Pain mechanisms in the transgender individual: a review.

Specific Aim: Provide an overview of the literature addressing major areas pertinent to pain in transgender persons and to identify areas of primary relevance for future research. Methods: A team of scholars that have previously published on different areas of related research met periodically though zoom conferencing between April 2021 and February 2023 to discuss relevant literature with the goal of providing an overview on the incidence, phenotype, and mechanisms of pain in transgender patients. Review sections were written after gathering information from systematic literature searches of published or publicly available electronic literature to be compiled for publication as part of a topical series on gender and pain in the Frontiers in Pain Research. Results: While transgender individuals represent a significant and increasingly visible component of the population, many researchers and clinicians are not well informed about the diversity in gender identity, physiology, hormonal status, and gender-affirming medical procedures utilized by transgender and other gender diverse patients. Transgender and cisgender people present with many of the same medical concerns, but research and treatment of these medical needs must reflect an appreciation of how differences in sex, gender, gender-affirming medical procedures, and minoritized status impact pain. Conclusions: While significant advances have occurred in our appreciation of pain, the review indicates the need to support more targeted research on treatment and prevention of pain in transgender individuals. This is particularly relevant both for gender-affirming medical interventions and related medical care. Of particular importance is the need for large long-term follow-up studies to ascertain best practices for such procedures. A multi-disciplinary approach with personalized interventions is of particular importance to move forward.

Young Adult Pain Rehabilitation: Interdisciplinary Development and Preliminary Outcomes of a Novel Treatment Program.

BACKGROUND: Young adults with chronic pain and symptoms experience disruptions to their social, emotional, physical, and vocational functioning. Interdisciplinary pain rehabilitation programs for pediatric and adult populations are not designed specifically to address the developmental needs of young adults. METHODS: This article describes the development of a novel intensive interdisciplinary outpatient rehabilitation program tailored to the unique needs of young adults with chronic pain and symptoms. Tailored content included vocational assessment and consultation, financial literacy education, and sexual health education. RESULTS: Outcome data demonstrate treatment gains, with reductions in pain interference, pain severity, pain catastrophizing, and depressive symptoms, as well as improvements in mental and physical quality of life, perceived performance, perceived satisfaction with performance, and objective measures of physical functioning. CONCLUSIONS: The article concludes with clinical recommendations for the management of chronic pain and symptoms in young adults, applicable across multiple treatment settings.

The Goals and Outcomes of Adolescent and Young Adults with POTS Attending an Intensive Interdisciplinary Treatment Program.

Postural Orthostatic Tachycardia Syndrome (POTS) affects approximately 1% of adolescents, however, little research has been done in this area. This retrospective chart review describes the treatment goals and perceived progress as measured by the Canadian Occupational Performance Measure (COPM) of 111 adolescents and young adults (AYAs) aged 12-22 (M = 15.8, SD = 1.8) diagnosed with POTS who were admitted to an interdisciplinary intensive pain treatment program (IIPT). This study also examined the change in progress and satisfaction in goals over a 3-week intensive pain treatment program, as well as the utility and validity of the COPM as an outcome measure for AYAs attending an IIPT. Results indicated adolescents and young adults endorsed treatment goals focused on self-care, school, and leisure and found that performance and satisfaction scores significantly improved from admission to discharge. The findings also suggest that the COPM is a useful and valid outcome measure for this population.

Ovarian response to follicle-stimulating hormone in women with polycystic ovary syndrome is diminished compared to ovulatory controls.

