Supraspinal Effects of Dorsal Root Ganglion Stimulation in Chronic Pain Patients

Objectives: Dorsal root ganglion stimulation (DRGS) has become a popular neuromodulatory treatment for neuropathic pain. We used magnetoencephalography (MEG) to investigate potential biomarkers of pain and pain relief, based on the differences in power spectral density (PSD) during varying degrees of pain and how these oscillations change during DRGS-mediated pain relief.Materials and Methods: Thirteen chronic pain patients with implanted dorsal root ganglion stimulators were included in the MEG analysis. MEG Recordings were performed at rest while the stimulator was turned ON or OFF. Numerical rating scale (NRS) scores were also recorded before and after DRGS was turned OFF and ON. Power spectral and source localization analyses were then performed on preprocessed MEG recordings.Results: With DRGS-OFF, patients in severe pain had significantly increased cortical theta (4–7 Hz) power and decreased cortical alpha (7–13 Hz) power compared to patients reporting less pain. This shift in power toward lower frequencies was contrasted by a shift toward the higher frequency power spectrum (low beta 13–20 Hz activity) during DRGS-mediated pain relief. A significant correlation was found between the increase in low beta activity and the degree of reported pain relief.Conclusion: Our results demonstrate increased low-frequency power spectral activity in chronic pain patients in the absence of stimulation which shifts toward higher frequency power spectrum activity in response to therapeutic DRGS. These cortical changes in response to DRGS provide support for the use of neuroimaging in the search for potential biomarkers of pain.     

Conventional Dorsal Root Ganglion Stimulation in an Experimental Model of Painful Diabetic Peripheral Neuropathy: A Quantitative Immunocytochemical Analysis of Intracellular γ-Aminobutyric Acid in Dorsal Root Ganglion Neurons

Background and Objective: The sensory cell somata in the DRG contain all equipment necessary for extensive GABAergic signaling and are able to release GABA upon depolarization. With this study, we hypothesize that pain relief induced by conventional dorsal root ganglion stimulation (Con-DRGS) in animals with experimental painful diabetic peripheral neuropathy is related to the release of GABA from DRG neurons. With use of quantitative immunocytochemistry, we hypothesize DRGS to result in a decreased intensity of intracellular GABA-immunostaining in DRG somata.Materials and Methods: Female Sprague-Dawley rats (n = 31) were injected with streptozotocin (STZ) in order to induce Diabetes Mellitus. Animals that developed neuropathic pain after four weeks (Von Frey) were implanted with a unilateral DRGS device at L4 (n = 14). Animals were then stimulated for 30 min with Con-DRGS (20 Hz, pulse width = 0.2 msec, amplitude = 67% of motor threshold, n = 8) or Sham-DRGS (n = 6), while pain behavior (von Frey) was measured. DRGs were then collected and immunostained for GABA, and a relation to size of sensory cell soma diameter (small: 12–26 μm, assumed to be C-fiber related sensory neurons; medium: 26–40 μm, assumed to be Aδ related sensory neurons; and large: 40–54 μm, assumed to be Aβ related sensory neurons) was made.Results: DRGS treated animals showed significant reductions in STZ-induced mechanical hypersensitivity. No significant differences in GABA immunostaining intensity per sensory neuron cell soma type (small-, medium-, or large-sized) were noted in DRGs of stimulated (Con-DRGS) animals versus Sham animals. No differences in GABA immunostaining intensity per sensory cell soma type in ipsi- as compared to contralateral DRGs were observed.Conclusion: Con-DRGS does not affect the average intracellular GABA immunofluorescence staining intensity in DRG sensory neurons of those animals which showed significant pain reduction. Similarly, no soma size related changes in intracellular GABA immunofluorescence were observed following Con-DRGS.     

