Insights into the pathophysiology and response of persistent spinal pain syndrome type 2 to spinal cord stimulation: a human genome-wide association study.

BACKGROUND: Spinal cord stimulation (SCS) provides pain relief for some patients with persistent spinal pain syndrome type 2 (PSPS 2), but the precise mechanisms of action and prognostic factors for a favorable pain response remain obscure. This in vivo human genome-wide association study provides some pathophysiological clues. METHODS: We performed a high-density oligonucleotide microarray analysis of serum obtained from both PSPS 2 cases and pain-free controls who had undergone lower back spinal surgery at the study site. Using multivariate discriminant analysis, we tried to identify different expressions between mRNA transcripts from PSPS 2 patients relative to controls, SCS responders to non-responders, or SCS responders to themselves before starting SCS. Gene ontology enrichment analysis was used to identify the biological processes that best discriminate between the groups of clinical interest. RESULTS: Thirty PSPS 2 patients, of whom 23 responded to SCS, were evaluated together with 15 pain-free controls. We identified 11 significantly downregulated genes in serum of PSPS 2 patients compared with pain-free controls and two significantly downregulated genes once the SCS response became apparent. All were suggestive of enhanced inflammation, tissue repair mechanisms and proliferative responses among the former. We could not identify any gene differentiating patients who responded to SCS from those who did not respond. CONCLUSIONS: This study points out various biological processes that may underlie PSPS 2 pain and SCS therapeutic effects, including the modulation of neuroimmune response, inflammation and restorative processes.

Effect of Conventional Spinal Cord Stimulation on Serum Protein Profile in Patients With Persistent Spinal Pain Syndrome: A Case-Control Study.

BACKGROUND: Spinal cord stimulation (SCS) provides pain relief for most patients with persistent spinal pain syndrome type 2 (PSPS 2). Evidence is mounting on molecular changes induced by SCS as one of the mechanisms to explain pain improvement. We report the SCS effect on serum protein expression in vivo in patients with PSPS 2. MATERIALS AND METHODS: Serum proteins were identified and quantified using mass spectrometry. Proteins with significantly different expression among patients with PSPS 2 relative to controls, responders, and nonresponders to SCS, or significantly modulated by SCS relative to baseline, were identified. Those most correlated with the presence and time course of pain were selected using multivariate discriminant analysis. Bioinformatic tools were used to identify related biological processes. RESULTS: Thirty patients with PSPS 2, of whom 23 responded to SCS, were evaluated, together with 14 controls with no pain who also had undergone lumbar spinal surgery. A significant improvement in pain intensity, disability, and quality of life was recorded among responders. Five proteins differed significantly at baseline between patients with PSPS 2 and controls, with three proteins, mostly involved in immune processes and inflammation, being downregulated and two, mostly involved in vitamin metabolism, synaptic transmission, and restorative processes, being upregulated. In addition, four proteins, mostly related to immune processes and inflammation, decreased significantly, and three, mostly related to iron metabolism and containment of synaptic sprouting, increased significantly during SCS. CONCLUSION: This study identifies various biological processes that may underlie PSPS 2 pain and SCS therapeutic effects, including the modulation of neuroimmune response and inflammation, synaptic sprouting, vitamin and iron metabolism, and restorative processes.

Predictive Clinical Decision Support System Using Machine Learning and Imaging Biomarkers in Patients With Neurostimulation Therapy: A Pilot Study.

