Enhancing spinal cord stimulation-induced pain inhibition by augmenting endogenous adenosine signalling after nerve injury in rats.

BACKGROUND: The mechanisms for spinal cord stimulation (SCS) to alleviate chronic pain are only partially known. We aimed to elucidate the roles of adenosine A1 and A3 receptors (A1R, A3R) in the inhibition of spinal nociceptive transmission by SCS, and further explored whether 2'-deoxycoformycin (dCF), an inhibitor of adenosine deaminase, can potentiate SCS-induced analgesia. METHODS: We used RNAscope and immunoblotting to examine the distributions of adora1 and adora3 expression, and levels of A1R and A3R proteins in the spinal cord of rats after tibial-spared nerve injury (SNI-t). Electrophysiology recording was conducted to examine how adenosine receptor antagonists, virus-mediated adora3 knockdown, and dCF affect SCS-induced inhibition of C-fibre-evoked spinal local field potential (C-LFP). RESULTS: Adora1 was predominantly expressed in neurones, whereas adora3 is highly expressed in microglial cells in the rat spinal cord. Spinal application of antagonists (100 µl) of A1R (8-cyclopentyl-1,3-dipropylxanthine [DPCPX], 50 µM) and A3R (MRS1523, 200 nM) augmented C-LFP in SNI-t rats (DPCPX: 1.39 [0.18] vs vehicle: 0.98 [0.05], P=0.046; MRS1523: 1.21 [0.07] vs vehicle: 0.91 [0.03], P=0.002). Both drugs also blocked inhibition of C-LFP by SCS. Conversely, dCF (0.1 mM) enhanced SCS-induced C-LFP inhibition (dCF: 0.60 [0.04] vs vehicle: 0.85 [0.02], P<0.001). In the behaviour study, dCF (100 nmol 15 µl-1, intrathecal) also enhanced inhibition of mechanical hypersensitivity by SCS in SNI-t rats. CONCLUSIONS: Spinal A1R and A3R signalling can exert tonic suppression and also contribute to SCS-induced inhibition of spinal nociceptive transmission after nerve injury. Inhibition of adenosine deaminase may represent a novel adjuvant pharmacotherapy to enhance SCS-induced analgesia.

A Definition of Neuromodulation and Classification of Implantable Electrical Modulation for Chronic Pain.

OBJECTIVES: Neuromodulation therapies use a variety of treatment modalities (eg, electrical stimulation) to treat chronic pain. These therapies have experienced rapid growth that has coincided with escalating confusion regarding the nomenclature surrounding these neuromodulation technologies. Furthermore, studies are often published without a complete description of the effective stimulation dose, making it impossible to replicate the findings. To improve clinical care and facilitate dissemination among the public, payors, research groups, and regulatory bodies, there is a clear need for a standardization of terms. APPROACH: We formed an international group of authors comprising basic scientists, anesthesiologists, neurosurgeons, and engineers with expertise in neuromodulation. Because the field of neuromodulation is extensive, we chose to focus on creating a taxonomy and standardized definitions for implantable electrical modulation of chronic pain. RESULTS: We first present a consensus definition of neuromodulation. We then describe a classification scheme based on the 1) intended use (the site of modulation and its indications) and 2) physical properties (waveforms and dose) of a neuromodulation therapy. CONCLUSIONS: This framework will help guide future high-quality studies of implantable neuromodulatory treatments and improve reporting of their findings. Standardization with this classification scheme and clear definitions will help physicians, researchers, payors, and patients better understand the applications of implantable electrical modulation for pain and guide informed treatment decisions.

Spinal Cord Stimulation Increases Chemoefficacy and Prevents Paclitaxel-Induced Pain via CX3CL1.

