effective method to treat neuropathic pain; however, it is challenging to compare different stimulation modalities in an individual patient, and thus, it is largely unknown which of the many available SCS modalities is most effective. Specifically, electrodes leading out through the skin would have to be consecutively connected to different, incompatible SCS devices and be tested over a time period of several weeks or even months. The risk of wound infections for such a study would be unacceptably high and blinding of the trial difficult. The PARS-trial seizes the capacity of a new type of wireless SCS device, which enables a blinded and systematic intra-patient comparison of different SCS modalities over extended time periods and without increasing wound infection rates.

Methods

The PARS-trial is designed as a double-blinded, randomized, and placebo-controlled multi-center crossover study. It will compare the clinical effectiveness of the three most relevant SCS paradigms in individual patients. The trial will recruit 60 patients suffering from intractable neuropathic pain of the lower extremities, who have been considered for SCS therapy and were already implanted with a wireless SCS device prior to study participation. Over a time period of 35?days, patients will be treated consecutively with three different SCS paradigms ("burst," "1?kHz," and "1.499?kHz") and placebo stimulation. Each SCS paradigm will be applied for 5?days with a washout period of 70?h between stimulation cycles. The primary endpoint of the study is the level of pain self-assessment on the visual analogue scale after 5?days of SCS. Secondary, exploratory endpoints include self-assessment of pain quality (as determined by painDETECT questionnaire), quality of life (as determined by Quality of Life EQ-5D-5L questionnaire), anxiety perception (as determined by the Hospital Anxiety and Depression Scale), and physical restriction (as determined by the Oswestry Disability Index).

Discussion

Combining paresthesia-free SCS modalities with wireless SCS offers a unique opportunity for a blinded and systematic comparison of different SCS modalities in individual patients. This trial will advance our understanding of the clinical effectiveness of the most relevant SCS paradigms.

Trial registration

German Clinical Trials Register, DRKS00018929 . Registered on 14 January 2020.

SUBMITTER: Ahmadi R

PROVIDER: S-EPMC7830748 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Efficacy of different spinal cord stimulation paradigms for the treatment of chronic neuropathic pain (PARS-trial): study protocol for a double-blinded, randomized, and placebo-controlled crossover trial.

Ahmadi Rezvan R Campos Benito B Hajiabadi Mohammad Mehdi MM Doerr-Harim Colette C Tenckhoff Solveig S Rasche Dirk D Unterberg Andreas A Vesper Jan J Bruckner Tom T Tronnier Volker V

Trials 20210125 1

<h4>Background</h4>Spinal cord stimulation (SCS) is an effective method to treat neuropathic pain; however, it is challenging to compare different stimulation modalities in an individual patient, and thus, it is largely unknown which of the many available SCS modalities is most effective. Specifically, electrodes leading out through the skin would have to be consecutively connected to different, incompatible SCS devices and be tested over a time period of several weeks or even months. The risk o ...[more]

PMID: 33494781

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Project description:ImportanceIndividuals with spinal cord injury (SCI) have significant autonomic nervous system dysfunction. However, despite recent findings postulated to support that spinal cord stimulation improves dynamic autonomic regulation, limited scope of previous testing means the true effects remain unknown.ObjectiveTo determine whether transcutaneous spinal cord stimulation improves dynamic autonomic regulation after SCI.DesignSingle-blinded, randomized crossover trial with matched cohorts.SettingAcademic autonomic physiology laboratory.ParticipantsTwo pairs of well-matched individuals with and without high-thoracic, complete SCI.InterventionsSub-motor threshold transcutaneous spinal cord stimulation delivered at T10-T11 using 120Hz, 30Hz, and 30Hz with 5kHz carrier frequency at separate autonomic testing sessions.Main outcomes and measuresBaseline autonomic regulation was characterized with tests of above injury level sympathoexcitation (Valsalva's maneuver), sympathoinhibition (progressive doses of bolus intravenous phenylephrine), and below level sympathoexcitation (foot cold pressor test). At three subsequent visits, this testing battery was repeated with the addition of spinal cord stimulation at each frequency. Changes in autonomic regulation for each frequency were then analyzed relative to baseline testing for each individual and within matched cohorts.ResultsUninjured controls demonstrated no autonomic deficits at baseline and had no changes with any frequency of stimulation. Contrasting this, and as expected, individuals with SCI had baseline autonomic dysfunction. In a frequency-dependent manner, spinal cord stimulation enhanced sympathoexcitatory responses, normalizing previously impaired Valsalva's maneuvers. However, stimulation exacerbated already impaired sympathoinhibitory responses, resulting in significantly greater mean arterial pressure increases with the same phenylephrine doses compared to baseline. Impaired sympathoexcitatory response below the level of injury were also further exacerbated with spinal cord stimulation. At baseline, neither individual with SCI demonstrated autonomic dysreflexia with the noxious foot cold pressor test; the addition of stimulation led to a dysreflexic response in every trial, with greater relative hypertension and bradycardia indicating no improvement in autonomic regulation.Conclusions and relevanceTranscutaneous spinal cord stimulation does not improve autonomic regulation after SCI, and instead likely generates tonic, frequency-dependent sympathoexcitation which may lower the threshold for autonomic dysreflexia.

