Paresthesia-Free Dorsal Root Ganglion Stimulation: An ACCURATE Study Sub-Analysis.

INTRODUCTION: ACCURATE, a randomized controlled trial comparing dorsal root ganglion (DRG) stimulation to spinal cord stimulation, showed that DRG stimulation is a safe and effective therapy in individuals with lower extremity chronic pain due to complex regional pain syndrome (CRPS) type I or II. Investigators noted that DRG stimulation programming could be adjusted to minimize, or eliminate, the feeling of paresthesia while maintaining adequate pain relief. The present study explores treatment outcomes for DRG subjects who were paresthesia-free vs. those who experienced the sensation of paresthesia, as well as the factors that predicted paresthesia-free analgesia. METHODS: A retrospective analysis of therapy outcomes was conducted for 61 subjects in the ACCURATE study who received a permanent DRG neurostimulator. Outcomes of subjects who were paresthesia-free were compared to those who experienced paresthesia-present therapy at 1, 3, 6, 9, and 12-month follow-ups. Predictor variables for the presence or absence of paresthesias with DRG stimulation were also explored. RESULTS: The percentage of subjects with paresthesia-free pain relief increased from 16.4% at 1-month to 38.3% at 12-months. Paresthesia-free subjects generally had similar or better outcomes for pain severity, pain interference, quality of life, and mood state as subjects with paresthesia-present stimulation. Factors that increased the odds of a subject feeling paresthesia were higher stimulation amplitudes and frequencies, number of implanted leads, and younger age. CONCLUSIONS: Some DRG subjects achieved effective paresthesia-free analgesia in the ACCURATE trial. This supports the observation that paresthesia is not synonymous with pain relief or required for optimal analgesia with DRG stimulation.

Safety Analysis of Dorsal Root Ganglion Stimulation in the Treatment of Chronic Pain.

BACKGROUND: Stimulation of the dorsal root ganglion (DRG) in the treatment of chronic, intractable pain has shown excellent clinical results in multiple published studies, including a large prospective, randomized, controlled trial. Both safety and efficacy have been demonstrated utilizing this therapeutic approach for many chronic complaints. Continued assessment of neuromodulation therapies, such as DRG stimulation, are not only an important aspect of vigilant care, but are also necessary for the evaluation for safety. MATERIALS AND METHODS: Safety and complaint records for DRG and spinal cord stimulation (SCS) stimulation were obtained from the manufacturer, analyzed and compiled to further assess ongoing device safety. Complaint event data were stratified according to complain type as well as overall rates. Data from similar time periods were compared between epidural neurostimulation devices by the same manufacturer as well as rates reported in the literature. RESULTS: Overall, DRG stimulation device event rates were lower or comparable to similar epidurally placed neurostimulation devices. Rates of events varied from 0 to 1.0% for DRG stimulation (n >500+ implants) which was similar to the event rate for SCS by the same manufacturer (n >2000+ implants). In comparison, complaints and adverse events ranged from 0 to 14% for SCS in the literature. DISCUSSIONS: The current results from a large consecutive cohort obtained from manufacturer records indicates that DRG stimulation demonstrates an excellent safety profile. Reported event rates are similar to previously reported adverse event and complaint rates in the literature for this therapy. Similarly, safety events rates were lower or similar to previously reported rates for SCS, further demonstrating the comparative safety of this neuromodulation technique for chronic pain treatment.

Unilateral L4-dorsal root ganglion stimulation evokes pain relief in chronic neuropathic postsurgical knee pain and changes of inflammatory markers: part II whole transcriptome profiling.

