Ian Carroll, MD, MS

All Publications

• A causative role for remote dural puncture and resultant arachnoid bleb in new daily persistent headache: A case report. Headache Callen, A. L., Lennarson, P., Carroll, I. R. 2023

  Abstract

  A 24-year-old woman experienced a postdural puncture headache following a labor epidural, recovered following bedrest, and was then without headache for 12years. She then experienced sudden onset of daily, holocephalic headache persisting for 6years prior to presentation. Pain reduced with prolonged recumbency. MRI brain, MRI myelography, and later bilateral decubitus digital subtraction myelography showed no cerebrospinal fluid (CSF) leak or CSF venous fistula, and normal opening pressure. Review of an initial noncontrast MRI myelogram revealed a subcentimeter dural outpouching at L3-L4, suspicious for a posttraumatic arachnoid bleb. Targeted epidural fibrin patch at the bleb resulted in profound but temporary symptom relief, and the patient was offered surgical repair. Intraoperatively, an arachnoid bleb was discovered and repaired followed by remission of headache. We report that a distant dural puncture can play a causative role in the long delayed onset of new daily persistent headache.

  View details for DOI 10.1111/head.14584

  View details for PubMedID 37358488

• Relationship of Bern Score, Spinal Elastance, and Opening Pressure in Patients With Spontaneous Intracranial Hypotension. Neurology Callen, A., Pattee, J., Thaker, A. A., Timpone, V. M., Zander, D., Turner, R., Birlea, M., Wilhour, D., O'Brien, C., Evan, J., Grassia, F., Carroll, I. 2023

  Abstract

  Existing tools to diagnose spontaneous intracranial hypotension (SIH), namely spinal opening pressure (OP) and brain MRI, have limited sensitivity. We investigated whether evaluation of brain MRI using the Bern Score, combined with calculated craniospinal elastance, would aid in diagnosing SIH and provide insight into its pathophysiology.A retrospective chart review was performed of patients who underwent brain MRI and pressure-augmented dynamic CT myelography (dCTM) for suspicion of SIH. Two blinded Neuroradiologists assigned Bern Scores for each brain MRI. OP and incremental pressure changes after intrathecal saline infusion were recorded to calculate craniospinal elastance. The relationship between Bern Score, OP, elastance, and whether a leak was found were analyzed.72 consecutive dCTMs were performed in 53 patients. 12 CSF-venous fistulae, two ruptured meningeal diverticula, two dural defects, and one dural bleb were found (17/53=32%). Among patients with imaging proven CSF leak/fistula, OP was normal in all but one patient, and was not significantly different in those with a leak compared to those without (15.1 vs 13.6 cm H2O, p = 0.24, A=0.40). Average Bern Score in individuals with a leak was significantly higher than in those without (5.35 vs 1.85, p < 0.001, A=0.85), even when excluding pachymeningeal enhancement from the score (3.77 vs 1.57, p = 0.001, A=0.78). Average elastance in those with a leak was higher than in those without, but this difference was not statistically significant (2.05 vs 1.20 mL/cm H2O, p = 0.19, A=0.40). Increased elastance was significantly associated with an increased Bern Score (p < 0.01, 95% CI -0.55, 0.12), and was significantly associated with venous distention, pachymeningeal enhancement, prepontine narrowing, and subdural collections, but not a narrowed mamillopontine or suprasellar distance.OP is not an effective predictor for diagnosing CSF leak, and if used in isolation would result in misdiagnosis of 94% of patients in our cohort. The Bern Score was associated with a higher diagnostic yield of dCTM. Elastance was significantly associated with certain components of the Bern Score.

  View details for DOI 10.1212/WNL.0000000000207267

  View details for PubMedID 37015821

• Phase Contrast Spine MRI for the Evaluation of CSF Leak, and Why It Matters. Neurology Carroll, I., Callen, A. 2022

  View details for DOI 10.1212/WNL.0000000000201694

  View details for PubMedID 36357186

• Popping the balloon. Headache Carroll, I. 1800

  View details for DOI 10.1111/head.14262

  View details for PubMedID 35084740

• Pearls and Oy-sters: Dural defect repair as treatment for refractory headache from CSF leak. Neurology Chan, T. L., Kim, D. D., Hashmi, S., Carrol, I. 2020

  View details for DOI 10.1212/WNL.0000000000010476

  View details for PubMedID 32753442

• Cerebrospinal Fluid Leak in the context of Pars Interarticularis Fracture: A Case Series Chan, L., Cowan, R., Hindiyeh, N., Hashmi, S., Lanzman, B., Carroll, I. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058001010

• Abnormal [18F]FDG PET MRI Findings in Paraspmal Muscles of Patients with Suspected Cerebrospinal Fluid Leak Cipriano, P., Yoon, D., Carroll, I., Penticuff, R., Xu, Y., Biswal, S. SOC NUCLEAR MEDICINE INC. 2019

  View details for Web of Science ID 000473116800095

• Correlation Between Ehlers-Danlos Syndrome (EDS), Spontaneous and Cerebral Spinal Fluid (CSF) Leaks, and GI Motility Disorders Schoenfeld, E., Hendler, S., Carroll, I., Linda Anh Nguyen NATURE PUBLISHING GROUP. 2017: S1397

  View details for Web of Science ID 000439259006163

• Sympathetic Block with Botulinum Toxin to Treat Complex Regional Pain Syndrome ANNALS OF NEUROLOGY Carroll, I., Clark, J. D., Mackey, S. 2009; 65 (3): 348-351

  Abstract

  Complex regional pain syndrome is a refractory pain condition with few tested therapies. We hypothesized that botulinum toxin A (BTA) would prolong analgesia after sympathetic blocks in patients with complex regional pain syndrome. We compared the duration of standard lumbar sympathetic block (LSB) with bupivacaine to LSB with bupivacaine and BTA in nine patients with refractory complex regional pain syndrome. Median time to analgesic failure was 71 (95% confidence interval, 12-253) days after LSB with BTA compared with fewer than 10 days (95% confidence interval, 0-12) after standard LSB (log-rank, p < 0.02). BTA profoundly prolonged the analgesia from sympathetic block in this preliminary study.

  View details for DOI 10.1002/ana.21601

  View details for PubMedID 19334078

• Preoperative Versus Perioperative Risk Factors for Delayed Pain and Opioid Cessation After Total Joint Arthroplasty: A Prospective Cohort Study. Pain and therapy Hah, J. M., Vialard, J. D., Efron, B., Mackey, S. C., Carroll, I. R., Amanatullah, D. F., Narasimhan, B., Hernandez-Boussard, T. 2023

  Abstract

  The evolution of pre- versus postoperative risk factors remains unknown in the development of persistent postoperative pain and opioid use. We identified preoperative versus comprehensive perioperative models of delayed pain and opioid cessation after total joint arthroplasty including time-varying postoperative changes in emotional distress. We hypothesized that time-varying longitudinal measures of postoperative psychological distress, as well as pre- and postoperative use of opioids would be the most significant risk factors for both outcomes.A prospective cohort of 188 patients undergoing total hip or knee arthroplasty at Stanford Hospital completed baseline pain, opioid use, and emotional distress assessments. After surgery, a modified Brief Pain Inventory was assessed daily for 3 months, weekly thereafter up to 6 months, and monthly thereafter up to 1 year. Emotional distress and pain catastrophizing were assessed weekly to 6 months, then monthly thereafter. Stepwise multivariate time-varying Cox regression modeled preoperative variables alone, followed by all perioperative variables (before and after surgery) with time to postoperative opioid and pain cessation.The median time to opioid and pain cessation was 54 and 152 days, respectively. Preoperative total daily oral morphine equivalent use (hazard ratio-HR 0.97; 95% confidence interval-CI 0.96-0.98) was significantly associated with delayed postoperative opioid cessation in the perioperative model. In contrast, time-varying postoperative factors: elevated PROMIS (Patient-Reported Outcomes Measurement Information System) depression scores (HR 0.92; 95% CI 0.87-0.98), and higher Pain Catastrophizing Scale scores (HR 0.85; 95% CI 0.75-0.97) were independently associated with delayed postoperative pain resolution in the perioperative model.These findings highlight preoperative opioid use as a key determinant of delayed postoperative opioid cessation, while postoperative elevations in depressive symptoms and pain catastrophizing are associated with persistent pain after total joint arthroplasty providing the rationale for continued risk stratification before and after surgery to identify patients at highest risk for these distinct outcomes. Interventions targeting these perioperative risk factors may prevent prolonged postoperative pain and opioid use.

  View details for DOI 10.1007/s40122-023-00543-9

  View details for PubMedID 37556071

  View details for PubMedCentralID 7317603

• Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial (vol 153, pg 303, 2018) JAMA SURGERY Hah, J., Mackey, S. C., Schmidt, P. 2022; 157 (6): 553

  View details for DOI 10.1001/jamasurg.2022.1392

  View details for Web of Science ID 000809213600033

• Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial (vol 153, pg 303, 2018) JAMA SURGERY Hah, J., Mackey, S. C., Schmidt, P. 2022

  View details for DOI 10.1001/jamasurg.2017.4915

  View details for Web of Science ID 000784959200002

• Prescription quantity and duration predict progression from acute to chronic opioid use in opioid-naive Medicaid patients. PLOS digital health Johnson, D. G., Ho, V. T., Hah, J. M., Humphreys, K., Carroll, I., Curtin, C., Asch, S. M., Hernandez-Boussard, T. 2022; 1 (8)

  Abstract

  Opiates used for acute pain are an established risk factor for chronic opioid use (COU). Patient characteristics contribute to progression from acute opioid use to COU, but most are not clinically modifiable. To develop and validate machine-learning algorithms that use claims data to predict progression from acute to COU in the Medicaid population, Adult opioid naive Medicaid patients from 6 anonymized states who received an opioid prescription between 2015 and 2019 were included. Five machine learning (ML) Models were developed, and model performance assessed by area under the receiver operating characteristic curve (auROC), precision and recall. In the study, 29.9% (53820/180000) of patients transitioned from acute opioid use to COU. Initial opioid prescriptions in COU patients had increased morphine milligram equivalents (MME) (33.2 vs. 23.2), tablets per prescription (45.6 vs. 36.54), longer prescriptions (26.63 vs 24.69 days), and higher proportions of tramadol (16.06% vs. 13.44%) and long acting oxycodone (0.24% vs 0.04%) compared to non- COU patients. The top performing model was XGBoost that achieved average precision of 0.87 and auROC of 0.63 in testing and 0.55 and 0.69 in validation, respectively. Top-ranking prescription-related features in the model included quantity of tablets per prescription, prescription length, and emergency department claims. In this study, the Medicaid population, opioid prescriptions with increased tablet quantity and days supply predict increased risk of progression from acute to COU in opioid-naive patients. Future research should evaluate the effects of modifying these risk factors on COU incidence.

  View details for DOI 10.1371/journal.pdig.0000075

  View details for PubMedID 36203857

• Association of Postoperative Opioid Misuse with Prolonged Postoperative Pain, Opioid Use, and Delayed Recovery Nwaneshiudu, C., Cramer, E., Mackey, S., Carroll, I., Hah, J. LIPPINCOTT WILLIAMS & WILKINS. 2021: 634

  View details for Web of Science ID 000752526600276

• Acute Pain Predictors of Remote Postoperative Pain Resolution After Hand Surgery. Pain and therapy Hah, J. M., Nwaneshiudu, C. A., Cramer, E. M., Carroll, I. R., Curtin, C. M. 2021

  Abstract

  INTRODUCTION: Chronic postsurgical pain (CPSP) is a global issue with high prevalence. This study compared acute pain descriptors among patients undergoing carpal tunnel release (CTR) or trigger finger release (TFR). We hypothesized worst pain intensity on postoperative day (POD) 10 would be best to predict the time to pain resolution.METHODS: In this secondary analysis of a negative, randomized, double-blind placebo-controlled trial, adult veterans undergoing CTR or TFR were enrolled January 2012-January 2014, with data analysis February 2020-October 2020. Participants were randomized to receive minocycline 200mg or placebo 2 h prior to the operation, then minocycline 100mg or placebo twice daily for 5days. The Brief Pain Inventory, assessed daily, captured three pain scores: average and worst pain over the past 24h, and current pain intensity. Fifteen acute pain descriptors based on the pain scores (clusters, mean, median, pain scores on POD 10, and linear slopes) were compared as predictors of time to pain resolution.RESULTS: Of 131 randomized participants, 114 (83 CTR, 31 TFR) were included. Average pain over the last 24h reported on POD 10 best predicted time to pain cessation. Every one-point increase in the average pain score was associated with a 36.0% reduced rate of pain cessation (HR, 0.64, 95% CI 0.55-0.74, p<0.001). Average pain on POD 10 was significantly associated with the development of CPSP at 90days (OR 1.74, 95% CI 1.30-2.33, pvalue<0.001). The optimal cutoff score for the high-risk group was determined as average pain on POD 10≥3.CONCLUSIONS: This study validates prior work and demonstrates the importance of assessing pain severity on POD 10 to identify patients at high risk for CPSP who are most likely to benefit from early pain intervention. Future research in diverse surgical cohorts is needed to further validate pain assessment on POD 10 as a significant predictor of CPSP.