INTRODUCTION: Despite increasing utilization of spinal cord stimulation (SCS), its effects on chemoefficacy, cancer progression, and chemotherapy-induced peripheral neuropathy (CIPN) pain remain unclear. Up to 30% of adults who are cancer survivors may suffer from CIPN, and there are currently no effective preventative treatments. MATERIALS AND METHODS: Through a combination of bioluminescent imaging, behavioral, biochemical, and immunohistochemical approaches, we investigated the role of SCS and paclitaxel (PTX) on tumor growth and PTX-induced peripheral neuropathy (PIPN) pain development in T-cell-deficient male rats (Crl:NIH-Foxn1rnu) with xenograft human non-small cell lung cancer. We hypothesized that SCS can prevent CIPN pain and enhance chemoefficacy partially by modulating macrophages, fractalkine (CX3CL1), and inflammatory cytokines. RESULTS: We show that preemptive SCS enhanced the antitumor efficacy of PTX and prevented PIPN pain. Without SCS, rats with and without tumors developed robust PIPN pain-related mechanical hypersensitivity, but only those with tumors developed cold hypersensitivity, suggesting T-cell dependence for different PIPN pain modalities. SCS increased soluble CX3CL1 and macrophages and decreased neuronal and nonneuronal insoluble CX3CL1 expression and inflammation in dorsal root ganglia. CONCLUSION: Collectively, our findings suggest that preemptive SCS is a promising strategy to increase chemoefficacy and prevent PIPN pain via CX3CL1-macrophage modulation.

Educational Curriculum for Peripheral Nerve Stimulation Developed by the North American Neuromodulation Society.

BACKGROUND: Peripheral nerve stimulation (PNS) is an effective neuromodulation therapy for chronic neuropathic and nociceptive pain. Although the total number of PNS implantations has increased over the last decade, no curriculum exists to guide training and learning of this therapy. The goal of the North American Neuromodulation Society (NANS) education committee is to develop a series of competency-based curriculums for neuromodulation therapies. The PNS curriculum is the latest part of such series, following the curriculums for spinal cord stimulation and intrathecal drug delivery system. MATERIALS AND METHODS: A multidisciplinary task force (anesthesiology, physical medicine and rehabilitation, neurosurgery, preventive medicine and public health, and neurology) was created by the educational committee of NANS to develop a PNS curriculum in accordance with the Accreditation Council for Graduate Medical Education (ACGME) milestones. The curriculum was created based on the best available evidence and expert knowledge (from our task force members) of available PNS systems. The final PNS curriculum was approved by the NANS board. RESULTS: A PNS curriculum was developed by the task force. Milestones included professionalism, practice-based learning, interpersonal communication, medical knowledge, systems-based practice, procedural skills, and patient care. Each milestone was defined into three categories: early learner, advanced learner, and practitioner. CONCLUSIONS: This manuscript provides a PNS training curriculum developed by a multidisciplinary task force of the NANS educational committee in accordance with the milestones described by ACGME for basic learners, advanced learners, and practitioners. This curriculum will help provide a structured training and evaluation process for obtaining proficiency in PNS treatment(s).

North American Neuromodulation Society Educational Curriculum for Intrathecal Drug Delivery Systems Implantation and Management.

OBJECTIVES: Intrathecal drug delivery systems (IDDSs) are used for the treatment of pain and spasticity. A wide range of educational criteria exist for these devices. The North American Neuromodulation Society (NANS) Education Committee developed a comprehensive IDDS curriculum to function as a standard for physician graduate education and assessment through training and into practice. MATERIAL AND METHODS: A multidisciplinary and diverse task force gathered by the NANS Education Committee met in person and virtually over several sessions and developed an IDDS curriculum modeling their previous work on spinal cord stimulation and following the Accreditation Council for Graduate Medical Education (ACGME) Milestones. There were iterative revisions and adaptations to the curriculum, and the final version was approved by the NANS Board of Directors. RESULTS: The curriculum was developed with distinction between implanting physicians and managing physician and physicians who perform both tasks. There is a lateral temporal progression from early learner to practitioner, with advanced learner in the middle. In addition, there is a modular vertical organization that divides the curriculum into the six educational competencies outlined by the ACGME. CONCLUSION: A comprehensive, modular, graduated, and segmented educational curriculum for IDDSs was developed by NANS. We propose the curriculum to be the standard for guidance and assessment of trainees and physicians pursuing training in implanting or managing IDDSs.