BACKGROUND: In our recent clinical trial, increased peripheral concentrations of pro-inflammatory molecular mediators were determined in complex regional pain syndrome (CRPS) patients. After 3 months adjunctive unilateral, selective L4 dorsal root ganglion stimulation (L4-DRGSTIM), significantly decreased serum IL-10 and increased saliva oxytocin levels were assessed along with an improved pain and functional state. The current study extended molecular profiling towards gene expression analysis of genes known to be involved in the gonadotropin releasing hormone receptor and neuroinflammatory (cytokines/chemokines) signaling pathways. METHODS: Blood samples were collected from 12 CRPS patients for whole-transcriptome profiling in order to assay 18,845 inflammation-associated genes from frozen blood at baseline and after 3 months L4-DRGSTIM using PANTHER™ pathway enrichment analysis tool. RESULTS: Pathway enrichment analyses tools (GOrilla™ and PANTHER™) showed predominant involvement of inflammation mediated by chemokines/cytokines and gonadotropin releasing hormone receptor pathways. Further, screening of differentially regulated genes showed changes in innate immune response related genes. Transcriptomic analysis showed that 21 genes (predominantly immunoinflammatory) were significantly changed after L4-DRGSTIM. Seven genes including TLR1, FFAR2, IL1RAP, ILRN, C5, PKB and IL18 were down regulated and fourteen genes including CXCL2, CCL11, IL36G, CRP, SCGB1A1, IL-17F, TNFRSF4, PLA2G2A, CREB3L3, ADAMTS12, IL1F10, NOX1, CHIA and BDKRB1 were upregulated. CONCLUSIONS: In our sub-group analysis of L4-DRGSTIM treated CRPS patients, we found either upregulated or downregulated genes involved in immunoinflammatory circuits relevant for the pathophysiology of CRPS indicating a possible relation. However, large biobank-based approaches are recommended to establish genetic phenotyping as a quantitative outcome measure in CRPS patients. Trial registration The study protocol was registered at the 15.11.2016 on German Register for Clinical Trials (DRKS ID 00011267). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011267.

Dorsal Root Ganglion Stimulation Is Paresthesia-Independent: A Retrospective Study.

INTRODUCTION: Neuromodulation is an important tool for achieving pain relief in otherwise-intractable neuropathic pain conditions. Dorsal root ganglion (DRG) stimulation, in which primary sensory neurons are stimulated prior to their entry into the spinal canal, provides treatment with high levels of dermatomal specificity and can provide advantages compared to conventional spinal cord stimulation. Although DRG stimulation can produce perceptible paresthesias, many patients operate their systems at subthreshold amplitudes that do not elicit this sensation. Pain relief both with and without paresthesia was investigated in this retrospective analysis. MATERIALS AND METHODS: A retrospective review of all qualifying permanent DRG stimulation systems at a single center over more than a three-year period was completed. Pain (0-10 numeric rating scale) was assessed at baseline, at the end of the trial, and after three, six, and twelve months of treatment. Patients were categorized based on their usage of the stimulator at amplitudes that either did or did not produce paresthesias. RESULTS: Of the 39 patients, 34 (87%) reported having no-paresthesias at any of the follow-up visits. Average pain relief was 73.9% after the trial period and 63.1% after 12 months of treatment. The responder rate (50% or better pain relief) after three months of treatment was more than 80%. Exploratory subgroup analyses showed that similar degrees of pain relief were achieved in numerous body regions and with various pain etiologies. The five patients who reported paresthesias during treatment had pain relief similar to those of the group that did not experience paresthesias. DISCUSSION: Clinically significant and sustained pain relief over more than a period of 12 months was achieved with DRG stimulation programmed at amplitudes below the perceptual level. Thus, the reported analgesia was paresthesia-independent. That good clinical outcomes were observed independent of the generation of paresthesia in DRG stimulation suggests several mechanisms of action, including the inhibition of supraspinal regions involved in somatic paresthesia sensation. The retrospective results presented here posit that future prospective study of DRG stimulation delivered at below the threshold of perceptible paresthesias is warranted.

Comparison of Paresthesia Coverage of Patient's Pain: Dorsal Root Ganglion vs. Spinal Cord Stimulation. An ACCURATE Study Sub-Analysis.

