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Various approaches have been developed with a view to treating the back pain component in patients with chronic low back pain (CLBP) and persistent spinal pain syndrome (PSPS). Emerging evidence shows that peripheral nerve field stimulation (PNFS) may be an efficacious therapeutic modality against axial low back pain. Hence, the aim of the review was to evaluate the analgesic efficacy and safety of PNFS, when used alone or as an adjunct to spinal cord stimulation (SCS), for managing CLBP and PSPS.A comprehensive search for clinical studies on PNFS and PNFS + SCS used for the management of CLBP and/or PSPS was performed using PubMed, EMBASE, MEDLINE via Proquest, and Web of Science.A total of 15 studies were included, of which four were randomized controlled trials (RCTs), nine were observational studies, and two were case series. For patients receiving PNFS, a significant decrease in back pain intensity and analgesic consumption, together with a significant improvement in physical functioning, was observed upon implant of the permanent system. Meanwhile, the addition of PNFS to SCS in refractory cases was associated with a significant reduction in back and leg pain, respectively.This review suggests that PNFS, when used alone or in combination with SCS, appears to be effective in managing back pain. However, high-quality evidence that supports the long-term analgesic efficacy and safety is still lacking. Hence, RCTs with a larger patient population and of a longer follow-up duration are warranted.

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.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.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.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).

Background: Impaired neuromuscular control and degeneration of the multifidus muscle have been linked to the development of refractory chronic low back pain (CLBP). An implantable restorative-neurostimulator system can override the underlying multifidus inhibition by eliciting episodic, isolated contractions. The ReActiv8-B randomized, active-sham-controlled trial provided effectiveness and safety evidence for this system, and all participants received therapeutic stimulation from four months onward. Objective: This study aimed to evaluate the two-year effectiveness of this restorative neurostimulator in patients with disabling CLBP secondary to multifidus muscle dysfunction and no indications for spine surgery. Materials and Methods: Open-label follow-up of 204 participants implanted with a restorative neurostimulation system (ReActiv8, Mainstay Medical, Dublin, Ireland) was performed. Pain intensity (visual analog scale [VAS]), disability (Oswestry disability index [ODI]), quality-of-life (EQ-5D-5L), and opioid intake were assessed at baseline, six months, one year, and two years after activation. Results: At two years (n = 156), the proportion of participants with ≥50% CLBP relief was 71%, and 65% reported CLBP resolution (VAS ≤ 2.5 cm); 61% had a reduction in ODI of ≥20 points, 76% had improvements of ≥50% in VAS and/or ≥20 points in ODI, and 56% had these substantial improvements in both VAS and ODI. A total of 87% of participants had continued device use during the second year for a median of 43% of the maximum duration, and 60% (34 of 57) had voluntarily discontinued (39%) or reduced (21%) opioid intake. Conclusions: At two years, 76% of participants experienced substantial, clinically meaningful improvements in pain, disability, or both. These results provide evidence of long-term effectiveness and durability of restorative neurostimulation in patients with disabling CLBP, secondary to multifidus muscle dysfunction. Clinical Trial Registration: The study is registered on clinicaltrials.gov with identifier NCT02577354.

Gabapentin is a recommended first-line agent for treating neuropathic pain; however, its efficacy rate is reportedly low, and the risk of adverse events is high. A plausible explanation for this lies with its wide range of actions, the entirety of which have yet to be fully elucidated.A review of the literature was conducted on gabapentin's known and proposed analgesic mechanisms of action, as well as potentially opposing or detrimental actions.Gabapentin's classical analgesic mechanisms involve direct attenuation of excitatory neurotransmission in the spinal cord via inhibition of neuronal ion channels, while indirect mechanisms include descending inhibition and block of injury-evoked synaptogenesis. Glial effects have also been reported; however, whether they are neuroprotective or detrimental is unknown. Furthermore, data from animal models do not reflect clinical outcomes.Gabapentin's clinical use should be reconsidered according to the net effects of its numerous assumed actions, including the tripartite synapse and oligodendrocyte effects. Whether it is doing more harm than good, especially in the scenarios of incomplete or loss of response, warrants consideration when prescribing gabapentin.

