Does This Child With High Blood Pressure Have Secondary Hypertension?: The Rational Clinical Examination Systematic Review.

Importance: Guidelines recommend that all children and adolescents with hypertension undergo evaluation for secondary causes. Identifying clinical factors associated with secondary hypertension may decrease unnecessary testing for those with primary hypertension. Objective: To determine the utility of the clinical history, physical examination, and 24-hour ambulatory blood pressure monitoring for differentiating primary hypertension from secondary hypertension in children and adolescents (aged ≤21 years). Data Sources and Study Selection: The databases of MEDLINE, PubMed Central, Embase, Web of Science, and Cochrane Library were searched from inception to January 2022 without language limits. Two authors identified studies describing clinical characteristics in children and adolescents with primary and secondary hypertension. Data Extraction and Synthesis: For each clinical finding in each study, a 2 × 2 table was created that included the number of patients with and without the finding who had primary vs secondary hypertension. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. Main Outcomes and Measures: Random-effects modeling was used to calculate sensitivity, specificity, and likelihood ratios (LRs). Results: Of 3254 unique titles and abstracts screened, 30 studies met inclusion criteria for the meta-analysis and 23 (N = 4210 children and adolescents) were used for pooling in the meta-analysis. In the 3 studies conducted at primary care clinics or school-based screening clinics, the prevalence of secondary hypertension was 9.0% (95% CI, 4.5%-15.0%). In the 20 studies conducted at subspecialty clinics, the prevalence of secondary hypertension was 44% (95% CI, 36%-53%). The demographic findings most strongly associated with secondary hypertension were family history of secondary hypertension (sensitivity, 0.46; specificity, 0.90; LR, 4.7 [95% CI, 2.9-7.6]), weight in the 10th percentile or lower for age and sex (sensitivity, 0.27; specificity, 0.94; LR, 4.5 [95% CI, 1.2-18]), history of prematurity (sensitivity range, 0.17-0.33; specificity range, 0.86-0.94; LR range, 2.3-2.8), and age of 6 years or younger (sensitivity range, 0.25-0.36; specificity range, 0.86-0.88; LR range, 2.2-2.6). Laboratory studies most associated with secondary hypertension were microalbuminuria (sensitivity, 0.13; specificity, 0.99; LR, 13 [95% CI, 3.1-53]) and serum uric acid concentration of 5.5 mg/dL or lower (sensitivity range, 0.70-0.73; specificity range, 0.65-0.89; LR range, 2.1-6.3). Increased daytime diastolic blood pressure load combined with increased nocturnal systolic blood pressure load on 24-hour ambulatory blood pressure monitoring was associated with secondary hypertension (sensitivity, 0.40; specificity, 0.82; LR, 4.8 [95% CI, 1.2-20]). Findings associated with a decreased likelihood of secondary hypertension were asymptomatic presentation (LR range, 0.19-0.36), obesity (LR, 0.34 [95% CI, 0.13-0.90]), and family history of any hypertension (LR, 0.42 [95% CI, 0.30-0.57]). Hypertension stage, headache, and left ventricular hypertrophy did not distinguish secondary from primary hypertension. Conclusions and Relevance: Family history of secondary hypertension, younger age, lower body weight, and increased blood pressure load using 24-hour ambulatory blood pressure monitoring were associated with a higher likelihood of secondary hypertension. No individual sign or symptom definitively differentiates secondary hypertension from primary hypertension.

Elevated tacrolimus levels after treatment with nirmatrelvir/ritonavir (Paxlovid) for COVID-19 infection in a child with a kidney transplant.

BACKGROUND: Paxlovid (nirmatrelvir/ritonavir) is a novel drug available under emergency use authorization by the Food and Drug Administration for the treatment of COVID-19 infection. Tacrolimus, a calcineurin inhibitor, is commonly used as an immunosuppressant medication in children with kidney transplants. While tacrolimus is metabolized by the cytochrome P450 system (CYP3A4), ritonavir is a potent CYP3A4 inhibitor. There is a paucity of data regarding the drug-drug interaction between nirmatrelvir/ritonavir and tacrolimus in children with kidney transplants. CASE-DIAGNOSIS/TREATMENT: This is a case report of a 14-year-old female with a history of a kidney transplant, maintained on tacrolimus and prednisone, who starts nirmatrelvir/ritonavir for a COVID-19 infection. She subsequently develops supratherapeutic tacrolimus levels and an increase in serum creatinine. Her tacrolimus was held, and the nirmatrelvir/ritonavir was stopped. Over time, her kidney function returned to baseline, her tacrolimus levels returned to the therapeutic goal, and her tacrolimus was resumed. CONCLUSIONS: Our case report highlights the strong interaction with concomitant use of tacrolimus and nirmatrelvir/ritonavir in a pediatric kidney transplant recipient and the development of supratherapeutic tacrolimus levels. Providers should therefore be cautious when prescribing nirmatrelvir/ritonavir to a pediatric patient currently on tacrolimus.