  View details for DOI 10.1007/s40122-021-00263-y

  View details for PubMedID 33870479

• Cerebellar tonsillar descent: A diagnostic dilemma between Chiari malformation type 1 and spinal cerebrospinal fluid leak. Heliyon Chan, T. L., Vuong, K., Chugh, T., Carroll, I. 2021; 7 (4): e06795

  Abstract

  Cerebellar tonsillar descent can be seen on head magnetic resonance imaging in both Chiari malformation type 1 and spinal cerebrospinal fluid leak creating the potential for misdiagnosis. We report five cases of spinal cerebrospinal fluid leak at Stanford University initially misdiagnosed and treated as Chiari malformation type 1 based on cerebellar tonsillar descent demonstrated on imaging. All five cases had sustained relief at the 6-month follow up visit from epidural blood patches for the treatment of spinal cerebrospinal leak after unsuccessful suboccipital decompression surgeries. A misdiagnosis of Chiari malformation type 1 in patients with spinal cerebrospinal fluid leak may lead to unnecessary surgeries instead of the less invasive treatment, such as epidural blood patches. It is imperative to consider a spinal cerebrospinal fluid leak in the differential based on clinical-radiological correlation and not solely on cerebellar tonsillar descent demonstrated on imaging.

  View details for DOI 10.1016/j.heliyon.2021.e06795

  View details for PubMedID 33981879

• Neuroimaging for Spontaneous Intracranial Hypotension Turned on its Side. Neurology Carroll, I. R., Friedman, D. I. 2021

  View details for DOI 10.1212/WNL.0000000000011518

  View details for PubMedID 33472920

• Abnormal [18F]FDG PET/MRI findings in paraspinal structures of patients with suspected cerebrospinal fluid leak. Scientific reports Yoon, D., Cipriano, P. W., Penticuff, R., Castillo, J. B., Xu, Y., Carroll, I. R., Biswal, S. 2021; 11 (1): 15926

  Abstract

  A combination of magnetic resonance imaging (MRI), computed tomography (CT), and radionuclide cisternography are typically used to locate a cerebrospinal fluid (CSF) leak. However, the site of leakage cannot be determined, making treatment more difficult. Therefore, more sensitive imaging tools are needed. A whole-body [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/MRI was conducted on six patients with suspected CSF leak and the resulting images were reviewed in comparison with those from six healthy controls. Paraspinal regions of focally increased uptake of [18F]FDG were quantified using maximum standardized uptake values (SUVmax) and compared to the SUVmax of corresponding regions in the healthy controls. All six patients with suspected CSF leak showed paraspinal regions of significantly greater [18F]FDG uptake compared to the corresponding areas in controls (P < 0.05). Two patients treated with local injections (epidural blood patches and/or epidural fibrin patches) on the site of abnormal PET/MRI findings reported temporary but significant improvement in symptoms. Our results suggest [18F]FDG PET/MRI is sensitive to abnormalities potentially due to suspected CSF leak, which are not necessarily visible on conventional MRI alone or by the standard-of-care imaging methods.

  View details for DOI 10.1038/s41598-021-95056-w

  View details for PubMedID 34354104

• Characteristics of Patients With Complex Limb Pain Evaluated Through an Interdisciplinary Approach Utilizing Magnetic Resonance Neurography Frontiers in Pain Research Johnson, E. M., Yoon, D., Biswal, S., Curtin, C., Fox, P., Wilson, T. J., Carroll, I., Lutz, A., Tawfik, V. 2021

  View details for DOI 10.3389/fpain.2021.689402

• Neurovascular, muscle, and skin changes on [18F]FDG PET/MRI in complex regional pain syndrome of the foot: A Prospective Clinical Study. Pain medicine (Malden, Mass.) Yoon, D., Xu, Y., Cipriano, P. W., Alam, I. S., Mari Aparici, C. A., Tawfik, V. L., Curtin, C. M., Carroll, I. R., Biswal, S. 2021

  Abstract

  The goal of this study is to demonstrate the feasibility of simultaneous [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI) for non-invasive visualization of muscular, neurovascular, and skin changes secondary to complex regional pain syndrome (CRPS).Seven adult patients with CRPS of the foot and seven healthy adult controls participated in our [18F]FDG PET/MRI study.All participants received whole-body PET/MRI scans one hour after the injection of 370MBq [18F]FDG. Resulting PET/MRI images were reviewed by two radiologists. Metabolic and anatomic abnormalities identified, were grouped into muscular, neurovascular, and skin lesions. The [18F]FDG uptake of each lesion was compared with that of corresponding areas in controls using a Mann-Whitney U-test.On PET images, muscular abnormalities were found in five patients, neurovascular abnormalities in four patients, and skin abnormalities in two patients. However, on MRI images, no muscular abnormalities were detected. Neurovascular abnormalities and skin abnormalities in the affected limb were identified on MRI in one and two patients, respectively. The difference in [18F]FDG uptake between the patients and the controls was significant in muscle (p = 0.018) and neurovascular bundle (p = 0.0005).The increased uptake of [18F]FDG in the symptomatic areas likely reflects the increased metabolism due to the inflammatory response causing pain. Therefore, our approach combining metabolic [18F]FDG PET and anatomic MR imaging may offer non-invasive monitoring of the distribution and progression of inflammatory changes associated with CRPS.

  View details for DOI 10.1093/pm/pnab315

  View details for PubMedID 34718774

• Return to work and productivity loss after surgery: A health economic evaluation. International journal of surgery (London, England) M Hah, J., Lee, E., Shrestha, R., Pirrotta, L., Huddleston, J., Goodman, S., Amanatullah, D. F., Dirbas, F. M., Carroll, I. R., Schofield, D. 2021: 106100

  Abstract

  We aimed to identify preoperative psychosocial factors associated with return-to-work (RTW) and the associated cost of productivity loss due to work absenteeism following surgery. Research demonstrates a high economic burden from productivity loss after surgery, but the comparative cost of productivity loss relative to income across different operations has not been examined.A mixed surgical cohort recruited for a randomized controlled trial were prospectively followed for up to two years following surgery with daily phone assessments to three months, weekly assessments thereafter to six months, then monthly assessments thereafter to determine RTW status, opioid use and pain.183 of 207 (88.3%) patients in paid employment prior to surgery, who provided at least one day of follow-up, were included in this analysis. The average cost of productivity loss due to work absenteeism was $13 761 (median $9064). Patients who underwent total knee replacement incurred the highest income loss. Medical claims filed before surgery were significantly associated with relative income loss (AOR 5.09; 95% CI 1.73-14.96; p < 0.01) and delayed postoperative RTW. Elevated preoperative PTSD symptoms were associated with delayed RTW (HR 0.78; 95%CI 0.63-0.96; p-value = 0.02) while male gender (HR 1.63; 95%CI 1.11-2.38; p-value = 0.01) was associated with faster postoperative RTW.Surgery places a high economic burden on individuals due to postoperative productivity loss. Multidisciplinary approaches, such as pathways, that facilitate the operation and recovery may mitigate the economic consequences for patients, employers, and the healthcare system.

  View details for DOI 10.1016/j.ijsu.2021.106100

  View details for PubMedID 34600123

• Did she have an epidural? The long-term consequences of postdural puncture headache and the role of unintended dural puncture. Headache Barad, M., Carroll, I., Reina, M. A., Ansari, J., Flood, P. 2021

  Abstract

  This narrative literature review examines the long-term impact of postdural puncture headache (PDPH) in postpartum women following an unintended dural puncture (UDP) with a large bore needle commonly used for epidural catheter placement. It seeks to bridge the knowledge gap for the neurologist as to the mounting body of obstetric anesthesia literature on the development of chronic headache after PDPH with this unique needle.Headache is the most common complication of dural puncture, and the risk is greatest in the parturient population. Preexisting risk factors for this population include youth and sex, and after UDP with a large bore needle, almost 70%-80% report a headache. Additionally, there appears to be a significant cohort who experience long-term, persistent headache after UDP.We performed a narrative review of literature using PubMed, searching terms that included long-term follow-up after UDP with a large bore needle in the postpartum population.In women who had UDP with a large bore needle used for epidural catheter placement at delivery, the rate of chronic debilitating headache is around 30% in the months following delivery and may persist for up to a year or longer.Based on the existing literature, we have mounting evidence that UDP with the large bore needle used to place an epidural catheter should be understood as a high-risk inciting event for the development of long-term headaches not simply a high risk of acute PDPH. Additionally, consideration should be given to stratifying the etiology of PDPH, based on needle type, and recognizing the entity of chronic PDPH, thus allowing for improvements in research and diagnosis.

  View details for DOI 10.1111/head.14221

  View details for PubMedID 34570902

• Efficacy of motivational-interviewing and guided opioid tapering support for patients undergoing orthopedic surgery (MI-Opioid Taper): A prospective, assessor-blind, randomized controlled pilot trial. EClinicalMedicine Hah, J. M., Trafton, J. A., Narasimhan, B., Krishnamurthy, P., Hilmoe, H., Sharifzadeh, Y., Huddleston, J. I., Amanatullah, D., Maloney, W. J., Goodman, S., Carroll, I., Mackey, S. C. 2020; 28: 100596

  Abstract

  Background: Postoperative opioid use can lead to chronic use and misuse. Few studies have examined effective approaches to taper postoperative opioid use while maintaining adequate analgesia.Methods: This randomized, assessor-blinded, pilot trial of postoperative motivational interviewing and guided opioid tapering support (MI-Opioid Taper) added to usual care (UC) enrolled patients undergoing total hip or knee arthroplasty at a single U.S. academic medical center. MI-Opioid Taper involved weekly (to seven weeks) and monthly (to one year) phone calls until patient-reported opioid cessation. Opioid tapering involved 25% weekly dose reductions. The primary feasibility outcome was study completion in the group to which participants were randomized. The primary efficacy outcome, time to baseline opioid use, was the first of five consecutive days of return to baseline preoperative dose. Intention-to-treat analysis with Cox proportional hazards regression was adjusted for operation. ClinicalTrials.gov registration: NCT02070003.Findings: From November 26, 2014, to April 27, 2018, 209 patients were screened, and 104 patients were assigned to receive MI-Opioid Taper (49 patients) or UC only (55 patients). Study completion after randomization was similar between groups (96.4%, 53 patients receiving UC, 91.8%, 45 patients receiving MI-Opioid Taper). Patients receiving MI-Opioid Taper had a 62% increase in the rate of return to baseline opioid use after surgery (HR 1.62; 95%CI 1.06-2.46; p=003). No trial-related adverse events occurred.Interpretation: In patients undergoing total joint arthroplasty, MI-Opioid Taper is feasible and future research is needed to establish the efficacy of MI-Opioid Taper to promote postoperative opioid cessation.Funding: National Institute on Drug Abuse.