BACKGROUND: Chronic pain is correlated with alterations in brain structure and function. The selection process for the ideal candidate for spinal cord stimulation (SCS) therapy is based on functional variables analysis and pain evaluation scores. In addition to the difficulties involved in the initial selection of patients and the predictive analysis of the trial phase, the large rate of explants is one of the most important concerns in the analysis of the suitability of implanted candidates. OBJECTIVE: To investigate the usefulness of imaging biomarkers, functional connectivity (FC) and volumetry of the whole brain in patients with Failed back surgery syndrome (FBSS) and to create a clinical patient-based decision support system (CDSS) combining neuroimaging and clinical data for predicting the effectiveness of neurostimulation therapy after a trial phase. STUDY DESIGN: A prospective, consecutive, observational, single center study. SETTING: The Multidisciplinary Pain Management Department of the General University Hospital in Valencia, Spain. METHODS: A prospective, consecutive, and observational single-center study. Using Resting-state functional magnetic resonance imaging (rs-fMRI) and Region of interest (ROI) to ROI analysis, we compared the functional connectivity between regions to detect differences in FC and volume changes. Basal magnetic resonance images were obtained in a 1.5T system and clinical variables were collected twice, at the basal condition and at 6-months post-SCS implant. We also conducted a seed-to-voxel analysis with 9 items as seed-areas characterizing the functional connectivity networks. A decreased in 10 units in the Pain Detect Questionnaire (PD-Q) score was established to define the subgroup of Responders Group (R-G) to neurostimulation therapy. The clinical variables collected and the imaging biomarkers obtained (FC and volumes) were tested on a set of 6 machine learning approaches in an effort to find the best classifier system for predicting the effectiveness of the neurostimulator. RESULTS: Twenty-four patients were analyzed and only seven were classified in the R-G. Volumetric differences were found in the left putamen, F = 34.06, P = 0.02. Four pairwise brain areas showed statistical differences in the rs-fMRI including the right insular cortex. Linear Discriminant Analysis showed the best performance for building the CDSS combining clinical variables and significant imaging biomarkers, the prediction increased diagnostic accuracy in the R-G patients from 29% in current practice to 96% of long-term success. CONCLUSION: These findings confirm a major role of the left putamen and the four pairs of brain regions in FBBS patients and suggest that a CDSS would be able to select patients susceptible to benefitting from SCS therapy adding imaging biomarkers.

Intrathecal Drug Delivery.

Targeted intrathecal (IT) drug delivery systems (IDDS) are well established as an effective treatment of patients with chronic nonmalignant or malignant pain, and as a tool for management of patients with severe spasticity. The risk to benefit ratio of IDD makes it a relatively safe therapy for both cancer- and noncancer-related pain, but it is not free of risks, so it should be managed at specific centers. Recent technological advances, new therapeutic applications, reported complications, and the costs as well as maintenance required for this therapy require the need to stay up to date about new recommendations that may improve outcomes. This chapter reviews all technological issues regarding IDDS implantation with follow-up and pharmacological recommendations published during recent years that provide evidence-based decision-making process in the management of chronic pain and spasticity in patients.

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.

OBJECTIVES: Spinal cord stimulation (SCS) for patients with failed back surgery syndrome (FBSS) show variable results and limited to moderate evidence. In the last years the stimulation of high frequency (HF) has been considered as a better alternative in this pathology for its supposed benefits compared to the stimulation with conventional frequency (CF). To compare in one year follow-up, the efficacy of high-frequency SCS (HF) versus conventional frequency SCS (CF) on the patients with FBSS. DESIGN: Prospective, Randomized blind trial. SETTING: Academic University Pain Medicine Center. SUBJECT: Seventy eight patients with FBSS diagnosis based on internationally recognized criteria, and refractory to conservative therapy for at least 6 months, have been initially recruited, and. METHODS: Sixty subjects met the eligibility criteria and were randomized and scheduled for the trial phase.The patients were randomly assigned in either, one of the two groups: CF SCS or HF SCS. Within the study methods, special attention was paid to standardizing patient programming, so that these parameters would not impact the results.The trial period was considered successful if there was ?50% reduction in the NRS from baseline. RESULTS: A total of 55 subjects successfully completed all assessments during one year follow-up. Change patterns in scores do not differ based on high versus conventional frequency, with significant global average reduction at 1 year similarly for both groups. Among all the items included in the Short Form-12 questionnaire (SF-12), only the variations in the social function score between the instants t1 and t2 are somewhat higher in the high frequency group. CONCLUSION: The evolutionary pattern of the different parameters studied in our patients with FBSS does not differ according to their treatment by spinal stimulation, with conventional or high frequency, in one year follow-up.

Vulvodynia--An Evidence-Based Literature Review and Proposed Treatment Algorithm.

