Proteomic Analysis to Identify Prospective Biomarkers of Treatment Outcome After Microvascular Decompression for Trigeminal Neuralgia: A Preliminary Study.

Trigeminal neuralgia (TN) is a severe neuropathic facial pain disorder, often caused by vascular or neuronal compression of the trigeminal nerve. In such cases, microvascular decompression (MVD) surgery can be used to treat TN, but pain relief is not guaranteed. The molecular mechanisms that affect treatment response to MVD are not well understood. In this exploratory study, we performed label-free quantitative proteomic profiling of plasma and cerebrospinal fluid samples from patients undergoing MVD for TN, then compared the proteomic profiles of patients graded as responders (n = 7) versus non-responders (n = 9). We quantified 1,090 proteins in plasma and 1,087 proteins in the cerebrospinal fluid, of which 12 were differentially regulated in the same direction in both sample types. Functional analyses of differentially regulated proteins in protein-protein interaction networks suggested pathways of the immune system, axon guidance, and cellular stress response to be associated with response to MVD. These findings suggest potential biomarkers of response to MVD, as well as possible mechanisms of variable treatment success in TN patients. PERSPECTIVE: This exploratory study evaluates proteomic profiles in plasma and cerebrospinal fluid of patients undergoing microvascular decompression surgery for trigeminal neuralgia. Differential expression of proteins between surgery responders versus non-responders may serve as biomarkers to predict surgical success and provide insight into surgical mechanisms of pain relief in trigeminal neuralgia.

Pro-Con Debate: Superior Versus Inferior Triangle Needle Placement in Transforaminal Epidural Injections.

Although transforaminal epidural injections have long been used for radicular pain, there is no universal standard injection approach to the neural foramen. The intervertebral foramen and its surrounding structures comprise an anatomically sensitive area that includes bone and joint structures, the intervertebral disk, blood vessels (in particular, the radicular arteries), the epidural sheath, and the spinal nerve root. Given the relatively high risk of inadvertent injury or injection to these nearby structures, image guidance for transforaminal epidural steroid injections (TFESIs) is standard of care. However, there is a lack of consensus regarding the optimal approach to the neural foramen: from the traditional superior ("safe") triangle or from the inferior (Kambin's) triangle. In this Pro-Con commentary article, we discuss the relative advantages and disadvantages of each approach for TFESIs.

Peripheral nerve stimulation for chronic knee pain following total knee arthroplasty: a systematic review.

Chronic knee pain following total knee arthroplasty (TKA) affects a subset of patients that is refractory to pharmacological and non-pharmacological modalities. Peripheral nerve stimulation (PNS) has been used in patients with chronic knee pain following TKA and has shown some efficacy. Methods: Comprehensive search of Ovid Medline, Elsevier Embase, Cochrane Central Register of Controlled Trials, CINAHL Plus with Full Text, Scopus, SPORTDiscus with Full Text and the Web of Science platform. From inception to August 2022, for studies using PNS to treat chronic knee pain following TKA. Primary outcomes included pain scores, functional status and medication usage. Results: Nine studies were extrapolated with all demonstrating effectiveness of PNS for patients with chronic knee pain following TKA. Discussion: PNS for chronic knee pain following TKA has been shown to be an efficacious treatment modality. The level of evidence is low and more research is needed to assess its safety and effectiveness.

Evidence-based consensus guidelines on patient selection and trial stimulation for spinal cord stimulation therapy for chronic non-cancer pain.