Project description:BACKGROUND:The introduction of modern sub-perception modalities has improved the efficacy of spinal cord stimulation (SCS) in refractory pain syndromes of the trunk and lower limbs. The objective of this study was to evaluate the effectiveness of low and high frequency SCS among patients with chronic pain. MATERIAL AND METHODS:A randomised, semi-double-blind, placebo controlled, four period (4 × 2 weeks) crossover trial was conducted from August 2018 to January 2020. Eighteen patients with SCS due to failed back surgery syndrome and/or complex regional pain syndrome were randomised to four treatment arms without washout periods: (1) low frequency (40-60 Hz), (2) 1 kHz, (3) clustered tonic, and (4) sham SCS (i.e., placebo). The primary outcome was pain scores measured by visual analogue scale (VAS) preoperatively and during subsequent treatment arms. RESULTS:Pain scores (VAS) reported during the preoperative period was M (SD) = 8.13 (0.99). There was a 50% reduction in pain reported in the low frequency tonic treatment group (M (SD) = 4.18 (1.76)), a 37% reduction in the 1 kHz treatment group (M (SD) = 5.17 (1.4)), a 34% reduction in the clustered tonic settings group (M (SD) = 5.27 (1.33)), and a 34% reduction in the sham stimulation group (M (SD) = 5.42 (1.22)). The reduction in pain from the preoperative period to the treatment period was significant in each treatment group (p < 0.001). Overall, these reductions were of comparable magnitude between treatments. However, the modality most preferred by patients was low frequency (55% or 10 patients). CONCLUSIONS:The pain-relieving effects of SCS reached significance and were comparable across all modes of stimulation including sham. Sub-perception stimulation was not superior to supra-perception. SCS was characterised by a high degree of placebo effect. No evidence of carryover effect was observed between subsequent treatments. Contemporary neuromodulation procedures should be tailored to the individual preferences of patients.

Project description:ObjectiveTo examine the combined effects of neuromuscular electrical stimulation-resistance training (NMES-RT) and functional electrical stimulation-lower extremity cycling (FES-LEC) compared to passive movement training (PMT) and FES-LEC in adults with SCI on (1) oxygen uptake (VO2), insulin sensitivity and glucose disposal in adults with SCI; (2) Metabolic and inflammatory biomarkers; (3) skeletal muscle, intramuscular fat (IMF) and visceral adipose tissue (VAT) cross-sectional areas (CSAs).Materials and methodsThirty-three participants with chronic SCI (AIS A-C) were randomized to 24 weeks of NMES-RT + FES or PMT + FES. The NMES-RT + FES group underwent 12 weeks of evoked surface NMES-RT using ankle weights followed by an additional 12 weeks of progressive FES-LEC. The control group, PMT + FES performed 12 weeks of passive leg extension movements followed by an additional 12 weeks of FES-LEC. Measurements were performed at baseline (BL; week 0), post-intervention 1 (P1; week 13) and post-intervention 2 (P2; week 25) and included FES-VO2 measurements, insulin sensitivity and glucose effectiveness using the intravenous glucose tolerance test; anthropometrics and whole and regional body composition assessment using dual energy x-ray absorptiometry (DXA) and magnetic resonance imaging to measure muscle, IMF and VAT CSAs.ResultsTwenty-seven participants completed both phases of the study. NMES-RT + FES group showed a trend of a greater VO2 peak in P1 [p = 0.08; but not in P2 (p = 0.25)] compared to PMT + FES. There was a time effect of both groups in leg VO2 peak. Neither intervention elicited significant changes in insulin, glucose, or inflammatory biomarkers. There were modest changes in leg lean mass following PMT + FES group. Robust hypertrophy of whole thigh muscle CSA, absolute thigh muscle CSA and knee extensor CSA were noted in the NMES-RT + FES group compared to PMT + FES at P1. PMT + FES resulted in muscle hypertrophy at P2. NMES-RT + FES resulted in a decrease in total VAT CSA at P1.ConclusionNMES-RT yielded a greater peak leg VO2 and decrease in total VAT compared to PMT. The addition of 12 weeks of FES-LEC in both groups modestly impacted leg VO2 peak. The addition of FES-LEC to NMES-RT did not yield additional increases in muscle CSA, suggesting a ceiling effect on signaling pathways following NMES-RT.Clinical trial registrationidentifier NCT02660073.