OBJECTIVE: The mechanisms underlying ovarian dysfunction in polycystic ovary syndrome (PCOS) have not been definitively established. Our objective was to perform a detailed examination of ovarian responses to recombinant follicle-stimulating hormone (rFSH) in women with PCOS and controls. DESIGN: This prospective, crossover, dose-response study included three rFSH stimulation periods. Each stimulation period involved three consecutive, daily, subcutaneous injections of rFSH administered at a single dose. Low, medium and high rFSH doses were weight-adjusted, corresponding to 0.5, 1.1 and 2.2 IU/kg/d, respectively. Stimulation periods occurred in randomized order and were separated by 8-week washouts. PATIENTS: Thirty participants (8 PCOS and 22 controls) were studied. PCOS was defined by oligomenorrhea and clinical or biochemical androgen excess, excluding other aetiologies of ovulatory dysfunction. MEASUREMENTS: Blood samples were obtained for hormone measurements before and 24 h after each rFSH injection. RESULTS: Participants with PCOS had significantly greater body mass index, antral follicle count and circulating testosterone, anti-mullerian hormone (AMH) and luteinizing hormone concentrations compared with controls participants. Baseline estradiol (E2) concentrations were similar in both groups. At the lowest dose of rFSH, PCOS participants did not demonstrate E2 increments, whereas a significant increase occurred in controls. rFSH-induced E2 production per follicle was significantly reduced in PCOS participants compared with controls at all rFSH doses. Increasing T and decreasing AMH concentrations were associated with augmented E2 production per follicle. COONCLUSIONS: Women with PCOS exhibited diminished initial E2 responses to rFSH compared with controls. These findings suggest that the mechanism of anovulation in PCOS may involve altered ovarian response to gonadotropins.

Effect of the spatial-temporal specific theca cell Cyp17 overexpression on the reproductive phenotype of the novel TC17 mouse.

BACKGROUND: In the ovarian follicle, the Theca Cells (TCs) have two main functions: preserving morphological integrity and, importantly, secreting steroid androgen hormones. TCs express the essential enzyme 17α-hydroxylase/17,20-desmolase (CYP17), which permits the conversion of pregnenolone and progesterone into androgens. Dysregulation of CYP17 enzyme activity due to an intrinsic ovarian defect is hypothesized to be a cause of hyperandrogenism in women. Androgen excess is observed in women with polycystic ovary syndrome (PCOS) resulting from excess endogenous androgen production, and in transgender males undergoing exogenous testosterone therapy after female sex assignment at birth. However, the molecular and morphological effects of Cyp17 overexpression and androgen excess on folliculogenesis is unknown. METHODS: In this work, seeking a comprehensive profiling of the local outcomes of the androgen excess in the ovary, we generated a transgenic mouse model (TC17) with doxycycline (Dox)-induced Cyp17 overexpression in a local and temporal manner. TC17 mice were obtained by a combination of the Tet-dependent expression system and the Cre/LoxP gene control system. RESULTS: Ovaries of Dox-treated TC17 mice overexpressed Cyp17 specifically in TCs, inducing high testosterone levels. Surprisingly, TC17 ovarian morphology resembled the human ovarian features of testosterone-treated transgender men (partially impaired folliculogenesis, hypertrophic or luteinized stromal cells, atretic follicles, and collapsed clusters). We additionally assessed TC17 fertility denoting a perturbation of the normal reproductive functions (e.g., low pregnancy rate and numbers of pups per litter). Finally, RNAseq analysis permitted us to identify dysregulated genes (Lhcgr, Fshr, Runx1) and pathways (Extra Cellular Matrix and Steroid Synthesis). CONCLUSIONS: Our novel mouse model is a versatile tool to provide innovative insights into study the effects of Cyp17 overexpression and hyperandrogenism in the ovary.

Central Sensitization in Chronic Pain and Eating Disorders: A Potential Shared Pathogenesis.

Although less recognized than other disruptions in functioning, individuals with chronic pain frequently display disturbances in eating associated with pain, changes in appetite, medication side effects, and prescribed elimination diets. Not only may changes in nutritional status and weight increase the risk for the development of an eating disorder, there is evidence that individuals with chronic pain and those with eating disorders share similar vulnerabilities that place them at risk for both conditions, as well as their comorbidity. This review will describe the temperamental, behavioral, and neurobiological risk factors linking chronic pain and eating disorders. We propose that these risk factors may reflect central sensitization, a condition of over-activation of the central nervous system that increases sensitivity to internal and external conditions. To manage high levels of sensitivity, individuals may develop unique patterns of behavioral avoidance, pain behaviors and/or restrictive eating. Using the framework of central sensitization, this review will discuss relevant assessment and intervention strategies to address sensitivity in eating disorders and chronic pain.