Spinal cord stimulation (SCS) has demonstrated effectiveness for neuropathic pain. Unfortunately, some patients report inadequate long-term pain relief. Patient selection is emphasized for this therapy; however, the prognostic capabilities and deployment strategies of existing selection techniques, including an SCS trial, have been questioned. After approval by the Board of Directors of the American Society of Regional Anesthesia and Pain Medicine, a steering committee was formed to develop evidence-based guidelines for patient selection and the role of an SCS trial. Representatives of professional organizations with clinical expertize were invited to participate as committee members. A comprehensive literature review was carried out by the steering committee, and the results organized into narrative reports, which were circulated to all the committee members. Individual statements and recommendations within each of seven sections were formulated by the steering committee and circulated to members for voting. We used a modified Delphi method wherein drafts were circulated to each member in a blinded fashion for voting. Comments were incorporated in the subsequent revisions, which were recirculated for voting to achieve consensus. Seven sections with a total of 39 recommendations were approved with 100% consensus from all the members. Sections included definitions and terminology of SCS trial; benefits of SCS trial; screening for psychosocial characteristics; patient perceptions on SCS therapy and the use of trial; other patient predictors of SCS therapy; conduct of SCS trials; and evaluation of SCS trials including minimum criteria for success. Recommendations included that SCS trial should be performed before a definitive SCS implant except in anginal pain (grade B). All patients must be screened with an objective validated instrument for psychosocial factors, and this must include depression (grade B). Despite some limitations, a trial helps patient selection and provides patients with an opportunity to experience the therapy. These recommendations are expected to guide practicing physicians and other stakeholders and should not be mistaken as practice standards. Physicians should continue to make their best judgment based on individual patient considerations and preferences.

Nonorganic (Behavioral) Signs and Their Association With Epidural Corticosteroid Injection Treatment Outcomes and Psychiatric Comorbidity in Cervical Radiculopathy: A Multicenter Study.

OBJECTIVE: To determine the association between cervical nonorganic pain signs and epidural corticosteroid injection outcomes and coexisting pain and psychiatric conditions. PATIENTS AND METHODS: Seventy-eight patients with cervical radiculopathy who received epidural corticosteroid injection were observed to determine the effects that nonorganic signs have on treatment outcome. A positive outcome was a decrease of 2 or more points in average arm pain, coupled with a score of 5 on a 7-point Patient Global Impression of Change scale 4 weeks after treatment. Nine tests in 5 categories (abnormal tenderness, regional disturbances deviating from normal anatomy, overreaction, discrepancies in examination findings with distraction, and pain during sham stimulation) were modified from previous studies and standardized. Other variables examined for their association with nonorganic signs and outcomes included disease burden, psychopathology, coexisting pain conditions, and somatization. RESULTS: Of the 78 patients, 29% (n=23) had no nonorganic signs, 21% (n=16) had signs in 1 category, 10% (n=8) had signs in 2 categories, 21% (n=16) had signs in 3 categories, 10% (n=8) had signs in 4 categories, and 9% (n=7) had signs in 5 categories. The most common nonorganic sign was superficial tenderness (44%; n=34). Mean number of positive nonorganic categories was higher in individuals with negative treatment outcomes (2.5±1.8; 95% CI, 2.0 to 3.1) compared with those with positive outcomes (1.1±1.3; 95% CI, 0.7 to 1.5; P=.0002). Negative treatment outcomes were most strongly associated with regional disturbances and overreaction. Positive associations were noted between nonorganic signs and multiple pain (P=.011) and multiple psychiatric (P=.028) conditions. CONCLUSION: Cervical nonorganic signs correlate with treatment outcome, pain, and psychiatric comorbidities. Screening for these signs and psychiatric symptoms may improve treatment outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04320836.

Chronic pain and infection: mechanisms, causes, conditions, treatments, and controversies.

Throughout human history, infection has been the leading cause of morbidity and mortality, with pain being one of the cardinal warning signs. However, in a substantial percentage of cases, pain can persist after resolution of acute illness, manifesting as neuropathic, nociplastic (eg, fibromyalgia, irritable bowel syndrome), or nociceptive pain. Mechanisms by which acute infectious pain becomes chronic are variable and can include immunological phenomena (eg, bystander activation, molecular mimicry), direct microbe invasion, central sensitization from physical or psychological triggers, and complications from treatment. Microbes resulting in a high incidence of chronic pain include bacteria such as the Borrelia species and Mycobacterium leprae, as well as viruses such as HIV, SARS-CoV-2 and herpeses. Emerging evidence also supports an infectious cause in a subset of patients with discogenic low back pain and inflammatory bowel disease. Although antimicrobial treatment might have a role in treating chronic pain states that involve active infectious inflammatory processes, their use in chronic pain conditions resulting from autoimmune mechanisms, central sensitization and irrevocable tissue (eg, arthropathy, vasculitis) or nerve injury, are likely to cause more harm than benefit. This review focuses on the relation between infection and chronic pain, with an emphasis on common viral and bacterial causes.

