Transcriptomic Profile of Patients Treated With Different Modalities of Spinal Cord Stimulation
NCT ID: NCT05712980
Last Updated: 2023-02-06
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
UNKNOWN
Total Enrollment
40 participants
Study Classification
OBSERVATIONAL
Study Start Date
2023-02-28
Study Completion Date
2025-09-30
Brief Summary
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Failed Back Surgery Syndrome (FBSS) is a relatively common condition that can cause a severe disability in patients. Spinal cord stimulation (SCS) is used in those patients refractory to conventional therapies.In this project the investigators aim to identify new functional molecular basis, defined with transcriptomic profiling, differentially represented in the serum of patients suffering chronic pain caused by FBSS.
The investigators will try to Identify "omics" markers for diagnosing and monitoring the process of development and maintenance of pain as well as the evaluation of these as evolutionary disease markers or predictors of the response to SCS therapy. To carry out the project, 40 patients diagnosed with refractory FBSS and treated with an SCS system for pain management will be included. Blood samples will be obtained to analyze the transcription profiling in plasma of patients responding to different modalities of SCS therapy.
The investigators will try to Identify "omics" markers for diagnosing and monitoring the process of development and maintenance of pain as well as the evaluation of these as evolutionary disease markers or predictors of the response to SCS therapy. To carry out the project, 40 patients diagnosed with refractory FBSS and treated with an SCS system for pain management will be included. Blood samples will be obtained to analyze the transcription profiling in plasma of patients responding to different modalities of SCS therapy.
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Detailed Description
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Failed back surgery syndrome (FBSS) is a real challenge for the specialist because of its clinical complexity and economic importance not only in the cost of treatment but because of the high incidence of the syndrome in patients of working age and with normal life expectancy. This syndrome is a complication of lumbosacral surgery with an incidence ranging from 5-40%.
Spinal cord stimulation (SCS) has been used in the treatment of patients with FBSS for years safely and effectively . Although it was initially believed that the main mechanism of action was explained by the "Gate Control Theory" described by Wall and Melzack in 1965, it should be noted that other mechanisms beyond this could contribute to pain relief resulting from SCS. These include inhibition of neuronal excitability and hypersensitivity at the medullary level as well as changes in the release of neurotransmitters like GABA, acetylcholine, adenosine, serotonin and norepinephrine, involved in the transmission and modulation of pain. However, the molecular mechanisms underlying the therapeutic effect of SCS remain unknown.
Genetic studies are used to provide new insights into the molecular mechanisms underlying the onset and maintenance of pain. These can be driven by the hypothesis, thus evaluating the expression of default molecules, or independent of the hypothesis, exploring gene expression at the gene level at the whole genome. Microarray chips measure the expression of hundreds of genes in a given sample. Used to study a wide variety of biological systems, they have been used to evaluate extensive changes at the transcriptional level in different parts of the central or peripheral nervous system, leading to the discovery of new pain-related genes such as the Kv9.1 subunit of the potassium channel or KCNS1.
Recently, some animal model studies suggest that SCS produces extensive changes in gene expression. Tilley and collaborators found that SCS produced modulation in the expression of 5HTra, cFOS and GABAbr1 among others, with a strong correlation between the amount of current applied and the expression of GABAbr1, Na/K ATPase (negative correlation), 5HT3r and VIP (positive correlation) at the medular level and also at the level of the dorsal root ganglion. These authors focused on analyzing groups of genes that were shown altered in animal models of peripheral nerve injury. Stephens and collaborators performed an RNA seq of the spinal cord of rats with neuropathic pain secondary to the sciatic nerve ligation to which a spinal cord stimulator was implanted and found that gene expression changed after the application of SCS. They identified that the expression of some key genes in the expression of protein dense post-synaptic supporting proteins network in glutamaergic synapses is downregulated after SCS; this could destabilize this dense network, thus decreasing the effectiveness of synaptic signaling. They also found that SCS could activate nearby spinal tracts that affect neurons and gloss cells in the distal spinal segments. Vallejo and Tilley's group also performed extensive transcriptome analysis in animal models of neuropathic pain and found that SCS produces significant modulation in gene expression at the spinal cord and dorsal root ganglion level, with groups of genes and metabolic pathways similar in both tissues and which are directly or indirectly related to neural regeneration, regulation of inflammatory and immune responses and regulation of ion transport. Our group analyzed the gene expression of different markers (from cannabinoid receptors, opioid receptors and opioid peptides) using real-time polymerase chain reaction from lymphocyte RNA obtained from peripheral blood samples of patients with FBSS treated with SCS, observing a significant increase in proenkephalin (PNK) following SCS with respect to baseline levels and maintained over time.