Neuromodulation for chronic pain.

Neuromodulation is an expanding area of pain medicine that incorporates an array of non-invasive, minimally invasive, and surgical electrical therapies. In this Series paper, we focus on spinal cord stimulation (SCS) therapies discussed within the framework of other invasive, minimally invasive, and non-invasive neuromodulation therapies. These therapies include deep brain and motor cortex stimulation, peripheral nerve stimulation, and the non-invasive treatments of repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and transcutaneous electrical nerve stimulation. SCS methods with electrical variables that differ from traditional SCS have been approved. Although methods devoid of paraesthesias (eg, high frequency) should theoretically allow for placebo-controlled trials, few have been done. There is low-to-moderate quality evidence that SCS is superior to reoperation or conventional medical management for failed back surgery syndrome, and conflicting evidence as to the superiority of traditional SCS over sham stimulation or between different SCS modalities. Peripheral nerve stimulation technologies have also undergone rapid development and become less invasive, including many that are placed percutaneously. There is low-to-moderate quality evidence that peripheral nerve stimulation is effective for neuropathic pain in an extremity, low quality evidence that it is effective for back pain with or without leg pain, and conflicting evidence that it can prevent migraines. In the USA and many areas in Europe, deep brain and motor cortex stimulation are not approved for chronic pain, but are used off-label for refractory cases. Overall, there is mixed evidence supporting brain stimulation, with most sham-controlled trials yielding negative findings. Regarding non-invasive modalities, there is moderate quality evidence that repetitive transcranial magnetic stimulation does not provide meaningful benefit for chronic pain in general, but conflicting evidence regarding pain relief for neuropathic pain and headaches. For transcranial direct current stimulation, there is low-quality evidence supporting its benefit for chronic pain, but conflicting evidence regarding a small treatment effect for neuropathic pain and headaches. For transcutaneous electrical nerve stimulation, there is low-quality evidence that it is superior to sham or no treatment for neuropathic pain, but conflicting evidence for non-neuropathic pain. Future research should focus on better evaluating the short-term and long-term effectiveness of all neuromodulation modalities and whether they decrease health-care use, and on refining selection criteria and treatment variables.

Procedure-Related Outcomes Including Readmission Following Spinal Cord Stimulator Implant Procedures: A Retrospective Cohort Study.

BACKGROUND: Spinal cord stimulation (SCS) has been shown to reduce opioid consumption, reduce pain, improve quality of life compared to conventional therapy, and be more effective than spine reoperation in carefully selected patients. In this study, we evaluate readmissions after SCS implantation procedures, costs, predictors, and etiologies for readmission following implantation procedures. METHODS: The study was a retrospective cohort using the National Readmissions Database from 2013 to 2017. Administrative billing codes were used to identify patients undergoing SCS implantation procedures. The primary outcome of our study was 30-day readmission following the SCS implantation procedure. Continuous outcomes were compared between groups using the Student t test or Wilcoxon rank sum test. In addition, multivariable predictors of 30-day readmission were assessed by hierarchical logistic regression analysis. RESULTS: A total of 3737 (26.7% open surgical SCS implants [OS-SCS]) individuals admitted to the hospital for SCS implantation were included in the final cohort analysis. The cohort consisted of predominantly female patients (58.71%) and in the 50- to 64-year age group (35.46%). Patients who underwent open surgical SCS implantation had a longer length of stay during the initial admission and a higher 30-day readmission rate (9.4% vs 7% P = .01). OS-SCS, older age, lower socioeconomic status, patients with specific comorbidities (ie, hypertension or chronic obstructive pulmonary disease [COPD]), and home discharge are associated with readmission. CONCLUSIONS: Readmission rates after SCS implantation are around 7.7% in the United States. Infection and postoperative complications remain the top etiologies for readmission. Open surgical SCS implantation is associated with more extended initial hospitalization and a higher rate of readmission when compared to percutaneous SCS implantation procedures.