Dorsal Root Ganglion Stimulation for the Treatment of Non-Complex Regional Pain Syndrome Related Chronic Pain Syndromes: A Systematic Review

Background: While the majority of indications and approvals for dorsal root ganglion stimulation (DRGS) are for the refractory management of complex regional pain syndrome (CRPS), emerging evidence has suggested that DRGS may be favorably used for a plethora of other chronic pain phenomena. Consequently, we aimed to characterize the use and efficacy of DRGS for these non–CRPS-related chronic pain syndromes.Materials and Methods: A systematic review of clinical studies demonstrating the use of DRGS for non–CRPS-related chronic pain syndromes. The literature search was performed using PubMed, Cochrane Library, and CINAHL plus across August and September 2020.Results: A total of 28 reports comprising 354 total patients were included in the analysis. Of the chronic pain syndromes presented, axial low back pain, chronic pelvic and groin pain, other peripheral neuropathies, and studies with multiple concomitant pain syndromes, a majority demonstrated >50% mean pain reduction at the time of last follow-up following DRGS. Physical function, quality of life (QOL), and lesser pain medication usage also were repeatedly reported to be significantly improved.Conclusions: DRGS continues to lack supportive evidence from well designed, high level studies and recommendations from consensus committee experts. However, we present repeated and consistent evidence from lower level studies showing success with the use of DRGS for various non-CRPS chronic pain syndromes in reducing pain along with increasing function and QOL from one week to three years. Due to such low-level, high bias evidence, we strongly encourage the continuation of high-level studies in order to provide a stronger foundation for the use of DRGS in non-CRPS chronic pain patients. However, it may be reasonable and appropriate to evaluate patients for DRGS candidacy on a case-by-case basis particularly if they manifest focal pain syndromes refractory to noninterventional measures and may not be ideal candidates for other forms of neuromodulation.     

Quantitative Sensory Testing of Spinal Cord and Dorsal Root Ganglion Stimulation in Chronic Pain Patients

Background/Objectives: The physiological mechanisms underlying the pain-modulatory effects of clinical neurostimulation therapies, such as spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRGS), are only partially understood. In this pilot prospective study, we used patient-reported outcomes (PROs) and quantitative sensory testing (QST) to investigate the physiological effects and possible mechanisms of action of SCS and DRGS therapies.Materials and Methods: We tested 16 chronic pain patients selected for SCS and DRGS therapy, before and after treatment. PROs included pain intensity, pain-related symptoms (e.g., pain interference, pain coping, sleep interference) and disability, and general health status. QST included assessments of vibration detection theshold (VDT), pressure pain threshold (PPT) and tolerance (PPToL), temporal summation (TS), and conditioned pain modulation (CPM), at the most painful site.Results: Following treatment, all participants reported significant improvements in PROs (e.g., reduced pain intensity [p < 0.001], pain-related functional impairment [or pain interference] and disability [p = 0.001 for both]; better pain coping [p = 0.03], sleep [p = 0.002]), and overall health [p = 0.005]). QST showed a significant treatment-induced increase in PPT (p = 0.002) and PPToL (p = 0.011), and a significant reduction in TS (p = 0.033) at the most painful site, but showed no effects on VDT and CPM. We detected possible associations between a few QST measures and a few PROs. Notably, higher TS was associated with increased pain interference scores at pre-treatment (r = 0.772, p = 0.009), and a reduction in TS was associated with the reduction in pain interference (r = 0.669, p = 0.034) and pain disability (r = 0.690, p = 0.027) scores with treatment.Conclusions: Our preliminary findings suggest significant clinical and therapeutic benefits associated with SCS and DRGS therapies, and the possible ability of these therapies to modulate pain processing within the central nervous system. Replication of our pilot findings in future, larger studies is necessary to characterize the physiological mechanisms of SCS and DRGS therapies.     

Invasive Electrical Neuromodulation for the Treatment of Painful Diabetic Neuropathy: Systematic Review and Meta‐Analysis

