Essay on Opioid Agonist Therapy

Introduction

The opioid crisis is a troublesome public health issue that has widely spread across the United States. Opioid use disorder (OUD) is associated with HIV and HCV infection, addiction, criminal behaviors, and even death (Day, 2018; Nilsen, 2018). Overdoses linked to prescription opioids have raised, and the rates of illicit opioid abuse, including heroin and fentanyl, are growing (Rudd, Seth, David, & Scholl, 2016). About 400,000 American died from an opioid overdose from 1999 to 2017 in the United States (Scholl, Seth, Kariisa, Wilson, & Baldwin, 2018). The harms related to the OUD have contributed to declining life expectancy among middle-aged white Americans (Case & Deaton, 2015). The opioid epidemic has also caused an enormous economic cost, which estimated to $78.5 billion per year (Pacula & Powell, 2018).

Get Help With Your Nursing Essay

If you need assistance with writing your nursing essay, our professional nursing essay writing service is here to help!

Nursing Essay Writing Service

Opioid agonist therapy (OAT) includes methadone or buprenorphine, is the empirically supported and gold-standard treatment for OUD, which is confirmed to be effective in decreasing its negative consequences (Hagedorn et al., 2018; White, 2018). These medications temper withdrawal symptoms, improve mood, enhance phycological balance, and increase life expectancy, which allows the brain to recover and prevents relapse during long-term treatment (Mattick, Kimber, Breen, & Davoli, 2014; Saloner & Barry, 2018; Volkow, Frieden, Hyde, & Cha, 2014). Individuals who increased OAT utilization used fewer expensive health care services, resulting in overall reduced healthcare expenditure compared to non-adherent patients (Duber et al., 2018). Nevertheless, despite the strong and clear evidence supporting OAT and its use worldwide (Russia, China, Australia, France, and the United Kingdom), patients are often unable to access OAT (Saloner & Barry, 2018).

Problem Statement

Current policies do not solve the lack of available OAT for people who have OUD.

Roadmap

This paper will first provide an overview of growing concern regarding low OAT accessibility and origins of this problem. It will explore the related policies affecting this issue. Then it will analyze two potential solutions which will include benefits and detriments. Finally, it will make a recommendation and conclusion.

Overview of OAT Accessibility

Growing Concern Regarding OAT Accessibility

Only about one-fifth of people with OUD obtain OAT treatment in the United States (Saloner & Barry, 2018). Only half of the private treatment programs have utilized OAT, and in those that do offer OAT, only one-third of patients receive it (Hagedorn et al., 2018). Less than 4% of licensed physicians are permitted to prescribe buprenorphine for OUD (Christie et al., 2017). About 47% of counties and 72% of rural counties lacked a buprenorphine-waivered physician in 2016 (Christie et al., 2017). Remarkably, over 20 million Americans live in a rural county where there are no physicians who can order buprenorphine (Rosenblatt, Andrilla, Catlin, & Larson, 2015). Therefore, it is imperative to increase implementation of OAT due to the underutilization. The future success of treating individuals who are struggling in OUD depends on building a more coherent system to allow individuals more accessible to OAT with fewer restrictions.

Barriers to OAT

There are two relevant barriers of accessing to OAT is the insufficient buprenorphine utilization and lacking methadone treatment. To prescribe buprenorphine, physicians need to obtain a waiver from the U.S. Drug Enforcement Agency (DEA). Only 2.2% of eligible prescribers have taken the training that is required to prescribe buprenorphine (Vashishtha, Mittal, & Werb, 2017). These providers are also capped in their maximum patient volume (Hugh & Dunn, 2017). Even waived providers provide service in their maximum capacity, a gap of nearly one million people in need of OAT exists nationally (Jones, Campopiano, Baldwin, & McCance-Katz, 2015). Many studies conducted by providers highlighted out some workforce barriers contributing to buprenorphine underutilization, such as insufficient training, inadequate experience, lack of institutional peer support, poor care coordination, provider stigma, low insurance reimbursement, and burdensome regulatory procedures (DeFlavio, Rolin, Nordstrom, & Kazal, 2015; Haffajee, Bohnert, & Lagisetty, 2018; Mendoza, Rivera-Cabrero, & Hansen, 2016).

Methadone can only be administered through an Opioid treatment programs (OTPs) certified by Substance Abuse and Mental Health Services Administration (SAMHSA) (Saloner & Barry, 2018). However, a qualified OTP requires essential and logistical resources, including staffing and electronic medical record-keeping capability that ensures patients’ confidentiality (White, 2018). Methadone treatment also needs daily visits to an OTP which can interfere jobs or other important activities. The limitation of federal policies and regulations severely impair prescribers’ ability to effectively address the epidemic, particularly in many rural and underserved areas of the nation (Rosenblatt et al., 2015).

Policies Impacting OAT Accessibility

Drug Addiction Treatment Act(DATA) 2000

DATA 2000 is federal legislation, section 3502 of the Children’s Health Act, which became effective in October 2000 (SAMHSA, 2019). Historically, federal regulations of medication and treatment made it hard for physicians to treat OUD. Buprenorphine has become an essential treatment of OUD but might cause potential abuse. DATA 2000 permits physicians who meet specific qualifications to obtain a waiver to treat OUD with Schedule III-V narcotic medications (SAMHSA, 2018). DEA is authorized to manage and enforced periodic on-site inspections of all registrants. In 2000, DATA permitted doctors to treat only 30 patients at one time. Time has shown that the abuse potential for the drug is very low, yet doctors are still forced to turn away patients who directly come to them for help. In December 2006, one provision was added in DATA 2000, which allowed physicians who have been certified for more than one year could treat up to 100 patients (SAMHSA, 2019). In July 2016, federal regulations under DATA 2000 extended buprenorphine treatment by authorizing qualified physicians to treat up to 275 patients (SAMHSA, 2017). In addition, the Comprehensive Addiction and Recovery Act (CARA) of 2016 amended the Controlled Substances Act (CSA) to enable qualifying nurse practitioners and physician assistants to obtain a DATA 2000 waiver and prescribe buprenorphine up to 30 patients initially, and up to 100 patients following waiver approval after the first year (U.S. Department of Health and Human Services [HHS], 2019). Physicians need to take 8-hour mandatory training, and 24-hour training to advanced practice nurses and physician assistants to achieve a waiver (Hagedorn et al., 2018).