Prevalence of Secondary Hypertension in Otherwise Healthy Youths with a New Diagnosis of Hypertension: A Meta-Analysis.

OBJECTIVE: To estimate the prevalence of secondary hypertension among otherwise healthy children with hypertension diagnosed in the outpatient setting. STUDY DESIGN: The MEDLINE, PubMed Central, Embase, Web of Science, and Cochrane Library databases were systematically searched for observational studies reporting the prevalence of secondary hypertension in children who underwent evaluation for hypertension and had no known comorbidities associated with hypertension at the time of diagnosis. Two authors independently extracted the study-specific prevalence of secondary hypertension in children evaluated for hypertension. Prevalence estimates for secondary hypertension were pooled in a random-effects meta-analysis. RESULTS: Nineteen prospective studies and 7 retrospective studies including 2575 children with hypertension were analyzed, with a median of 65 participants (range, 9-486) in each study. Studies conducted in primary care or school settings reported a lower prevalence of secondary hypertension (3.7%; 95% CI, 1.2%-7.2%) compared with studies conducted in referral clinics (20.1%; 95% CI, 11.5%-30.3%). When stratified by study setting, there were no significant subgroup differences according to study design, country, participant age range, hypertension definition, blood pressure device, or study quality. Although the studies applied different approaches to diagnosing secondary hypertension, diagnostic evaluations were at least as involved as the limited testing recommended by current guidelines. CONCLUSIONS: The low prevalence of secondary hypertension among children with a new diagnosis of hypertension identified on screening reinforces clinical practice guidelines to avoid extensive testing in the primary care setting for secondary causes in most children with hypertension.

A pilot, feasibility, randomised controlled trial of midodrine as adjunctive vasopressor for low-dose vasopressor-dependent hypotension in intensive care patients: The MAVERIC study.

PURPOSE: To assess the feasibility and physiological efficacy of adjunctive midodrine in patients with vasopressor-dependent hypotension. MATERIALS AND METHODS: This was a pilot, open label, randomised controlled trial. Patients were enrolled from two tertiary intensive care units on low dose intravenous vasopressor therapy for more than 24 h. We randomly assigned patients to receive either adjunctive midodrine (10 mg every 8 h) or usual care. The primary efficacy outcome was time to cessation of intravenous vasopressor therapy. Secondary outcomes included protocol compliance, ICU and hospital length of stay. RESULTS: We screened 381 patients over 22-months and enrolled 62 (32 in midodrine group, 30 in usual care group). Median time to cessation of vasopressor infusion was 16.5 h for midodrine vs 19 h for usual care (p = 0.22). Time in ICU (50 [25.50, 74.00] hours for midodrine v 59 [38.50, 93.25] hours for usual care, p = 0.14) and hospital length of stay (9 days vs. 7.5 days, p = 0.92) were similar. Protocol compliance was 96.9%. One patient ceased midodrine early due to symptomatic bradycardia. CONCLUSIONS: Adjunctive midodrine therapy was feasible with acceptable compliance, duration of therapy, and safety profile. However, at the chosen dose, there was no evidence of physiological or clinical efficacy.

Development and Implementation of a Chief Resident for Research Role in a Psychiatry Residency Training Program.

Psychiatry residency programs with robust research training can prepare physician-scientists to make contributions that advance the mental health field. Our psychiatry residency developed a chief resident for research position to help provide mentorship, community building, and advising around scholarly activities for residents. We present the process of implementing this new position in our residency to offer a model for engaging psychiatry residents in research.

A Rare and Extreme Case of Vulvar Swelling in the Setting of Nephrotic Syndrome in a Prepubertal Girl.