Multicenter study evaluating factors associated with treatment outcome for low back pain injections.

BACKGROUND: There has been a worldwide surge in interventional procedures for low back pain (LBP), with studies yielding mixed results. These data support the need for identifying outcome predictors based on unique characteristics in a pragmatic setting. METHODS: We prospectively evaluated the association between over two dozen demographic, clinical and technical factors on treatment outcomes for three procedures: epidural steroid injections (ESIs) for sciatica, and sacroiliac joint (SIJ) injections and facet interventions for axial LBP. The primary outcome was change in patient-reported average pain intensity on a numerical rating scale (average NRS-PI) using linear regression. For SIJ injections and facet radiofrequency ablation, this was average LBP score at 1 and 3 months postprocedure, respectively. For ESI, it was average leg pain 1- month postinjection. Secondary outcomes included a binary indicator of treatment response (success). RESULTS: 346 patients were enrolled at seven hospitals. All groups experienced a decrease in average NRS-PI (p<0.0001; mean 1.8±2.6). There were no differences in change in average NRS-PI among procedural groups (p=0.50). Lower baseline pain score (adjusted coefficient -0.32, 95% CI -0.48 to -0.16, p<0.0001), depressive symptomatology (adjusted coefficient 0.076, 95% CI 0.039 to 0.113, p<0.0001) and obesity (adjusted coefficient 0.62, 95% CI 0.038 to 1.21, p=0.037) were associated with smaller pain reductions. For procedural outcome, depression (adjusted OR 0.94, 95% CI 0.91, 0.97, p<0.0001) and poorer baseline function (adjusted OR 0.59, 95% CI 0.36, 0.96, p=0.034) were associated with failure. Smoking, sleep dysfunction and non-organic signs were associated with negative outcomes in univariate but not multivariate analyses. CONCLUSIONS: Identifying treatment responders is a critical endeavor for the viability of procedures in LBP. Patients with greater disease burden, depression and obesity are more likely to fail interventions. Steps to address these should be considered before or concurrent with procedures as considerations dictate. TRIAL REGISTRATION NUMBER: NCT02329951.

AAAPT Diagnostic Criteria for Acute Neuropathic Pain.

OBJECTIVE: Acute neuropathic pain is a significant diagnostic challenge, and it is closely related to our understanding of both acute pain and neuropathic pain. Diagnostic criteria for acute neuropathic pain should reflect our mechanistic understanding and provide a framework for research on and treatment of these complex pain conditions. METHODS: The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration (FDA), the American Pain Society (APS), and the American Academy of Pain Medicine (AAPM) collaborated to develop the ACTTION-APS-AAPM Pain Taxonomy (AAAPT) for acute pain. A working group of experts in research and clinical management of neuropathic pain was convened. Group members used literature review and expert opinion to develop diagnostic criteria for acute neuropathic pain, as well as three specific examples of acute neuropathic pain conditions, using the five dimensions of the AAAPT classification of acute pain. RESULTS: AAAPT diagnostic criteria for acute neuropathic pain are presented. Application of these criteria to three specific conditions (pain related to herpes zoster, chemotherapy, and limb amputation) illustrates the spectrum of acute neuropathic pain and highlights unique features of each condition. CONCLUSIONS: The proposed AAAPT diagnostic criteria for acute neuropathic pain can be applied to various acute neuropathic pain conditions. Both the general and condition-specific criteria may guide future research, assessment, and management of acute neuropathic pain.

Waddell (Nonorganic) Signs and Their Association With Interventional Treatment Outcomes for Low Back Pain.