Postural Orthostatic Tachycardia Syndrome and Disordered Eating: Clarifying the Overlap.

OBJECTIVE: Postural orthostatic tachycardia syndrome (POTS) is estimated to occur in up to 1% of adolescents, with symptoms of dizziness, fatigue, and pain impacting daily functioning. However, many risk factors and symptoms for POTS overlap with those of youth with disordered eating, and adolescents with POTS may be at increased risk for developing eating disorders. Therefore, the present study sought to better understand this overlap. We hypothesized that patients with POTS would have higher than expected rates of weight change, restrictive eating patterns, and food sensitivities. METHODS: We conducted a retrospective chart review of 96 adolescents and young adults diagnosed with POTS who were participating in a 3-week intensive interdisciplinary pain rehabilitation program. We conducted descriptive and correlational statistical analyses on data from self-report measures, biomarkers of nutritional status, and abstracted information about eating and weight concerns from medical notes. RESULTS: Nearly 3 quarters of participants described engaging in restrictive eating, and more than half of them described experiencing weight loss. They also endorsed experiencing food allergies, celiac disease, and eating disorder at higher rates than would be expected in the general population. One-fifth of the sample had experienced invasive interventions to correct for nutritional imbalances, such as having a feeding tube. CONCLUSION: Weight and eating are clear areas of risk for patients with orthostatic intolerance. It is essential that treatment team members thoroughly screen for eating disturbances and make recommendations that support regular and balanced eating habits.

An Innovative and Accessible Biofeedback Intervention for Improving Self-Regulatory Skills in Pediatric Chronic Pain: A Pilot Study.

Objectives: Although biofeedback has been considered an effective treatment component for pediatric chronic pain, little research has examined the generalizability to activities outside of the treatment setting. The current study aimed to examine the effects of a biofeedback intervention involving individual and group sessions to facilitate increased self-regulatory skills for chronic pain management and to translate these skills to meaningful activities promoting functional restoration. Methods: Participants included 104 adolescents (ages 12-18) attending an intensive interdisciplinary pain rehabilitation program for chronic pain/symptoms and completed biofeedback training as part of the program. The biofeedback protocol consisted of six sessions, including an assessment of baseline physiologic states, diaphragmatic breath training, and various biofeedback screens to reinforce self-regulatory skills within individual- and group-based formats. Results: As expected, patients showed significant reductions in respiration rates and muscle tension from admission to discharge. Ratings of perceived confidence also increased from admission to post-treatment, suggesting greater self-efficacy in patients using self-regulatory skills during their daily functional activities. Conclusions: An individual- and group-based biofeedback protocol with a focus on training skills in activities relevant to adolescents' lives has the potential to improve self-regulation skills and generalize these skills to real-world settings. Future randomized controlled trials are necessary to examine the efficacy of biofeedback interventions to improve physiologic regulation and enhance treatment outcomes for pediatric chronic pain.

Executive Functioning in Pediatric Chronic Pain: Do Deficits Exist?