ObjectiveNeuromodulation is a treatment option for people suffering from painful diabetic neuropathy (PDN) unresponsive to conventional pharmacotherapy. We systematically examined the pain outcomes of patients with PDN receiving any type of invasive neuromodulation for treatment of neuropathic pain.Materials and MethodsMEDLINE and Embase were searched through 10 January 2020, without language restriction. All study types were included. Two reviewers independently screened publications and extracted data. Quantitative meta-analysis was performed with pain scores converted to a standard 100-point scale. Randomized controlled trial (RCT) scores were pooled using the inverse variance method and expressed as mean differences.ResultsRCTs of tonic spinal cord stimulation (t-SCS) showed greater pain improvement than best medical therapy at six months (intention-to-treat: 38/100, 95% CI: 29–47). By per-protocol analysis, case series of t-SCS and dorsal root ganglion stimulation (DRGS) showed improvement by 56 (95% CI: 39–73) and 55 (22–87), respectively, at 12 months. For t-SCS, the rate of failing a therapeutic stimulation trial was 16%, the risk of infection was 4%, and the rate of lead problems requiring surgery to resolve was 4% per year of follow-up. High-frequency SCS and burst SCS both showed efficacy, with few patients studied.ConclusionEfficacious, lasting and safe surgical pain management options are available to diabetic patients suffering from PDN. Tonic-SCS is the established standard of treatment; however, other SCS paradigms and DRGS are emerging as promising treatments offering comparable pain benefits, but with few cases published to date. Randomized controlled trials are ongoing to assess their relative merits.     

Infectious Complications of Dorsal Root Ganglion Stimulation: A Systematic Review and Pooled Analysis of Incidence

Background and ObjectivesDorsal root ganglion stimulation (DRGS) is a newer form of neuromodulation that targets the dorsal root ganglion. DRGS has superior efficacy in complex regional pain syndrome compared to spinal cord stimulation (SCS) and may have efficacy in other forms of chronic pain. While decades of safety data are available for SCS, there is less available safety information for DRGS. The objectives of this systematic review and pooled analysis of incidence are to determine the overall incidence of DRGS infections, incidence at each stage (trial vs implant vs revision), infection characteristics, and outcomes.Materials and MethodsA comprehensive search of databases from January 1980 to January 2021 was conducted.ResultsTen studies met inclusion criteria. Eight studies reported patients with trial data (n = 291), ten studies reported patients with implant data (n = 250), and seven studies reported data with revisions (n = 26). The pooled incidence of trial infections was 1.03% (95% CI 0.35–2.99%), implant infections was 4.80% (95% CI 2.77–8.20%), revision infections was 3.85% (95% CI 0.20–21.59%), and overall infections was 2.82% (95% CI 1.62–4.54%). There was a statistically significant difference in infection rates between the trial, implant, and revision stages, X² (2, N = 567) = 8.9839, p = 0.01.ConclusionsThis is the first systematic review and pooled analysis that followed PRISMA guidelines to report infectious complications of DRGS by stage (trial vs implant vs revision). DRGS trial appears to be low risk for infection but that risk is significantly increased with DRGS implant. Our findings highlight the need for further study of infectious complications, their risks, and optimal prophylaxis.     

Real world,open label experience with lacosamide against acute painful oxaliplatin‐induced peripheral neurotoxicity

We report the outcome of a pilot, open‐label study that tested the potential of lacosamide (200 mg/bi.d) as an effective and safe symptomatic treatment against acute painful oxaliplatin‐induced peripheral neurotoxicity (OXAIPN). Lacosamide was introduced in 18 colorectal cancer patients with evidence of clinically significant acute, painful OXAIPN after infusion of the third course (T1) of oxaliplatin‐based chemotherapy (FOLFOX4) and was maintained until completion of all 12 courses (T4). The OXA‐Neuropathy Questionnaire (OXA‐NQ) was used to record the severity of acute OXAIPN; the PI‐NRS estimated the severity of neuropathic pain, while the chronic OXAIPN was graded with TNSc. The EuroQOL ( EQ‐5D) instrument was also applied. The Patient Global Impression of Change (PGIC) scale measured the lacosamide‐attributed perception of change. LCM‐responders were considered those with ≥50% reduction in PI‐NRS and OXA‐NQ scores at T4, compared to T1. Patients experienced on T1 a median number of acute OXAIPN symptoms of 4 and had a median neuropathic pain severity score of 6, which was strongly related to lower quality of life, according to EQ‐VAS (P < .001). At T4, 12 patients (66.7%) were classified as responders. A significant clinical improvement was documented in the severity of acute OXAIPN and neuropathic pain in relation to lacosamide (P < .001) at T4 compared to T1, which was associated with improved EQ‐VAS scores (P < .001). Twelve patients scored PGIC ≥5 (lacosamide‐attributed) at T4. There were no incidences of early drop‐outs for safety reasons. Lacosamide appears to be an effective and well‐tolerated symptomatic treatment against acute, painful OXAIPN.     