  View details for DOI 10.1016/j.eclinm.2020.100596

  View details for PubMedID 33294812

• Of mice, microglia, and (wo)men: a case series and mechanistic investigation of hydroxychloroquine for complex regional pain syndrome. Pain reports Haight, E. S., Johnson, E. M., Carroll, I. R., Tawfik, V. L. 2020; 5 (5): e841

  Abstract

  Introduction: Complex regional pain syndrome (CRPS) is a condition that occurs after minor trauma characterized by sensory, trophic, and motor changes. Although preclinical studies have demonstrated that CRPS may be driven in part by autoinflammation, clinical use of immune-modulating drugs in CRPS is limited. Hydroxychloroquine (HCQ) is a disease-modifying antirheumatic drug used to treat malaria and autoimmune disorders that may provide benefit in CRPS.Objectives: To describe the use of HCQ in patients with refractory CRPS and investigate possible mechanisms of benefit in a mouse model of CRPS.Methods: We initiated HCQ therapy in 7 female patients with refractory CRPS undergoing treatment at the Stanford Pain Management Center. We subsequently undertook studies in the mouse tibial fracture-casting model of CRPS to identify mechanisms underlying symptom reduction. We evaluated behavior using mechanical allodynia and spinal cord autoinflammation by immunohistochemistry and enzyme-linked immunosorbent assay.Results: We treated 7 female patients with chronic, refractory CRPS with HCQ 200 mg twice daily for 2 months, followed by 200 mg daily thereafter. Two patients stopped HCQ secondary to lack of response or side effects. Overall, HCQ significantly improved average numerical rating scale pain from 6.8 ± 1.1 before HCQ to 3.8 ± 1.9 after HCQ treatment. In the tibial fracture-casting mouse model of CRPS, we observed reductions in allodynia, paw edema, and warmth following daily HCQ treatment starting at 3 weeks after injury. Spinal cord dorsal horn microglial activation and cytokine levels were also reduced by HCQ treatment.Conclusion: Together, these preclinical and clinical results suggest that HCQ may benefit patients with CRPS at least in part by modulating autoinflammation and support further investigation into the use of HCQ for CRPS.

  View details for DOI 10.1097/PR9.0000000000000841

  View details for PubMedID 33490839

• Abnormal [18F]FDG PET/MRI Findings In Paraspinal Muscles of Patients with Suspected Cerebrospinal Fluid Leak. Cipriano, P., Yoon, D., Xu, Y., Carroll, I., Biswal, S. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290501468

• Sigma-1 receptor PET/MRI for identifying nociceptive sources of radiating low back pain Yoon, D., Cipriano, P., Carroll, I., Curtin, C., Roh, E., Wilson, T., Biswal, S. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290500159

• 18F-FDG PET/MRI of patients with chronic pain alters management. Cipriano, P., Yoon, D., Carroll, I., Curtin, C., Tawfik, V., Xu, Y., Biswal, S. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290500352

• Integrating Adjuvant Analgesics into Perioperative Pain Practice: Results from an Academic Medical Center PAIN MEDICINE Chin, K., Carroll, I., Desai, K., Asch, S., Seto, T., McDonald, K. M., Curtin, C., Hernandez-Boussard, T. 2020; 21 (1): 161–70

  View details for DOI 10.1093/pm/pnz053

  View details for Web of Science ID 000522867400020

• Spinal cerebrospinal fluid leak in the context of pars interarticularis fracture. BMC neurology Chan, T. L., Cowan, R. n., Hindiyeh, N. n., Hashmi, S. n., Lanzman, B. n., Carroll, I. n. 2020; 20 (1): 162

  Abstract

  Spinal cerebrospinal fluid (CSF) leak can lead to intracranial hypotension and is an important differential diagnosis to consider in patients with sudden-onset chronic daily headaches. Pars interarticularis (PI) fracture is a potential rare cause of suspected spinal CSF leak.This is a retrospective case series of 6 patients with suspected spinal CSF leak evaluated between January 2016 and September 2019. All patients received a magnetic resonance imaging (MRI) of the brain with and without gadolinium, MRI whole spine and full spine computed tomography (CT) myelogram. Targeted epidural patches with fibrin sealant were performed. Treatment response at return visit (3 months post-patch) was documented.Six patients (4 females, 2 males) were diagnosed with a suspected spinal CSF leak and PI fracture. Mean age at the time of headache onset was 39 years old, and a range from 32 to 50 years old. Mean time to targeted epidural patches with fibrin sealant was 4.5 years. All 6 patients had PI fractures identified on CT myelogram and received targeted epidural patches with fibrin sealant at the site of the PI fracture. All patients had significant improvement in their headache intensity.Our study highlights: 1) the importance of PI fracture as a possible culprit of suspected spinal CSF leak in patients with intracranial hypotension; 2) the added benefit of CT imaging for detecting bony abnormalities such as fractures in patients with intracranial hypotension; and 3) the successful treatment of suspected spinal CSF leak when targeting the fracture site.

  View details for DOI 10.1186/s12883-020-01740-1

  View details for PubMedID 32349710

• Diagnosis and Successful Management of an Unusual Presentation of Chronic Foot Pain Using Positron Emission Tomography/Magnetic Resonance Imaging and a Simple Surgical Procedure CLINICAL JOURNAL OF SPORT MEDICINE Cipriano, P., Yoon, D., Holley, D., Hargreaves, B., Carroll, I., Curtin, C., Biswal, S. 2020; 30 (1): E11–E14

  View details for DOI 10.1097/JSM.0000000000000651

  View details for Web of Science ID 000524358800006

• Preoperative Factors Associated with Remote Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: Post Hoc Analysis of a Perioperative Gabapentin Trial. Journal of pain research Hah, J. M., Hilmoe, H. n., Schmidt, P. n., McCue, R. n., Trafton, J. n., Clay, D. n., Sharifzadeh, Y. n., Ruchelli, G. n., Hernandez Boussard, T. n., Goodman, S. n., Huddleston, J. n., Maloney, W. J., Dirbas, F. M., Shrager, J. n., Costouros, J. G., Curtin, C. n., Mackey, S. C., Carroll, I. n. 2020; 13: 2959–70

  Abstract

  Preoperative patient-specific risk factors may elucidate the mechanisms leading to the persistence of pain and opioid use after surgery. This study aimed to determine whether similar or discordant preoperative factors were associated with the duration of postoperative pain and opioid use.In this post hoc analysis of a randomized, double-blind, placebo-controlled trial of perioperative gabapentin vs active placebo, 410 patients aged 18-75 years, undergoing diverse operations underwent preoperative assessments of pain, opioid use, substance use, and psychosocial variables. After surgery, a modified Brief Pain Inventory was administered over the phone daily up to 3 months, weekly up to 6 months, and monthly up to 2 years after surgery. Pain and opioid cessation were defined as the first of 5 consecutive days of 0 out of 10 pain or no opioid use, respectively.Overall, 36.1%, 19.8%, and 9.5% of patients continued to report pain, and 9.5%, 2.4%, and 1.7% reported continued opioid use at 3, 6, and 12 months after surgery. Preoperative pain at the future surgical site (every 1-point increase in the Numeric Pain Rating Scale; HR 0.93; 95% CI 0.87-1.00; P=0.034), trait anxiety (every 10-point increase in the Trait Anxiety Inventory; HR 0.79; 95% CI 0.68-0.92; P=0.002), and a history of delayed recovery after injury (HR 0.62; 95% CI 0.40-0.96; P=0.034) were associated with delayed pain cessation. Preoperative opioid use (HR 0.60; 95% CI 0.39-0.92; P=0.020), elevated depressive symptoms (every 5-point increase in the Beck Depression Inventory-II score; HR 0.88; 95% CI 0.80-0.98; P=0.017), and preoperative pain outside of the surgical site (HR 0.94; 95% CI 0.89-1.00; P=0.046) were associated with delayed opioid cessation, while perioperative gabapentin promoted opioid cessation (HR 1.37; 95% CI 1.06-1.77; P=0.016).Separate risk factors for prolonged post-surgical pain and opioid use indicate that preoperative risk stratification for each outcome may identify patients needing personalized care to augment universal protocols for perioperative pain management and conservative opioid prescribing to improve long-term outcomes.

  View details for DOI 10.2147/JPR.S269370

  View details for PubMedID 33239904

  View details for PubMedCentralID PMC7680674

• Trajectory analysis for postoperative pain using electronic health records: A nonparametric method with robust linear regression and K-medians cluster analysis. Health informatics journal Weng, Y., Tian, L., Tedesco, D., Desai, K., Asch, S. M., Carroll, I., Curtin, C., McDonald, K. M., Hernandez-Boussard, T. 2019: 1460458219881339

  Abstract

  Postoperative pain scores are widely monitored and collected in the electronic health record, yet current methods fail to fully leverage the data with fast implementation. A robust linear regression was fitted to describe the association between the log-scaled pain score and time from discharge after total knee replacement. The estimated trajectories were used for a subsequent K-medians cluster analysis to categorize the longitudinal pain score patterns into distinct clusters. For each cluster, a mixture regression model estimated the association between pain score and time to discharge adjusting for confounding. The fitted regression model generated the pain trajectory pattern for given cluster. Finally, regression analyses examined the association between pain trajectories and patient outcomes. A total of 3442 surgeries were identified with a median of 22 pain scores at an academic hospital during 2009-2016. Four pain trajectory patterns were identified and one was associated with higher rates of outcomes. In conclusion, we described a novel approach with fast implementation to model patients' pain experience using electronic health records. In the era of big data science, clinical research should be learning from all available data regarding a patient's episode of care instead of focusing on the "average" patient outcomes.

  View details for DOI 10.1177/1460458219881339

  View details for PubMedID 31621460

• Perioperative opioid use and pain-related outcomes in the Veterans Health Administration. American journal of surgery Hernandez-Boussard, T., Graham, L. A., Carroll, I., Dasinger, E. A., Titan, A. L., Morris, M. S., Hawn, M. T. 2019

  Abstract

  Understanding variation in perioperative opioid exposure and its effect on patients' outcomes is critical for pain management. This study characterized perioperative exposure to morphine and its association with postoperative pain and 30-day readmissions. We utilized nationwide Veterans Healthcare Administration (VHA) data on four high-volume surgical procedures, 2007-2014. We identified 235,239 Veterans undergoing orthopedic, general, or vascular surgery; 5.4% high trajectories (116.1 OME/Day), 53.2% medium trajectories (39.7 OME/Day), and 41.4% low trajectories (19.1 OME/Day). Modeled estimates suggest that patients in the high OME group had higher risk of a pain-related readmission (OR: 1.59; CI: 1.39, 1.83) compared to the low OME trajectory. Yet when stratified by pain trajectory, patients with high pain and high OME had lower risk of a pain-related readmission compared to patients in the high pain low OME group (OR: 0.76, CI: 0.62, 0.94). In conclusion, patients receiving high perioperative OME are more likely to return to care for pain-related problems. This study highlights opportunities to reduce the amount of prescriptions opioids in the communities.

  View details for DOI 10.1016/j.amjsurg.2019.06.022

  View details for PubMedID 31280840

• 18F-FDG PET/MRI of patients with chronic pain alters management. Cipriano, P., Yoon, D., Carroll, I., Curtin, C., Tawfik, V., Xu, Y., Biswal, S. SOC NUCLEAR MEDICINE INC. 2019

  View details for Web of Science ID 000473116800093

• Musculoskeletal changes on [18F]FDG PET/MRI from complex regional pain syndrome in foot Yoon, D., Xu, Y., Cipriano, P., Tawfik, V., Curtin, C., Carroll, I., Biswal, S. SOC NUCLEAR MEDICINE INC. 2019

  View details for Web of Science ID 000473116800094

• Integrating Adjuvant Analgesics into Perioperative Pain Practice: Results from an Academic Medical Center. Pain medicine (Malden, Mass.) Chin, K., Carroll, I., Desai, K., Asch, S., Seto, T., McDonald, K. M., Curtin, C., Hernandez-Boussard, T. 2019

  Abstract

  BACKGROUND: Opioid-sparing postoperative pain management therapies are important considering the opioid epidemic. Total knee arthroplasty (TKA) is a common and painful procedure accounting for a large number of opioid prescriptions. Adjuvant analgesics, nonopioid drugs with primary indications other than pain, have shown beneficial pain management and opioid-sparing effects following TKA in clinical trials. We evaluated the adjuvant analgesic gabapentin for its usage patterns and its effects on opioid use, pain, and readmissions.METHODS: This retrospective, observational study included 4,046 patients who received primary TKA between 2009 and 2017 using electronic health records from an academic tertiary care medical institute. Descriptive statistics and multivariate modeling were used to estimate associations between inpatient gabapentin use and adverse pain outcomes as well as inpatient oral morphine equivalents per day (OME).RESULTS: Overall, there was an 8.72% annual increase in gabapentin use (P<0.001). Modeled estimates suggest that gabapentin is associated with a significant decrease in opioid consumption (estimate = 0.63, 95% confidence interval = 0.49-0.82, P<0.001) when controlling for patient characteristics. Patients receiving gabapentin had similar discharge pain scores, follow-up pain scores, and 30-day unplanned readmission rates compared with patients receiving no adjuvant analgesics (P>0.05).CONCLUSIONS: When assessed in a real-world setting over a large cohort of TKA patients, gabapentin is an effective pain management therapy that is associated with reduced opioid consumption-a national priority in this time of opioid crisis-while maintaining the same quality of pain management.