BACKGROUND: We present a rare case of severe vulvar edema secondary to steroid-refractory nephrotic syndrome in a prepubertal girl. CASE: The patient is an 8-year-old girl who presented during nephrotic syndrome relapse. She exhibited severe mons pubis and labial edema. She was treated with local symptomatic measures such as sitz baths, barrier ointment, and labial sling, with minimal relief. Improvement ultimately occurred after bilateral nephrectomy. SUMMARY AND CONCLUSION: Vulvar edema is rare in prepubertal girls. In this case, the edema was secondary to steroid-refractory nephrotic syndrome and was not responsive to local treatment measures. There is a paucity of data on effective treatment of vulvar edema in young girls. Our goal is to raise awareness of such pathology, which might lead to development of uniform guidelines for treatment of this condition.

Embedded Maternal Mental Health Care in a Pediatric Primary Care Clinic: A Qualitative Exploration of Mothers' Experiences.

OBJECTIVE: The American Academy of Pediatrics recommends screening parents for postpartum depression during pediatric primary care visits. Unfortunately, many women who screen positive do not obtain treatment. Providing mental health services for women in the same location as their children's primary care may facilitate treatment, but few such clinics exist. We designed a qualitative study to evaluate women's perceptions and experiences with receiving mental health services from psychiatrists embedded in a safety-net pediatric primary care clinic. METHODS: Semistructured interviews were conducted with women receiving mental health care from embedded psychiatrists in a safety-net pediatric clinic. Data were analyzed using an inductive approach. RESULTS: Twenty women participated. Five major themes emerged: 1) barriers to maternal mental health care, including psychiatric symptoms impairing access, stigma, and fear of Child Protective Services; 2) benefits of embedded care, including convenience, low barrier to entry and trust; 3) motherhood as facilitator to care, with early motherhood described as a time of vulnerability to relapse; 4) focus on parenting, including appreciation for parenting skills and normalization of the mothering experience; 5) treatment modality preferences, including concerns about medications and a preference for psychotherapy. CONCLUSIONS: Postpartum women face many barriers to psychiatric care. Mental health care embedded within the pediatric setting lowers barriers to care during this critical period. These insights should inform further collaboration between adult psychiatrists and pediatric care providers.

The effect of early child care attendance on childhood asthma and wheezing: A meta-analysis.

OBJECTIVE: Research evidence offers mixed results regarding the relationship between early child care attendance and childhood asthma and wheezing. A meta-analysis was conducted to synthesize the current research evidence of the association between early child care attendance and the risk of childhood asthma and wheezing. METHOD: Peer reviewed studies published from 1964-January 2017 were identified in MEDLINE, CINAL, and EMBASE using MeSH headings relevant to child care and asthma. Two investigators independently reviewed the selected articles from this search. All relevant articles that met our inclusion criteria were selected for further analysis. Data were extracted from studies that had sufficient data to analyze the odds of asthma or wheezing among children who attended child care. RESULTS: The meta-analysis of 32 studies found that (1) early child care attendance is protective against asthma in children 3-5 years of age but not for children with asthma 6 years of age or older. (2) Early child care attendance increases the risk of wheezing among children 2 years of age or younger, but not the risk of wheezing for children over 2 years of age. CONCLUSIONS: This meta-analysis shows that early child care attendance is not significantly associated with the risk of asthma or wheeze in children 6 years of age or older.

Misclassification of self-reported smoking in adult survivors of childhood cancer.

We investigated misclassification rates, sensitivity, and specificity of self-reported cigarette smoking through serum cotinine concentration (liquid chromatography tandem mass spectrometry) among 287 adult survivors of childhood cancer. Overall, 2.5-6.7% and 19.7-36.9% of the self-reported never and past smokers had cotinine levels indicative of active smoking. Sensitivity and specificity of self-reported smoking were 57.5-67.1% and 96.6-99.2%. Misclassification was associated with younger age (OR = 3.2; 95% CI = 1.4-7.4), male (OR = 2.1; 95% CI = 1.1-4.0), and past (OR = 2.7; 95% CI = 1.3-5.8) or current (OR = 2.6; 95% CI = 1.0-6.6) marijuana use. After adjusting for tobacco-related variables, current marijuana use remained a significant risk for misclassification. Clinicians/researchers should consider bio-verification to measure smoking status among survivors.

San Francisco childcare centers' preparedness in the prevention and management of asthma among preschool-aged children.

