Chronic Opiod Use after Hysterectomy

Chronic Opiod Use after HysterectomySpecific take upsThe rapid maturation in the incidence of opioid- lad overdoses and deaths has become a big public health threat in the unite States. This opioid epidemic affects more women than men delinquent to higher opioid prescribing and dose, longer period physical exertion, and more opioid dependence in women.1 From 1999 to 2010, the say of opioid overdose ca employ death enlarged 5-fold among women.2 Besides the illicit purchase for most women, the sign moving-picture show to opioids for m to each one new(prenominal)s may excessively come from the symmetric medical treatment as prescription medicine medicine(prenominal) opioids argon widely pulmonary tuberculosisd for bruise management after mental process.3 As such, the critical question rift on opioids utilization is that the evidence is insufficient to draw conclusions about optimum strategies for inductive reasoning and titration of opioid therapy.4 Several ob servational studies imbibe investigated the patterns of opioid call for noncancer anguish in patients pre and localise-surgery, and set the danger factors of continuing opioid put on post-surgery.5-11 Most of these studies examined the counterion of baseline demographic and clinical characteristics of patients for prolonged opioid surgical exercising and suggested that surgery is a risk factor for degenerative opioid operative use.5-9 Only two studies examined the initial opioid picture show within 6 or 7 days of the surgery date and results argon controversial.10,11 One airfield report that initial icon of opioid poses 44% increase risk of inveterate postoperative opioid use and some different one suggested that this risk would be low and statistically in noteworthy.10,11 Similar probe has not been done specifically for hysterectomy, the most much performed non-obstetric surgeries in the coupled States for women of reproductive age.3,12 Pain has been demonstra ted as a common sign before and after hysterectomy.13,14 A small cross-sectional study has examined the predictors for opioid prescription in women of productive age and identified that opioid use was seriously brotherd with hysterectomy shape and pang-related dys parting.15 Another cross-sectional survey study reported that 32% patients had degenerative twinge after hysterectomy.14 Neither chronic opioid postoperative use nor initial opioid scene for cutting surgery pain was examined in these two studies.14,15 filling this gap in knowledge is critical since identifying the risk factors of chronic opioid postoperative use could lead to optimized initial opioid prescribing for acute pain management and cut chronic opioid postoperative use and improved women health.Our semipermanent goal is to sponsor bowdlerize chronic use of opioids and optimize the pain management in women after obstetric and gynecologic surgery done identification and dissemination the safer initial opioid prescribing for acute post-operative pain. Our objective here, which is the next step in our long-term goal, is to comp atomic number 18 the patters of opioid use pre and post hysterectomy and determine the important risk factors that swain with chronic use of opioids in women post hysterectomy.The subject OptumInsight Clinformatics data offers an immanent resource to investigate these aims. The availability of clinical diagnoses and chemists medical dispensing offers a significant advantage for investigating drug habit with corresponding clinical conditions in large tribe.Our team is salubrious suited to conduct this research given extensive expertise in contemporary pharmacoepidemiology, many a(prenominal) long measure of experience on opioid abuse research, former drug utilization studies victimisation large claims data, and clinical expertise from obstetric and gynecologic physicians.Our specific aims are to investigate patterns and predictors of chronic opioi d use in women pre and post hysterectomy with the following analyses claim 1 To characterize the patterns of chronic opioid use in women after hysterectomy.Aim 2 To determine the significant risk factors for chronic use of opioids in women after hysterectomy.The first specific aim for this study is to identify patients who inveterate take opioids during six months post hysterectomy, and investigate the time and geographical patterns of chronic opioid use in women after hysterectomy. The pattern of chronic opioid use pre- and post-surgery get out besides be compared in women with varied age, comorbidities, co-medicaments, as well as causes and doses of initial opioid prescribing. The trice specific aim is to determine the risk factors that importantly relate to chronic opioid use, and determine if characteristics of initial change opioid prescriptions importantly associate with the chronic use of opioids after adjusting for other potential risk factors. many another(prenominal) pain related studies pay back demonstrated