BACKGROUND: The rising use of injections to treat low back pain (LBP) has led to efforts to improve selection. Nonorganic (Waddell) signs have been shown to portend treatment failure for surgery and other therapies but have not been studied for minimally invasive interventions. METHODS: We prospectively evaluated the association between Waddell signs and treatment outcome in 3 cohorts: epidural steroid injections (ESI) for leg pain and sacroiliac joint (SIJ) injections and facet interventions for LBP. Categories of Waddell signs included nonanatomic tenderness, pain during sham stimulation, discrepancy in physical examination, overreaction, and regional disturbances divulging from neuroanatomy. The primary outcome was change in patient-reported "average" numerical rating scale for pain intensity (average NRS-PI), modeled as a function of the number of Waddell signs using simple linear regression. Secondary outcomes included a binary indicator of treatment response. We conducted secondary and sensitivity analyses to account for potential confounders. RESULTS: We enrolled 318 patients: 152 in the ESI cohort, 102 in the facet cohort, and 64 in the SIJ cohort, having sufficient data for primary analysis on 308 patients. Among these, 62% (n = 192) had no Waddell signs, 18% (n = 54) had 1 sign, 11% (n = 33) had 2, 5% (n = 16) had 3, 2% (n = 7) had 4, and about 2% (n = 6) had all 5 signs. The mean change in average NRS-PI in each of these 6 groups was -1.6 ± 2.6, -1.1 ± 2.7, -1.5 ± 2.5, -1.6 ± 2.6, -1 ± 1.5, and 0.7 ± 2.1, respectively, and their corresponding treatment failure rates were 54% (102 of 192), 67% (36 of 54), 70% (23 of 33), 75% (12 of 16), 71% (5 of 7), and 83% (5 of 6). In the primary analysis, an increasing number of Waddell signs were not associated with a significant decrease in average NRS-PI (coefficient [Coef] = 0.19; 95% confidence interval [CI], -0.43 to 0.05; P = .12). A higher number of Waddell signs were associated with treatment failure, with a 1.35 increased odds of treatment failure per cumulative number of signs (P = .008). CONCLUSIONS: Whereas this study found no consistent relationship between Waddell signs and decreased mean pain scores, a significant relationship between the number of Waddell signs and treatment failure was observed.

Representation of women plenary speakers at the American Academy of Neurology Annual Meeting.

OBJECTIVE: To determine whether women have been equitably represented among plenary speakers at the American Academy of Neurology (AAN) Annual Meeting by counting and categorizing speakers and comparing outcomes to AAN membership and US neurology workforce data. METHODS: Lists of plenary speakers between 1958 and 2019 (62 years) were obtained from the AAN. The primary outcome measures were numbers and proportions of men and women in aggregate and among physicians. RESULTS: We identified 635 plenary speakers, including 148 (23.3%) women. Specifically, women made up 14.6% (19 of 130) of presidential and 25.5% (129 of 505) of nonpresidential plenary session speakers. The inclusion of women plenary speakers was meaningfully higher (h = 0.33; difference 14.9%; 95% confidence interval 4.2%-26.7%) for nonphysicians (27 of 74 [36.5%]) than physicians (121 of 561 [21.6%]). Although at zero levels for Annual Meetings held between 1958 and 1990 and at mostly low but varying levels thereafter, the representation of women and women physicians has been at or above their proportions in the AAN membership and US neurology workforce since 2017. Comparison of representation by plenary session name revealed an unequal distribution of women, with women physicians concentrated in the Sidney Carter Award in Child Neurology presidential session. CONCLUSION: Historically and recently, women and women physicians were underrepresented among AAN plenary speakers. As the AAN has taken active steps to address equity, women have been included in more representative proportions overall. However, notable gaps remain, especially in specific prestigious plenary sessions, and further research is needed to determine causality.

Biomarkers in Temporomandibular Disorder and Trigeminal Neuralgia: A Conceptual Framework for Understanding Chronic Pain.

In this review, we will explore the use of biomarkers in chronic pain, using the examples of two prototypical facial pain conditions: trigeminal neuralgia and temporomandibular disorder. We will discuss the main categories of biomarkers and identify various genetic/genomic, molecular, neuroradiological, and psychophysical biomarkers in both facial pain conditions, using them to compare and contrast features of neuropathic, non-neuropathic, and mixed pain. By using two distinct model facial pain conditions to explore pain biomarkers, we aim to familiarize readers with different types of biomarkers currently being studied in chronic pain, and explore how these biomarkers may be used to develop new precision medicine approaches to pain diagnosis, prognosis, and management.