  View details for PubMedID 30933284

• Diagnosis and Successful Management of an Unusual Presentation of Chronic Foot Pain Using Positron Emission Tomography/Magnetic Resonance Imaging and a Simple Surgical Procedure. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine Cipriano, P. W., Yoon, D., Holley, D., Hargreaves, B. A., Carroll, I. R., Curtin, C. M., Biswal, S. 2019

  Abstract

  A 61-year-old man presented with chronic dorsal foot pain of 9 years that worsened with ambulation. Conventional diagnostic imaging and medical workup were unrevealing, and ankle arthrodesis had been recommended by an orthopedic surgeon for pain relief. Instead, the patient participated in a clinical imaging trial designed for identifying pain generators using whole-body fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI). The scan revealed not only high 18F-FDG uptake at the site of pain, but also a hematoma and an inflamed, fibrotic, ruptured plantaris muscle. The fibrotic plantaris likely altered biomechanics with walking, explaining why symptoms worsened with activity. A simple tenotomy of the plantaris tendon was performed to decouple ankle movement from the plantaris injury, resulting in pain relief. This case illustrates the potential of whole-body 18F-FDG PET/MRI to better localize pain generators.

  View details for PubMedID 30908328

• Factors Associated With Acute Pain Estimation, Postoperative Pain Resolution, Opioid Cessation, and Recovery Secondary Analysis of a Randomized Clinical Trial JAMA NETWORK OPEN Hah, J. M., Cramer, E., Hilmoe, H., Schmidt, P., McCue, R., Trafton, J., Clay, D., Sharifzadeh, Y., Ruchelli, G., Goodman, S., Huddleston, J., Maloney, W. J., Dirbas, F. M., Shrager, J., Costouros, J. G., Curtin, C., Mackey, S. C., Carroll, I. 2019; 2 (3)

  View details for DOI 10.1001/jamanetworkopen.2019.0168

  View details for Web of Science ID 000465424000048

• Predicting inadequate postoperative pain management in depressed patients: A machine learning approach PLOS ONE Parthipan, A., Banerjee, I., Humphreys, K., Asch, S. M., Curtin, C., Carroll, I., Hernandez-Boussard, T. 2019; 14 (2)

  View details for DOI 10.1371/journal.pone.0210575

  View details for Web of Science ID 000457874000021

• Extremely large outlier treatment effects may be a footprint of bias in trials from less developed countries: randomized trials of gabapentinoids JOURNAL OF CLINICAL EPIDEMIOLOGY Desai, K., Carroll, I., Asch, S., Hernandez-Boussard, T., Ioannidis, J. A. 2019; 106: 80–87

  View details for DOI 10.1016/j.jclinepi.2018.10.012

  View details for Web of Science ID 000457818700010

• Utilization and effectiveness of multimodal discharge analgesia for postoperative pain management. The Journal of surgical research Desai, K., Carroll, I., Asch, S. M., Seto, T., McDonald, K. M., Curtin, C., Hernandez-Boussard, T. 2018; 228: 160–69

  Abstract

  BACKGROUND: Although evidence-based guidelines recommend a multimodal approach to pain management, limited information exists on adherence to these guidelines and its association with outcomes in a generalized population. We sought to assess the association between discharge multimodal analgesia and postoperative pain outcomes in two diverse health care settings.METHODS: We evaluated patients undergoing four common surgeries associated with high pain in electronic health records from an academic hospital (AH) and Veterans Health Administration (VHA). Multimodal analgesia at discharge was characterized as opioids in combination with acetaminophen (O+A) and nonsteroidal antiinflammatory (O+A+N) drugs. Hierarchical models estimated associations of analgesia with 45-d follow-up pain scores and 30-d readmissions.RESULTS: We identified 7893 patients at AH and 34,581 at VHA. In both settings, most patients were discharged with O+A (60.6% and 54.8%, respectively), yet a significant proportion received opioids alone (AH: 24.3% and VHA: 18.8%). Combining acetaminophen with opioids was associated with decreased follow-up pain in VHA (Odds ratio [OR]: 0.86, 95% confidence interval [CI]: 0.79, 0.93) and readmissions (AH OR: 0.74, CI: 0.60, 0.90; VHA OR: 0.89, CI: 0.82, 0.96). Further addition of nonsteroidal antiinflammatory drugs was associated with further decreased follow-up pain (AH OR: 0.71, CI: 0.53, 0.96; VHA OR: 0.77, CI: 0.69, 0.86) and readmissions (AH OR: 0.46, CI: 0.31, 0.69; VHA OR: 0.84, CI: 0.76, 0.93). In both systems, patients receiving multimodal analgesia received 10%-40% less opioids per day compared to opioids only.CONCLUSIONS: A majority of surgical patients receive a multimodal pain approach at discharge yet many receive only opioids. Multimodal regimen at discharge was associated with better follow-up pain and all-cause readmissions compared to the opioid-only regimen.

  View details for PubMedID 29907207

• Ondansetron does not prevent physical dependence in patients taking opioid medications chronically for pain control. Drug and alcohol dependence Chu, L. F., Rico, T. n., Cornell, E. n., Obasi, H. n., Encisco, E. M., Vertelney, H. n., Gamble, J. G., Crawford, C. W., Sun, J. n., Clemenson, A. n., Erlendson, M. J., Okada, R. n., Carroll, I. n., Clark, J. D. 2018; 183: 176–83

  Abstract

  In this study, we investigated the co-administration of ondansetron with morphine, and whether it could prevent the development of physical dependence in patients taking opioids for the treatment of chronic pain.A total of 48 chronic back pain patients (N = 48) participated in this double-blinded, placebo-controlled, randomized study. Patients were titrated onto sustained-release oral morphine and randomized to take 8 mg ondansetron or placebo three times daily concurrently with morphine during the 30-day titration. Following titration, patients underwent Naloxone induced opioid withdrawal. Opioid withdrawal signs and symptoms were then assessed by a blinded research assistant (objective opioid withdrawal score: OOWS) and by the research participant (subjective opioid withdrawal score: SOWS).We observed clinically significant signs of naloxone-precipitated opioid withdrawal in all participants (ΔOOWS = 4.3 ± 2.4, p < 0.0001; ΔSOWS = 14.1 ± 11.7, p < 0.0001), however no significant differences in withdrawal scores were detected between treatment groups.We hypothesized that ondansetron would prevent the development of physical dependence in human subjects when co-administered with opioids, but found no difference in naloxone-precipitated opioid withdrawal scores between ondansetron and placebo treatment groups. These results suggest that further studies are needed to determine if 5HT3 receptor antagonists are useful in preventing opioid physical dependence.

  View details for PubMedID 29278818

• Ondansetron Does Not Reduce Withdrawal in Patients With Physical Dependence on Chronic Opioid Therapy. Journal of addiction medicine Chu, L. F., Sun, J., Clemenson, A., Erlendson, M. J., Rico, T., Cornell, E., Obasi, H., Sayyid, Z. N., Encisco, E. M., Yu, J., Gamble, J. G., Carroll, I., Clark, J. D. 2017

  Abstract

  Individuals taking opioids for an extended period of time may become physically dependent, and will therefore experience opioid withdrawal should they stop taking the medication. Previous work in animal and human models has shown that the serotonin (5-HT3) receptor may be implicated in opioid withdrawal. In this study, we investigated if ondansetron, a 5-HT3-receptor antagonist, could reduce the symptoms of opioid withdrawal after chronic opioid exposure in humans.In this double-blinded, randomized, crossover study, 33 chronic back pain patients (N = 33) were titrated onto sustained-release oral morphine for 30 days. After titration, participants attended 2 study sessions, 1 week apart, in which opioid withdrawal was induced with intravenous naloxone, with or without 8 mg intravenous ondansetron pretreatment. Opioid withdrawal symptoms were assessed by a blinded research assistant (objective opioid withdrawal score [OOWS]) and by the research participant (subjective opioid withdrawal score [SOWS]).Clinically significant signs of withdrawal were observed during both the ondansetron (ΔOOWS = 3.58 ± 2.22, P < 0.0001; ΔSOWS = 12.48 ± 11.18, P < 0.0001) and placebo sessions (ΔOOWS = 3.55 ± 2.39, P < 0.0001; ΔSOWS = 12.21 ± 10.72, P < 0.0001), but no significant differences were seen between the treatment sessions in either the OOWS or SOWS scores.We hypothesized that ondansetron would reduce opioid withdrawal symptoms in human subjects, but found no difference in withdrawal severity between ondansetron and placebo sessions. These findings suggest that more investigation may be necessary to determine if 5-HT3-receptor antagonists are suitable treatment options for opioid withdrawal.

  View details for DOI 10.1097/ADM.0000000000000321

  View details for PubMedID 28514235

• A Randomized Trial of Perioperative Gabapentin to Promote Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort Hah, J., Mackey, S., Efron, B., Mccue, R., Goodman, S., Curtin, C., Carroll, I. LIPPINCOTT WILLIAMS & WILKINS. 2017: 813–17

  View details for Web of Science ID 000412683000420

• A Double-Blind Placebo Randomized Controlled Trial of Minocycline to Reduce Pain After Carpal Tunnel and Trigger Finger Release. journal of hand surgery Curtin, C. M., Kenney, D., Suarez, P., Hentz, V. R., Hernandez-Boussard, T., Mackey, S., Carroll, I. R. 2017; 42 (3): 166-174

  Abstract

  Minocycline is a microglial cell inhibitor and decreases pain behaviors in animal models. Minocycline might represent an intervention for reducing postoperative pain. This trial tested whether perioperative administration of minocycline reduced time to pain resolution (TPR) after standardized hand surgeries with known prolonged pain profiles: carpal tunnel release (CTR) and trigger finger release (TFR).This double-blinded randomized controlled trial included patients undergoing CTR or TFR under local anesthesia. Before surgery, participants recorded psychological and pain measures. Participants received oral minocycline, 200 mg, or placebo 2 hours prior to procedure, and then 100 mg of minocycline or placebo 2 times a day for 5 days. After surgery, participants were called daily assessing their pain. The primary end point of TPR was when participants had 3 consecutive days of 0 postsurgical pain. Futility analysis and Kaplan-Meier analyses were performed.A total of 131 participants were randomized and 56 placebo and 58 controls were analyzed. Median TPR for CTR was 3 weeks, with 15% having pain more than 6 weeks. Median TPR for TFR was 2 weeks with 18% having pain more than 6 weeks. The overall median TPR for the placebo group was 2 weeks (10% pain > 6 weeks) versus 2.5 weeks (17% pain > 6 weeks) for the minocycline group. Futility analysis found that the likelihood of a true underlying clinically meaningful reduction in TPR owing to minocycline was only 3.5%. Survival analysis found minocycline did not reduce TPR. However, subgroup analysis of those with elevated posttraumatic distress scores found the minocycline group had longer TPR.Oral administration of minocycline did not reduce TPR after minor hand surgery. There was evidence that minocycline might increase length of pain in those with increased posttraumatic stress disorder symptoms.Therapeutic I.