Using the advantages of large-scale study of the genome using microarrays, we have carried out a research project in recent years with the main objective of identifying new molecular bases, defined with transcriptomic profiles, differentially expressed in the plasma of patients affected by FBSS and treated with tonic or conventional SCS. This study has been funded by Instituto de Salud Carlos III through the Project PI16/01364 (Co-funded by European Regional Development Fund/European Social Fund "A way to make Europe"/"Investing in your future"). The project was approved by the Ethical Committee for Clinical Research of the University General Hospital of Valencia. The study complied with local regulations, Good Clinical Practice guidelines, and the principles of the Declaration of Helsinki, as well as with current legislation and regulations governing protection of personal data and the rights and responsibilities regarding information and documentation in health care. Our group performed a transcriptomic analysis of the blood of patients affected of FBSS and treated with SCS (responder patients); we obtained samples before and at different times after implantation of the system in order to find differential gene expression in response to treatment and that could serve as potential biomarkers of effectiveness to therapy. We also performed transcriptomic analysis of patients in which SCS was not effective (non-responders), comparing the results with the responding patients with the intention of finding differential expression of potential biomarkers of response to SCS therapy. Finally, we compared the expression of patients diagnosed with FBSS with a group of spine-intervened patients who did not develop pain and served as a control group; we try to find differences in the gene expression between the two populations with the aim of finding possible biomarkers of disease development. We included 30 patients with SCS-treated FBSS (of whom 7 were non-responders and 23 responders) and 15 control patients. We have completed the recruitment and analysis of the samples periods and we are currently in the interpretation phase of the final results and development of the corresponding publications. Although the results are not definitive, preliminary analysis shows that there are more than 190 differentially expressed genes (p \< 0.05) at baseline when comparing control patients and patients with FBSS treated with SCS. We also found more than 750 genes differentially expressed in patients implanted before and after the onset of SCS therapy.
HYPOTHESIS
The biochemical and molecular processes associated with FBSS are unknown as are the changes that occur in patients undergoing SCS. The transcriptomic analysis seem promising tools to provide insight on the mechanisms underlying chronic pain. Quantification of RNA with RT-PCR will allow to identify differential genes implicated and solid conclusions to be drawn.
Our hypothesis is based on the fact that different genetic expression must occur in clinical situations related to pain and that these alterations should be differentially modified in patients successfully treated with spinal cord stimulation.
The identification of these possible biomarkers of state or evolution of the pathology and its treatment will contribute significantly to establish more accurate therapeutic strategies and can serve as predictive biomarkers of response to treatment, guiding the selection of therapeutic targets for the development of future treatment strategies.
AIMS OF THE STUDY
Based on these hypotheses and with the hopeful results previously obtained by our group, the investigators aim to compare whether the DTM programming of the SCS system produces a different expression-level effect than conventional programming with the intention of seeking biomarkers of response and evolution to this programming modality.
The investigators also aim to study whether these differences could be in relation to significantly different clinical outcomes and correlate with the intensity of the effect of the different modalities.