Transgrade Dorsal Root Ganglion Stimulation as a Salvage Technique for Three Different Anatomical Barriers: A Case Series

BackgroundDorsal root ganglion stimulation (DRGS) is an effective treatment for complex regional pain syndrome (CRPS) and post-surgical neuropathic pain. However, some patients have surgical and anatomical conditions that are contraindications to traditional DRGS technique. A novel transgrade approach to DRGS placement has been described and demonstrated effective for post spine surgery patients. We present three patients, each with a different reason in which DRGS would not be accessible via the traditional anterograde approach, who all had successful DRGS transgrade placement.Materials and MethodsThe case series includes three patients with either CRPS or post-surgical neuropathic pain who had an anatomical or post-surgical condition that historically would have rendered DRGS contraindicated. Two patients had previously failed dorsal column stimulation. All three patients had successful placement with the transgrade approach—entry into the contralateral epidural space at the level of the targeted foramen from a cephalad angle. Each patient gave their verbal and written consent to be included in the case series.ResultsFollowing treatment with a transgrade approach, all three patients had significant pain relief and improvement in function without complication.ConclusionBarriers to anterograde foraminal access including previous implantation, previous instrumentation, and epidural adhesions may prevent DRGS placement in certain indicated patients. This can be especially challenging in patients who have failed other neuromodulation options like dorsal column stimulation. Our case series demonstrated that the transgrade technique can be successfully used in these cases to increase access to DRGS.     

The Predictive Value of Transcutaneous Electrical Nerve Stimulation for Patient Selection in Peripheral Nerve Field Stimulation for Chronic Low Back Pain: A Prospective Study

ObjectivePeripheral nerve field stimulation (PNFS) is an effective alternative treatment for patients with chronic low back pain. Transcutaneous electrical nerve stimulation (TENS) is frequently used in pain therapy. Aim of this prospective study was to examine the predictive value of TENS for later PNFS treatment.Materials and MethodsBetween 2014 and 2019, a prospective cohort study of 41 patients with chronic lumbar pain was conducted. Pain intensity (NRS) was assessed before and after TENS use, preoperatively/postoperatively and in the follow-up after three and six months, SF12v2 questionnaires with physical (PCS) and mental component summary (MCS) scores, and Oswestry disability index (ODI) questionnaire at baseline as well as three and six months after PNFS implantation. Implantation of the PNFS-system with two percutaneous leads was performed after four to seven days of positive testing. Statistical analysis was performed using depending t-test, ANOVA, and Spearman correlation.ResultsThe cohort consisted of 41 patients (19 females, 22 males) with a median age of 60.5 years (IQR^25-75 52–67). Two patients were lost to follow-up. After positive PNFS testing a pulse generator (IPG) was implanted in 15 patients with positive TENS effect and 15 patients without TENS effect. Leads were explanted in nine patients after negative PNFS trial phase. TENS positive patients showed significant correlation to a positive effect in the PNFS trial phase in NRS reduction (p = 0.042) indicating that TENS responders will also respond to PNFS (94% patients). After three and six months follow-up median NRS and SF12v2 (PCS) improved significantly in both cohorts, SF12v2 (MCS) and ODI only in the TENS positive cohort, respectively.ConclusionTENS can be predictive for patient selection in PNFS, as TENS positive patients showed significant correlation with a positive PNFS trial period. Therefore, TENS positive patients might be justifiable to be directly implanted with leads and IPG. TENS positive patients further tend to show a better improvement in the follow-up.     