  View details for DOI 10.1016/j.jhsa.2016.12.011

  View details for PubMedID 28259273

• Drug-Free Interventions to Reduce Pain or Opioid Consumption After Total Knee Arthroplasty: A Systematic Review and Meta-analysis. JAMA surgery Tedesco, D. n., Gori, D. n., Desai, K. R., Asch, S. n., Carroll, I. R., Curtin, C. n., McDonald, K. M., Fantini, M. P., Hernandez-Boussard, T. n. 2017: e172872

  Abstract

  There is increased interest in nonpharmacological treatments to reduce pain after total knee arthroplasty. Yet, little consensus supports the effectiveness of these interventions.To systematically review and meta-analyze evidence of nonpharmacological interventions for postoperative pain management after total knee arthroplasty.Database searches of MEDLINE (PubMed), EMBASE (OVID), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews, Web of Science (ISI database), Physiotherapy Evidence (PEDRO) database, and ClinicalTrials.gov for the period between January 1946 and April 2016.Randomized clinical trials comparing nonpharmacological interventions with other interventions in combination with standard care were included.Two reviewers independently extracted the data from selected articles using a standardized form and assessed the risk of bias. A random-effects model was used for the analyses.Postoperative pain and consumption of opioids and analgesics.Of 5509 studies, 39 randomized clinical trials were included in the meta-analysis (2391 patients). The most commonly performed interventions included continuous passive motion, preoperative exercise, cryotherapy, electrotherapy, and acupuncture. Moderate-certainty evidence showed that electrotherapy reduced the use of opioids (mean difference, -3.50; 95% CI, -5.90 to -1.10 morphine equivalents in milligrams per kilogram per 48 hours; P = .004; I2 = 17%) and that acupuncture delayed opioid use (mean difference, 46.17; 95% CI, 20.84 to 71.50 minutes to the first patient-controlled analgesia; P < .001; I2 = 19%). There was low-certainty evidence that acupuncture improved pain (mean difference, -1.14; 95% CI, -1.90 to -0.38 on a visual analog scale at 2 days; P = .003; I2 = 0%). Very low-certainty evidence showed that cryotherapy was associated with a reduction in opioid consumption (mean difference, -0.13; 95% CI, -0.26 to -0.01 morphine equivalents in milligrams per kilogram per 48 hours; P = .03; I2 = 86%) and in pain improvement (mean difference, -0.51; 95% CI, -1.00 to -0.02 on the visual analog scale; P < .05; I2 = 62%). Low-certainty or very low-certainty evidence showed that continuous passive motion and preoperative exercise had no pain improvement and reduction in opioid consumption: for continuous passive motion, the mean differences were -0.05 (95% CI, -0.35 to 0.25) on the visual analog scale (P = .74; I2 = 52%) and 6.58 (95% CI, -6.33 to 19.49) opioid consumption at 1 and 2 weeks (P = .32, I2 = 87%), and for preoperative exercise, the mean difference was -0.14 (95% CI, -1.11 to 0.84) on the Western Ontario and McMaster Universities Arthritis Index Scale (P = .78, I2 = 65%).In this meta-analysis, electrotherapy and acupuncture after total knee arthroplasty were associated with reduced and delayed opioid consumption.

  View details for PubMedID 28813550

• Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial. JAMA surgery Hah, J. n., Mackey, S. C., Schmidt, P. n., McCue, R. n., Humphreys, K. n., Trafton, J. n., Efron, B. n., Clay, D. n., Sharifzadeh, Y. n., Ruchelli, G. n., Goodman, S. n., Huddleston, J. n., Maloney, W. J., Dirbas, F. M., Shrager, J. n., Costouros, J. n., Curtin, C. n., Carroll, I. n. 2017

  Abstract

  Guidelines recommend using gabapentin to decrease postoperative pain and opioid use, but significant variation exists in clinical practice.To determine the effect of perioperative gabapentin on remote postoperative time to pain resolution and opioid cessation.A randomized, double-blind, placebo-controlled trial of perioperative gabapentin was conducted at a single-center, tertiary referral teaching hospital. A total of 1805 patients aged 18 to 75 years scheduled for surgery (thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, and shoulder arthroscopy) were screened. Participants were enrolled from May 25, 2010, to July 25, 2014, and followed up for 2 years postoperatively. Intention-to-treat analysis was used in evaluation of the findings.Gabapentin, 1200 mg, preoperatively and 600 mg, 3 times a day postoperatively or active placebo (lorazepam, 0.5 mg) preoperatively followed by inactive placebo postoperatively for 72 hours.Primary outcome was time to pain resolution (5 consecutive reports of 0 of 10 possible levels of average pain at the surgical site on the numeric rating scale of pain). Secondary outcomes were time to opioid cessation (5 consecutive reports of no opioid use) and the proportion of participants with continued pain or opioid use at 6 months and 1 year.Of 1805 patients screened for enrollment, 1383 were excluded, including 926 who did not meet inclusion criteria and 273 who declined to participate. Overall, 8% of patients randomized were lost to follow-up. A total of 202 patients were randomized to active placebo and 208 patients were randomized to gabapentin in the intention-to-treat analysis (mean [SD] age, 56.7 [11.7] years; 256 (62.4%) women and 154 (37.6%) men). Baseline characteristics of the groups were similar. Perioperative gabapentin did not affect time to pain cessation (hazard ratio [HR], 1.04; 95% CI, 0.82-1.33; P = .73) in the intention-to-treat analysis. However, participants receiving gabapentin had a 24% increase in the rate of opioid cessation after surgery (HR, 1.24; 95% CI, 1.00-1.54; P = .05). No significant differences were noted in the number of adverse events as well as the rate of medication discontinuation due to sedation or dizziness (placebo, 42 of 202 [20.8%]; gabapentin, 52 of 208 [25.0%]).Perioperative administration of gabapentin had no effect on postoperative pain resolution, but it had a modest effect on promoting opioid cessation after surgery. The routine use of perioperative gabapentin may be warranted to promote opioid cessation and prevent chronic opioid use. Optimal dosing and timing of perioperative gabapentin in the context of specific operations to decrease opioid use should be addressed in further research.clinicaltrials.gov Identifier: NCT01067144.

  View details for PubMedID 29238824

• [18F]FDG PET/MRI of patients with chronic pain alters management: Early experience. Xu, Y., Yoon, D., Behera, D., Holley, D., Carroll, I., Smuck, M., Hargreaves, B., Mittra, E., Biswal, S. SOC NUCLEAR MEDICINE INC. 2016

  View details for Web of Science ID 000442211000319

• Pharmacologic Management of Upper Extremity Chronic Nerve Pain. Hand clinics Carroll, I. 2016; 32 (1): 51-61

  Abstract

  The treatment of pain is a complex process that requires a team approach. This article provides an overview of the pharmaceutical treatments available. It gives providers treating upper extremity disorders more tools to treat their patients with chronic pain. Another goal is to improve hand providers' understanding of the medications their pain colleagues prescribe in shared patients. Pharmaceuticals are an important component in the treatment of chronic pain and opioids are often not a good solution. Knowing what other medications are available can improve the care for these challenging patients.

  View details for DOI 10.1016/j.hcl.2015.08.011

  View details for PubMedID 26611389

• Pain Duration and Resolution following Surgery: An Inception Cohort Study. Pain medicine Carroll, I. R., Hah, J. M., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Mackey, S. C. 2015; 16 (12): 2386-2396

  Abstract

  Preoperative determinants of pain duration following surgery are poorly understood. We identified preoperative predictors of prolonged pain after surgery in a mixed surgical cohort.We conducted a prospective longitudinal study of patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured pain and opioid use after surgery until patients reported the cessation of both opioid consumption and pain. The primary endpoint was time to opioid cessation, and those results have been previously reported. Here, we report preoperative determinants of time to pain resolution following surgery in Cox proportional hazards regression.Between January 2007 and April 2009, we enrolled 107 of 134 consecutively approached patients undergoing the aforementioned surgical procedures. In the final multivariate model, preoperative self-perceived risk of addiction predicted more prolonged pain. Unexpectedly, anxiety sensitivity predicted more rapid pain resolution after surgery. Each one-point increase (on a four point scale) of self-perceived risk of addiction was associated with a 38% (95% CI 3-61) reduction in the rate of pain resolution (P = 0.04). Furthermore, higher anxiety sensitivity was associated with an 89% (95% CI 23-190) increased rate of pain resolution (P = 0.004).Greater preoperative self-perceived risk of addiction, and lower anxiety sensitivity predicted a slower rate of pain resolution following surgery. Each of these factors was a better predictor of pain duration than preoperative depressive symptoms, post-traumatic stress disorder symptoms, past substance use, fear of pain, gender, age, preoperative pain, or preoperative opioid use.

  View details for DOI 10.1111/pme.12842

  View details for PubMedID 26179223

• Pain Duration and Resolution following Surgery: An Inception Cohort Study PAIN MEDICINE Carroll, I. R., Hah, J. M., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Mackey, S. C. 2015; 16 (12): 2386-2396

  Abstract

  Preoperative determinants of pain duration following surgery are poorly understood. We identified preoperative predictors of prolonged pain after surgery in a mixed surgical cohort.We conducted a prospective longitudinal study of patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured pain and opioid use after surgery until patients reported the cessation of both opioid consumption and pain. The primary endpoint was time to opioid cessation, and those results have been previously reported. Here, we report preoperative determinants of time to pain resolution following surgery in Cox proportional hazards regression.Between January 2007 and April 2009, we enrolled 107 of 134 consecutively approached patients undergoing the aforementioned surgical procedures. In the final multivariate model, preoperative self-perceived risk of addiction predicted more prolonged pain. Unexpectedly, anxiety sensitivity predicted more rapid pain resolution after surgery. Each one-point increase (on a four point scale) of self-perceived risk of addiction was associated with a 38% (95% CI 3-61) reduction in the rate of pain resolution (P = 0.04). Furthermore, higher anxiety sensitivity was associated with an 89% (95% CI 23-190) increased rate of pain resolution (P = 0.004).Greater preoperative self-perceived risk of addiction, and lower anxiety sensitivity predicted a slower rate of pain resolution following surgery. Each of these factors was a better predictor of pain duration than preoperative depressive symptoms, post-traumatic stress disorder symptoms, past substance use, fear of pain, gender, age, preoperative pain, or preoperative opioid use.

  View details for DOI 10.1111/pme.12842

  View details for Web of Science ID 000368297000020

  View details for PubMedCentralID PMC4706803

• [18F]FDG PET/MRI of patients with chronic pain alters management: early experience. EJNMMI physics Biswal, S., Behera, D., Yoon, D. H., Holley, D., Ith, M. A., Carroll, I., Smuck, M., Hargreaves, B. 2015; 2: A84-?

  View details for DOI 10.1186/2197-7364-2-S1-A84

  View details for PubMedID 26956346

  View details for PubMedCentralID PMC4798651

• Opioids and Lactation: Insufficient Evidence of Safety PAIN MEDICINE Carroll, I. R. 2015; 16 (4): 628–30

  View details for PubMedID 25833473

• Factors Associated with Opioid Use in a Cohort of Patients Presenting for Surgery. Pain research and treatment Hah, J. M., Sharifzadeh, Y., Wang, B. M., Gillespie, M. J., Goodman, S. B., Mackey, S. C., Carroll, I. R. 2015; 2015: 829696-?

  Abstract

  Objectives. Patients taking opioids prior to surgery experience prolonged postoperative opioid use, worse clinical outcomes, increased pain, and more postoperative complications. We aimed to compare preoperative opioid users to their opioid naïve counterparts to identify differences in baseline characteristics. Methods. 107 patients presenting for thoracotomy, total knee replacement, total hip replacement, radical mastectomy, and lumpectomy were investigated in a cross-sectional study to characterize the associations between measures of pain, substance use, abuse, addiction, sleep, and psychological measures (depressive symptoms, Posttraumatic Stress Disorder symptoms, somatic fear and anxiety, and fear of pain) with opioid use. Results. Every 9-point increase in the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) score was associated with 2.37 (95% CI 1.29-4.32) increased odds of preoperative opioid use (p = 0.0005). The SOAPP-R score was also associated with 3.02 (95% CI 1.36-6.70) increased odds of illicit preoperative opioid use (p = 0.007). Also, every 4-point increase in baseline pain at the future surgical site was associated with 2.85 (95% CI 1.12-7.27) increased odds of legitimate preoperative opioid use (p = 0.03). Discussion. Patients presenting with preoperative opioid use have higher SOAPP-R scores potentially indicating an increased risk for opioid misuse after surgery. In addition, legitimate preoperative opioid use is associated with preexisting pain.