OBJECTIVES: This was a sub-analysis of the ACCURATE clinical trial that evaluated the accuracy and necessity of targeting paresthesia coverage of painful areas with dorsal root ganglion (DRG) stimulation vs. tonic spinal cord stimulation (SCS). MATERIALS AND METHODS: On diagrams of the torso and lower limbs, subjects marked where they felt pain at baseline and paresthesias at three months postimplant. Seventy-five subjects (41 DRG and 34 SCS) with diagrams of sufficient quality were scanned, digitized, and included in this analysis. Subject completed diagrams were digitized and superimposed with a grid of 1398 squares. Quantification of the percentage of bodily areas affected by pain and stimulation induced paresthesias was performed. RESULTS: The percent of painful areas covered by paresthesia was significantly lower for DRG subjects than for SCS subjects (13% vs. 28% of the painful regions, p < 0.05), possibly because significantly more DRG subjects felt no paresthesia during stimulation when compared to SCS subjects (13/41 DRG vs. 3/34 SCS) (p < 0.05). The amount of paresthesia produced outside the painful areas (unrequired paresthesia) was significantly lower in DRG subjects than that of SCS subjects. On average, the percent of unrequired paresthesia was only 20% of the subjects' total painful body surface area in the DRG group compared to 210% in the SCS group (p < 0.01). CONCLUSIONS: The results of this ACCURATE study sub-analysis show that DRG stimulation produces paresthesias, on average, that are less frequent, less intense, with a smaller footprint on the body and less dependent on positional changes.

Selective L4 Dorsal Root Ganglion Stimulation Evokes Pain Relief and Changes of Inflammatory Markers: Part I Profiling of Saliva and Serum Molecular Patterns.

OBJECTIVES: Complex regional pain syndrome (CRPS) and associated comorbidities have been linked to a pro-inflammatory state driven by different mediators. Targeted dorsal root ganglion stimulation (DRGSTIM ) suppressed pain levels and improved functional capacity in intractable CRPS. However, clinical trials assessing the impact of DRG stimulation on the neuroimmune axis are lacking. METHODS: This study enrolled 24 subjects (12 refractory CRPS patients plus suitably matched healthy controls) and performed immunoassays of inflammatory mediators in saliva and serum along with score-based assessments of pain, mood, and sleep quality at baseline and after three months of selective L4-DRGSTIM . RESULTS: After three-month L4-DRGSTIM CRPS associated pain significantly decreased. In addition, disturbed sleep and mood improved post-DRGSTIM , although statistically not significant. Significantly increased serum values of pro-inflammatory markers were detected pre- and post L4-DRGSTIM for high-mobility group box 1, tumor-necrosis factor α, interleukin (IL) 6, and leptin. IL-1ß was significantly elevated pre-L4 DRGSTIM , but not posttreatment. Elevated anti-inflammatory IL-10 significantly decreased after three months in serum, while saliva oxytocin concentrations increased in CRPS subjects after L4-DRGSTIM (p = 0.65). No severe implantation and stimulation associated adverse events were recorded. CONCLUSIONS: Selective L4-DRGSTIM improved neuropathic pain and functional impairment in CRPS as previously reported. CRPS patients displayed a pro-inflammatory molecular pattern in serum. Serum anti-inflammatory IL-10 significantly declined, while saliva oxytocin nonsignificantly increased after L4-DRGSTIM . An evidence-based relational interpretation of our study is limited due to the uncontrolled study design. However, molecular profiling of biofluids (saliva, serum) represents a novel and experimental field in applied neuromodulation, which warrant further investigations to unveil mechanisms of neuroimmune modulation.

Evaluating Dorsal Root Ganglion Stimulation in a Prospective Dutch Cohort.

OBJECTIVES: Dorsal root ganglion (DRG) stimulation is a recent neuromodulation option that has delivered safe, effective pain relief for a number of etiologies. This prospective observational study was intended to establish the effectiveness of this treatment in a typical real-world clinical context. MATERIALS AND METHODS: Participants with chronic, intractable pain of the trunk or lower limbs were recruited from multiple pain clinics in the Netherlands. Subjects were trialed and implanted with DRG stimulation systems. Pain, function, mood, and quality of life, ratings were collected through 12 months postimplant. RESULTS: Of the 66 subjects enrolled, failed back surgery syndrome, peripheral nerve injury, and complex regional pain syndrome formed the largest etiologies. Permanent implants were placed in 86.2% subjects (56/65). After 12 months of treatment, average pain ratings in subjects' primary area of pain decreased from 8.0 cm at baseline to 4.1 cm, and 49% of subjects had ≥50% reduction in pain (visual analog scale). In addition, functional capacity was increased, and mood and quality of life improved. No confirmed lead migrations were observed, and there was a low rate of infection. CONCLUSIONS: DRG stimulation significantly reduced the severity of subjects' pain and enabled participatory changes that improved quality of life through 12-months postimplant.