Postoperative Oral Antibiotic Use and Infection-Related Complications After Spinal Cord Stimulator Surgery.

OBJECTIVES: Spinal cord stimulation (SCS) is considered a minimally invasive and reversible neuromodulation therapy for various chronic pain disorders. The rates of infection following SCS surgery reported in the literature range from 2.8% to 10%. Several studies indicated no potential benefit of postoperative antibiotics (beyond 24 hours) on subsequent device infection. This study aimed to understand the characteristics of postoperative antibiotic prescriptions and subsequent infections following SCS surgery. MATERIALS AND METHODS: The study was a retrospective cohort using the IBM® MarketScan® Commercial and Medicare Supplemental Databases from 2013 to 2018. Adult patients undergoing SCS surgical procedures with at least 90 days of follow-up were identified using Current Procedural Terminology (CPT®) codes. Postprocedural oral antibiotics within 14 days and preprocedural corticosteroid use within seven days were identified using National Drug Codes (NDC). Administrative claims were analyzed to understand the characteristics of prescribed postoperative antibiotics. Infection-related complications within 90 days were identified using administrative codes. RESULTS: A total of 18,105 patients (age 55.5 ± 13.1 years, 40.2% male) underwent SCS surgery during the study period. Postprocedural oral antibiotics and preprocedural steroids were prescribed for 35.3% and 2.6%, respectively, for SCS surgery patients. The most commonly used postprocedural antibiotics were cephalexin (55.4%) and sulfamethoxazole-trimethoprim (10.6%). The most common duration of antibiotic prescriptions was seven, ten, and five days in our study, from most to least common duration. Superficial surgical site infection (SSI), deep SSI, device infection, or any infection within 90 days occurred in 2.9%, 1.0%, 1.8%, and 4%, respectively, of the patients undergoing SCS surgery. CONCLUSIONS: Prospective studies are needed to understand the reasons for noncompliance with expert consensus recommendations on postoperative antibiotic use beyond 24 hours of SCS surgery. Neuromodulation team members should play an important role in antibiotic stewardship.

Industry Payments to Pain Medicine Physicians: An Analysis of the Centers for Medicare and Medicaid Services Open Payments Program.

OBJECTIVE: To analyze industry payments to pain medicine physicians in the United States. DESIGN: Retrospective cohort study using publicly available databases. SUBJECTS: The study includes U.S. pain medicine physicians (PMPs) with reports in the Open Payments program from 2013 to 2018. METHODS: The Centers for Medicare and Medicaid Services Open Payments program was analyzed for general, investment, and ownership payments to PMPs reported from 2013 to 2018. The nature, type, and geographic variation of payments were analyzed. RESULTS: The main findings of the study are as follows: 1) Payments made to PMPs constituted a small proportion of the payments made to all physicians in the United States, and the number of transactions and the total dollar amount seem to have decreased from 2016 to 2018. 2) The median number of payments among physicians with reported payments was around 4 (interquartile range: 18), and the majority of them were under $20. 3) The majority of payments were for in-kind items and services (85%) and were made for food and beverages (91%), travel and lodging (5.5%). 4) Some of the ownership and investment interest payments exceeded $500,000. 5) The top five drugs associated with physician payments included medications with opioids. 6) A very small minority of payments were made for entertainment or gifts. 7) A third of PMPs with reports had payments reported under more than one taxonomy. CONCLUSIONS: Overall payments made to PMPs seem to be decreasing since 2016. The majority of the payments are made for the food, beverage, and travel categories. Public and physician awareness of the Open Payments system reports is essential to promote transparency and to minimize adverse effects of financial relationships on patient care.

Opioid Prescriptions by Pain Medicine Physicians in the Medicare Part D Program: A Cross-Sectional Study.