Dorsal root ganglion stimulation for chronic pain modulates Aβ-fiber activity but not C-fiber activity: A computational modeling study

ObjectiveThe goal of this project was to use computational models to investigate which types of primary sensory neurons are modulated by dorsal root ganglion stimulation (DRGS) to provide pain relief.MethodsWe modeled DRGS by coupling an anatomical finite element model of a human L5 dorsal root ganglion to biophysical models of primary sensory neurons. We calculated the stimulation amplitude needed to elicit an action potential in each neuron, and examined how DRGS affected sensory neuron activity.ResultsWe showed that within clinical ranges of stimulation parameters, DRGS drives the activity of large myelinated Aβ-fibers but does not directly activate small nonmyelinated C-fibers. We also showed that the position of the active and return electrodes and the polarity of the stimulus pulse influence neural activation.ConclusionsOur results indicate that DRGS may provide pain relief by activating pain-gating mechanisms in the dorsal horn via repeated activation of large myelinated afferents.SignificanceUnderstanding the mechanisms of action of DRGS-induced pain relief may lead to innovations in stimulation technologies that improve patient outcomes.     

Paired Acute Invasive/Non-invasive Stimulation (PAINS) study: A phase I/II randomized,sham-controlled crossover trial in chronic neuropathic pain

BackgroundDorsal root ganglion (DRG) stimulation, an invasive method of neuromodulation, and transcranial direct current stimulation (tDCS), a non-invasive method of altering cortical excitability, have both proven effective in relieving chronic pain.ObjectiveWe employed a randomized, sham-controlled crossover study design to investigate whether single-session tDCS would have an additive therapeutic effect alongside DRG stimulation (DRGS) in the treatment of chronic pain.MethodsSixteen neuropathic pain patients who were previously implanted with DRG stimulators were recruited. Baseline pain scores were established with DRGS-OFF. Pain scores were then recorded with DRGS-ON, after paired sham tDCS stimulation, and after paired active anodal tDCS (a-tDCS) stimulation. For active tDCS, patients were randomized to ‘MEG (magnetoencephalography) localized’ tDCS or contralateral motor cortex (M1) tDCS for 30 min. EEG recordings and evaluations of tDCS adverse effects were also collected.ResultsAll participants reported the interventions to be tolerable with no significant adverse effects during the session. Paired DRGS/active tDCS resulted in a significant reduction in pain scores compared to paired DRGS-ON/sham tDCS or DRGS alone. There was no difference in the additive effect of M1 vs. MEG-localized tDCS. Significant augmentation of beta activity was observed between DRGS-OFF and DRGS-ON conditions, as well as between paired DRGS-ON/sham tDCS and paired DRGS-ON/active tDCS.ConclusionOur results indicate that a single session of tDCS alongside DRGS is safe and can significantly reduce pain acutely in neuropathic pain patients. Paired invasive/non-invasive neuromodulation is a promising new treatment strategy for pain management and should be evaluated further to assess long-term benefits.     

Open-label study of combination therapy with isoniazid for management of refractory neuropathic pain

Although there have been improvements in treatment, neuropathic pain often remains unresponsive to all treatment modalities. This pilot study assessed the efficacy of combination therapy with isoniazid for the treatment of intractable neuropathic pain. We conducted this prospective, open-label, add-on study in 45 consecutive patients who suffered from treatment-refractory neuropathic pain. The patients were given combination therapy with 8 mg/kg of isoniazid and were followed for a minimum of eight weeks. Pain relief was recorded using the visual analogue scale (VAS) score. Secondary measures included sleep interference scores and the Patient Global Impression of Change (PGIC) scale. There was a significant decrease in the mean VAS score following eight weeks of treatment compared with the baseline. In addition, PGIC and mean sleep score also improved. This study suggests that combination therapy with isoniazid has potent analgesic properties and may therefore be useful in the management of intractable neuropathic pain.     

Long Term Results of Microsurgical Dorsal Root Entry Zonotomy for Upper Extremity Spasticity

Objective

The purpose of the present study is to assess the long-term results of microsurgical dorsal root entry zonotomy (MDT) for the treatment of medically intractable upper-extremity spasticity.