INTRODUCTION: Asthma is a common health condition for children in childcare. National recommendations for asthma in childcare exist. However, no studies have investigated the extent to which childcare centers adhere to these recommendations. We aimed to assess childcare center adherence to National Asthma Education and Prevention Program (NAEPP) recommendations for asthma care and preparedness and to identify characteristics associated with increased adherence to national asthma recommendations. METHODS: We developed a standardized instrument. Each childcare center received a score of 0 through 7 based on number of recommendations met. We conducted t-tests, chi square tests and linear regression to identify childcare center factors associated with increased asthma preparedness. RESULTS: 36 out of 40 eligible childcare centers (90%) participated. These sites served 1570 children primarily between the ages of 2 to 5 years. On average, centers met 3.8 out of 7 (SD = 1.3) recommendations. Staff familiarity caring for children with asthma (p < 0.001) and the center's asthma prevalence (p = 0.01) was positively associated with the center's asthma preparedness. The 3 areas most in need of improvement related to asthma medications, asthma action plans and asthma policies. None of the managers reported being familiar with the NAEPP recommendations. DISCUSSION: There is room for improvement in the asthma care and preparedness of childcare centers. The 3 areas in which centers performed poorly (appropriate asthma medication management, use of asthma action plans, and presence of appropriate asthma policies) suggest that closer collaboration between clinicians and childcare centers may be a key to improving asthma management for young children.

Characterization of gait and olfactory behaviors in the Balb/c mouse model of autism spectrum disorders.

Abnormalities of gait and olfaction have been reported in persons with autism spectrum disorders (ASDs), which could reflect involvement of the cerebellum and nodes related to olfaction (e.g., olfactory bulb and ventral temporal olfactory cortex) in neural circuits subserving social, cognitive, and motor domains of psychopathology in these disorders. We hypothesized that the Balb/c mouse model of ASD would express "abnormalities" of gait and olfaction, relative to the Swiss Webster comparator strain. Contrary to expectation, Balb/c and Swiss Webster mice did not differ in terms of quantitative measurements of gait and mouse rotarod behavior, and Balb/c mice displayed a shorter latency to approach an unscented cotton swab, suggesting that there was no disturbance of its locomotor behavior. However, Balb/c mice showed significant inhibition of locomotor activity in the presence of floral scents, including novel and familiar floral scents, and a socially salient odor (i.e., concentrated mouse urine); the inhibitory effect on the locomotor behavior of the Balb/c mouse was especially pronounced with the salient social odor. Unlike the Swiss Webster strain, mouse urine lacks social salience for the Balb/c mouse strain, a model of ASD, which does not appear to be an artifact of diminished olfactory sensitivity or impaired locomotion.

Development of a Tool to Evaluate Asthma Preparedness and Management in Child-Care Centers.

Introduction: Asthma is a common condition affecting many children in child-care centers. The National Asthma Education and Prevention Program offers recommendations about creating an asthma-friendly child-care setting. However, no studies have investigated the extent to which child-care centers adhere to these recommendations. This study describes the development of a novel instrument to determine the ability of child-care centers to meet national recommendations for asthma. Methods: The Preparing for Asthma in Child Care (PACC) Instrument was developed using information from existing recommendations and standards, the peer-reviewed literature, site visits, and expert interviews. The survey questions were pilot-tested at 36 child-care centers throughout San Francisco. Results: The instrument is composed of 43 items across seven domains: smoking exposure, presence of a medical consultant and policies, management of ventilation and triggers, access to medication, presence of asthma action plans, staff training, and encouragement of physical activity. Discussion: The PACC Instrument is an evidence-based and comprehensive tool designed to identify areas to target to improve asthma care for children in child-care centers.

Novel nanocomposite biomaterial to differentiate bone marrow mesenchymal stem cells to the osteogenic lineage for bone restoration.

BACKGROUND/OBJECTIVE: As the bone engineering field moves away from nonviable implants to more biocompatible and natural structures, nanomedicine has emerged as a superior tool for developing implantable materials. METHODS: Here, we describe the fabrication and testing of a nanocomposite structure composed of chitosan and a biocompatible thermoplastic (PMMA). RESULTS: Our nanocomposite material displayed morphologically similar characteristics to an extracted murine femur during microscopic and spectroscopic analysis as seen through SEM and FTIR. Crosslinking our nanocomposite enhanced structural and strength characteristics significantly above the noncrosslinked sample, mimicking the strength of an extracted mammalian bone. When cocultured with bone marrow mesenchymal stem cells, the composite material proved to be osteoinductive and osteogenic via DAPI and actin staining, differentiating BMSCs into the osteogenic lineage and promoting mineral deposition. Nodule formation, indicative of mineralization during BMSC differentiation, was confirmed spectroscopically via FTIR and autofluorescence of the nodule. CONCLUSION: These encouraging results show promise for in vivo implantation of our novel scaffold that is both biocompatible and biomimetic in strength and composition.