BACKGROUND: Pain medicine physicians (PMP) are a group of physicians with background training in various primary specialties with interest and expertise in managing chronic pain disorders. Our objective is to analyze prescription drug (PD) claims from the Medicare Part D program associated with PMP to gain insights into patterns, associated costs, and potential cost savings areas. METHODS: The primary data source for Part D claims data is the Centers for Medicare and Medicaid Services (CMS) Chronic Conditions Data Warehouse, which contains Medicare Part D prescription drug events (PDE) records received through the claims submission cutoff date. Only providers with taxonomies of pain management (PM) and interventional pain management (IPM) were included in the study. The analysis of PDE was restricted to drugs with >250 claims. The distribution of claims and costs were analyzed based on drug class and provider specialty. Subsequently, we explored claims and expenses for opioid drug prescriptions in detail. Prescribing characteristics of the top 5% of providers by costs and claims were examined to gain additional insights. The costs and claims were explored for the top 10 drugs prescribed by PMP in 2017. RESULTS: There were a total of unique 3280 PMP-prescribed drugs with an associated expense of 652 million dollars in the 2017 Medicare Part D program. Prescriptions related to PMP account for a tiny fraction of the program's drug expenditure (0.4%). Opioids, anticonvulsants, and gabapentinoids were associated with the largest number of claims and the largest expenses within this fraction. Among opioid drug prescriptions, brand-named drugs account for a small fraction of claims (8%) compared to generic drugs. However, the expenses associated with brand name drugs were higher than generic drugs. Prescribers in the top 5% by PD costs had a higher number of claims, prescribed a higher proportion of branded medications, and had prescriptions associated with longer day supply compared to an average PMP. There were several opioid medications in the top 10 PD list by cost associated with PMP. CONCLUSIONS: Opioids were the most common medications among Medicare part D claims prescribed by PMP. Only 12% of the total opioid PD claims were by PMP. The top 5% of PMP prescribers had 10 times more claims than the average PMP.

Outcomes Associated With Infection of Chronic Pain Spinal Implantable Electronic Devices: Insights From a Nationwide Inpatient Sample Study.

OBJECTIVES: Chronic pain spinal implantable electronic devices (CPSIEDs) include devices that provide spinal cord stimulation and intrathecal drug therapy. In this study, we sought to evaluate the trends of CPSIED infections, related complications, and outcomes following the treatment of infection. MATERIALS AND METHODS: The Nationwide Inpatient Sample database contains data from 48 states, and the District of Columbia was used to identify patients with a primary diagnosis of CPSIED infection during the years 2005-2014. Patients with intrathecal pumps for the treatment of spasticity were excluded to limit the study population to patients with chronic pain disorders. Treatments were categorized as: 1) without device removal, 2) pulse generator or pump only removal, 3) intrathecal pump system removal, and 4) spinal cord stimulation system removal. Complications associated with CPSIED infections were identified using administrative billing codes. RESULTS: During the study period 2005-2014, a total of 11,041 patients were admitted to the hospital with CPSIED infections. The majority of the patients were treated without surgical intervention (56%), and a smaller proportion underwent complete system explantation (22.7%). In-hospital mortality or permanent disability due to paralysis after CPSIED infection was around 1.83% and 2.77%, respectively. Infectious complications such as meningitis, abscess formation, and osteomyelitis occurred in 4.93%, 5.08%, and 1.5%, respectively. The median cost of hospitalization was around US $14,118.00, and the median length of stay was approximately six days (interquartile range = 4-13 days). CONCLUSIONS: The complications of CPSIED infection were higher among patients that did not undergo device removal.

Adverse Events and Complications Associated With Intrathecal Drug Delivery Systems: Insights From the Manufacturer and User Facility Device Experience (MAUDE) Database.