that long term opioid prescribing was significantly predicted by patients clinical characteristics and psychosocial factors, including pain conditions, psychiatric disorders, frequency of medical visits, smoking, and pain-related dysfunction.16-18 Therefore, the correct covariates in this study would entangle both demographic and clinical characteristics.B. entailment and InnovationCurrently the United States is experiencing an unprecedented opioid epidemic. According to the Centers for Disease mesh and Prevention (CDC), opioid-related deaths increased 200% overall from 2000 to 2014.19 During 2014, about 1.9 million throng had an addiction of opioids, with overall 47,055 overdose deaths, 18,243 overdose deaths in women, and 18,893 overdose deaths related to prescription pain relievers.20,21 Based on the data reported by the CDC, women are more wish wellly to have chronic pain, be impose opioids with higher dose and longer period, a nd hence progress to dependence.22 Although opioid abuse is a public health crisis, opioid analgesics are mum the mainstay for treatment for acute pain after major surgery. In 2014, total 245 million prescriptions for opioids were parcel out from U.S. retail pharmacies.23,24During 1998-2010, approximately 7.4 million hysterectomies were performed, making hysterectomy one of the most frequently performed surgeries for women in the United States.25 With over 60% of hysterectomies performed abdominal musclely and up to 85% of patients experiencing moderate-to-severe pain after hysterectomy, postoperative pain management becomes very important.26,27 Evidence suggests that enthusiastic and long-lasting postsurgical pain can increase postsurgical morbidity, delay recovery, and lead to chronic pain.28 Opioids such as morphine, meperidine, and oxycodone are widely use postoperatively to reduce and manage pain in patients after hysterectomy.29 Women with hysterectomy and high levels of p ain-related dysfunction were most twice as likely to have opioid prescription. More than 85% of women with hysterectomy and a high level of pain-related dysfunction were found to use opioid.15 Hormonal disturbance, hyperalgesia, and induced effectuate are potential adverse effects from opioid use in women after hysterectomy.14,15 The interaction of opioid-induced adverse effects and post-hysterectomy hormonal dysregulation may deepen pain and promote continued use of opioids.15 There are no known studies that evaluate the connection between acute and chronic postsurgical opiate prescription in women experienced hysterectomy. In consideration of the current opioid epidemic it is important to to a lower placestand how post-surgical pain is managed, and if this setting presents increased risk of opioid addiction among trusted groups, or related to particular prescribing practices. The goal of this proposed study is to examine whether opioids order in women following hysterectomy is associated with chronic use of opioids, and to evaluate which factors may predict patterns of opioid use that indicate overuse or addiction. Accordingly, this study first aims to give away the incidence pattern of chronic opioid use in women post hysterectomy. The second aim is to explore the significant risk factors and determine if the characteristics of initial opioid prescribing significantly associate with chronic opioid use after adjusting for other potential risk factors.This study go forth reveal important insights regarding post-surgical pain management for a common procedure, and determine if genuine patient or treatment characteristics increase the risk of chronic opioid use in this setting. We expect that this research giveing propose evidence for the need to improve clinical practice towards optimized pain management and reduced chronic opioid use in women after hysterectomy through identification the specific opioid, drug type (short-acting or long-acting), a nd doses that significantly associate with chronic opioid use in women after hysterectomy. Our study forget provide sufficient evidence to draw conclusion about optimal strategies for initiation and titration of post-surgery opioid therapy, and enhance evidence-establish medicine for opioid use in Rhode Island, and also the United State.This pl chthonic would enhance my capabilities on handling interdisciplinary studies and further help me to set up my own research projects and seek for external funding.InnovationOur proposed observational studies based on the administrative claims data get out allow for investigation of time apparent motions and geographic variability of drug use in large creation and address for well-characterized clinical conditions. Our approach ordain employ state of the art, modernistic pharmacoepidemiologic study designs and statistical influences, to improve the precision of outcome definition and defame measured and unbounded throw and bias in our estimation of significant predictors for chronic opioid use after