Spinal cord stimulation (SCS) has been used in the treatment of patients with FBSS for years safely and effectively . Although it was initially believed that the main mechanism of action was explained by the "Gate Control Theory" described by Wall and Melzack in 1965, it should be noted that other mechanisms beyond this could contribute to pain relief resulting from SCS. These include inhibition of neuronal excitability and hypersensitivity at the medullary level as well as changes in the release of neurotransmitters like GABA, acetylcholine, adenosine, serotonin and norepinephrine, involved in the transmission and modulation of pain. However, the molecular mechanisms underlying the therapeutic effect of SCS remain unknown.
Genetic studies are used to provide new insights into the molecular mechanisms underlying the onset and maintenance of pain. These can be driven by the hypothesis, thus evaluating the expression of default molecules, or independent of the hypothesis, exploring gene expression at the gene level at the whole genome. Microarray chips measure the expression of hundreds of genes in a given sample. Used to study a wide variety of biological systems, they have been used to evaluate extensive changes at the transcriptional level in different parts of the central or peripheral nervous system, leading to the discovery of new pain-related genes such as the Kv9.1 subunit of the potassium channel or KCNS1.
Recently, some animal model studies suggest that SCS produces extensive changes in gene expression. Tilley and collaborators found that SCS produced modulation in the expression of 5HTra, cFOS and GABAbr1 among others, with a strong correlation between the amount of current applied and the expression of GABAbr1, Na/K ATPase (negative correlation), 5HT3r and VIP (positive correlation) at the medular level and also at the level of the dorsal root ganglion. These authors focused on analyzing groups of genes that were shown altered in animal models of peripheral nerve injury. Stephens and collaborators performed an RNA seq of the spinal cord of rats with neuropathic pain secondary to the sciatic nerve ligation to which a spinal cord stimulator was implanted and found that gene expression changed after the application of SCS. They identified that the expression of some key genes in the expression of protein dense post-synaptic supporting proteins network in glutamaergic synapses is downregulated after SCS; this could destabilize this dense network, thus decreasing the effectiveness of synaptic signaling. They also found that SCS could activate nearby spinal tracts that affect neurons and gloss cells in the distal spinal segments. Vallejo and Tilley's group also performed extensive transcriptome analysis in animal models of neuropathic pain and found that SCS produces significant modulation in gene expression at the spinal cord and dorsal root ganglion level, with groups of genes and metabolic pathways similar in both tissues and which are directly or indirectly related to neural regeneration, regulation of inflammatory and immune responses and regulation of ion transport. Our group analyzed the gene expression of different markers (from cannabinoid receptors, opioid receptors and opioid peptides) using real-time polymerase chain reaction from lymphocyte RNA obtained from peripheral blood samples of patients with FBSS treated with SCS, observing a significant increase in proenkephalin (PNK) following SCS with respect to baseline levels and maintained over time.
Using the advantages of large-scale study of the genome using microarrays, we have carried out a research project in recent years with the main objective of identifying new molecular bases, defined with transcriptomic profiles, differentially expressed in the plasma of patients affected by FBSS and treated with tonic or conventional SCS. This study has been funded by Instituto de Salud Carlos III through the Project PI16/01364 (Co-funded by European Regional Development Fund/European Social Fund "A way to make Europe"/"Investing in your future"). The project was approved by the Ethical Committee for Clinical Research of the University General Hospital of Valencia. The study complied with local regulations, Good Clinical Practice guidelines, and the principles of the Declaration of Helsinki, as well as with current legislation and regulations governing protection of personal data and the rights and responsibilities regarding information and documentation in health care. Our group performed a transcriptomic analysis of the blood of patients affected of FBSS and treated with SCS (responder patients); we obtained samples before and at different times after implantation of the system in order to find differential gene expression in response to treatment and that could serve as potential biomarkers of effectiveness to therapy. We also performed transcriptomic analysis of patients in which SCS was not effective (non-responders), comparing the results with the responding patients with the intention of finding differential expression of potential biomarkers of response to SCS therapy. Finally, we compared the expression of patients diagnosed with FBSS with a group of spine-intervened patients who did not develop pain and served as a control group; we try to find differences in the gene expression between the two populations with the aim of finding possible biomarkers of disease development. We included 30 patients with SCS-treated FBSS (of whom 7 were non-responders and 23 responders) and 15 control patients. We have completed the recruitment and analysis of the samples periods and we are currently in the interpretation phase of the final results and development of the corresponding publications. Although the results are not definitive, preliminary analysis shows that there are more than 190 differentially expressed genes (p \< 0.05) at baseline when comparing control patients and patients with FBSS treated with SCS. We also found more than 750 genes differentially expressed in patients implanted before and after the onset of SCS therapy.