Marc Russo,1– 3 Danielle Santarelli,2 Robert Wright,4 Chris Gilligan5 1Hunter Pain Specialists, Broadmeadow, NSW, Australia; 2Genesis Research Services, Broadmeadow, NSW, Australia; 3School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia; 4Sydney Pain Management Centre, Wahroonga, NSW, Australia; 5Brigham & Women’s Hospital, Boston, MA, USACorrespondence: Marc RussoHunter Pain Specialists, 91 Chatham Street, Broadmeadow, NSW, 2292, AustraliaTel +61 2 4985 1800Fax +61 2 4940 0322Email algoguy@gmail.comAbstract: The technique of lumbar medial branch radiofrequency neurotomy for facet joint pain has an intriguing history involving a diverse timeline of medical specialists. This paper aims to chart the pathway that led to its invention and the series of modifications and refinements that have led to modern practice. The story begins with the treatment of World War I soldiers by Nesfield, who used scalpels to cut “trapped” nerves. Inspired by Nesfield’s treatment, Rees developed the “percutaneous rhizolysis” technique in 1960. Shealy was the first to use radiofrequency electrodes for denervation of the facet joints, introducing his technique in 1971. Several radiofrequency electrode developments came about from collaborations with Cosman medical device entrepreneurs during the 1970s, including the Shealy Rhizolysis Kit, the Ray Rhizotomy Electrode, and the Sluijter-Mehta Kit. Subsequent dissections of Rees’ technique and modification of Shealy’s procedure by Bogduk saw the development of “percutaneous lumbar medial branch neurotomy” in 1980 by Bogduk and Long. Bogduk continued to contribute significantly to validation, refinement and acceptance of the technique. In 1998, the technique of pulsed radiofrequency was invented by Sluijter, Cosman, Rittman and van Kleef. Subsequent innovations have consisted of cooled radiofrequency neurotomy, multi-tined cannulae, endoscopic systems, and alternative denervation targets, such as the facet joint capsule. As we pass the first 100 years of the story, we believe there are more chapters to be written on this fascinating subject.Keywords: radiofrequency, neurotomy, low back pain, facet joint, history, medial branch

Chronic low back pain can be caused by impaired control and degeneration of the multifidus muscles and consequent functional instability of the lumbar spine. Available treatment options have limited effectiveness and prognosis is unfavorable. We conducted an international randomized, double-blind, sham-controlled trial at 26 multidisciplinary centers to determine safety and efficacy of an implantable, restorative neurostimulator designed to restore multifidus neuromuscular control and facilitate relief of symptoms (clinicaltrials.gov identifier: NCT02577354). Two hundred four eligible participants with refractory mechanical (musculoskeletal) chronic LBP and a positive prone instability test indicating impaired multifidus control were implanted and randomized to therapeutic (N = 102) or low-level sham (N = 102) stimulation of the medial branch of the dorsal ramus nerve (multifidus nerve supply) for 30 minutes twice daily. The primary endpoint was the comparison of responder proportions (≥30% relief on the LBP visual analogue scale without analgesics increase) at 120 days. After the primary endpoint assessment, participants in the sham-control group switched to therapeutic stimulation and the combined cohort was assessed through 1 year for long-term outcomes and adverse events. The primary endpoint was inconclusive in terms of treatment superiority (57.1% vs 46.6%; difference: 10.4%; 95% confidence interval, -3.3% to 24.1%, P = 0.138). Prespecified secondary outcomes and analyses were consistent with a modest but clinically meaningful treatment benefit at 120 days. Improvements from baseline, which continued to accrue in all outcome measures after conclusion of the double-blind phase, were clinically important at 1 year. The incidence of serious procedure- or device-related adverse events (3.9%) compared favorably with other neuromodulation therapies for chronic pain.

BACKGROUND: Treatment response to spinal cord stimulation (SCS) is focused on the magnitude of effects on pain intensity. However, chronic pain is a multidimensional condition that may affect individuals in different ways and as such it seems reductionist to evaluate treatment response based solely on a unidimensional measure such as pain intensity. AIM: The aim of this article is to add to a framework started by IMMPACT for assessing the wider health impact of treatment with SCS for people with chronic pain, a "holistic treatment response". DISCUSSION: Several aspects need consideration in the assessment of a holistic treatment response. SCS device data and how it relates to patient outcomes, is essential to improve the understanding of the different types of SCS, improve patient selection, long-term clinical outcomes, and reproducibility of findings. The outcomes to include in the evaluation of a holistic treatment response need to consider clinical relevance for patients and clinicians. Assessment of theholistic response combines two key concepts of patient assessment: (1) patients level of baseline (pre-treatment) unmet need across a range of health domains; (2) demonstration of patient-relevant improvements in these health domains with treatment. The minimal clinical important difference (MCID) is an established approach to reflect changes after a clinical intervention that are meaningful for the patient and can be used to identify treatment response to each individual domain. A holistic treatment response needs to account for MCIDs in all domains of importance for which the patient presents dysfunctional scores pre-treatment. The number of domains included in a holistic treatment response may vary and should be considered on an individual basis. Physiologic confirmation of therapy delivery and utilisation should be included as part of the evaluation of a holistic treatment response and is essential to advance the field of SCS and increase transparency and reproducibility of the findings.