Representation of Women in Pain Medicine Fellowships in the United States, 2017-2018.

OBJECTIVE: To quantify the representation of women trainees and faculty and to explore associations between them at Pain Medicine (PM) fellowship programs in the United States. SETTING: PM fellowship programs accredited by the Accreditation Council for Graduate Medical Education. METHODS: All PM programs approved for at least four fellows as of December 2017 were identified. Websites of these programs were reviewed to determine the number and gender of current fellows and faculty, and programs were contacted to verify the information. RESULTS: A total of 56 PM programs were eligible; of these, 48 PM programs (86%) provided information about the gender distribution of fellows. Women comprised ∼25% of PM fellows. PM programs with a female rather than male fellowship program director (PD) had 2.40 times increased odds of a female trainee. Proportion of female faculty and division chief gender were not significantly associated with trainee gender composition. The adjusted odds of a faculty member being female was 1.99 times greater for PM programs with a female vs male PD and 3.13 times greater for programs with a female vs male division chief. CONCLUSIONS: Women are underrepresented throughout all levels of academic pain medicine. The presence of women in leadership roles is associated with higher proportions of female trainees and faculty, highlighting the need for more female role models in academic pain medicine.

Effectiveness of Lumbar Facet Joint Blocks and Predictive Value before Radiofrequency Denervation: The Facet Treatment Study (FACTS), a Randomized, Controlled Clinical Trial.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: With facet interventions under scrutiny, the authors' objectives were to determine the effectiveness of different lumbar facet blocks and their ability to predict radiofrequency ablation outcomes. METHODS: A total of 229 participants were randomized in a 2:2:1 ratio to receive intraarticular facet injections with bupivacaine and steroid, medial branch blocks, or saline. Those with a positive 1-month outcome (a 2-point or more reduction in average pain score) and score higher than 3 (positive satisfaction) on a 5-point satisfaction scale were followed up to 6 months. Participants in the intraarticular and medial branch block groups with a positive diagnostic block (50% or more relief) who experienced a negative outcome proceeded to the second phase and underwent radiofrequency ablation, while all saline group individuals underwent ablation. Coprimary outcome measures were average reduction in numerical rating scale pain score 1 month after the facet or saline blocks, and average numerical rating scale pain score 3 months after ablation. RESULTS: Mean reduction in average numerical rating scale pain score at 1 month was 0.7 ± 1.6 in the intraarticular group, 0.7 ± 1.8 in the medial branch block group, and 0.7 ± 1.5 in the placebo group; P = 0.993. The proportions of positive blocks were higher in the intraarticular (54%) and medial branch (55%) groups than in the placebo group (30%; P = 0.01). Radiofrequency ablation was performed on 135 patients (45, 48, and 42 patients from the intraarticular, medial branch, and saline groups, respectively). The average numerical rating scale pain score at 3 months was 3.0 ± 2.0 in the intraarticular, 3.2 ± 2.5 in the medial branch, and 3.5 ± 1.9 in the control group (P = 0.493). At 3 months, the proportions of positive responders in the intraarticular, medial branch block, and placebo groups were 51%, 56%, and 24% for the intraarticular, medial branch, and placebo groups, respectively (P = 0.005). CONCLUSIONS: This study establishes that facet blocks are not therapeutic. The higher responder rates in the treatment groups suggest a hypothesis that facet blocks might provide prognostic value before radiofrequency ablation.

Why Aren't There More Female Pain Medicine Physicians?

Despite a growing awareness about the importance of gender equity and the rising number of women in medicine, women remain persistently underrepresented in pain medicine and anesthesiology. Pain medicine ranks among the bottom quartile of medical specialties in terms of female applicants, female trainees, and proportion of female practitioners. Female pain medicine physicians are also notably disadvantaged compared with their male colleagues in most objective metrics of gender equity, which include financial compensation, career advancement, public recognition, and leadership positions. Increased gender diversity among pain medicine physicians is vital to fostering excellence in pain research, education, and clinical care, as well as creating a high-quality work environment. Pain medicine stands at a crossroads as a specialty, and must examine reasons for its current gender gap and consider a call to action to address this important issue.