Mixing an energy drink with an alcoholic beverage increases motivation for more alcohol in college students.

BACKGROUND: There has been a dramatic rise in the consumption of alcohol mixed with energy drinks (AmEDs) in social drinkers. It has been suggested that AmED beverages might lead individuals to drink greater quantities of alcohol. This experiment was designed to investigate whether the consumption of AmEDs would alter alcohol priming (i.e., increasing ratings of wanting another drink) compared with alcohol alone. METHODS: Participants (n = 80) of equal gender attended 1 session where they were randomly assigned to receive 1 of 4 doses (0.91 ml/kg vodka, 1.82 ml/kg energy drink, 0.91 ml/kg vodka mixed with 1.82 ml/kg energy drink [AmED], or a placebo beverage). Alcohol-induced priming of the motivation to drink was assessed by self-reported ratings on the Desire for Drug questionnaire. RESULTS: The priming dose of alcohol increased the subjective ratings of "desire" for more alcohol, consistent with previous research that small doses of alcohol can increase the motivation to drink. Furthermore, higher desire ratings over time were observed with AmEDs compared with alcohol alone. Finally, ratings of liking the drink were similar for the alcohol and AmED conditions. CONCLUSIONS: An energy drink may elicit increased alcohol priming. This study provides laboratory evidence that AmED beverages may lead to greater motivation to drink versus the same amount of alcohol consumed alone.

Preparing Interns for Anesthesiology Residency Training: Development and Assessment of the Successful Transition to Anesthesia Residency Training (START) E-Learning Curriculum.

BACKGROUND: The transition from internship to residency training may be a stressful time for interns, particularly if it involves a change among programs or institutions after completing a preliminary year. OBJECTIVE: We explored whether an e-learning curriculum would increase interns' preparedness for the transition to the first year of clinical anesthesiology training and reduce stress by improving confidence and perceived competence in performing professional responsibilities. INTERVENTION: We tested a 10-month e-learning program, Successful Transition to Anesthesia Residency Training (START), as a longitudinal intervention to increase interns' self-perceived preparedness to begin anesthesiology residency training in a prospective, observational study and assessed acceptance and sustainability. After a needs assessment, we administered the START modules to 22 interns, once a month, using an integrated learning management and lecture-capture system. We surveyed interns' self-assessed preparedness to begin anesthesiology residency before and after completing the START modules. Interns from the prior year's class, who did not participate in the online curriculum, served as controls. RESULTS: After participation in the START intervention, self-assessed preparedness to begin residency improved by 72% (P  =  .02). Interns also felt more connected to, and had improved positive feelings toward, their new residency program and institution. CONCLUSION: Participation in our novel 10-month e-learning curriculum and virtual mentorship program improved interns' impression of their residency program and significantly increased interns' subjective assessment of their preparedness to begin anesthesiology residency. This e-learning concept could be more broadly applied and useful to other residency programs.

Analgesic tolerance without demonstrable opioid-induced hyperalgesia: a double-blinded, randomized, placebo-controlled trial of sustained-release morphine for treatment of chronic nonradicular low-back pain.

Although often successful in acute settings, long-term use of opioid pain medications may be accompanied by waning levels of analgesic response not readily attributable to advancing underlying disease, necessitating dose escalation to attain pain relief. Analgesic tolerance, and more recently opioid-induced hyperalgesia, have been invoked to explain such declines in opioid effectiveness over time. Because both phenomena result in inadequate analgesia, they are difficult to distinguish in a clinical setting. Patients with otherwise uncomplicated low-back pain were titrated to comfort or dose-limiting side effects in a prospective, randomized, double-blind, placebo-controlled clinical trial using sustained-release morphine or weight-matched placebo capsules for 1 month. A total of 103 patients completed the study, with an average end titration dose of 78 mg morphine/d. After 1 month, the morphine-treated patients developed tolerance to the analgesic effects of remifentanil, but did not develop opioid-induced hyperalgesia. On average, these patients experienced a 42% reduction in analgesic potency. The morphine-treated patients experienced clinically relevant improvements in pain relief, as shown by a 44% reduction in average visual analogue scale pain levels and a 31% improvement in functional ability. The differences in visual analogue scale pain levels (P = .003) and self-reported disability (P = .03) between both treatment groups were statistically significant. After 1 month of oral morphine therapy, patients with chronic low-back pain developed tolerance but not opioid-induced hyperalgesia. Improvements in pain and functional ability were observed.

Modulation of remifentanil-induced postinfusion hyperalgesia by the ß-blocker propranolol in humans.