Retrospective Case Series on the Treatment of Painful Diabetic Peripheral Neuropathy With Dorsal Root Ganglion Stimulation.

BACKGROUND: The dorsal root ganglion (DRG) has been identified as an important neural structure in the development and maintenance of chronic pain. We present a retrospective case series of patients with refractory painful diabetic peripheral neuropathy (PDPN) that underwent electrical stimulation of the DRG and report on changes in their overall perceived pain and complication rates. METHODS: Ten diabetic males (mean age 65.2 [SD 8.8] years) with painful symptoms of the lower limbs were enrolled and trialed with up to four quadripolar percutaneous DRG stimulation leads between L2 and L5 spinal levels. Patients received a fully implantable neurostimulation system (Abbott Laboratories, Sunnyvale, CA, USA) immediately or after a successful trial period (>50% reduction in pain). Overall perceived pain was measured by visual analogue scale (VAS) at baseline, one-week postimplantation and one-, three-, six-, and twelve-month follow-up (n = 5). RESULTS: Ten patients were included in this retrospective study. Seven of these subjects received permanent stimulator implants after successful externalized or intraoperative trials. Two of those patients subsequently required explantation, due to failure to capture primary pain area (n = 1) and personal reasons (n = 1). For the five subjects that proceeded to clinical follow-ups, baseline VAS was reduced by an average of 63.90% (SD 21.39; p < 0.001) postimplantation. For four patients with available 12-month follow-up data, mean relative reduction in overall perceived pain averaged 64.16% (SD 35.8; p< 0.001). CONCLUSION: Early findings from this small retrospective case series, suggest DRG is a safe and effective neuromodulation modality to improve painful symptoms in PDPN patients. Future prospective trials are required to further investigate the use of DRG stimulation for this clinical indication.

Mechanisms of Dorsal Root Ganglion Stimulation in Pain Suppression: A Computational Modeling Analysis.

OBJECTIVE: The mechanisms of dorsal root ganglion (DRG) stimulation for chronic pain remain unclear. The objective of this work was to explore the neurophysiological effects of DRG stimulation using computational modeling. METHODS: Electrical fields produced during DRG stimulation were calculated with finite element models, and were coupled to a validated biophysical model of a C-type primary sensory neuron. Intrinsic neuronal activity was introduced as a 4 Hz afferent signal or somatic ectopic firing. The transmembrane potential was measured along the neuron to determine the effect of stimulation on intrinsic activity across stimulation parameters, cell location/orientation, and membrane properties. RESULTS: The model was validated by showing close correspondence in action potential (AP) characteristics and firing patterns when compared to experimental measurements. Subsequently, the model output demonstrated that T-junction filtering was amplified with DRG stimulation, thereby blocking afferent signaling, with cathodic stimulation at amplitudes of 2.8-5.5 × stimulation threshold and frequencies above 2 Hz. This amplified filtering was dependent on the presence of calcium and calcium-dependent small-conductance potassium channels, which produced a hyperpolarization offset in the soma, stem, and T-junction with repeated somatic APs during stimulation. Additionally, DRG stimulation suppressed somatic ectopic activity by hyperpolarizing the soma with cathodic or anodic stimulation at amplitudes of 3-11 × threshold and frequencies above 2 Hz. These effects were dependent on the stem axon being relatively close to and oriented toward a stimulating contact. CONCLUSIONS: These results align with the working hypotheses on the mechanisms of DRG stimulation, and indicate the importance of stimulation amplitude, polarity, and cell location/orientation on neuronal responses.

Stimulation of the L2-L3 Dorsal Root Ganglia Induces Effective Pain Relief in the Low Back.