OBJECTIVE: We searched the medical literature from the last 15 years (1998 to 2013) relating to the etiology, diagnosis, and treatment of vulvodynia. The evidence was reviewed supporting the therapeutic proposals currently in use and propose the incorporation of novel, minimally invasive, interventional therapies, within the context of a multidisciplinary approach. METHODS: This was a systematic review of all relevant studies with no language restrictions. Studies were identified through Medline/PubMed (1998 to March 2013), the Cochrane Library (2001 to 2013), and conference records and book chapters. The keywords used included "chronic pelvic pain," "vulvodynia," "vestibulodynia," and search terms "etiology," "diagnosis," and "treatment" were added. The levels of evidence were assessed using grading system for "Therapy/Prevention/Etiology/Harm" developed by the Centre for Evidence-Based Medicine (CEBM). The grading system assists in clinical decision-making, and we decided to use "The Grading of Recommendations Assessment, Development, and Evaluation (GRADE)." RESULTS: A total of 391 papers were assessed. Of these, 215 were analyzed and 175 were excluded, as they pertained to areas not directly related to the disease under review. CONCLUSION: The optimal therapy for vulvar pain syndrome remains elusive, with low percentages of therapeutic success, using either local or systemic pharmacological approaches. Surgery involving invasive and often irreversible therapeutic procedures has resulted in success for certain subtypes of vulvodynia. We present a multidisciplinary approach whereby pain treatment units may provide an intermediate level of care between standard medical and surgical treatments.

Management of acute pain in patients on treatment with opioids.

The use of opioids for both benign and cancer-related chronic pain has increased exponentially over the last few years. For this reason, increasing numbers of such patients are presenting for surgery. It is known that continuous use of opioids is associated with an increase in postoperative analgesic requirements. This is believed to be mediated by the development of tolerance and opioid-induced hyperalgesia. Patients treated with opioids have special needs in the perioperative setting and it is the anesthesiologist's responsibility to manage these needs optimally. The aim of the present paper is to briefly orient the reader in the management of postoperative pain in patients chronically treated with licit opioids.

Computer-tomographic verification of ultrasound-guided piriformis muscle injection: a feasibility study.

BACKGROUND: Approximately 6% to 8% of lumbar pain cases, whether associated with radicular pain or not, may be attributed to the presence of piriformis muscle syndrome. Available treatments, among others, include pharmacotherapy, physical therapy, and injections of different substances into the muscle. Various methods have been used to confirm correct needle placement during these procedures, including electromyography (EMG), fluoroscopy, computed tomography (CT), or magnetic resonance imaging (MRI). Ultrasonography (US) has now become a widely used technique and therefore may be an attractive alternative for needle guidance when injecting this muscle. OBJECTIVE: The objective of this study was to assess the reliability of US in piriformis injection of patients with piriformis syndrome. STUDY DESIGN: Feasibility study; 10 patients with piriformis muscle syndrome were injected with botulinum toxin A using a US-guided procedure. Then patients were administered 2 mL iodinated contrast and were then transferred to the CT scanner, where they underwent pelvic and hip imaging to assess intramuscular distribution of the iodinated contrast. SETTING: Multidisciplinary Pain Management Department in Spain. RESULTS: Of all 10 study patients (8 women, 2 men), 9 had intramuscular or intrafascial contrast distribution. Distribution did not go deeper than the piriformis muscle in any of the patients. The absence of contrast (intravascular injection) was not observed in any case. LIMITATIONS: The main limitation of our study is the use of ionizing radiation as confirmation technique. CONCLUSION: Ultrasound-guided puncture may be a reliable and simple procedure for injection of the piriformis muscle, as long as good education and training are provided to the operator. US has a number of advantages over traditional approaches, including accessibility and especially no ionizing radiation exposure for both health care providers and patients.

Intrathecal delivery of analgesics.