Project description:Riluzole is a sodium-glutamate antagonist that attenuates neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favorable results in promoting recovery in pre-clinical models of traumatic spinal cord injury (tSCI) and in early phase clinical trials. This study aimed to evaluate the efficacy and safety of riluzole in acute cervical tSCI. An international, multi-center, prospective, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial (NCT01597518) was undertaken. Patients with American Spinal Injury Association Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 h from injury were randomized to receive either riluzole, at an oral dose of 100 mg twice per day (BID) for the first 24 h followed by 50 mg BID for the following 13 days, or placebo. The primary efficacy end-point was change in Upper Extremity Motor (UEM) scores at 180 days. The primary efficacy analyses were conducted on an intention to treat (ITT) and completed cases (CC) basis. The study was powered at a planned enrolment of 351 patients. The trial began in October 2013 and was halted by the sponsor on May 2020 (and terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the pre-planned enrolment) were randomized with a follow-up rate of 82.7% at 180 days. At 180 days, in the CC population the riluzole-treated patients compared with placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor scores (CI: -6.79-12.52). No drug-related serious adverse events were associated with the use of riluzole. Additional pre-planned sensitivity analyses revealed that in the AIS C population, riluzole was associated with significant improvement in total motor scores (estimate: standard error [SE] 8.0; CI 1.5-14.4) and upper extremity motor scores (SE 13.8; CI 3.1-24.5) at 6 months. AIS B patients had higher reported independence, measured by the Spinal Cord Independence Measure score (45.3 vs. 27.3; d: 18.0 CI: -1.7-38.0) and change in mental health scores, measured by the Short Form 36 mental health domain (2.01 vs. -11.58; d: 13.2 CI: 1.2-24.8) at 180 days. AIS A patients who received riluzole had a higher average gain in neurological levels at 6 months compared with placebo (mean 0.50 levels gained vs. 0.12 in placebo; d: 0.38, CI: -0.2-0.9). The primary analysis did not achieve the predetermined end-point of efficacy for riluzole, likely related to insufficient power. However, on pre-planned secondary analyses, all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with riluzole showed significant gains in functional recovery. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.

Project description:ObjectiveThe WHISPER randomized controlled trial (RCT) evaluates safety and clinical effectiveness of subperception spinal cord stimulation (SCS) at ≤1.2 kHz in subjects previously implanted with an SCS system for treatment of chronic, neuropathic pain.MethodsWHISPER is a prospective, multicenter RCT with a crossover design sponsored by Boston Scientific, Marlborough, MA (ClinicalTrials.gov: NCT02314000). Eligible subjects were randomized (N = 140) to receive subperception or supraperception for three months and then crossed over to receive the alternative. Upon completion of crossover period, subjects who preferred subperception were followed up to one year. Overall pain, quality-of-life, and other outcomes were collected in the study. The primary endpoint was the overall pain responder rate (≥50% improvement from baseline) with no increase in medications. Secondary endpoints consisted of pain scores, physical disability, quality of life, and treatment preference.ResultsThe study met its primary endpoint and demonstrated noninferiority between supraperception and subperception in a prespecified cohort of 70 randomized subjects (Interim Analysis). Thirty-nine percent of subjects with subperception settings and 29% with supraperception settings had a greater than or equal to 50% reduction in their overall pain scores with no increase in average daily medication at three-months post-activation as compared with baseline. Further assessment of all participating study subjects (N = 140) revealed similar results. Subjects were previously implanted 3.8 ± 2 years and had a disability score (Oswestry Disability Index) of 70.2 ± 11.4 at study start. Of the randomized subjects that completed the End of Period 2 Visit, 93 (66%) preferred subperception SCS and their mean overall pain reduced from 7.3 ± 1.1 (N = 89) at baseline to 4.0 ± 2.1 (N = 80) at 12-months post-activation. Post hoc analysis also demonstrated that multiple options provide superior outcomes, as supported by a 74% increase in the responder rate when subjects could choose their most effective option (47%) compared with supraperception alone (27%).DiscussionSubperception SCS at ≤1.2 kHz is safe and effective in subjects with extreme physical disability and previously implanted for chronic pain. Further, by providing study participants with different waveform options, increased pain relief was achieved.

Dataset Information

Efficacy of different spinal cord stimulation paradigms for the treatment of chronic neuropathic pain (PARS-trial): study protocol for a double-blinded, randomized, and placebo-controlled crossover trial.

Background

Methods

Discussion

Trial registration

Publications

Efficacy of different spinal cord stimulation paradigms for the treatment of chronic neuropathic pain (PARS-trial): study protocol for a double-blinded, randomized, and placebo-controlled crossover trial.

Similar Datasets

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