INTRODUCTION: Chronic low back pain affects millions of people worldwide and can arise through a variety of clinical origins. In the case of failed back surgery syndrome (FBSS), previous surgical procedures can contribute to low back pain that is often unresponsive to intervention. Although spinal cord stimulation (SCS) can be an effective treatment modality, it does not provide sufficient pain relief for some intractable cases. Recently, alternative neuromodulation options have been developed, including dorsal root ganglion (DRG) stimulation. The objective of this report is to further investigate these clinical observations. METHODS: Twelve patients with significant chronic discogenic low back pain due to FBSS were included. All subjects underwent implantation of DRG stimulation systems that had at least 1 lead placed at L2 or L3. Subjects' pain ratings, mood, and quality of life were tracked prospectively for up to 12 months. RESULTS: More than half of subjects reported 50% or better pain relief in the low back, and the average low back pain relief was 45.5% at 12 months. Concomitant reductions in overall pain, leg pain, pain interference, mood, and quality of life were also found. DISCUSSION: For the studied population, DRG stimulation at the L2-L3 levels was effective at relieving low back pain. These reductions in pain were associated with improvements in quality of life. Thus, DRG stimulation at these levels may be effective for low back pain by recruiting both segmental and nonsegmental neural pathways that are not otherwise accessible via traditional SCS.

Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: a randomized comparative trial.

Animal and human studies indicate that electrical stimulation of dorsal root ganglion (DRG) neurons may modulate neuropathic pain signals. ACCURATE, a pivotal, prospective, multicenter, randomized comparative effectiveness trial, was conducted in 152 subjects diagnosed with complex regional pain syndrome or causalgia in the lower extremities. Subjects received neurostimulation of the DRG or dorsal column (spinal cord stimulation, SCS). The primary end point was a composite of safety and efficacy at 3 months, and subjects were assessed through 12 months for long-term outcomes and adverse events. The predefined primary composite end point of treatment success was met for subjects with a permanent implant who reported 50% or greater decrease in visual analog scale score from preimplant baseline and who did not report any stimulation-related neurological deficits. No subjects reported stimulation-related neurological deficits. The percentage of subjects receiving ≥50% pain relief and treatment success was greater in the DRG arm (81.2%) than in the SCS arm (55.7%, P < 0.001) at 3 months. Device-related and serious adverse events were not different between the 2 groups. Dorsal root ganglion stimulation also demonstrated greater improvements in quality of life and psychological disposition. Finally, subjects using DRG stimulation reported less postural variation in paresthesia (P < 0.001) and reduced extraneous stimulation in nonpainful areas (P = 0.014), indicating DRG stimulation provided more targeted therapy to painful parts of the lower extremities. As the largest prospective, randomized comparative effectiveness trial to date, the results show that DRG stimulation provided a higher rate of treatment success with less postural variation in paresthesia intensity compared to SCS.

Dorsal root ganglion stimulation attenuates the BOLD signal response to noxious sensory input in specific brain regions: Insights into a possible mechanism for analgesia.

Targeted dorsal root ganglion (DRG) electrical stimulation (i.e. ganglionic field stimulation - GFS) is an emerging therapeutic approach to alleviate chronic pain. Here we describe blood oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) responses to noxious hind-limb stimulation in a rat model that replicates clinical GFS using an electrode implanted adjacent to the DRG. Acute noxious sensory stimulation in the absence of GFS caused robust BOLD fMRI response in brain regions previously associated with sensory and pain-related response, such as primary/secondary somatosensory cortex, retrosplenial granular cortex, thalamus, caudate putamen, nucleus accumbens, globus pallidus, and amygdala. These regions differentially demonstrated either positive or negative correlation to the acute noxious stimulation paradigm, in agreement with previous rat fMRI studies. Therapeutic-level GFS significantly attenuated the global BOLD response to noxious stimulation in these regions. This BOLD signal attenuation persisted for 20minutes after the GFS was discontinued. Control experiments in sham-operated animals showed that the attenuation was not due to the effect of repetitive noxious stimulation. Additional control experiments also revealed minimal BOLD fMRI response to GFS at therapeutic intensity when presented in a standard block-design paradigm. High intensity GFS produced a BOLD signal map similar to acute noxious stimulation when presented in a block-design. These findings are the first to identify the specific brain region responses to neuromodulation at the DRG level and suggest possible mechanisms for GFS-induced treatment of chronic pain.