Introduction Chronic pain is a major public health concern, as is the associated use of opioid medications, highlighting the importance of alternative treatments, such as spinal cord stimulation (SCS). Here, we present the final 24‐month results of the Avalon study, which investigated the use of the first closed‐loop SCS system in patients with chronic pain. The system measures the evoked compound action potentials (ECAPs) elicited by each stimulus pulse and drives a feedback loop to maintain the ECAP amplitude near constant. Methods Fifty patients were implanted with the Evoke system (Saluda Medical) and followed over 24‐months. Pain, quality of life (QOL), function, sleep, and medication use were collected at baseline and each scheduled visit. ECAP amplitudes and programming adjustments were also monitored. Results At 24 months, responder rates (≥ 50% pain reduction) and high responder rates (≥ 80% pain reduction) for overall pain were 89.5% and 68.4%, respectively, the latter up from 42.2% at 3 months. Significant improvements from baseline were observed in QOL, function, and sleep over the 24 months, including ≥ 80% experiencing a minimally important difference in QOL and > 50% experiencing a clinically significant improvement in sleep. At 24 months, 82.8% of patients with baseline opioid use eliminated or reduced their opioid intake. Over the course of the study, reprogramming need fell to an average of less than once a year. Conclusion Over a 24‐month period, the Evoke closed‐loop SCS maintained its therapeutic efficacy despite a marked reduction in opioid use and steady decrease in the need for reprogramming.

Background: Restorative neurostimulation is a rehabilitative treatment for patients with refractory chronic low back pain (CLBP) associated with dysfunction of the lumbar multifidus muscle resulting in impaired neuromuscular control. The ReActiv8-B randomized, sham-controlled trial provided evidence of the effectiveness and safety of an implanted, restorative neurostimulator. The two-year analysis previously published in this journal demonstrated accrual of clinical benefits and long-term durability. Objective: Evaluation of three-year effectiveness and safety in patients with refractory, disabling CLBP secondary to multifidus muscle dysfunction and no indications for spine surgery. Materials and Methods: Prospective, observational follow-up of the 204 implanted trial participants. Low back pain visual analog scale (VAS), Oswestry Disability Index (ODI), EuroQol quality of life survey, and opioid intake were assessed at baseline, six months, and one, two, and three years after activation. The mixed-effects model repeated measures approach was used to provide implicit imputations of missing data for continuous outcomes and multiple imputation for proportion estimates. Results: Data were collected from 133 participants, and 16 patients missed their three-year follow-up because of coronavirus disease restrictions but remain available for future follow-up. A total of 62% of participants had a ≥ 70% VAS reduction, and 67% reported CLBP resolution (VAS ≤ 2.5cm); 63% had a reduction in ODI of ≥ 20 points; 83% had improvements of ≥ 50% in VAS and/or ≥ 20 points in ODI, and 56% had these substantial improvements in both VAS and ODI. A total of 71% (36/51) participants on opioids at baseline had voluntarily discontinued (49%) or reduced (22%) opioid intake. The attenuation of effectiveness in the imputed (N = 204) analyses was relatively small and did not affect the statistical significance and clinical relevance of these results. The safety profile remains favorable, and no lead migrations have been observed to date. Conclusion: At three years, 83% of participants experienced clinically substantial improvements in pain, disability, or both. The results confirm the long-term effectiveness, durability, and safety of restorative neurostimulation in patients with disabling CLBP associated with multifidus muscle dysfunction. Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT02577354.

ObjectiveTo conduct a systematic literature review of dorsal root ganglion (DRG) stimulation for pain.DesignGrade the evidence for DRG stimulation.MethodsAn international, interdisciplinary work group conducted a literature search for DRG stimulation. Abstracts were reviewed to select studies for grading. General inclusion criteria were prospective trials (randomized controlled trials and observational studies) that were not part of a larger or previously reported group. Excluded studies were retrospective, too small, or existed only as abstracts. Studies were graded using the modified Interventional Pain Management Techniques–Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria.ResultsDRG stimulation has Level II evidence (moderate) based upon one high-quality pivotal randomized controlled trial and two lower-quality studies.ConclusionsModerate-level evidence supports DRG stimulation for treating chronic focal neuropathic pain and complex regional pain syndrome.