Objective: Despite ample research documenting deficits in executive functioning for adults with chronic pain, the literature on pediatric patients with chronic pain is limited and provides mixed results. The current study sought to further investigate the nature of executive dysfunction in this population and also examine the relationships between pain intensity, duration, and catastrophizing with sustained attention, working memory, and self- and parent-report of executive functioning. Settings: Pediatric pain clinic and rehabilitation program. Participants: Forty adolescents with chronic pain and their parents participated in this study. Methods: Participants completed neuropsychological measures and standardized self-report questionnaires during a 45- to 60-minute testing session. Results: Fifty percent of this sample of adolescents with chronic pain demonstrated significant difficulties on at least one measure, with nine participants indicating difficulties on multiple measures. Pain significantly increased during the testing session. Pain variables of intensity, duration, and catastrophizing are related to sustained attention and working memory. Conclusions: This study adds support to previous findings suggesting subclinical struggles with executive functioning for adolescents with chronic pain. One-half of the sample indicated difficulties in either sustained attention and/or working memory. Future studies that would more thoroughly examine more complex executive functioning skills in this population would be helpful to further guide multidisciplinary treatment of these patients, particularly regarding whether or not school accommodations are warranted.

Eating Disorders in Adolescents With Chronic Pain.

INTRODUCTION: Given that youth with chronic pain frequently experience disruptions in eating patterns that may place them at risk for disordered eating, the purpose of this study was to examine the clinical characteristics and illness course of adolescents with chronic pain and comorbid eating disorders. METHODS: Using a retrospective chart review, 34 adolescents with chronic pain and concurrent eating disorders were identified. These adolescents were compared with 34 age-, gender-, and eating disorder symptom-matched adolescents who had an eating disorder without chronic pain. RESULTS: The majority of adolescents with chronic pain and an eating disorder had a primary medical diagnosis of abdominal pain (n = 14), followed by autonomic dysfunction (n = 10) and headache (n = 6). Although in 41.2% of teens with chronic pain, eating disorder symptoms developed after the onset of their pain, 35.3% reported having eating disorder symptoms before they experienced chronic pain. Body mass index did not differ between the groups, but the duration of eating disorder symptoms was significantly longer for the chronic pain group (p < .001). DISCUSSION: Despite comparable severity, eating disorders are undetected for longer periods in patients with chronic pain, which may contribute to a poorer prognosis. Implications for eating disorder conceptualization, detection, and treatment are discussed.

Development of an Interdisciplinary Pediatric Pain Rehabilitation Program: The First 1000 Consecutive Patients.

OBJECTIVE: To describe the development of a clinically and financially successful interdisciplinary pediatric pain rehabilitation program at a large tertiary academic medical center and present demographic and clinical information on the first 1000 patients. PATIENTS AND METHODS: All patients who were consecutively admitted to this program between October 1, 2008, and March 31, 2015 were included in this review. The patients ranged in age from 9 to 24 years. The program is a 3-week, hospital-based outpatient treatment program that requires substantial parental involvement. At admission and discharge, patients completed the Center for Epidemiologic Studies of Depression Scale for Children, the Functional Disability Inventory, and the Pain Catastrophizing Scale for Children. Opioid use was also assessed. RESULTS: At admission, patients reported substantial pain-associated disability and depressive symptoms; they had elevated pain catastrophizing scores, and 16% were taking opioids. Primary sites/types of pain included head, abdomen, and generalized. Functional disability scores decreased significantly, from 27 to 9 after the program (P<.001). Depression scale scores improved from 27 to 14 (P<.001). Pain catastrophizing scores decreased significantly, from 26 to 14 (P<.001), at discharge from the program. All but 4 patients successfully tapered off of all opioid use by the conclusion of the program. CONCLUSION: Participation in a multidisciplinary pediatric pain rehabilitation program can be successful, with significant decreases in disability, depression symptoms, and pain catastrophizing, as well as discontinuation of opioid use.

Getting Back to Living: Further Evidence for the Efficacy of an Interdisciplinary Pediatric Pain Treatment Program.