Dorsal Root Ganglionic Field Stimulation Relieves Spontaneous and Induced Neuropathic Pain in Rats.

Dorsal root ganglion (DRG) electrical stimulation (ganglionic field stimulation [GFS]) is effective in relieving clinical pain, but its mechanism is unknown. We therefore developed a rat model for GFS to test analgesic effects in the context of neuropathic pain. GFS was applied with a bipolar electrode at L4, using parameters replicating clinical use (20 Hz, 150-µs pulse width, current at 80% of motor threshold). Neuropathic pain was generated by tibial nerve injury (TNI). Pain behavior was monitored by determining the threshold for withdrawal from punctate mechanical stimuli, by identifying hyperalgesic responses to noxious mechanical stimuli, and by hypersensitivity to cold. The affective dimension of pain was measured using conditioned place preference. We found that electrode insertion caused no behavioral evidence of pain and produced no histological evidence of DRG damage. GFS reversed TNI-induced hypersensitivity to cold and mechanical hyperalgesia and allodynia. Allodynia remained diminished 15 minutes after GFS. Conditioned place preference showed that GFS was not rewarding in uninjured control animals but was rewarding in animals subjected to TNI, which reveals analgesic efficacy of GFS for spontaneous pain. We conclude that GFS relieves neuropathic pain in rats. This model may provide a platform for identifying mechanisms and novel applications of GFS. PERSPECTIVE: We show that electrical stimulation of the DRG in rats reverses neuropathic pain behavior and provides a rewarding effect to animals with spontaneous neuropathic pain. This confirms analgesic efficacy of DRG stimulation in an animal model, and provides a platform for preclinical exploration.

Dorsal Root Ganglion (DRG) Stimulation in the Treatment of Phantom Limb Pain (PLP).

OBJECTIVES: Phantom limb pain (PLP) is a neuropathic condition in which pain is perceived as arising from an amputated limb. PLP is distinct from, although associated with, pain in the residual limb and nonpainful phantom sensations of the missing limb. Its treatment is extremely challenging; pharmaceutical options, while commonly employed, may be insufficient or intolerable. Neuromodulatory interventions such as spinal cord stimulation have generated mixed results and may be limited by poor somatotopic specificity. It was theorized that dorsal root ganglion (DRG) neuromodulation may be more effective. MATERIALS AND METHODS: Patients trialed a DRG neurostimulation system for their PLP and were subsequently implanted if results were positive. Retrospective chart review was completed, including pain ratings on a 100-mm visual analogue scale (VAS) and patient-reported outcomes. RESULTS: Across eight patients, the average baseline pain rating was 85.5 mm. At follow-up (mean of 14.4 months), pain was rated at 43.5 mm. Subjective ratings of quality of life and functional capacity improved. Some patients reduced or eliminated pain medications. Patients reported precise concordance of the paresthesia with painful regions, including in their phantom limbs; in one case, stimulation eliminated PLP as well as nonpainful phantom sensations. Three patients experienced a diminution of pain relief, despite good initial outcomes. CONCLUSIONS: DRG neuromodulation may be an effective tool in treating this pain etiology. Clinical outcomes in this report support recent converging evidence suggesting that the DRG may be the site of PLP generation and/or maintenance. Further research is warranted to elucidate mechanisms and optimal treatment pathways.

Lack of body positional effects on paresthesias when stimulating the dorsal root ganglion (DRG) in the treatment of chronic pain.