Targeted intrathecal (IT) drug delivery systems (IDDS) are an option in algorithms for the treatment of patients with moderate to severe chronic refractory pain when more conservative options fail. This therapy is well established and supported by several publications. It has shown efficacy and is an important tool for the treatment of spasticity, and both cancer and nonmalignant pain. Recent technological advances, new therapeutic applications, reported complications, and the costs as well as maintenance required for this therapy require the need to stay up-to-date about new recommendations that may improve outcomes. This chapter reviews all technological issues regarding IDDS implantation with follow-up, and pharmacological recommendations published during recent years that provide evidence-based decision making process in the management of chronic pain and spasticity in patients.

Role of lumbosacral retrograde neuromodulation in the treatment of painful disorders.

BACKGROUND: Neuromodulation is an effective and reversible treatment option for chronic intractable pain. Spinal cord stimulation (SCS) represents a field of application of neuromodulation and is known to be effective for several conditions including complex regional pain syndrome (CRPS), failed back surgery syndrome (FBSS), and chronic leg and back pain. SCS has some technical limitations that can be bypassed through retrograde neuromodulation. OBJECTIVE: To examine the safety and efficacy of retrograde neuromodulation in consecutive patients with neuropathic pain in the perineum or lower limb. STUDY DESIGN: Prospective chart review analyzing one year of retrograde stimulation in our department. METHODS: We present a series of 10 patients who underwent retrograde neuromodulation at the University General Hospital of Valencia (Spain). We analyzed the variables that can improve the outcome and help physicians choose retrograde neuromodulation. RESULTS: Seven of 10 patients had an effective treatment and 3 patients had an ineffective stimulation. In the group with the effective treatment the most represented type of pain was radiculopathy and perineal pain. LIMITATIONS: This is a prospective, single-center study with a relatively small number of patients and no control group. CONCLUSION: Retrograde neuromodulation seems to be effective in patients that present with a well localized pain with a clear dermatome distribution. We found retrograde neuromodulation to be effective in radiculopathy related to FBSS. We found it to be limited in the treatment of perineal pain probably due to technical limitations and anatomical reasons besides the lack of knowledge of the etiology of this pain model and the exact mechanisms of action of neuromodulation.

Peripheral subcutaneous vulvar stimulation in the management of severe and refractory vulvodynia.

BACKGROUND: Vulvodynia is a complex and multifactorial clinical condition with severe pain that occurs in the absence of visible infectious, inflammatory, neoplastic, or neurological findings. CASE: A 35-year-old woman with 3 years of dysesthetic vulvodynia tried conventional and interventional medical treatment with inadequate relief. She was offered peripheral subcutaneous vulvar field stimulation and underwent implantation of two vulvar subcutaneous electrodes. At 15 days after treatment and during 1-year follow-up, the patient scored 1 out of 15 on Friedrich scale, 1 out of 10 on the visual analog scale, and 1 out of 10 on the tampon test. The patient no longer requires oral medication. CONCLUSION: Stimulation with subcutaneous electrodes provided relief from vulvodynia to a patient in whom all previous therapeutic approaches had failed.

Role of Catheter's Position for Final Results in Intrathecal Drug Delivery. Analysis Based on CSF Dynamics and Specific Drugs Profiles

Intrathecal drug delivery is an effective and safe option for the treatment of chronic pathology refractory to conventional pain therapies. Typical intrathecal administered drugs are opioids, baclofen, local anesthetics and adjuvant medications. Although knowledge about mechanisms of action of intrathecal drugs are every day more clear many doubt remain respect the correct location of intrathecal catheter in order to achieve the best therapeutic result. We analyze the factors that can affect drug distribution within the cerebrospinal fluid. Three categories of variables were identified: drug features, cerebrospinal fluid (CSF) dynamics and patients features. First category includes physicochemical properties and pharmacological features of intrathecal administered drugs with special attention to drug lipophilicity. In the second category, the variables in CSF flow, are considered that can modify the drug distribution within the CSF with special attention to the new theories of liquoral circulation. Last category try to explain inter-individual difference in baclofen response with difference that are specific for each patients such as the anatomical area to treat, patient posture or reaction to inflammatory stimulus. We conclude that a comprehensive evaluation of the patients, including imaging techniques to study the anatomy and physiology of intrathecal environment and CSF dynamics, could become essential in the future to the purpose of optimize the clinical outcome of intrathecal therapy.