OBJECTIVE To identify relationships between clinical assessments of chronic pain to enable the generation of a multivariate model to predict patient satisfaction with spinal cord stimulation (SCS) treatment. MATERIALS AND METHODS Data from an exploratory clinical trial of sub-perception SCS (SPSCS) were reviewed. Forty-seven subjects tested multiple SPSCS programs for three to four days each. At the end of each program period, subjects recorded pain intensity, patient satisfaction with treatment (PSWT), modified patient global impression of change, and physical activity tolerance times. Twelve outcome variables were evaluated. Pearson's correlation coefficient was used to assess pair-wise correlations. Multigenerational mixed effects modeling was performed to create a model to best explain relationships between those variables. RESULTS A final model was generated that predicted PSWT using evening pain intensity (EPI) and the interaction between EPI and walking tolerance time. The mixed effects model allows for visualization of the interactions between EPI, walking tolerance time, and patient satisfaction with SCS. CONCLUSIONS Patient-centered outcomes are desirable when evaluating complex multidimensional health impairments but accurately predicting patient satisfaction with treatment remains a challenge. Understanding the variables that predict (either by causation or association) satisfaction would be useful for clinicians. The results of this study suggest that a composite measure of activity tolerance (i.e., walking tolerance) and pain intensity can predict patient satisfaction with SCS therapy. This study highlights the utility of composite outcomes metrics in evaluating the benefits of SCS for chronic low back and leg pain.

Intractable upper limb and neck pain has traditionally been a challenging pain condition to treat, with conventional spinal cord stimulation (SCS) often inducing positional variation in paraesthesia and/or inadequate coverage of axial neck pain. The purpose of this Australian multi-centre prospective, clinical trial was to assess the safety and effectiveness of paraesthesia-independent 10 kHz SCS for the treatment of upper limb and neck pain. Subjects with chronic, intractable neck and/or upper limb pain of ≥ 5 cm (on a 0–10-cm visual analogue scale) were enrolled (ACTRN12614000153617) following human research ethics committee approval. Subjects were implanted with two epidural leads spanning C2–C6 vertebral bodies. Subjects with successful trial stimulation were implanted with a Senza® system (Nevro Corp., Redwood City, CA, USA) and included in the safety and effectiveness evaluation at 3 months post-implant (primary endpoint assessment, PEA) and followed to 12 months. Overall, 31/38 (82.6%) subjects reported a successful 10 kHz SCS trial and proceeded to a permanent implant. Twenty-three of 30 subjects (76.7%) met the PEA. Subjects reported a reduction in neck pain and upper limb pain from baseline at the PEA (8.1 ± 0.2 cm vs. 2.9 ± 0.5 cm, 7.3 ± 0.3 cm vs. 2.5 ± 0.5 cm, respectively, p ≤ 0.0001). Disability, as measured by pain disability index score, decreased from 42.6 ± 2.6 at baseline to 22.7 ± 3.2 at PEA. Results were maintained 12 months post-implant. No neurological deficits, nor reports of paraesthesia, were observed. Stable, long-term results demonstrated that 10 kHz SCS is a promising therapy option for intractable chronic upper limb and neck pain.

Chronic pain remains a leading cause of disability worldwide, and there is still a clinical reliance on opioids despite the medical side effects associated with their use and societal impacts associated with their abuse. An alternative approach is the use of electrical neuromodulation to produce analgesia. Direct current can block action potential propagation but leads to tissue damage if maintained. We have developed a form of ultra low frequency (ULF) biphasic current and studied its effects. In anesthetized rats, this waveform produced a rapidly developing and completely reversible conduction block in >85% of spinal sensory nerve fibers excited by peripheral stimulation. Sustained ULF currents at lower amplitudes led to a slower onset but reversible conduction block. Similar changes were seen in an animal model of neuropathic pain, where ULF waveforms blocked sensory neuron ectopic activity, known to be an important driver of clinical neuropathic pain. Using a computational model, we showed that prolonged ULF currents could induce accumulation of extracellular potassium, accounting for the slowly developing block observed in rats. Last, we tested the analgesic effects of epidural ULF currents in 20 subjects with chronic leg and back pain. Pain ratings improved by 90% after 2 weeks. One week after explanting the electrodes, pain ratings reverted to 72% of pretreatment screening value. We conclude that epidural spinal ULF neuromodulation represents a promising therapy for treating chronic pain.