OBJECTIVE: This study examined key functional outcomes following a 3-week interdisciplinary pediatric pain rehabilitation program for adolescents with chronic pain. Maintenance of gains was evaluated at 3-month follow-up. METHODS: Participants included 171 adolescents (12 to 18 y of age) with chronic pain who completed a hospital-based outpatient pediatric pain rehabilitation program. Participants completed measures of functional disability, depressive symptoms, pain catastrophizing, opioid use, school attendance, and pain severity at admission, discharge, and at 3-month follow-up. RESULTS: Similar to other interdisciplinary pediatric pain rehabilitation program outcome studies, significant improvements were observed at the end of the program. These improvements appeared to be maintained or further improved at 3-month follow-up. Nearly 14% of the patients were taking daily opioid medication at admission to the program. All adolescents were completely tapered off of these medications at the end of the 3-week program and remained abstinent at 3-month follow-up. DISCUSSION: This study adds to the available data supporting interdisciplinary pediatric pain rehabilitation as effective in improving functioning and psychological distress even when discontinuing opioids. Implications for future research and limitations of the study are discussed.

Improvement in Functioning and Psychological Distress in Adolescents With Postural Orthostatic Tachycardia Syndrome Following Interdisciplinary Treatment.

Significant functional impairment and psychological distress have been observed in adolescent patients with postural orthostatic tachycardia syndrome (POTS). Interdisciplinary rehabilitation programs have been shown to be beneficial in the treatment of chronic pain in adults and adolescents. Only preliminary data have examined interdisciplinary rehabilitation efforts in patients with POTS. This study evaluated the impact of an interdisciplinary rehabilitation program on the functional impairment and psychological distress in 33 adolescents diagnosed with POTS. Patients included in the study were adolescents ages 11 to 18 diagnosed with POTS. Measures completed at admission and discharge from the program included the Functional Disability Index, Center for Epidemiological Studies-Depression-Child scale, and the Pain Catastrophizing Scale for Children. After participation in the 3-week program, adolescents with POTS demonstrated a significant increase in overall functional ability and significant reductions in depression and catastrophizing.

Interdisciplinary Treatment of Maladaptive Behaviors Associated with Postural Orthostatic Tachycardia Syndrome (POTS): A Case Report.

The prevalence of postural orthostatic tachycardia syndrome (POTS) in adolescents and young adults has been increasing during the past decade. Despite this increase, documentation regarding treatment of these patients is just beginning to emerge. In addition, despite a call for a multidisciplinary or interdisciplinary approach, no studies have examined the efficacy of such an approach to treatment. This paper describes a case study of a 19-year-old male with debilitating POTS seen at a tertiary clinic for evaluation and subsequent intensive interdisciplinary treatment. The treatment approach is described and outcomes are presented.

Pain relief as a primary treatment goal: at what point does functioning and well-being become more important? A case study of an adolescent with debilitating chronic pain.

BACKGROUND: Pediatric chronic pain is a common problem with significant economic implications and devastating consequences on quality of life. The present report describes a case involving a 15-year-old girl with severe and debilitating chronic pain. RESULTS: Before her referral to a pain rehabilitation program, the patient saw numerous specialists who treated her with an aggressive medical regimen and two spinal cord stimulators. She was then referred for intensive interdisciplinary treatment and, after three weeks of rehabilitation, she reported clinically significant changes in anxiety, pain catastrophizing and functional disability. The patient was successfully titrated off all of her opioid medications and, eventually, both neurostimulator implants were removed. DISCUSSION: Interdisciplinary pain rehabilitation is a useful treatment for patients with chronic pain. With its primary emphasis on functional restoration as opposed to strictly pain reduction, patients can regain a higher quality of life with reduced pain and fewer medications, surgeries and hospitalizations.

Management of neonatal abstinence syndrome from opioids.

Most infants at risk for neonatal abstinence syndrome have opioid plus another drug exposure; polypharmacy is the rule rather than the exception. Scales for evaluation of neonatal abstinence syndrome are primarily based for opioid withdrawal. A standard protocol to treat neonatal abstinence syndrome has not been developed. Institute nonpharmacologic strategies for all neonates at risk. The American Academy of Pediatrics recommends mechanism-directed therapy (treat opioid withdrawal with an opioid) as the first-line therapy. Second-line medications are currently under evaluation.