BACKGROUND: Modern intrathecal drug delivery systems (IDDS) are technologically advanced to deliver medication through various automated and patient-controlled programs. They also are associated with unique complications ranging from post-operative complications, medication-related adverse events (AE), device malfunction, to refill associated AE. OBJECTIVES: To systematically analyze real-world complications and AE reported on the Food and Drug Administration's Manufacturer and User Facility Device Experience database (MAUDE) associated with IDDS among patients predominantly with chronic pain disorders. MATERIALS AND METHODS: MAUDE database was sampled for a month four times a year during the study period, February 2018 to February 2019. The database was resampled every six months till August 2020 to evaluate for any additional reported cases during the index months. The two FDA approved IDDS, were included. AE were broadly classified into causes related to catheter malfunction, pump malfunction, biologic, and medication-related AE. RESULTS: A total of 1001 reports were included in the final analysis. The top three reasons for adverse report are infection/erosion (15.7%, n = 157), motor stall (12.4%, n = 125) and adverse medication reactions (11.8%, n = 119), respectively. There were five deaths among patients with IDDS. Epidural hematoma (n = 3) after IDDS surgery resulted in a death and residual neurological deficits after surgical evacuation. Programming errors, medication concentration discrepancy, and failure to turn on the pump after reprogramming are various preventable causes of medication-related IDDS AEs. CONCLUSIONS: Analysis of AE associated with IDDS from the MAUDE database provided a real-world perspective different from reported registry complications. Awareness and vigilance of preventable IDDS-related complications is the first step toward mitigating risks to provide safe and effective intrathecal drug delivery for chronic pain management.

Mechanism of Peripheral Nerve Stimulation in Chronic Pain.

INTRODUCTION: With the advancement of technology, peripheral nerve stimulation (PNS) has been increasingly used to treat various chronic pain conditions. Its origin is based on the gate control theory postulated by Wall and Melzack in 1965. However, the exact mechanism behind PNS' analgesic effect is largely unknown. In this article, we performed a comprehensive literature review to overview the PNS mechanism of action. DESIGN: A comprehensive literature review on the mechanism of PNS in chronic pain. METHODS: Comprehensive review of the available literature on the mechanism of PNS in chronic pain. Data were derived from database searches of PubMed, Scopus, and the Cochrane Library and manual searches of bibliographies and known primary or review articles. RESULTS: Animal, human, and imaging studies have demonstrated the peripheral and central analgesic mechanisms of PNS by modulating the inflammatory pathways, the autonomic nervous system, the endogenous pain inhibition pathways, and involvement of the cortical and subcortical areas. CONCLUSIONS: Peripheral nerve stimulation exhibits its neuromodulatory effect both peripherally and centrally. Further understanding of the mechanism of PNS can help guide stimulation approaches and parameters to optimize the use of PNS.

Modulation of Spinal Nociceptive Transmission by Sub-Sensory Threshold Spinal Cord Stimulation in Rats After Nerve Injury.

OBJECTIVES: High-frequency spinal cord stimulation (SCS) administered below the sensory threshold (subparesthetic) can inhibit pain, but the mechanisms remain obscure. We examined how different SCS paradigms applied at intensities below the threshold of Aß-fiber activation (sub-sensory threshold) affect spinal nociceptive transmission in rats after an L5 spinal nerve ligation (SNL). MATERIALS AND METHODS: Electrophysiology was used to record local field potential (LFP) at L4 spinal cord before, during, and 0-60 min after SCS in SNL rats. LFP was evoked by high-intensity paired-pulse test stimulation (5 mA, 0.2 msec, 400 msec interval) at the sciatic nerve. Epidural SCS was delivered through a miniature electrode placed at T13-L1 and L2-L3 spinal levels. Four patterns of SCS (200 Hz, 1 msec; 500 Hz, 0.5 msec; 1200 Hz; 0.2 msec; 10,000 Hz, 0.024 msec, 30 min, bipolar) were tested at 90% Aß-threshold as a subthreshold intensity. As a positive control, traditional SCS (50 Hz, 0.2 msec) was tested at 100% Aß-plateau as a suprathreshold intensity. RESULTS: Traditional suprathreshold SCS at T13-L1 level significantly reduced LFP to C-fiber inputs (C-LFP). Subthreshold SCS of 200 and 500 Hz, but not 1200 or 10,000 Hz, also reduced C-LFP, albeit to a lesser extent than did traditional SCS (n = 7-10/group). When SCS was applied at the L2-L3 level, only traditional SCS and subthreshold SCS of 200 Hz inhibited C-LFP (n = 8-10/group). CONCLUSIONS: Traditional suprathreshold SCS acutely inhibits spinal nociceptive transmission. Low-frequency subthreshold SCS with a long pulse width (200 Hz, 1 msec), but not higher-frequency SCS, also attenuates C-LFP.