Methods

The records of nine adult patients who underwent MDT by one operating neurosurgeon from March 1999 to June 2004 were retrospectively reviewed by another investigator who had no role in the management of these patients. In all patients, MDT was performed on all roots of the upper limb (from C5 to T1) for spasticity of the upper extremity. The degree of spasticity was measured by the Modified Ashworth Scale (grade 0-4). Severity of the pain level was determined using the Numeric Rating Scale (NRS, score 0-10). Also, patient satisfaction of the post-operative outcome was assessed.

Results

Comparing the preoperative and postoperative spasticity using the Modified Ashworth Scale, we observed improvement in all patients, particularly in five of the nine patients (55.6%) who improved by three grades over an average of 66.4 months (range, 40-96). Regarding patient satisfaction, seven patients (77.8%) had affirmative results. None of the patients experienced severe, life-threatening, postoperative complications. We observed a decrease in the intensity of painful spasms to less than three scores as measured by NRS in all four patients with associated pain.

Conclusion

This study shows that MDT provides significant, long-term reduction of harmful spasticity and associated pain in the upper limbs.     

Effectiveness of Repetitive Transcranial Magnetic Stimulation on Fibromyalgia Patients Responding to a First Repetitive Transcranial Magnetic Stimulation Induction Course After Six Months of Maintenance Treatment: A Randomized Pilot-Controlled Study

BackgroundFibromyalgia is a chronic painful condition without real, effective treatment. The administration of repetitive transcranial magnetic stimulation (rTMS) has been shown to have a therapeutic effect on pain, but there are still questions about the maintenance of its effect over time. Continuation of the treatment upon clinical response through maintenance sessions is promising and merits further exploration.Materials and MethodsWe conducted a randomized, parallel-group, controlled study involving 78 patients to evaluate the effect of rTMS vs sham stimulation after a three-week induction treatment and six months of maintenance treatment (three-week periodicity) on 22 patients who presented a clinical response to the induction treatment. The clinical response was defined as a ≥30% decrease of the baseline visual analog scale (VAS) for pain and a score for the Patient Global Impression of Change (PGIC) >5. The clinic global impression, fibromyalgia impact questionnaire, symptom severity score, and Beck’s depression inventory were also studied.ResultsA significant clinical response to treatment with rTMS was observed after the induction phase and maintained over six months, particularly as measured by the PGIC parameter of pain, as well as of the intensity of fatigue and depression, with an absence of adverse effects induced by this method.ConclusionA three-week rTMS treatment, characterized by a reduction in pain, as evaluated by VAS, should be continued with the administration of rTMS maintenance sessions for an additional six months to maintain the best possible long-term effects.     

The Effect of Clinically Controllable Factors on Neural Activation During Dorsal Root Ganglion Stimulation

ObjectiveDorsal root ganglion stimulation (DRGS) is an effective therapy for chronic pain, though its mechanisms of action are unknown. Currently, we do not understand how clinically controllable parameters (e.g., electrode position, stimulus pulse width) affect the direct neural response to DRGS. Therefore, the goal of this study was to utilize a computational modeling approach to characterize how varying clinically controllable parameters changed neural activation profiles during DRGS.Materials and MethodsWe coupled a finite element model of a human L5 DRG to multicompartment models of primary sensory neurons (i.e., Aα-, Aβ-, Aδ-, and C-neurons). We calculated the stimulation amplitudes necessary to elicit one or more action potentials in each neuron, and examined how neural activation profiles were affected by varying clinically controllable parameters.ResultsIn general, DRGS predominantly activated large myelinated Aα- and Aβ-neurons. Shifting the electrode more than 2 mm away from the ganglion abolished most DRGS-induced neural activation. Increasing the stimulus pulse width to 500 μs or greater increased the number of activated Aδ-neurons, while shorter pulse widths typically only activated Aα- and Aβ-neurons. Placing a cathode near a nerve root, or an anode near the ganglion body, maximized Aβ-mechanoreceptor activation. Guarded active contact configurations did not activate more Aβ-mechanoreceptors than conventional bipolar configurations.ConclusionsOur results suggest that DRGS applied with stimulation parameters within typical clinical ranges predominantly activates Aβ-mechanoreceptors. In general, varying clinically controllable parameters affects the number of Aβ-mechanoreceptors activated, although longer pulse widths can increase Aδ-neuron activation. Our data support several Neuromodulation Appropriateness Consensus Committee guidelines on the clinical implementation of DRGS.     