hysterectomy.The unintended outcomes from adverse drug effects make the prospective trials unethical. In this circumstance, a well-designed, retrospective observational study with sufficient sample size offers an efficient design to determine if in that respect is an adequate signal for impropriate opioid prescribing to women post obstetrics and Gynecology surgery.The generalizability of study results are guaranteed due to the nationwide large health plan data that the analyses are based upon.C. ApproachData Sources ruminate data impart be derived from the national OptumInsight Clinformatics Data MartTM, a research database spanning January 01, 2010 through December 31, 2013. The Optum seek Database includes about 23 million beneficiaries from the nationwide commercial health insurer, United Healthcare. The data contains health care utilization with transactional reimbursement data from outpatient pharmacy disp ensing, inmate and outpatient services.30 It links administrative enrollment data with the important medical enactments including the national drug cypher (NDC) for pharmacy dispensing, the Current Procedural Terminology (CPT) code for medical procedure, and International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for diagnosis. The claims data in this database have been adjudicated, ascertained, and deidentified for research purpose. The University of Rhode Island (URI) and OptumInsight Inc have approved utilization of these data. URI already licenses this database that it is freely available for faculties to use.Study PopulationThis study leave behind include adult women who receive the hysterectomy surgery between July 01 2010 and June 31 2013 and have at least 6 months of continuous prior coverage under this health insurance plan. This continuous 6-month coverage provides a baseline for delimitate new drug users, as well as baseline cli nical characteristics, such as comorbidities and co-medications. The hysterectomy procedures will be derived from the ICD-9-CM diagnostic codes 68.3x-68.7x, and 68.9x, where 68.3x indicates a subtotal abdominal hysterectomy, 68.4x indicates a total abdominal hysterectomy, 68.5x indicates a vaginal hysterectomy, 68.6x indicates a total abdominal hysterectomy, 68.7x indicates a radical vaginal hysterectomy, and 68.9x indicates other and unspecified hysterectomy.13,31 Patients with pelvic evisceration (ICD-9-CM 68.8x) will be excluded. We also will exclude patients with any cancer diagnoses, including malignant neoplasm of the young-bearing(prenominal) genitourinary organs-cancer (ICD-9-CM 179-184), and carcinoma in situ of female genitourinary system (ICD-9-CM 233).Exposure AssessmentOpioids in this study include the following medications codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, and oxymorphone. Tramadol and propoxyphene, considered as weak opioids or already off market, will not be included.11,15 The moving picture group involves adult women who receive the hysterectomy surgery and fill more than one prescription for opioids on the day of hospital discharge or within 7 days after hysterectomy surgery, provided that they have no exposure to opioids for at least 6 months prior to hysterectomy.11 The 7 days of window is based on the assumption that a filled prescription during this period would likely to treat acute postoperative pain caused by hysterectomy. A comparison group, defined as the patients with no opioids use on the day of hospital discharge or within 7 days after hysterectomy surgery, will serve as a defend to make a comparison of risks for chronic use of opioids. The control patients also have no exposure to opioids for at least 6 months prior to hysterectomy. The exposure of opioids will be identified using NDC codes from pharmacy claims data.In this study, exposure assessment includes all chara cteristics of the initial filled opioid prescription at the day of hospital discharge from hysterectomy or during 7 days post-hysterectomy. The diverse type of opioids ( separate as long or short acting), number of cater days, and oral morphine equivalent daily dose (milligrams) will be assessed and analyzed.Outcome AssessmentSince the study focuses on the risk of chronic opioid use after initial exposure to opioids following hysterectomy, patients were followed from the 8th day after hysterectomy to the first day of outcome occurrence. The outcome, chronic use of opioids after hysterectomy, will be defined using flying models.11 in which patients with similar patterns of medication filling during reexamination will be grouped together. The trajectory model was initially generated for the purpose of the assessment of medication adherence.32,33In order to crystalise the trajectory groups for opioid use during the defined follow through window, we first generate 6 dichotomous va riables to indicate if a study participant fills a prescription of an opioid medication during each of 6 consecutive 30 day follow-up periods.11 we