  View details for DOI 10.1155/2015/829696

  View details for PubMedID 26881072

• In reply. Anesthesiology Schmidt, P. C., Ruchelli, G., Mackey, S. C., Carroll, I. R. 2014; 121 (2): 424-426

  View details for DOI 10.1097/ALN.0000000000000299

  View details for PubMedID 25050501

• Self-Loathing Aspects of Depression Reduce Postoperative Opioid Cessation Rate PAIN MEDICINE Hah, J. M., Mackey, S., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Schmidt, P. C., Carroll, I. R. 2014; 15 (6): 954-964

  Abstract

  We previously reported that increased preoperative Beck Depression Inventory II (BDI-II) scores were associated with a 47% (95% CI 24%-64%) reduction in the rate of opioid cessation following surgery. We aimed to identify the underlying factors of the BDI-II (affective/cognitive vs somatic) associated with a decreased rate of opioid cessation after surgery.We conducted a secondary analysis of the data from a previously reported prospective, longitudinal, observational study of opioid use after five distinct surgical procedures (total hip replacement, total knee replacement, thoracotomy, mastectomy, and lumpectomy) in 107 patients. The primary endpoint was time to opioid cessation. After exploratory factor analysis of the BDI-II, mean summary scores were calculated for each identified factor. These scores were evaluated as predictors of time to opioid cessation using Cox proportional hazards regression.The exploratory factor analysis produced three factors (self-loathing symptoms, motivational symptoms, emotional symptoms). All three factors were significant predictors in univariate analysis. Of the three identified factors of the BDI-II, only preoperative self-loathing symptoms (past failure, guilty feelings, self-dislike, self-criticalness, suicidal thoughts, worthlessness) independently predicted a significant decrease in opioid cessation rate after surgery in the multivariate analysis (HR 0.86, 95% CI 0.75-0.99, P value 0.037).Our results identify a set of negative cognitions predicting prolonged time to postoperative opioid cessation. Somatic symptoms captured by the BDI-II were not primarily responsible for the association between preoperative BDI-II scores and postoperative prolonged opioid use.

  View details for DOI 10.1111/pme.12439

  View details for Web of Science ID 000338025900009

  View details for PubMedCentralID PMC4083472

• Self-loathing aspects of depression reduce postoperative opioid cessation rate. Pain medicine Hah, J. M., Mackey, S., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Schmidt, P. C., Carroll, I. R. 2014; 15 (6): 954-964

  Abstract

  We previously reported that increased preoperative Beck Depression Inventory II (BDI-II) scores were associated with a 47% (95% CI 24%-64%) reduction in the rate of opioid cessation following surgery. We aimed to identify the underlying factors of the BDI-II (affective/cognitive vs somatic) associated with a decreased rate of opioid cessation after surgery.We conducted a secondary analysis of the data from a previously reported prospective, longitudinal, observational study of opioid use after five distinct surgical procedures (total hip replacement, total knee replacement, thoracotomy, mastectomy, and lumpectomy) in 107 patients. The primary endpoint was time to opioid cessation. After exploratory factor analysis of the BDI-II, mean summary scores were calculated for each identified factor. These scores were evaluated as predictors of time to opioid cessation using Cox proportional hazards regression.The exploratory factor analysis produced three factors (self-loathing symptoms, motivational symptoms, emotional symptoms). All three factors were significant predictors in univariate analysis. Of the three identified factors of the BDI-II, only preoperative self-loathing symptoms (past failure, guilty feelings, self-dislike, self-criticalness, suicidal thoughts, worthlessness) independently predicted a significant decrease in opioid cessation rate after surgery in the multivariate analysis (HR 0.86, 95% CI 0.75-0.99, P value 0.037).Our results identify a set of negative cognitions predicting prolonged time to postoperative opioid cessation. Somatic symptoms captured by the BDI-II were not primarily responsible for the association between preoperative BDI-II scores and postoperative prolonged opioid use.

  View details for DOI 10.1111/pme.12439

  View details for PubMedID 24964916

• Perioperative Gabapentinoids Choice of Agent, Dose, Timing, and Effects on Chronic Postsurgical Pain ANESTHESIOLOGY Schmidt, P. C., Ruchelli, G., Mackey, S. C., Carroll, I. R. 2013; 119 (5): 1215-1221

  View details for DOI 10.1097/ALN.0b013e3182a9a896

  View details for Web of Science ID 000329797900029

  View details for PubMedID 24051389

• Management of Chronic Pain Following Nerve lnjuries/CRPS Type II HAND CLINICS Carroll, I., Curtin, C. M. 2013; 29 (3): 401-?

  Abstract

  Chronic pain affects quality of life and adversely affects functional outcomes. Chronic postoperative pain is a frustrating problem for the surgeon because it ruins a technically perfect procedure, and the surgeon may be unsure of treatment strategies. There is much information on chronic pain and its treatment, but it is often published outside of surgery and diffusion of this information across disciplines is slow. This article synthesizes some of this literature and provides a systematic presentation of the evidence on pain associated with peripheral nerve injury. It highlights the use of perioperative and early intervention to decrease this debilitating problem.

  View details for DOI 10.1016/j.hcl.2013.04.009

  View details for Web of Science ID 000323627800009

  View details for PubMedID 23895720

• Perioperative interventions to reduce chronic postsurgical pain. Journal of reconstructive microsurgery Carroll, I., Hah, J., Mackey, S., Ottestad, E., Kong, J. T., Lahidji, S., Tawfik, V., Younger, J., Curtin, C. 2013; 29 (4): 213-222

  Abstract

  Approximately 10% of patients following a variety of surgeries develop chronic postsurgical pain. Reducing chronic postoperative pain is especially important to reconstructive surgeons because common operations such as breast and limb reconstruction have even higher risk for developing chronic postsurgical pain. Animal studies of posttraumatic nerve injury pain demonstrate that there is a critical time frame before and immediately after nerve injury in which specific interventions can reduce the incidence and intensity of chronic neuropathic pain behaviors-so called "preventative analgesia." In animal models, perineural local anesthetic, systemic intravenous local anesthetic, perineural clonidine, systemic gabapentin, systemic tricyclic antidepressants, and minocycline have each been shown to reduce pain behaviors days to weeks after treatment. The translation of this work to humans also suggests that brief perioperative interventions may protect patients from developing new chronic postsurgical pain. Recent clinical trial data show that there is an opportunity during the perioperative period to dramatically reduce the incidence and severity of chronic postsurgical pain. The surgeon, working with the anesthesiologist, has the ability to modify both early and chronic postoperative pain by implementing an evidence-based preventative analgesia plan.

  View details for DOI 10.1055/s-0032-1329921

  View details for PubMedID 23463498

• Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology JOURNAL OF TRANSLATIONAL MEDICINE Stringer, E. A., Baker, K. S., Carroll, I. R., Montoya, J. G., Chu, L., Maecker, H. T., Younger, J. W. 2013; 11

  Abstract

  Chronic fatigue syndrome (CFS) is a debilitating disorder characterized by persistent fatigue that is not alleviated by rest. The lack of a clearly identified underlying mechanism has hindered the development of effective treatments. Studies have demonstrated elevated levels of inflammatory factors in patients with CFS, but findings are contradictory across studies and no biomarkers have been consistently supported. Single time-point approaches potentially overlook important features of CFS, such as fluctuations in fatigue severity. We have observed that individuals with CFS demonstrate significant day-to-day variability in their fatigue severity.Therefore, to complement previous studies, we implemented a novel longitudinal study design to investigate the role of cytokines in CFS pathophysiology. Ten women meeting the Fukuda diagnostic criteria for CFS and ten healthy age- and body mass index (BMI)-matched women underwent 25 consecutive days of blood draws and self-reporting of symptom severity. A 51-plex cytokine panel via Luminex was performed for each of the 500 serum samples collected. Our primary hypothesis was that daily fatigue severity would be significantly correlated with the inflammatory adipokine leptin, in the women with CFS and not in the healthy control women. As a post-hoc analysis, a machine learning algorithm using all 51 cytokines was implemented to determine whether immune factors could distinguish high from low fatigue days.Self-reported fatigue severity was significantly correlated with leptin levels in six of the participants with CFS and one healthy control, supporting our primary hypothesis. The machine learning algorithm distinguished high from low fatigue days in the CFS group with 78.3% accuracy.Our results support the role of cytokines in the pathophysiology of CFS.

  View details for DOI 10.1186/1479-5876-11-93

  View details for Web of Science ID 000318117400001

  View details for PubMedID 23570606

  View details for PubMedCentralID PMC3637529

• Exploratory factor analysis of the beck depression inventory: predictors of delayed opioid cessation after surgery in a pilot cohort study Hah, J., Carroll, I., Younger, J., Mackey, S. CHURCHILL LIVINGSTONE. 2013: S25–S25

  View details for Web of Science ID 000317639400100

• Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. Journal of translational medicine Stringer, E. A., Baker, K. S., Carroll, I. R., Montoya, J. G., Chu, L., Maecker, H. T., Younger, J. W. 2013; 11: 93-?

  Abstract

  Chronic fatigue syndrome (CFS) is a debilitating disorder characterized by persistent fatigue that is not alleviated by rest. The lack of a clearly identified underlying mechanism has hindered the development of effective treatments. Studies have demonstrated elevated levels of inflammatory factors in patients with CFS, but findings are contradictory across studies and no biomarkers have been consistently supported. Single time-point approaches potentially overlook important features of CFS, such as fluctuations in fatigue severity. We have observed that individuals with CFS demonstrate significant day-to-day variability in their fatigue severity.Therefore, to complement previous studies, we implemented a novel longitudinal study design to investigate the role of cytokines in CFS pathophysiology. Ten women meeting the Fukuda diagnostic criteria for CFS and ten healthy age- and body mass index (BMI)-matched women underwent 25 consecutive days of blood draws and self-reporting of symptom severity. A 51-plex cytokine panel via Luminex was performed for each of the 500 serum samples collected. Our primary hypothesis was that daily fatigue severity would be significantly correlated with the inflammatory adipokine leptin, in the women with CFS and not in the healthy control women. As a post-hoc analysis, a machine learning algorithm using all 51 cytokines was implemented to determine whether immune factors could distinguish high from low fatigue days.Self-reported fatigue severity was significantly correlated with leptin levels in six of the participants with CFS and one healthy control, supporting our primary hypothesis. The machine learning algorithm distinguished high from low fatigue days in the CFS group with 78.3% accuracy.Our results support the role of cytokines in the pathophysiology of CFS.

  View details for DOI 10.1186/1479-5876-11-93

  View details for PubMedID 23570606

• Local anesthetics and other interventional approaches NEUROPATHIC PAIN: CAUSES, MANAGEMENT, AND UNDERSTANDING Carroll, I., Hah, J., Nicholson, D., Coleman, S., Toth, C., Moulin, D. E. 2013: 267–72

  View details for Web of Science ID 000326439500023

• A Pilot Cohort Study of the Determinants of Longitudinal Opioid Use After Surgery ANESTHESIA AND ANALGESIA Carroll, I., Barelka, P., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F., Whyte, R. I., Donington, J. S., Cannon, W. B., Mackey, S. C. 2012; 115 (3): 694-702

  Abstract

  Determinants of the duration of opioid use after surgery have not been reported. We hypothesized that both preoperative psychological distress and substance abuse would predict more prolonged opioid use after surgery.Between January 2007 and April 2009, a prospective, longitudinal inception cohort study enrolled 109 of 134 consecutively approached patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured the daily use of opioids until patients reported the cessation of both opioid consumption and pain. The primary end point was time to opioid cessation. All analyses were controlled for the type of surgery done.Overall, 6% of patients continued on new opioids 150 days after surgery. Preoperative prescribed opioid use, depressive symptoms, and increased self-perceived risk of addiction were each independently associated with more prolonged opioid use. Preoperative prescribed opioid use was associated with a 73% (95% confidence interval [CI] 0.51%-87%) reduction in the rate of opioid cessation after surgery (P = 0.0009). Additionally, each 1-point increase (on a 4-point scale) of self-perceived risk of addiction was associated with a 53% (95% CI 23%-71%) reduction in the rate of opioid cessation (P = 0.003). Independent of preoperative opioid use and self-perceived risk of addiction, each 10-point increase on a preoperative Beck Depression Inventory II was associated with a 42% (95% CI 18%-58%) reduction in the rate of opioid cessation (P = 0.002). The variance in the duration of postoperative opioid use was better predicted by preoperative prescribed opioid use, self-perceived risk of addiction, and depressive symptoms than postoperative pain duration or severity.Preoperative factors, including legitimate prescribed opioid use, self-perceived risk of addiction, and depressive symptoms each independently predicted more prolonged opioid use after surgery. Each of these factors was a better predictor of prolonged opioid use than postoperative pain duration or severity.