Supraspinal Mechanisms of Spinal Cord Stimulation for Modulation of Pain: Five Decades of Research and Prospects for the Future.

The field of spinal cord stimulation is expanding rapidly, with new waveform paradigms asserting supraspinal sites of action. The scope of treatment applications is also broadening from chronic pain to include cerebral ischemia, dystonia, tremor, multiple sclerosis, Parkinson disease, neuropsychiatric disorders, memory, addiction, cognitive function, and other neurologic diseases. The role of neurostimulation as an alternative strategy to opioids for chronic pain treatment is under robust discussion in both scientific and public forums. An understanding of the supraspinal mechanisms underlying the beneficial effects of spinal cord stimulation will aid in the appropriate application and development of optimal stimulation strategies for modulating pain signaling pathways. In this review, the authors focus on clinical and preclinical studies that indicate the role of supraspinal mechanisms in spinal cord stimulation-induced pain inhibition, and explore directions for future investigations.

The Impact of Electrical Charge Delivery on Inhibition of Mechanical Hypersensitivity in Nerve-Injured Rats by Sub-Sensory Threshold Spinal Cord Stimulation.

OBJECTIVES: Spinal cord stimulation (SCS) represents an important neurostimulation therapy for pain. A new ultra-high frequency (10,000 Hz) SCS paradigm has shown improved pain relief without eliciting paresthesia. We aim to determine whether sub-sensory threshold SCS of lower frequencies also can inhibit mechanical hypersensitivity in nerve-injured rats and examine how electric charge delivery of stimulation may affect pain inhibition by different patterns of subthreshold SCS. MATERIALS AND METHODS: We used a custom-made quadripolar electrode (Medtronic Inc., Minneapolis, MN, USA) to provide bipolar SCS epidurally at the T10 to T12 vertebral level. According to previous findings, SCS was tested at 40% of the motor threshold, which is considered to be a sub-sensory threshold intensity in rats. Paw withdrawal thresholds to punctate mechanical stimulation were measured before and after SCS in rats that received an L5 spinal nerve ligation. RESULTS: Both 10,000 Hz (10 kHz, 0.024 msec) and lower frequencies (200 Hz, 1 msec; 500 Hz, 0.5 msec; 1200 Hz; 0.2 msec) of subthreshold SCS (120 min) attenuated mechanical hypersensitivity, as indicated by increased paw withdrawal thresholds after stimulation in spinal nerve ligation rats. Pain inhibition from different patterns of subthreshold SCS was not governed by individual stimulation parameters. However, correlation analysis suggests that pain inhibition from 10 kHz subthreshold SCS in individual animals was positively correlated with the electric charges delivered per second (electrical dose). CONCLUSIONS: Inhibition of neuropathic mechanical hypersensitivity can be achieved with low-frequency subthreshold SCS by optimizing the electric charge delivery, which may affect the effect of SCS in individual animals.

RNA-seq of spinal cord from nerve-injured rats after spinal cord stimulation.