then model these 6 binary indicators of using opioids in each 30 day follow-up period as a longitudinal response in a logistic group-based trajectory.34,35 With a trajectory model, we will estimate the probability of membership of patients in each group, and the probability of the certain opioid exposure over time as a smooth function of time. We will fit the model using 2 to 4 opioid exposure groups with comparison of the Bayesian Information Criterion.36 The number of groups will be chosen based on the value of the Bayesian Information Criterion. In each group, a third-order polynomial (including linear, squared, and cubic terms) of time will be used to model the probability of being exposed to opioids. Patients will be assign to different trajectory groups, which are generated from these models and have highest probability of the me mbership. Based on the model results, the group of patients with the highest probability of filling opioids over time will be defined as the chronic use. Other trajectory groups were classified as nonchronic users. The trajectory models provide new advanced approaches to utilize the observed data to determine distinct filling patterns of opioids in our study population during the year after hysterectomy surgery. It classifies patients into groups with similar opioid exposure patterns without relying on a priori and prejudiced cutoff line for the definition of chronic opioid use. The trajectory models will be conducted using SAS Proc Traj (SAS, version 9.4, SAS Institute Inc., Cary, NC, USA).Patterns of Chronic Opioid UseAfter chronic opioid use is defined using trajectory models, we will compare the frequency of the incidence of chronic opioid use over time from 2010 to 2013. The secular trend will be analyzed using Joinpoint regression program (National genus Cancer Institute, C alverton, MD) to identify the joint points and slopes. The rates of chronic opioid use in women post hysterectomy will also be compared with varied age, comorbidities, co-medications, as well as characteristics of initial opioids exposure, including opioid types and doses.The geographic variation of chronic opioid use will be mapped and analyzed using ArcGIS 10.5 geographic information systems software (ESRI, Redlands, CA). The opioid prescription policies and socioeconomic status in different states will be compared with the geographic variation of chronic opioid use.Predictors of Chronic Opioid UseWe will identify the predictors of chronic opioid use at baseline or the time of the initial opioid prescription. A previous study demonstrated that hysterectomy, older age, and higher levels of pain-related dysfunction were associated with opioid prescription.15 Potential predictors in this study would include age, year of surgery, smoking, illicit substance abuse, alcohol abuse, hyster ectomy type, hallucinogenic medication use, pre-operative depression, pre-operative pain condition, primary winding mark for hysterectomy, co-medications, and characteristics of the initial opioid exposure. Although the benefits of minimally invasive surgical procedures have been documented,37 hysterectomies performed for benign indications in 2010 in the US still consisted of 40.1% total or subtotal abdominal hysterectomies, 30.5% laparoscopic hysterectomy, 19.9% vaginal hysterectomy, and 9.5% robotic-assisted hysterectomy.21,25 Hysterectomy type has been related to the initial opioid prescription,15 however, the results from randomized clinical trials showed that abdominal hysterectomies didnt increase postoperative chronic pain.38,39The primary indication for hysterectomy is defined based on the following algorithm (i) precancerous conditions will be assigned the primary indication if endometrial cystic hyperplasia or carcinoma in situ of female genitourinary system is listed as an indication associated with hysterectomy surgery (ii) whichever is listed first of endometriosis, uterine prolapse, or uterine leiomyoma will be assigned the primary diagnosis associated with hysterectomy if cancer or a precancerous condition is not listed (iii) endometrial cystic hyperplasia is combined with in situ under precancerous and that pain and bleeding were included as reported reasons for hysterectomy, and (iv) other was assigned the leading for the remaining diagnoses.19Over 60% of patients have reported pain as pre-operative symptoms for hysterectomy.39 After hysterectomy, the prevalent pain was reduced to 4.7% to 31.9% during 1-2 eld after surgery, while new onset pain at follow-up was reported in 1-14.9% patients and increased pain was in 2.9-5% of patients with pre-operative pelvic pain.39 Therefore, in our study, we plan to assess pre- and post-operative pain, as well as the pain conditions, including pelvic pain, back pain, fibromyalgia, and migraine or othe r headache syndromes using ICD-9-CM codes.Patients with pharmacy claims for opioids or diagnoses for opioid abuse (ICD-9-CM 304.xx) during the 6-month