Failed back surgery syndrome (FBSS) is a stigmatizing and misleading term, and in many cases surgery is not relevant to the development, persistence, worsening or recurrence of the symptoms. An international panel recently proposed the notion of Persistent spinal pain syndrome (PSPS) as the preferred option to replace FBSS. The new label avoids ambiguity and inappropriately-implied causation. PSPS type 1 applies when there was no spinal surgery; type 2 applies when surgery had occurred. PSPS is therefore broader than FBSS but more accurate.

Objectives The purpose of the ongoing follow‐up of ReActiv8‐A clinical trial is to document the longitudinal benefits of episodic stimulation of the dorsal ramus medial branch and consequent contraction of the lumbar multifidus in patients with refractory mechanical chronic low back pain (CLBP). We report the four‐year outcomes of this trial. Materials and Methods ReActiv8‐A is a prospective, single‐arm trial performed at nine sites in the United Kingdom, Belgium, and Australia. Eligible patients had disabling CLBP (low back pain Numeric Rating Scale [NRS] ≥6; Oswestry Disability Index [ODI] ≥25), no indications for spine surgery or spinal cord stimulation, and failed conventional management including at least physical therapy and medications for low back pain. Fourteen days postimplantation, stimulation parameters were programmed to elicit strong, smooth contractions of the multifidus, and participants were given instructions to activate the device for 30‐min stimulation‐sessions twice daily. Annual follow‐up through four years included collection of NRS, ODI, and European Quality of Life Score on Five Dimensions (EQ‐5D). Background on mechanisms, trial design, and one‐year outcomes were previously described. Results At baseline (N = 53) (mean ± SD) age was 44 ± 10 years; duration of back pain was 14 ± 11 years, NRS was 6.8 ± 0.8, ODI 44.9 ± 10.1, and EQ‐5D 0.434 ± 0.185. Mean improvements from baseline were statistically significant (p

Diabetic neuropathic pain is a common and devastating complication of type 1 diabetes, but the mechanism by which it develops and persists is yet to be fully elucidated. This study utilised high-dimensional suspension mass cytometry in a pilot cohort to investigate differences in peripheral blood immunophenotypes between type 1 diabetes patients with (n ​= ​9) and without (n ​= ​9) peripheral neuropathic pain. The abundance and activation of several leukocyte subsets were investigated with unsupervised clustering approaches FlowSOM and SPADE, as well as by manual gating. Major findings included a proportional increase in CD4+ central memory T cells and an absolute increase in classical monocytes, non-classical monocytes, and mature natural killer cells in type 1 diabetes patients with pain compared to those without pain. The expression of CD27, CD127, and CD39 was upregulated on select T cell populations, and the phosphorylated form of pro-inflammatory transcription factor MK2 was upregulated across most populations. These results provide evidence that distinct immunological signatures are associated with painful neuropathy in type 1 diabetes patients. Further research may link these changes to mechanisms by which pain in type 1 diabetes is initiated and maintained, paving the way for much needed targeted treatments.

ObjectiveFor many medical professionals dealing with patients with persistent pain following spine surgery, the term Failed back surgery syndrome (FBSS) as a diagnostic label is inadequate, misleading, and potentially troublesome. It misrepresents causation. Alternative terms have been suggested, but none has replaced FBSS. The International Association for the Study of Pain (IASP) published a revised classification of chronic pain, as part of the new International Classification of Diseases (ICD-11), which has been accepted by the World Health Organization (WHO). This includes the term Chronic pain after spinal surgery (CPSS), which is suggested as a replacement for FBSS.MethodsThis article provides arguments and rationale for a replacement definition. In order to propose a broadly applicable yet more precise and clinically informative term, an international group of experts was established.Results14 candidate replacement terms were considered and ranked. The application of agreed criteria reduced this to a shortlist of four. A preferred option—Persistent spinal pain syndrome—was selected by a structured workshop and Delphi process. We provide rationale for using Persistent spinal pain syndrome and a schema for its incorporation into ICD-11. We propose the adoption of this term would strengthen the new ICD-11 classification.ConclusionsThis project is important to those in the fields of pain management, spine surgery, and neuromodulation, as well as patients labeled with FBSS. Through a shift in perspective, it could facilitate the application of the new ICD-11 classification and allow clearer discussion among medical professionals, industry, funding organizations, academia, and the legal profession.