No adrenergic sensitization of afferent neurons in painful sensory polyneuropathy

Introduction The aim of the present study was to determine (1) if an adrenergic sensitivity of afferent neurons is present in patients with painful polyneuropathy as compared with non–painful polyneuropathy and (2) if there is a correlation between adrenergic sensitisation and the severity of afferent and sympathetic small fiber damage. Methods 10 patients with painful and non painful polyneuropathy and 10 healthy controls were included. The function of small afferent and efferent sympathetic neurons was evaluated. Adrenergic sensitivity of afferent neurons was assessed by cutaneous iontophoresis of norepinephrine. Spontaneous pain, mechanical hyperalgesia as well as warm and heat pain thresholds were measured. Results Iontophoresis of norepinephrine did not induce or enhance spontaneous pain or mechanical allodynia, either in painless or painful polyneuropathies. There was no difference in norepinephrineinduced heat hyperalgesia between both neuropathy groups and healthy controls. The response of afferent neurons to norepinephrine was not correlated with the severity of damage to afferent small fibers or efferent sympathetic vasoconstrictor neurons. Conclusion The results do not support the assumption that in painful polyneuropathies afferent neurons acquire an adrenergic sensitivity after nerve injury and that adrenergic stimulation leads to an exacerbation of spontaneous pain and thermal and mechanical hyperalgesia. This work was supported by the Deutsche Forschungsgemeinschaft (DFG Ba 1921/1–1/2), and the Bundesministerium für Bildung und Forschung (BMBF) Research Network “Neuropathic Pain” and an unrestricted educational grant from Pfizer, Germany.     

Comparison of Spinal Cord Stimulation Outcomes Between Preoperative Opioid Users and Nonusers: A Cohort Study of 467 Patients

ObjectivesSpinal cord stimulation (SCS) is a surgical treatment modality reserved for a subset of patients with neuropathic pain in which conventional pharmacologic treatment has proven insufficient. Previous studies have suggested a possible negative relationship between opioid use at referral and subsequent success of SCS therapy. The aim of this cohort study was to investigate whether preoperative opioid use was associated with inferior SCS outcomes.Materials and MethodsData were obtained from the Danish Neurizon Neuromodulation Database and comprised preoperative registrations of analgesic use, postoperative Patients’ Global Impression of Change (PGIC) ratings, pre- and postoperative pain intensity scores (Numeric Rating Scale), and detailed surgical data. Patients were dichotomized according to preoperative opioid use (users vs nonusers) with subsequent assessment of the latest PGIC rating, reduction in pain intensity, and current treatment status (implanted/explanted). In addition, daily preoperative opioid dosages were quantified in oral morphine equivalents (OME) and correlated to the treatment outcomes.ResultsA total of 467 patients were included; 296 consumed opioids before SCS implantation (median 80 OME/d). Preoperative opioid use was not associated with the latest PGIC rating, reduction in pain intensity (30% or 50%), or risk of undergoing explantation (median follow-up = 3.0 years). Likewise, preoperative median OME per day of opioid users was not correlated with any of the defined outcomes.ConclusionsPreoperative opioid usage did not predict the outcome of SCS therapy in a large cohort of patients permanently implanted with an SCS system. The results do not support withholding otherwise well-indicated SCS therapy in patients with chronic neuropathic pain conditions based merely on preoperative opioid usage.     

Effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in diabetic polyneuropathy

BACKGROUND: The treatment of painful diabetic polyneuropathy (DPN) is often inadequate and frequently limited by the systemic adverse effects of medications, necessitating the evaluation of novel treatments. OBJECTIVE: To evaluate the effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in painful diabetic polyneuropathy. DESIGN: Open-label, flexible-dosing, 3-week study with a 5-week extension. SETTING: Outpatient clinics and clinical research centers.Patients Volunteer sample of 56 patients with clinically defined painful diabetic polyneuropathy of longer than 3 months' duration.Intervention The 5% lidocaine patch, with a maximum of 4 patches daily for 18 hours. MAIN OUTCOME MEASURES: Change in mean daily pain diary ratings from baseline to week 3. Secondary end points included assessments of safety, tolerability, and quality of life. RESULTS: Patients with painful diabetic polyneuropathy showed significant improvements in pain and quality-of-life outcome measures during a 3-week treatment period. These benefits were maintained in a subgroup of patients treated for an additional 5 weeks, during which taper of concomitant analgesic therapy was permitted. Adverse events were minimal, and systemic accumulation of lidocaine did not occur. CONCLUSIONS: Up to four 5% lidocaine patches for up to 18 h/d are well tolerated in patients with painful diabetic polyneuropathy, significantly improve pain and quality-of-life ratings, and may allow tapering of concomitant analgesic therapy. Given the open-label design of this trial, a randomized controlled trial is necessary to confirm these results.     

Painful polyneuropathy associated with restless legs syndrome. Clinical features and sensory profile

BackgroundThe association of restless legs syndrome (RLS) with polyneuropathy, and its prevalence, have been evaluated differently throughout various studies. As subtypes of polyneuropathy characterized by neuropathic pain seem to be preferentially associated with RLS, we intended to investigate the prevalence and the features of RLS occurring with painful neuropathy, and to define whether there is a specific sensory phenotype.MethodsWe prospectively investigated 58 consecutive patients with distal symmetric polyneuropathy and neuropathic pain or dysesthesia, using a bedside protocol for sensory assessment. RLS was diagnosed with an interview assessing the International RLS Study Group diagnostic criteria.ResultsOverall, RLS was reported by 21 patients (36.2%), but it was occurring at the time of the evaluation in 12 patients (20.7%), significantly more than in controls. RLS was chronic in nine patients and remitting–intermittent in 12 patients. No difference was demonstrated between patients with or without RLS. Comparing patients with chronic RLS and remitting-intermittent RLS, the latter had more severe electrophysiological changes, whereas hyperalgesia, suggesting central sensitization, was significantly more frequent in chronic RLS patients.ConclusionsRLS is frequently associated with painful polyneuropathy, in keeping with the hypothesis that its occurrence is favored by small fiber involvement. It represents a heterogeneous entity, differentiated in chronic and remitting-intermittent subtypes, possibly conditioned by indolent or aggressive neuropathy course and phenomena of central sensitisation.     

Factors Associated With Implantable Pulse Generator Site Pain: A Multicenter Cross-Sectional Study

ObjectivesImplantable pulse generator (IPG) site pain following neuromodulation procedures is a recognized complication. The site of the IPG placement varies depending on the neuromodulation type and physician preference. The incidence of IPG site pain as a function of the site of IPG implantation has not been studied systematically.Materials and MethodsWe performed a multicenter cross-sectional survey of the incidence, severity, and quality of IPG site pain, location of the IPG, the pain management needs, functional impairment, and cosmetic appearance related to the IPG placement. Contingency table analysis was conducted for categorical variables, and logistic regression analysis and linear regression model was used.ResultsThe survey response rate was 60.5% (n = 510). Overall, 31.0% of patients reported pain at the IPG site in the last 72 hours with 31.4% reporting moderate to severe pain and 7.6% reporting severe pain. Older age was inversely associated with IPG-related pain (OR = 0.97, 95% CI = 0.96–0.99, p = 0.001). IPG implantation site did not have a statistically significant interaction with IPG site pain (p > 0.05). The most important factor for IPG site-associated pain was having a spinal cord stimulator implanted as compared to a deep brain stimulator, or sacral nerve stimulator. Most subjects reported no functional impairment related to IPG site pain (91%), found the IPG site pain as expected (80%), and found IPG site cosmetic appearance as expected (96%).ConclusionsThe incidence of IPG site pain is an important complication of invasive neuromodulation. The anatomic location of the IPG placement does not appear to affect the incidence or severity of IPG site pain. However, the presence of a pre-implant chronic pain disorder does appear to affect the frequency and severity of IPG site pain.