OBJECTIVES: One prominent side effect from neurostimulation techniques, and in particular spinal cord stimulation (SCS), is the change in intensity of stimulation when moving from an upright (vertical) to a recumbent or supine (horizontal) position and vice versa. It is well understood that the effects of gravity combined with highly conductive cerebrospinal fluid provide the mechanism by which changes in body position can alter the intensity of stimulation-induced paresthesias. While these effects are well established for leads that are placed within the more medial aspects of the spinal canal, little is known about these potential effects in leads placed in the lateral epidural space and in particular within the neural foramina near the dorsal root ganglion (DRG). MATERIALS AND METHODS: We prospectively validated a newly developed paresthesia intensity rating scale and compared perceived paresthesia intensities when subjects assumed upright vs. supine bodily positions during neuromodulation of the DRG. RESULTS: On average, the correlation coefficient between stimulation intensity (pulse amplitude) and perceived paresthesia intensity was 0.83, demonstrating a strong linear relationship. No significant differences in paresthesia intensities were reported within subjects when moving from an upright (4.5 ± 0.14) to supine position 4.5 (± 0.12) (p > 0.05). This effect persisted through 12 months following implant. CONCLUSIONS: Neuromodulation of the DRG produces paresthesias that remain consistent across body positions, suggesting that this paradigm may be less susceptible to positional effects than dorsal column stimulation.

A systematic review: current and future directions of dorsal root ganglion therapeutics to treat chronic pain.

OBJECTIVE: The purpose of the study was to systematically review the historical therapeutics for chronic pain care directed at the dorsal root ganglion (DRG) and to identify future trends and upcoming treatment strategies. METHODS: A literature search on bibliographic resources, including EMBASE, PubMed Cochrane Database of Systemic Reviews from literature published from 1966 to December 1, 2012 to identify studies and treatments directed at the DRG to treat chronic pain, and was limited to the English language. Case series, case reports, and preclinical work were excluded. Information on emerging technologies and pharmacologics were captured separately, as they did not meet the inclusion criteria. RESULTS: The literature review yielded three current clinical treatment strategies: ganglionectomy, conventional radiofrequency treatment of the dorsal root ganglion, and pulsed radiofrequency treatment of the DRG. Seven studies were identified utilizing ganglionectomy, 14 for conventional radiofrequency, and 16 for pulsed radiofrequency. Electrical stimulation and novel therapeutic delivery strategies have been proposed and are in development. CONCLUSIONS: Despite a robust understanding of the DRG and its importance in acute nociception, as well as the development and maintenance of chronic pain, relatively poor evidence exists regarding current therapeutic strategies. Novel therapies like electrical and pharmacologic strategies are on the horizon, and more prospective study is required to better qualify the role of the DRG in chronic pain care.

A multicenter, prospective trial to assess the safety and performance of the spinal modulation dorsal root ganglion neurostimulator system in the treatment of chronic pain.

OBJECTIVES: This multicenter prospective trial was conducted to evaluate the clinical performance of a new neurostimulation system designed to treat chronic pain through the electrical neuromodulation of the dorsal root ganglia (DRG) neurophysiologically associated with painful regions of the limbs and/or trunk. MATERIALS AND METHODS: Thirty-two subjects were implanted with a novel neuromodulation device. Pain ratings during stimulation were followed up to six months and compared with baseline ratings. Subjects also completed two separate reversal periods in which stimulation was briefly stopped in order to establish the effects of the intervention. RESULTS: At all assessments, more than half of subjects reported pain relief of 50% or better. At six months postimplant, average overall pain ratings were 58% lower than baseline (p < 0.001), and the proportions of subjects experiencing 50% or more reduction in pain specific to back, leg, and foot regions were 57%, 70%, and 89%, respectively. When stimulation was discontinued for a short time, pain returned to baseline levels. Discrete coverage of hard-to-treat areas was obtained across a variety of anatomical pain distributions. Paresthesia intensity remained stable over time and there was no significant difference in the paresthesia intensity perceived during different body postures/positions (standing up vs. lying down). CONCLUSIONS: Results of this clinical trial demonstrate that neurostimulation of the DRG is a viable neuromodulatory technique for the treatment of chronic pain. Additionally, the capture of discrete painful areas such as the feet combined with stable paresthesia intensities across body positions suggest that this stimulation modality may allow more selective targeting of painful areas and reduce unwanted side-effects observed in traditional spinal cord stimulation (SCS).

A prospective study of dorsal root ganglion stimulation for the relief of chronic pain.