baseline period will be identified as opioid users prior to hysterectomy.Preoperative depression that has been found significantly associated with postoperative chronic pain,40 will be identified using diagnoses, as well as medication use at baseline. Antipsychotropic medication use will be obtained using prescription information. The psychiatric comorbidity, will be assessed using prescription information instead of ICD-9-CM codes for greater specificity.11 Co-medications refer to the use of other medications on postoperative pain management. The postoperative use of Nonsteroidal anti-inflammatory drug drugs (NSAIDs) or Acetaminophen with opioids has been found safe and effective on pain relieve with reduced opioid dose.41All potential predictors, including characteristics of initial opioid use, will be adjusted in variable analyses to identify the significant predictors for chronic use of opioids in patients post hysterectomy.Statistical AnalysisStatistical tests and modeling will be conducted to identify potential significant risk factors for chronic use of prescribed opioids in women post-hysterectomy. Categorical variables will be examined and compared using qi square or the Fisher exact test. Continuous variables will be compared using the student t test. The covariates will be selected from all demographic and clinical variables using statistical modeling. A univariate analysis will be performed with the initial opioid exposure variable and then with each covariate added one at a time to monitor the change of the estimate of the major exposure variable. The covariates that modify the estimate of opioid exposure (variable 5%) or significantly predict the chronic use of opioids will be selected for further multivariate analysis. To account for many confounding factors, we will also utilize propensity score unified method to combine all confounding factors into a propensity score. The patients with initial opioid exposure will be 15 matched with the patients without initial opioid exposure using the propensity score with a caliper of 0.01. A multivariate conditional logistic regression model will be employ to measure the adjusted odds ratio of initial opioid exposure on chronic opioid use in two matched groups.A probability of type 1 error (alpha) = 0.05 will be considered to be the threshold of statistical significance. Tukey-Kramer method will be applied to correct the inflated p value due to multiple comparisons. Statistical analysis will be performed using SAS software (version 9.4, Cary, NC).Sensitivity StudiesIn order to address unmeasured confounding factors, sensibility analyses will be conducted in two sections subgroup analyses and subservient variables.Subgroup analysisIn order to investigate the effects of initial opioid exposure in women post hysterectomy, multivariate analysis will be conducted in the following subgroups women with postoperative chronic pain, women without postoperative chronic pain, women with postoperative NSAIDs use, women without postoperative NSAIDs use, women with postoperative Acetaminophen use, and women without postoperative Acetaminophen use. Interactions between the drug exposure and the important factors will be examined in the multivariate analyses. Subgroup analyses will likewise be conducted if the interaction is statistically significant. instrumental Variable We plan to use propensity score matching to address all measurable confounding factors and generate two balanced comparison groups. However, the measureless confounding factors, like confounding by indication, may still impact the study validity. Instrumental variable is an advanced methodology that has been utilized in pharmocoepidemiological studies to control for the unmeasurable confounding factors, such as confounding by indication. In the sensitivity study, we will use the physicians preference as an instrumental variable and critique the initial opioid exposure on chronic use of opioids post hysterectomy.D. TimelineTable. Study Timeline of the Study.Time PeriodStudy ProgressBefore 07/01/2017Obtain IRB praise and Optum data use permission07/01/2017 08/01/2017Complete data cleaning, manipulating, and variable editing.08/01/2017 10/01/2017Complete analyses for demographic and clinical characteristics10/01/2017 01/31/2018Complete trajectory modeling to determine chronic opioid use. Analyze the time and geographic trends.02/01/2018 02/28/2018Submit an abstract to the annual meeting of International Society of Pharmacoepidemiology (ISPE)03/01/2018 06/30/2018Complete analyses for specific aim 107/01/2018 01/31/2019Complete prophetic modeling as described in specific aim 202/01/2019 02/28/2019Submit an R21 to NIH, and an abstract to the annual meeting of ISPE03/01/2019 06/30/2019 fight analyses for specific aim 2, including all sensitivity studies. Submit a final exam paper to a high impact journal09/01/2017 12/15/2017Complete course PHP 209001/01/2018 05/15/2018Complete course PHP 2470