INTRODUCTION The technique of radiofrequency neurotomy (RFN) of the facet joints has been used for decades to treat persistent low back pain to good effect in carefully selected patients. Traditionally, the target is the medial branches of the dorsal root supplying the facet joint. An alternative denervation target is the facet joint capsule. Capsule-targeting techniques may spare the multifidus muscle, a possible unintended target of traditional RFN that is thought to be important in recovering from low back pain, and have shown promising results. METHODS A modified RFN technique that targets the capsule and spares the multifidus (multifidus-sparing RFN) is described here, along with a brief report of its application in patients with symptomatic facet joint low back pain as compared to traditional medial branch RFN (MBRF). RESULTS Over a 2-year period, a total of 401 initial multifidus-sparing RFN and 94 initial MBRF procedures were performed on patients attending a multidisciplinary pain clinic. The proportion of repeat procedures was similar: 28.4% of multifidus-sparing procedures and 23.4% of MBRF procedures. The median repeat interval was 12 months for both groups and interquartile range was 10 months (8-18 months) for multifidus-sparing RFN and 4 months (11-15 months) for MBRF. Effectiveness and safety profiles appear to be similar, although limited, retrospective outcome information prevented robust analysis. CONCLUSION Multifidus-sparing RFN represents an intriguing technique to denervate the facet joint pain generator while maintaining normal multifidus function. Further study is warranted, particularly in order to identify the appropriate patient criteria and long-term outcomes.

ObjectiveTo conduct a systematic literature review of spinal cord stimulation (SCS) for pain.DesignGrade the evidence for SCS.MethodsAn international, interdisciplinary work group conducted literature searches, reviewed abstracts, and selected studies for grading. Inclusion/exclusion criteria included randomized controlled trials (RCTs) of patients with intractable pain of greater than one year’s duration. Full studies were graded by two independent reviewers. Excluded studies were retrospective, had small numbers of subjects, or existed only as abstracts. Studies were graded using the modified Interventional Pain Management Techniques–Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria.ResultsSCS has Level 1 evidence (strong) for axial back/lumbar radiculopathy or neuralgia (five high-quality RCTs) and complex regional pain syndrome (one high-quality RCT).ConclusionsHigh-level evidence supports SCS for treating chronic pain and complex regional pain syndrome. For patients with failed back surgery syndrome, SCS was more effective than reoperation or medical management. New stimulation waveforms and frequencies may provide a greater likelihood of pain relief compared with conventional SCS for patients with axial back pain, with or without radicular pain.

Complex Regional Pain Syndrome (CRPS) has defied a clear unified pathological explanation to date. Not surprisingly, treatments for the condition are limited in number, efficacy and their ability to enact a cure. Whilst many observations have been made of physiological abnormalities, how these explain the condition and who does and doesn't develop CRPS remains unclear. We propose a new overarching hypothesis to explain the condition that invokes four dynamically changing and interacting components of tissue trauma, pathological pain processing, autonomic dysfunction (both peripheral and central) and immune dysfunction, primarily involving excessive and pathological activation of dendritic cells following trauma or atrophy. We outline pathophysiological changes that may initiate a cascade of events involving dendritic cells and the cholinergic anti-inflammatory pathway resulting in the condition, and the changes that maintain the condition into its chronic phase. This hypothesis should provide fertile ground for further investigations and development of new treatments that holistically address the nature of the disorder along its developmental continuum.

Aim: Evaluate the efficacy of flurbiprofen 8.75 mg spray for sore throat relief. Patients & methods: Randomized, double-blind study in adults with sore throat due to upper respiratory tract infection who took flurbiprofen (n = 249) or placebo spray (n = 256). Pain relief was assessed using the Sore Throat Relief Rating Scale. Results: Flurbiprofen spray provided significantly greater relief versus placebo from 20 min to 6 h (p < 0.0001; maximum difference: 75 min). Sore throat severity was reduced ≥-2.2 on the Sore Throat Scale from 75 min to 6 h, indicating meaningful relief. Significantly more patients taking flurbiprofen spray reported ≥30 min of ‘at least moderate’ relief versus placebo over 6 h (p < 0.0001). Most adverse events were mild. Conclusion: Flurbiprofen spray provides rapid, long-lasting and clinically meaningful relief from sore throat (ANZCTR: ACTRN12612000457842).