Acute and chronic exposure to opioids has been associated with hyperalgesia in both animals and humans. A genetic analysis of opioid-induced hyperalgesia in mice linked the ß(2)-adrenergic receptor to mechanical sensitization after opioid exposure. In humans, expansion of the area of mechanical hyperalgesia surrounding an experimentally induced lesion after the cessation of remifentanil infusion is a commonly used model of opioid hyperalgesia (remifentanil-induced postinfusion hyperalgesia, RPH). The purpose of our translational study was to test the hypothesis that the ß-adrenergic receptor antagonist propranolol modulates the expression of RPH in humans. This double-blinded, randomized, placebo-controlled, crossover study was performed in 10 healthy human volunteers. During test sessions, intracutaneous electrical stimulation was used to generate areas of secondary mechanical hyperalgesia. The area of this sensitization was measured before, during, and after remifentanil infusion. Heat pain sensitivity was also followed. During one test session, subjects received propranolol infusion. We observed an average increase in the areas of secondary mechanical hyperalgesia to 141% of the baseline in subjects infused with remifentanil and placebo (P=0.00040). However, when remifentanil infusion was combined with propranolol, the area of secondary hyperalgesia after terminating remifentanil was not significantly different than the area before beginning the opioid infusion (P=0.13). Thermal hyperalgesia was not observed after remifentanil infusion. Propranolol infusion at the selected dose had minor hemodynamic effects. Concomitant infusion of propranolol with remifentanil prevented the expression of RPH. ß-adrenergic receptor blockade may be a useful pharmacological strategy for preventing hyperalgesia in patients exposed to opioids.

Effects of energy drinks mixed with alcohol on information processing, motor coordination and subjective reports of intoxication.

The consumption of alcohol mixed with energy drinks (AmED) has become a popular and controversial practice among young people. Increased rates of impaired driving and injuries have been associated with AmED consumption. The purpose of this study was to examine if the consumption of AmED alters cognitive processing and subjective measures of intoxication compared with the consumption of alcohol alone. Eighteen participants (nine men and nine women) attended four test sessions where they received one of four doses in random order (0.65 g/kg alcohol, 3.57 ml/kg energy drink, AmED, or a placebo beverage). Performance on a psychological refractory period (PRP) task was used to measure dual-task information processing and performance on the Purdue pegboard task was used to measure simple and complex motor coordination following dose administration. In addition, various subjective measures of stimulation, sedation, impairment, and level of intoxication were recorded. The results indicated that alcohol slowed dual-task information processing and impaired simple and complex motor coordination. The coadministration of the energy drink with alcohol did not alter the alcohol-induced impairment on these objective measures. For subjective effects, alcohol increased various ratings indicative of feelings of intoxication. More importantly, coadministration of the energy drink with alcohol reduced perceptions of mental fatigue and enhanced feelings of stimulation compared to alcohol alone. In conclusion, AmED may contribute to a high-risk scenario for a drinker. The mix of behavioral impairment with reduced fatigue and enhanced stimulation may lead AmED consumers to erroneously perceive themselves as better able to function than is actually the case.

The endogenous opioid system is not involved in modulation of opioid-induced hyperalgesia.

UNLABELLED: Some recent studies suggested a role of the endogenous opioid system in modulating opioid-induced hyperalgesia (OIH). In order to test this hypothesis, we conducted a prospective randomized, placebo-controlled, 2-way crossover study in healthy human volunteers. We utilized a well-established model of inducing OIH after a brief exposure to the µ-opioid agonist remifentanil using intradermal electrical stimulation. Patients were exposed to a randomized 90-minute infusion of remifentanil or saline placebo during 2 separate occasions. Development of OIH was quantified using changes in the average radius of the area of secondary hyperalgesia generated by electrical pain stimulation. A 23.6% (20.2) increase in area of secondary hyperalgesia over baseline was observed in the postinfusion period of the remifentanil session, demonstrating development of OIH (P = .03). In order to test endogenous opioid system modulation of OIH, patients were given a 1-time bolus of naloxone, which had no effect on the size of the hyperalgesic lesion in either the remifentinal or placebo session. These results suggested that the endogenous opioid system did not appear to modulate OIH. PERSPECTIVE: Experimental evidence suggested that the endogenous opioid system did not significantly affect opioid-induced hyperalgesia. Consequently, this study suggested that alternative mechanisms such as pronociceptive stimulation and neuroplastic changes might be responsible for expression of OIH.