  View details for DOI 10.1213/ANE.0b013e31825c049f

  View details for PubMedID 22729963

• Sensory Pain Qualities in Neuropathic Pain JOURNAL OF PAIN Mackey, S., Carroll, I., Emir, B., Murphy, T. K., Whalen, E., Dumenci, L. 2012; 13 (1): 58-63

  Abstract

  The qualities of chronic neuropathic pain (NeP) may be informative about the different mechanisms of pain. We previously developed a 2-factor model of NeP that described an underlying structure among sensory descriptors on the Short-Form McGill Pain Questionnaire. The goal of this study was to confirm the correlated 2-factor model of NeP. Individual descriptive scores from the Short-Form McGill Pain Questionnaire were analyzed. Confirmatory factor analysis was used to test a correlated 2-factor model. Factor 1 (stabbing pain) was characterized by high loadings on stabbing, sharp, and shooting sensory items; factor 2 (heavy pain) was characterized by high loadings on heavy, gnawing, and aching items. Results of the confirmatory factor analysis strongly supported the correlated 2-factor model.This article validates a model that describes the qualities of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. These data suggest that specific pain qualities may be associated with pain mechanisms or may be useful for predicting treatment response.

  View details for DOI 10.1016/j.jpain.2011.10.002

  View details for Web of Science ID 000299198300007

  View details for PubMedID 22172451

  View details for PubMedCentralID PMC3249485

• Human Response to Unintended Intrathecal Injection of Botulinum Toxin PAIN MEDICINE Carroll, I., Fischbein, N., Barad, M., Mackey, S. 2011; 12 (7): 1094-1097

  Abstract

  Describe the first reported human intrathecal (IT) botulinum toxin injection.Case report.We report here the sequelae to an unintended IT injection of botulinum toxin type B (BTB) in a 60-year-old woman with chronic back pain.Following the IT administration of BTB, the patient experienced the onset of symmetric ascending stocking distribution painful dysesthesias, which persisted for approximately 6 months before receding. Objective neurologic deficits were not appreciated, and analgesic effects were prominently absent.Analgesic actions of botulinum toxins in animals and in humans have led to speculation that IT botulinum toxin might exert significant analgesic effects. The unusual and unexpected subsequent clinical course, neurologic sequelae, dysesthesias, and absence of analgesia suggest that botulinum toxin will not be a therapeutic modality to treat pain as proposed by those studying botulinum toxin in animal models.

  View details for DOI 10.1111/j.1526-4637.2011.01135.x

  View details for Web of Science ID 000292697100016

  View details for PubMedID 21627762

• Chronic Pain After Surgery for Breast Cancer BREAST SURGICAL TECHNIQUES AND INTERDISCIPLINARY MANAGEMENT Barelka, P., Carroll, I. R., Dirbas, F. M., ScottConner, C. E. 2011: 1029–37

  View details for DOI 10.1007/978-1-4419-6076-4_85

  View details for Web of Science ID 000288230500085

• Variable expression of soluble fms-like tyrosine kinase 1 in patients at high risk for preeclampsia JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE Dwyer, B. K., Krieg, S., Balise, R., Carroll, I. R., Chueh, J., Nayak, N., Druzin, M. 2010; 23 (7): 705-711

  Abstract

  To explore angiogenic factor differences in preeclamptic patients according to the absence or presence of underlying vascular disease.We prospectively compared serum soluble fms-like tyrosine kinase 1 (sFlt1), soluble endoglin, and placental growth factor (PlGF) from 41 normal-risk and 32 high-risk (preexisting conditions) subjects at serial gestational ages.Median sFlt1 was lower at delivery in preeclamptic patients with underlying chronic hypertension and/or chronic proteinuria (5115 pg/ml) compared with normal risk preeclamptic patients (16375 pg/ml). PlGF was consistently low in patients who developed preeclampsia.Effects of sFlt1 may be contextual, varying according to the health or disease state of vascular endothelium.

  View details for DOI 10.3109/14767050903258753

  View details for Web of Science ID 000279865300024

  View details for PubMedID 19895348

• Pain Quality Predicts Lidocaine Analgesia among Patients with Suspected Neuropathic Pain PAIN MEDICINE Carroll, I. R., Younger, J. W., Mackey, S. C. 2010; 11 (4): 617-621

  Abstract

  Oral sodium channel blockers have shown mixed results in randomized controlled trials despite the known importance of sodium channels in generating pain. We hypothesized that differing baseline pain qualities (e.g. "stabbing" vs "dull") might define specific subgroups responsive to intravenous (IV) lidocaine-a potent sodium channel blocker.A prospective cohort study of 71 patient with chronic pain suspected of being neuropathic were recruited between January 2003 and July 2007 and underwent lidocaine infusions at Stanford University Hospital in a single-blind nonrandomized fashion. Baseline sensory pain qualities were measured with the Short-Form McGill Pain Questionnaire (SF-MPQ). Pain intensity was measured with a visual analog scale (VAS).Factor analysis demonstrated two underlying pain quality factors among SF-MPQ sensory items: a heavy pain and a stabbing pain. Baseline heavy pain quality, but not stabbing quality predicted subsequent relief of pain intensity in response to lidocaine. In contrast, these factors did not predict divergent analgesic responses to placebo infusions. In response to each 1 mcg/mL increase in lidocaine plasma level, patients with high heavy pain quality drop their VAS 0.24 (95% CI 0.05-0.43) more points than those with low heavy pain quality (P < 0.013)."Heavy" pain quality may indentify patients with enhanced lidocaine responsiveness. Pain quality may identify subgroups among patients with suspected neuropathic pain responsive to IV lidocaine. Further investigation is warranted to validate and extend these findings.

  View details for Web of Science ID 000276223500020

  View details for PubMedID 20210867

• A Novel CT-Guided Transpsoas Approach to Diagnostic Genitofemoral Nerve Block and Ablation PAIN MEDICINE Parris, D., Fischbein, N., Mackey, S., Carroll, I. 2010; 11 (5): 785-789

  Abstract

  Inguinal hernia repair is associated with a high incidence of chronic postsurgical pain. This pain may be caused by injury to the iliohypogastric, ilioinguinal, or genitofemoral nerves. It is often difficult to identify the specific source of the pain, in part, because these nerves are derived from overlapping nerve roots and closely colocalize in the area of surgery. It is therefore technically difficult to selectively block these nerves individually proximal to the site of surgical injury. In particular, the genitofemoral nerve is retroperitoneal before entering the inguinal canal, a position that puts anterior approaches to the proximal nerve at risk of transgressing into the peritoneum. We report a computed tomography (CT)-guided transpsoas technique to selectively block the genitofemoral nerve for both diagnostic and therapeutic purposes while avoiding injury to the nearby ureter and intestines.A 39-year-old woman with chronic lancinating right groin pain after inguinal hernia repair underwent multiple pharmacologic interventions and invasive procedures without relief. Using CT and Stimuplex nerve stimulator guidance, the genitofemoral nerve was localized on the anterior surface of the psoas muscle and a diagnostic block with local anesthetic block was performed. The patient had immediate relief of her symptoms for 36 hours, confirming the diagnosis of genitofemoral neuralgia. She subsequently underwent CT-guided radiofrequency and phenol ablation of the genitofemoral nerve but has not achieved long-term analgesia.CT-guided transpsoas genitofemoral nerve block is a viable option for safely and selectively blocking the genitofemoral nerve for diagnostic or therapeutic purposes proximal to injury caused by inguinal surgery.

  View details for Web of Science ID 000277206200018

  View details for PubMedID 20546515

• Cutaneous neuroma physiology and its relationship to chronic pain. journal of hand surgery Curtin, C., Carroll, I. 2009; 34 (7): 1334-1336

  View details for DOI 10.1016/j.jhsa.2009.04.003

  View details for PubMedID 19481362

  View details for PubMedCentralID PMC2935247

• Cutaneous Neuroma Physiology and Its Relationship to Chronic Pain JOURNAL OF HAND SURGERY-AMERICAN VOLUME Curtin, C., Carroll, I. 2009; 34A (7): 1334-1336

  View details for DOI 10.1016/j.jhsa.2009.04.003

  View details for Web of Science ID 000269414600026

  View details for PubMedCentralID PMC2935247

• Factors contributing to pain chronicity CURRENT PAIN AND HEADACHE REPORTS Wang, C. K., Hah, J. M., Carroll, I. 2009; 13 (1): 7-11

  Abstract

  The chronicity of pain is the feature of pain that is least understood and most directly linked with our inability to effectively manage pain. Acute pain is relatively responsive to our current pharmacologic and interventional armamentarium. However, as pain persists, our ability to treat effectively diminishes and the patient's frustration and resource utilization increases. This article explores our current understanding of the factors linked to pain duration and the transition from acute to chronic pain in both human and animal models, and across a spectrum of human chronic pain conditions.

  View details for DOI 10.1007/s11916-009-0003-3

  View details for Web of Science ID 000263064900003

  View details for PubMedID 19126364

  View details for PubMedCentralID PMC2743454

• Serratus muscle stimulation effectively treats notalgia paresthetica caused by long thoracic nerve dysfunction: a case series. Journal of brachial plexus and peripheral nerve injury Wang, C. K., Gowda, A., Barad, M., Mackey, S. C., Carroll, I. R. 2009; 4: 17-?

  Abstract

  Currently, notalgia paresthetica (NP) is a poorly-understood condition diagnosed on the basis of pruritus, pain, or both, in the area medial to the scapula and lateral to the thoracic spine. It has been proposed that NP is caused by degenerative changes to the T2-T6 vertebrae, genetic disposition, or nerve entrapment of the posterior rami of spinal nerves arising at T2-T6. Despite considerable research, the etiology of NP remains unclear, and a multitude of different treatment modalities have correspondingly met with varying degrees of success. Here we demonstrate that NP can be caused by long thoracic nerve injury leading to serratus anterior dysfunction, and that electrical muscle stimulation (EMS) of the serratus anterior can successfully and conservatively treat NP. In four cases of NP with known injury to the long thoracic nerve we performed transcutaneous EMS to the serratus anterior in an area far lateral to the site of pain and pruritus, resulting in significant and rapid pain relief. These findings are the first to identify long thoracic nerve injury as a cause for notalgia paresthetica and electrical muscle stimulation of the serratus anterior as a possible treatment, and we discuss the implications of these findings on better diagnosing and treating notalgia paresthetica.

  View details for DOI 10.1186/1749-7221-4-17

  View details for PubMedID 19772656

  View details for PubMedCentralID PMC2758879

• Reduced Cold Pain Tolerance in Chronic Pain Patients Following Opioid Detoxification PAIN MEDICINE Younger, J., Barelka, P., Carroll, I., Kaplan, K., Chu, L., Prasad, R., Gaeta, R., Mackey, S. 2008; 9 (8): 1158-1163

  Abstract

  One potential consequence of chronic opioid analgesic administration is a paradoxical increase of pain sensitivity over time. Little scientific attention has been given to how cessation of opioid medication affects the hyperalgesic state. In this study, we examined the effects of opioid tapering on pain sensitivity in chronic pain patients.Twelve chronic pain patients on long-term opioid analgesic treatment were observed in a 7- to 14-day inpatient pain rehabilitation program, with cold pain tolerance assessed at admission and discharge. The majority of participants were completely withdrawn from their opioids during their stay.We hypothesized that those patients with the greatest reduction in daily opioid use would show the greatest increases in pain tolerance, as assessed by a cold pressor task.A linear regression revealed that the amount of opioid medication withdrawn was a significant predictor of pain tolerance changes, but not in the direction hypothesized. Greater opioid reduction was associated with decreased pain tolerance. This reduction of pain tolerance was not associated with opioid withdrawal symptoms or changes in general pain.These findings suggest that the withdrawal of opioids in a chronic pain sample leads to an acute increase in pain sensitivity.