HYPOTHESIS
The biochemical and molecular processes associated with FBSS are unknown as are the changes that occur in patients undergoing SCS. The transcriptomic analysis seem promising tools to provide insight on the mechanisms underlying chronic pain. Quantification of RNA with RT-PCR will allow to identify differential genes implicated and solid conclusions to be drawn.
Our hypothesis is based on the fact that different genetic expression must occur in clinical situations related to pain and that these alterations should be differentially modified in patients successfully treated with spinal cord stimulation.
The identification of these possible biomarkers of state or evolution of the pathology and its treatment will contribute significantly to establish more accurate therapeutic strategies and can serve as predictive biomarkers of response to treatment, guiding the selection of therapeutic targets for the development of future treatment strategies.
AIMS OF THE STUDY
Based on these hypotheses and with the hopeful results previously obtained by our group, the investigators aim to compare whether the DTM programming of the SCS system produces a different expression-level effect than conventional programming with the intention of seeking biomarkers of response and evolution to this programming modality.
The investigators also aim to study whether these differences could be in relation to significantly different clinical outcomes and correlate with the intensity of the effect of the different modalities.
Conditions
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Spinal Cord Stimulation
Failed Back Surgery Syndrome
Genetic Change
Study Design
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Observational Model Type
COHORT
Study Time Perspective
PROSPECTIVE
Study Groups
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DTM Cohort
Patients with Failed Back Surgery Syndrome treated with Spinal Cord Stimulation with DTM programming
Implanted pulse generator for SCS with different programming modalities
Intervention Type
DEVICE
Surgical technique
Patients recruited will be scheduled for the implantation of the SCS system in two phases. The implant procedure will be performed following our standardized clinical practice under local anesthesia and moderate sedation.
Clinical parameters
Clinical evaluation of study subjects shall include, in addition to demographic parameters, the assessment of parameters related to pain experience, disability, quality of life, as well as other psychological variables. All these parameters will be evaluated at different times of the study.
Sample processing
10 ml of peripheral blood will be obtained per venopuncture at different moments, always at the same time of day and in the same anatomical location.
Expression arrays
After a manual removal of RNA the expression arrays and the scanning of the crystals will be carried out after hybridization
Conventional Cohort
Patients with Failed Back Surgery Syndrome treated with Spinal Cord Stimulation with conventional programming
Implanted pulse generator for SCS with different programming modalities
Intervention Type
DEVICE
Surgical technique
Patients recruited will be scheduled for the implantation of the SCS system in two phases. The implant procedure will be performed following our standardized clinical practice under local anesthesia and moderate sedation.
Clinical parameters
Clinical evaluation of study subjects shall include, in addition to demographic parameters, the assessment of parameters related to pain experience, disability, quality of life, as well as other psychological variables. All these parameters will be evaluated at different times of the study.
Sample processing
10 ml of peripheral blood will be obtained per venopuncture at different moments, always at the same time of day and in the same anatomical location.
Expression arrays
After a manual removal of RNA the expression arrays and the scanning of the crystals will be carried out after hybridization
Interventions
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Implanted pulse generator for SCS with different programming modalities
Surgical technique
Patients recruited will be scheduled for the implantation of the SCS system in two phases. The implant procedure will be performed following our standardized clinical practice under local anesthesia and moderate sedation.