Background Spinal cord stimulation (SCS) activates the dorsal column fibers using electrical stimuli. Current SCS systems function in fixed-output mode, delivering the same stimulus regardless of spinal cord (SC) activation. Objective To present long-term outcomes of a novel closed-loop SCS system that aims to maintain the SC activation near a set target level and within a therapeutic window for each patient. SC activation is measured through the evoked compound action potential (ECAP) generated by each stimulus pulse. Methods Fifty patients with lower back and/or leg pain who were successfully trialed received a permanent system (Evoke; Saluda Medical, Sydney, Australia). Ratings of pain (visual analog scale), quality of life, function, sleep, and medication use were collected at baseline and at each visit. SC activation levels were reported in summary statistics. The therapeutic window for each individual patient was defined as the range of ECAP amplitudes between sensation threshold and uncomfortably strong stimulation. Results At 12 mo, the proportion of patients with ≥50% relief was 76.9% (back), 79.3% (leg), and 81.4% (overall), and the proportion with ≥80% pain relief was 56.4% (back), 58.6% (leg), and 53.5% (overall). Patients spent a median of 84.9% of their time with stimulation in their therapeutic window, and 68.8% (22/32) eliminated or reduced their opioid intake. Statistically significant improvements in secondary outcomes were observed. Conclusion The majority of patients experienced more than 80% pain relief with stable SC activation, as measured by ECAP amplitude at 12 mo, providing evidence for the long-term effectiveness of the Evoke closed-loop SCS system.

Objectives Conventional spinal cord stimulation (SCS) delivers a fixed-input of energy into the dorsal column. Physiologic effects such as heartbeat, respiration, spinal cord movement, and history of stimulation can cause both the perceived intensity and recruitment of stimulation to increase or decrease, with clinical consequences. A new SCS system controls stimulation dose by measuring the recruitment of fibers in the dorsal column and by using the amplitude of the evoked compound action potentials (ECAPs) to maintain stimulation within an individualized therapeutic range. Safety and efficacy of this closed-loop system was evaluated through six-month postimplantation. Materials and Methods Chronic pain subjects with back and/or leg pain who were successfully trialed received a permanent system (Evoke; Saluda Medical, Sydney, Australia). Ratings of pain (100-mm visual analogue scale [VAS] and Brief Pain Instrument [BPI]), quality of life (EuroQol instrument [EQ-5D-5L]), function (Oswestry Disability Index [ODI]), and sleep (Pittsburgh Sleep Quality Index [PSQI]) were collected at baseline and repeated three and six months after implantation. Results Fifty-one subjects underwent a trial procedure; permanent implants were placed in 36 subjects. The proportion of subjects with ≥50% relief was 92.6% (back) and 91.3% (leg) at three months, and 85.7% (back) and 82.6% (leg) at six months. The proportion with ≥80% pain relief was 70.4% (back) and 56.5% (leg) at three months, and 64.3% (back) and 60.9% (leg) at six months. Statistically significant improvements in mean BPI, EQ-5D-5L, ODI, and PSQI were also observed at both time points. Conclusions The majority of subjects experienced profound pain relief at three and six months, providing preliminary evidence for the effectiveness of the closed-loop SCS system. The exact mechanism of action for these outcomes is still being explored, although one likely hypothesis holds that ECAP feedback control may minimize recruitment of Aβ nociceptors and Aδ fibers during daily use of SCS.

Sir,Flawed nomenclature and classification inevitably hamper diagnosis, clinical communication and research, and may impede access to appropriate treatment. This is clearly illustrated by the term ...

Chronic pain is a devastating condition affecting the physical, psychological, and socioeconomic status of the patient. Inflammation and immunometabolism play roles in the pathophysiology of chronic pain disorders. Electrical neuromodulation approaches have shown a meaningful success in otherwise drug-resistant chronic pain conditions, including failed back surgery, neuropathic pain, and migraine. A literature review (PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles) was performed using the following search terms: chronic pain disorders, systemic inflammation, immunometabolism, prediction, biomarkers, metabolic disorders, and neuromodulation for chronic pain. Experimental studies indicate a relationship between the development and maintenance of chronic pain conditions and a deteriorated immunometabolic state mediated by circulating cytokines, chemokines, and cellular components. A few uncontrolled in-human studies found increased levels of pro-inflammatory cytokines known to drive metabolic disorders in chronic pain patients undergoing neurostimulation therapies. In this narrative review, we summarize the current knowledge and possible relationships of available neurostimulation therapies for chronic pain with mediators of central and peripheral neuroinflammation and immunometabolism on a molecular level. However, to address the needs for predictive factors and biomarkers, large-scale databank driven clinical trials are needed to determine the clinical value of molecular profiling.