  View details for DOI 10.1111/j.1526-4637.2008.00475.x

  View details for PubMedID 18564998

• Postoperative Pain Following Foot and Ankle Surgery: A Prospective Study FOOT & ANKLE INTERNATIONAL Chou, L. B., Wagner, D., Witten, D. M., Martinez-Diaz, G. J., Brook, N. S., Toussaint, M., Carroll, I. R. 2008; 29 (11): 1063-1068

  Abstract

  Orthopaedic procedures have been reported to have the highest incidence of pain compared to other types of operations. There are limited studies in the literature that investigate postoperative pain.A prospective study of 98 patients undergoing orthopedic foot and ankle operations was undertaken to evaluate their pain experience. A Short-Form McGill Pain Questionnaire (SF-MPQ) was administered preoperatively and postoperatively.The results showed that patients who experienced pain before the operation anticipated feeling higher pain intensity immediately postoperatively. Patients, on average, experienced higher pain intensity 3 days after the operation than anticipated. The postoperative pain intensity at 3 days was the most severe, while postoperative pain intensity at 6 weeks was the least severe. Age, gender and preoperative diagnosis (acute versus chronic) did not have a significant effect on the severity of pain that patients experienced. Six weeks following the operation, the majority of patients felt no pain. In addition, the severity of preoperative pain was highly predictive of their anticipated postoperative pain and 6-week postoperative pain, and both preoperative pain and anticipated pain predict higher immediate postoperative pain.The intensity of patients' preoperative pain was predictive of the anticipated postoperative pain. Patients' preoperative pain and anticipated postoperative pain were independently predictive of the 3-day postoperative pain. The higher pain intensity a patient experienced preoperatively suggested that their postoperative pain severity would be greater. Therefore, surgeons should be aware of these findings when treating postoperative pain after orthopaedic foot and ankle operations.

  View details for DOI 10.3113/FAI.2008.1063

  View details for PubMedID 19026197

• Prenatal diagnosis of placenta accreta - Sonography or magnetic resonance imaging? JOURNAL OF ULTRASOUND IN MEDICINE Dwyer, B. K., Belogolovkin, V., Tran, L., Rao, A., Carroll, I., Barth, R., Chitkara, U. 2008; 27 (9): 1275-1281

  Abstract

  The purpose of this study was to compare the accuracy of transabdominal sonography and magnetic resonance imaging (MRI) for prenatal diagnosis of placenta accreta.A historical cohort study was undertaken at 3 institutions identifying women at risk for placenta accreta who had undergone both sonography and MRI prenatally. Sonographic and MRI findings were compared with the final diagnosis as determined at delivery and by pathologic examination.Thirty-two patients who had both sonography and MRI prenatally to evaluate for placenta accreta were identified. Of these, 15 had confirmation of placenta accreta at delivery. Sonography correctly identified the presence of placenta accreta in 14 of 15 patients (93% sensitivity; 95% confidence interval [CI], 80%-100%) and the absence of placenta accreta in 12 of 17 patients (71% specificity; 95% CI, 49%-93%). Magnetic resonance imaging correctly identified the presence of placenta accreta in 12 of 15 patients (80% sensitivity; 95% CI, 60%-100%) and the absence of placenta accreta in 11 of 17 patients (65% specificity; 95% CI, 42%-88%). In 7 of 32 cases, sonography and MRI had discordant diagnoses: sonography was correct in 5 cases, and MRI was correct in 2. There was no statistical difference in sensitivity (P = .25) or specificity (P = .5) between sonography and MRI.Both sonography and MRI have fairly good sensitivity for prenatal diagnosis of placenta accreta; however, specificity does not appear to be as good as reported in other studies. In the case of inconclusive findings with one imaging modality, the other modality may be useful for clarifying the diagnosis.

  View details for Web of Science ID 000258853200002

  View details for PubMedID 18716136

• Urinalysis vs urine protein-creatinine ratio to predict significant proteinuria in pregnancy JOURNAL OF PERINATOLOGY Dwyer, B. K., Gorman, M., Carroll, I. R., Druzin, M. 2008; 28 (7): 461-467

  Abstract

  To compare the urine protein-creatinine ratio with urinalysis to predict significant proteinuria (>or=300 mg per day).A total of 116 paired spot urine samples and 24-h urine collections were obtained prospectively from women at risk for preeclampsia. Urine protein-creatinine ratio and urinalysis were compared to the 24-h urine collection.The urine protein-creatinine ratio had better discriminatory power than urinalysis: the receiver operating characteristic curve had a greater area under the curve, 0.89 (95% confidence interval (CI) 0.83 to 0.95) vs 0.71 (95% CI 0.64 to 0.77, P<0.001). When matched for clinically relevant specificity, urine protein-creatinine ratio (cutoff >or=0.28) is more sensitive than urinalysis (cutoff >or=1+): 66 vs 41%, P=0.001 (with 95 and 100% specificity, respectively). Furthermore, the urine protein-creatinine ratio predicted the absence or presence of proteinuria in 64% of patients; urinalysis predicted this in only 19%.The urine protein-creatinine ratio is a better screening test. It provides early information for more patients.

  View details for DOI 10.1038/jp.2008.4

  View details for Web of Science ID 000257271500003

  View details for PubMedID 18288120

  View details for PubMedCentralID PMC2743480

• Mexiletine therapy for chronic pain: Survival analysis identifies factors predicting clinical success JOURNAL OF PAIN AND SYMPTOM MANAGEMENT Carroll, I. R., Kaplan, K. M., Mackey, S. C. 2008; 35 (3): 321-326

  Abstract

  Mexiletine, a sodium channel blocker, treats neuropathic pain but its clinical value has been questioned due to its significant side effects and limited efficacy. We hypothesized that ongoing therapy with mexiletine would have limited patient acceptance, but that an analgesic response to intravenous (IV) lidocaine (a pharmacologically similar drug) would identify patients most likely to choose ongoing therapy with mexiletine. We identified a cohort of 37 patients with neuropathic pain who underwent IV lidocaine infusions at our institution and were subsequently prescribed mexiletine. Time until discontinuation of mexiletine was used as the primary endpoint. Time until discontinuation is a clinically relevant, discrete, objective endpoint gaining acceptance as a metric for assessing clinical performance of drugs with significant side effects and limited efficacy. We used the techniques of survival analysis to determine factors that predicted continued therapy with mexiletine. Median time to discontinuation of mexiletine was only 43 days. A stronger analgesic response to IV lidocaine significantly predicted continued acceptance of mexiletine therapy. Decreasing age and male gender also predicted continued acceptance of mexiletine therapy. Analyzing time to mexiletine discontinuation uncovers important limitations in mexiletine's clinical performance missed by studies with conventional endpoints, such as change in pain score. Despite claims of efficacy, acceptance of mexiletine therapy is poor overall. Test infusions with lidocaine identify patients most likely to continue mexiletine therapy. Further work is needed to confirm these results and evaluate the relative acceptance of mexiletine vs. other treatments of neuropathic pain.

  View details for DOI 10.1016/j.jpainsymman.2007.04.022

  View details for Web of Science ID 000253919000016

  View details for PubMedID 18222627

  View details for PubMedCentralID PMC2925416

• Multivariate analysis of chronic pain patients undergoing lidocaine infusions: Increasing pain severity and advancing age predict likelihood of clinically meaningful analgesia CLINICAL JOURNAL OF PAIN Carroll, I., Gaeta, R., Mackey, S. 2007; 23 (8): 702-706

  Abstract

  The proportion of chronic pain patients with suspected neuropathic pain who will have clinically meaningful pain relief with intravenous (IV) lidocaine and the clinical characteristics that identify these patients have not been described previously.We conducted a cohort study of 99 patients who underwent IV lidocaine infusions for suspected neuropathic pain. An 11-point Numerical Rating Score (NRS) of pain intensity was recorded at the beginning and end of each infusion. A predefined literature-based criteria for "clinically meaningful" reductions in pain score was used to classify patients as responders or nonresponders. Multivariate logistic regression was used to determine clinical variables that predicted an increased likelihood of being a lidocaine responder.The mean reduction in NRS during lidocaine infusions was 2.34 (95% confidence interval 2.83-1.85, P<0.001). Forty-two percent of patients (95% confidence interval 32.5%-52.8%) had NRS reductions of 30% or greater and met the predefined criteria as lidocaine responders. Univariate and multivariate analyses indicated that advancing age and pain severity significantly increased the odds of being a lidocaine responder. Controlled for all other factors, each decade of advancing age increased the odds of being a lidocaine responder by 36%. Each 1-point increase, on an 11-point scale of baseline pain severity, increased the odds of being a lidocaine responder by 29%.IV lidocaine effectively reduces pain in a minority of patients suspected of having neuropathic pain. Pain severity and patient age can be used to target therapy to those most likely to respond.

  View details for Web of Science ID 000249743000009

  View details for PubMedID 17885349

• Intravenous lidocaine for neuropathic pain: diagnostic utility and therapeutic efficacy. Current pain and headache reports Carroll, I. 2007; 11 (1): 20-24

  Abstract

  Lidocaine is a use-dependent sodium channel blocker that produces analgesia when administered intravenously to patients with neuropathic pain. This article reviews the role and limitations of intravenous lidocaine infusions for neuropathic pain. Lidocaine infusions rarely provide relief that persists significantly beyond the duration of the infusion. Diagnostically, systemic lidocaine may help establish the presence of neuropathic pain and the responsivity to oral sodium channel blockade. However, the data supporting diagnostic infusions remain sparse. Therapeutically, infusions should generally be restricted to patients with neuropathic pain who are unable to take oral medication.

  View details for PubMedID 17214917

• Celiac plexus block for visceral pain. Current pain and headache reports Carroll, I. 2006; 10 (1): 20-25

  Abstract

  Celiac plexus block has long been used to provide analgesia for upper abdominal pain. In particular, neurolytic celiac plexus block has been advocated for pancreatic cancer pain. In this article, recent advances clarifying the role and limitations of neurolytic celiac plexus block are reviewed. Neurolytic celiac plexus block provides persistent augmented analgesia when used as an adjunct to systemic opiates, but does not reliably decrease opiate requirements. In addition, neurolytic celiac plexus block may prolong survival, but the data supporting this remain controversial. The optimal technique for accomplishing neurolytic celiac plexus block remains undetermined.

  View details for PubMedID 16499826

• A vaccine to prevent herpes zoster NEW ENGLAND JOURNAL OF MEDICINE Carroll, I., Gaeta, R., Mackey, S. 2005; 353 (13): 1414-1415

  View details for Web of Science ID 000232146200022

  View details for PubMedID 16196123

• Management of perioperative pain in patients chronically consuming opioids REGIONAL ANESTHESIA AND PAIN MEDICINE Carroll, I. R., Angst, M. S., Clark, J. D. 2004; 29 (6): 576-591

  Abstract

  The prevalence of licit and illicit opioid use is growing, and a greater percentage of chronically opioid-consuming patients are presenting for surgery. These patients can be expected to experience increased postoperative pain, greater postoperative opioid consumption, and prolonged use of healthcare resources for managing their pain.Achieving adequate pain control in these patients can be challenging because commonly used strategies for alleviating postoperative pain may have diminished effectiveness. We explore the prevalence and characteristics of opioid use in the United States and discuss its impact on the perioperative management of pain. We examine mechanistically why adequate perioperative pain control in chronically opioid-consuming patients may be difficult.We present strategies for providing adequate analgesia to these patients that include the optimal use of opioids, adjuvant medications, and regional anesthetic techniques.

  View details for DOI 10.1016/j.rapm.2004.06.009

  View details for PubMedID 15635517

• HIV Tat represses transcription of the beta(2)-microglobulin promoter MOLECULAR IMMUNOLOGY Carroll, I. R., Wang, J., Howcroft, T. K., Singer, D. S. 1998; 35 (18): 1171-1178

  Abstract

  The MHC class I complex, which binds and presents peptide antigen, is composed of a class I heavy chain and the beta2-microglobulin light chain. HIV-1, which induces a profound immunodeficiency in infected individuals, encodes proteins that cause decreased expression of class I heavy chain. We now report that the HIV Tat protein, which is a potent transactivator of viral transcription, is also a potent repressor of the beta2-microglobulin gene. Repression is mediated through the basal promoter of the beta2-microglobulin gene, which is shown to be predominantly regulated by an initiator element. Tat repression is further augmented by the short viral transcript, TAR, which interacts with Tat. Tat-mediated repression of beta2-microglobulin expression, together with its known repression of class I gene transcription, provides an effective mechanism by which HIV could prevent cell surface expression of the MHC class I complex and avoid immune surveillance.

  View details for Web of Science ID 000079458800003

  View details for PubMedID 10199391