OBJECTIVE: The article aims to study the safety and effectiveness of dorsal root ganglion (DRG) stimulation with a new device in the treatment of chronic pain. DESIGN: This is a prospective, single-arm, pilot study. SETTING: Four clinical centers were used as setting for this study. PATIENTS: Ten (10) patients with chronic intractable pain of the trunk and/or limbs were included. INTERVENTION: A trial period of DRG stimulation was studied. Two to four leads, each with four electrical contacts, were inserted using a minimally invasive epidural approach and steered toward the lateral epidural space, near the DRG. Leads were attached to an external trial stimulator and stimulation therapy was provided for three to seven days. OUTCOME MEASURES: Pain reduction using a visual analog scale, subject and physician-rated improvement, adverse event (AE) rates, device programming settings, and medication utilization was evaluated at baseline and at prospective follow-up time points during stimulation. RESULTS: On average, there was a 70% reduction in pain following stimulation (p = 0.0007). Eight of the nine patients experienced a clinically meaningful (>30%) reduction in pain, and seven of the nine reduced their pain medication utilization. Pain relief in specific anatomical regions such as the leg, back, and foot was also observed. No device-related AEs were reported. CONCLUSIONS: These initial results suggest that stimulation of the DRG can reduce pain in those patients suffering from chronic pain. DRG stimulation may offer several potential benefits over other neuromodulation techniques, including the ability to target difficult-to-reach anatomies such as the low back and foot.

Citalopram enhances B cell numbers in a murine model of morphine-induced immunosuppression.

Patients with chronic pain are often challenged with depression stemming from the long-term psychophysiological effects of their condition. Consequently, patients with chronic pain are often treated with morphine, which can induce immunosuppression, along with an antidepressant. The antidepressant citalopram (CTP; Sigma-Aldrich Chemical, St. Louis, MO, U.S.A.) is a serotonin reuptake inhibitor that is reported to have immunomodulatory effects. Thus, we investigated whether CTP administration impacted immunity in morphine-treated animals. Adult mice were pretreated for 7 days with either saline or CTP (10 or 30 mg/kg intraperitoneal injections twice daily), followed by subcutaneous implantation of a 25 mg morphine pellet for 48 hours. Spleen, thymus, and lymph nodes were harvested to analyze total cell numbers, relative lymphocyte populations, and lymphocyte function. In this study, CTP had no effect on either total cell counts or lymphocyte populations in the thymus. However, in the spleen, total splenocyte numbers in all CTP-treated animals displayed an increasing trend over saline-treated animals. Interestingly, although more cells were found in the spleen, distribution of splenic lymphocyte populations did not differ between treatments. Despite no increase in total cell number, a high dose of CTP (30 mg/kg) resulted in a significantly higher B cell population in the lymph nodes, while T cell and NK cell numbers were not different. CTP did not significantly reverse morphine-induced weight loss or splenic B cell antibody secretion in vitro. Additionally, CTP treatment demonstrated a slight but not significant increase in both splenic B and T cell mitogen-induced proliferation in vitro. In summary, CTP may have a specific potential in the attenuation of morphine's immunosuppressive effect by enhancing splenocyte numbers and lymph node B cell populations.

Corticosteroid induced psychosis in the pain management setting.

BACKGROUND: Synthetic corticosteroids are commonly utilized in interventional pain management procedures. These substances have potential side-effects including psychological adverse events. OBJECTIVE: We describe a case of substance-induced psychotic disorder resulting from corticosteroids administration. DESIGN: Case Report. METHODS: We describe a 67-year-old male that, six months prior to being consulted at our center, received a cervical epidural, 4 level medial branch blocks, 4 trigger point injections and a tendon injection in the shoulder all including corticosteroids all in one treatment session. RESULTS: Approximately 7 days following the multiple injections, the patient developed psychotic episodes including racing thoughts, anger, agitation, pressured hyperverbal speech and paranoia. The symptoms spontaneously resolved in approximately 7-10 days. DISCUSSION: Although well known as a potential complication, corticosteroid induced psychosis secondary to interventional pain procedures have never been reported. We further discuss this potential side effect of utilizing corticosteroids and emphasize the need for guidelines regarding steroid utilization.