Complex regional pain syndrome (CRPS) is a debilitating condition where trauma to a limb results in devastating persistent pain that is disproportionate to the initial injury. The pathophysiology of CRPS remains unknown; however, accumulating evidence suggests it is an immunoneurological disorder, especially in light of evidence of auto-antibodies in ~ 30% of patients. Despite this, a systematic assessment of all circulating leukocyte populations in CRPS has never been performed.We characterised 14 participants as meeting the Budapest clinical criteria for CRPS and assessed their pain ratings and psychological state using a series of questionnaires. Next, we performed immunophenotyping on blood samples from the 14 CRPS participants as well as 14 healthy pain-free controls using mass cytometry. Using a panel of 38 phenotypic and activation markers, we characterised the numbers and intracellular activation status of all major leukocyte populations using manual gating strategies and unsupervised cluster analysis.We have shown expansion and activation of several distinct populations of central memory T lymphocytes in CRPS. The number of central memory CD8These findings represent the first mass cytometry immunophenotyping study in any chronic pain state and provide preliminary evidence of an antigen-mediated T lymphocyte response in CRPS. In particular, the presence of increased numbers of long-lived central memory CD4

Background Complex regional pain syndrome (CRPS) is a debilitating condition where trauma to a limb results in devastating persistent pain that is disproportionate to the initial injury. The pathophysiology of CRPS remains unknown; however, accumulating evidence suggests it is an immunoneurological disorder, especially in light of evidence of auto-antibodies in ~ 30% of patients. Despite this, a systematic assessment of all circulating leukocyte populations in CRPS has never been performed. Methods We characterised 14 participants as meeting the Budapest clinical criteria for CRPS and assessed their pain ratings and psychological state using a series of questionnaires. Next, we performed immunophenotyping on blood samples from the 14 CRPS participants as well as 14 healthy pain-free controls using mass cytometry. Using a panel of 38 phenotypic and activation markers, we characterised the numbers and intracellular activation status of all major leukocyte populations using manual gating strategies and unsupervised cluster analysis. Results We have shown expansion and activation of several distinct populations of central memory T lymphocytes in CRPS. The number of central memory CD8+ T cells was increased 2.15-fold; furthermore, this cell group had increased phosphorylation of NFkB and STAT1 compared to controls. Regarding central memory CD4+ T lymphocytes, the number of Th1 and Treg cells was increased 4.98-fold and 2.18-fold respectively, with increased phosphorylation of NFkB in both populations. We also found decreased numbers of CD1c+ myeloid dendritic cells, although with increased p38 phosphorylation. These changes could indicate dendritic cell tissue trafficking, as well as their involvement in lymphocyte activation. Conclusions These findings represent the first mass cytometry immunophenotyping study in any chronic pain state and provide preliminary evidence of an antigen-mediated T lymphocyte response in CRPS. In particular, the presence of increased numbers of long-lived central memory CD4+ and CD8+ T lymphocytes with increased activation of pro-inflammatory signalling pathways may indicate ongoing inflammation and cellular damage in CRPS.

Introduction The Neurostimulation Appropriateness Consensus Committee (NACC) was formed by the International Neuromodulation Society (INS) in 2012 to evaluate the evidence to reduce the risk of complications and improve the efficacy of neurostimulation. The first series of papers, published in 2014, focused on the general principles of appropriate practice in the surgical implantation of neurostimulation devices. The NACC was reconvened in 2014 to address specific patient care issues, including bleeding and coagulation. Methods The INS strives to improve patient care in an evidence-based fashion. The NACC members were appointed or recruited by the INS leadership for diverse expertise, including international clinical expertise in many areas of neurostimulation, evidence evaluation, and publication. The group developed best practices based on peer-reviewed evidence and, in the absence of specific evidence, on expert opinion. Recommendations were based on international evidence in accordance with guideline creation. Conclusions The NACC has recommended specific measures to reduce the risk of bleeding and neurological injury secondary to impairment of coagulation in the setting of implantable neurostimulation devices in the spine, brain, and periphery.

We investigated serum levels of 29 cytokines and immune-activated kynurenine and tetrahydrobiopterin pathway metabolites in 15 complex regional pain syndrome (CRPS) subjects and 14 healthy controls. Significant reductions in interleukin-37 and tryptophan were found in CRPS subjects, along with positive correlations between kynurenine/tryptophan ratio and TNF-α levels with kinesiophobia, tetrahydrobiopterin levels with McGill pain score, sRAGE, and xanthurenic acid and neopterin levels with depression, anxiety and stress scores. Using machine learning, we identified a set of binary variables, including IL-37 and GM-CSF, capable of distinguishing controls from established CRPS subjects. These results suggest possible involvement of various inflammatory markers in CRPS pathogenesis.