Clinical parameters
Clinical evaluation of study subjects shall include, in addition to demographic parameters, the assessment of parameters related to pain experience, disability, quality of life, as well as other psychological variables. All these parameters will be evaluated at different times of the study.
Sample processing
10 ml of peripheral blood will be obtained per venopuncture at different moments, always at the same time of day and in the same anatomical location.
Expression arrays
After a manual removal of RNA the expression arrays and the scanning of the crystals will be carried out after hybridization
Intervention Type
DEVICE
Eligibility Criteria
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Inclusion Criteria
* Adult patients affected by FBSS, defined as "surgical end stage after one or several interventions on the lumbar neuroaxis indicated to relief lower back pain, root pain or the combination of both, without effect"
* Age between 18 and 65 years
* Severe pain measured on a numerical rating scale (NRS \> 6/10), more than six months of evolution
* Refractory pain despite having carried out pharmacological treatment according to WHO's stratified approach; physical/rehabilitation therapy and/or interventional procedures (e.g. epidural steroid injections, radiofrequency, epiduroscopy/adhesiolysis)
* Age between 18 and 65 years
* Severe pain measured on a numerical rating scale (NRS \> 6/10), more than six months of evolution
* Refractory pain despite having carried out pharmacological treatment according to WHO's stratified approach; physical/rehabilitation therapy and/or interventional procedures (e.g. epidural steroid injections, radiofrequency, epiduroscopy/adhesiolysis)
Exclusion Criteria
* Patients with severe associated comorbidities (e.g. severe high blood pressure, diabetes mellitus, peripheral vasculopathy, severe heart disease, etc...) that may in themselves cause pain or aggravate the existence of previous pain.
* Extensive osteosynthesis encompassing the thoraco-lumbar region where the tips of the electrodes are routinely positioned.
* Abnormal pain behavior, unresolved psychiatric illness, unresolved issues of secondary gain or inappropriate medication use
* Patients not consenting or refusing to participate will be excluded
* Negative evaluation of the psychologist previous to the implant
* Extensive osteosynthesis encompassing the thoraco-lumbar region where the tips of the electrodes are routinely positioned.
* Abnormal pain behavior, unresolved psychiatric illness, unresolved issues of secondary gain or inappropriate medication use
* Patients not consenting or refusing to participate will be excluded
* Negative evaluation of the psychologist previous to the implant
Minimum Eligible Age
18 Years
Maximum Eligible Age
65 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Hospital General Universitario de Valencia
OTHER
Sponsor Role
lead
Responsible Party
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Gustavo Fabregat
Consultant of Anesthesiology and Principal Investigator
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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Gustavo Fabregat, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Consultant of Anesthesiology and Pain Medicine Department
Locations
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Consorcio Hospital General Universitario
Valencia, , Spain
Site Status
Countries
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Spain
Central Contacts
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Facility Contacts
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Gustavo Fabregat, MD, PhD
Role: primary
+34963131800
References
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Reference Type
BACKGROUND
Monsalve V, de Andres JA, Valia JC. Application of a psychological decision algorithm for the selection of patients susceptible to implantation of neuromodulation systems for the treatment of chronic pain. A proposal. Neuromodulation. 2000 Oct;3(4):191-200. doi: 10.1046/j.1525-1403.2000.00191.x.
Reference Type
BACKGROUND
De Andres J, Monsalve-Dolz V, Fabregat-Cid G, Villanueva-Perez V, Harutyunyan A, Asensio-Samper JM, Sanchis-Lopez N. Prospective, Randomized Blind Effect-on-Outcome Study of Conventional vs High-Frequency Spinal Cord Stimulation in Patients with Pain and Disability Due to Failed Back Surgery Syndrome. Pain Med. 2017 Dec 1;18(12):2401-2421. doi: 10.1093/pm/pnx241.
Reference Type
BACKGROUND
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
SCS - OMICS
Identifier Type: -
Identifier Source: org_study_id
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