Spinal cord stimulation has become an important modality in pain treatment especially for neuropathic pain conditions refractory to pharmacotherapy. However, the molecular control of inhibitory and excitatory mechanisms observed after spinal cord stimulation are poorly understood. Here, we used RNA-seq to identify differences in the expression of genes and gene networks in spinal cord tissue from nerve-injured rats with and without repetitive conventional spinal cord stimulation treatment. Five weeks after chronic constrictive injury to the left sciatic nerve, male and female rats were randomized to receive repetitive spinal cord stimulation or no treatment. Rats receiving spinal cord stimulation underwent epidural placement of a miniature stimulating electrode and received seven sessions of spinal cord stimulation (50 Hz, 80% motor threshold, 0.2 ms, constant current bipolar stimulation, 120 min/session) over four consecutive days. Within 2 h after the last spinal cord stimulation treatment, the L4-L6 spinal segments ipsilateral to the side of nerve injury were harvested and used to generate libraries for RNA-seq. Our RNA-seq data suggest further increases of many existing upregulated immune responses in chronic constrictive injury rats after repetitive spinal cord stimulation, including transcription of cell surface receptors and activation of non-neuronal cells. We also demonstrate that repetitive spinal cord stimulation represses transcription of several key synaptic signaling genes that encode scaffold proteins in the post-synaptic density. Our transcriptional studies suggest a potential relationship between specific genes and the therapeutic effects observed in patients undergoing conventional spinal cord stimulation after nerve injury. Furthermore, our results may help identify new therapeutic targets for improving the efficacy of conventional spinal cord stimulation and other chronic pain treatments.

Noninvasive Electrical Stimulation for the Treatment of Chronic Ocular Pain and Photophobia.

INTRODUCTION: "Dry eye" or "keratoconjunctivitis sicca" is a multifactorial disease estimated to have a worldwide prevalence of 5-33%. Conventional therapies targeting the ocular surface with artificial tears, anti-inflammatories, punctal closure, eyelid hygiene, and antibiotics do not provide relief in all patients, especially those with neuropathic-like ocular complaints (wind hyperalgesia and photophobia). We anticipated that ocular transcutaneous electrical nerve stimulation (TENS) would alleviate symptoms of ocular pain, photophobia, and dryness in these latter individuals. METHODS: All individuals who received electrical stimulation between May 10, 2016 and April 6, 2017 for the treatment of chronic ocular pain at the oculofacial pain clinic of the Miami Veterans Administration Hospital were included in this retrospective review. All patients had symptoms of dryness along with other neuropathic-like symptoms (e.g., photophobia) and minimal signs of tear dysfunction. Ocular pain intensity, symptoms of dryness, and light sensitivity were compared pre-treatment and five min post-treatment via a two-tailed paired Student's t-test. RESULTS: The use of TENS significantly reduced the mean pain intensity in both the right and left eyes five min after treatment compared to prior to treatment (p < 0.05, paired t-test). The use of TENS significantly decreased light sensitivity in both eyes (p < 0.05). The findings for symptoms of dryness, however, were equivocal with a significant decrease in the left eye but not the right (p < 0.05, paired t-test). DISCUSSION: Our data indicate that TENS may similarly provide analgesia in patients with dry eye symptoms as it does for many other chronic pain conditions. Furthermore, the noted effect on symptoms of photophobia and dryness suggest that all may be linked by similar trigeminal-thalamic-cortical pathways. Prospective studies with electrical stimulation of dry eye are needed to further elucidate its benefit and mechanism of action.

Opioid-induced Hallucinations: A Review of the Literature, Pathophysiology, Diagnosis, and Treatment.

Despite their association with multiple adverse effects, opioid prescription continues to increase. Opioid-induced hallucination is an uncommon yet significant adverse effect of opioid treatment. The practitioner may encounter patient reluctance to volunteer the occurrence of this phenomenon because of fears of being judged mentally unsound. The majority of the literature concerning opioid-induced hallucinations arises from treatment during end-of-life care and cancer pain. Because the rate of opioid prescriptions continues to increase in the population, the rate of opioid-associated hallucinations may also conceivably increase. With a forecasted increase in the patient-to-physician ratio, opioid therapy is predicted to be provided by practitioners of varying backgrounds and medical specialties. Hence, knowledge of the pharmacology and potential adverse effects of these agents is required. This review seeks to increase awareness of this potential complication through a discussion of the literature, potential mechanisms of action, diagnosis, and treatment strategies.