OTP Regulations

OTP regulations are a federal guideline for OTP, which became effective in May 2001 (Congressional Research Service, 2018). OTP regulations were emerged due to the rising concern about the safety and effectiveness of treatment and service in the OTP settings. OTP regulations describe a minimum acceptable federal standard for the operation of OTPs, which provide accreditation and certification-based system for OTPs (SAMHSA, 2019). OTP federal regulations had not changed since their initial approval in 2001. SAMHSA focused on demonstrating how these regulations may be utilized in the current context of clinical and medical issues in several revised editions (SAMHSA & HHS, 2015).

Policy Solutions

Eliminate Buprenorphine Waiver Requirement

Since buprenorphine had been approved in the early 2000s, the policy actors kept buprenorphine tightly restricted (Saloner, Daubresse, & Alexander, 2017). Initially, physicians waivered to prescribe the drug could only treat 30 patients, later relaxed to 100, then 275. However, it is unlikely to change most buprenorphine prescribers, who prescribe to 13 patients on average every month (Saloner & Barry, 2018). The time-consuming DATA waiver process and ongoing qualifications are likely to discourage participation (Berk, 2019). Also, the mandatory 8-hour or 24-hour training is not sufficient to help prescribers feel qualified and confident to provide OAT, especially to who had no prior experience in treating OUD (DeFlavio et al., 2015). Moreover, unlike methadone, the opioid in buprenorphine is not very potent, so it has minimal risk of abuse and rarely causes an overdose (Andraka-Christou, 2016). It is one of the only medications in the primary care setting that can help patients fight addiction. Buprenorphine is a safe, evidence-based, cost-effective treatment that can help restore millions of addicts’ lives and cut mortality of overdose-related deaths by more than 50% (Saloner et al., 2017). Therefore, it is unnecessary to have a waiver requirement for buprenorphine prescribing.

Find Out How NursingAnswers.net Can Help You!

Our academic experts are ready and waiting to assist with any writing project you may have. From simple essay plans, through to full dissertations, you can guarantee we have a service perfectly matched to your needs.

View our academic writing services

Benefits. Discontinuing the buprenorphine waiver would allow more providers to prescribe medication for opioid use disorder and would help empower individuals to overcome addiction (Berk, 2019). The government can mandate buprenorphine prescriber training in graduate school and continuing medical education, which will be more impactful and practical (Haffajee et al., 2018). Add OAT training into general medical education can reduce persistent stigma around buprenorphine provision and increase mentorship and shared expertise opportunities around buprenorphine (Pincus, Scholle, Spaeth-Rublee, Hepner, & Brown, 2016). The medical students who received OAT training in graduate school presented a better preparedness and willingness to treat OUD (Bäck, Tammaro, Lim, & Wakeman, 2018). A black market exists in part due to the lack of addiction treatment (Harper, 2018). Buprenorphine deregulation may take away the need for a black market.

Detriments. This change requires an upfront investment, likely requiring billions of dollars to set up a new continuous teaching system of OAT training in all medical schools to reach maximal effectiveness. It is also unfair to some primary care doctors who are not interested in treating substance abuse disorders. On the other hand, buprenorphine might be administered improperly without waivers and regulations. Buprenorphine deregulation may allow patients to be able to go to an emergency department for a buprenorphine refill without obtaining other supporting therapies to treat their addiction (Fiscella, Wakeman, & Beletsky, 2018). Patients who have prescriptions for buprenorphine sometimes sell or give it away in the black market (Harper, 2018). It is potential to fatally overdose on buprenorphine, particularly if users don’t have a tolerance to opioids or they combine it with other substances (Harper, 2018).

Increase Methadone Use in Primary Care

With few exemptions, the usage of methadone to treat OUD is limited to highly structured OTPs. The restriction of methadone to OTPs has generated a treatment gap in meeting the needs of the opioid crisis (Knopf, 2018). The coverage and accessibility of methadone are insufficient, especially in some rural regions. The calls for allowing methadone to be delivered in primary care settings is growing (Carrieri et al., 2014). The primary care setting can provide counseling to family members of the clients, make them understand the OAT, and assist the clients in cooperation with the health workers.

Benefits. Under proper circumstances, methadone induction in primary care is achievable and acceptable to both physicians and patients (Carrieri et al., 2014). It will extend the benefits, lessen street-opioid use, ensure engagement, and reduce risk of death (Cousins et al., 2016). The study by Zhang et al. (2018) showed that the expansion of methadone accessibility could have a great improvement in the retention of long-term treatment.

Detriments. Methadone has high abuse risk and are sought after on the illicit drugs market (Modesto-Lowe, Swiezbin, Chaplin, & Hoefer, 2017). A recent rise in methadone-related deaths in the United Kingdom was associated with the possibility of increased diversion and inappropriate OAT prescribing (Bachireddy, Weisberg, & Altice, 2015). Besides, methadone-maintained patients had a higher burden of chronic disease through using primary health services more intensively for drug-related illness and routine methadone care (O’Toole, Hambly, Cox, O’Shea, & Darker, 2014).

Recommendation

Justification

Opioid abuse negatively affects physical, mental, emotional, and financial health on individuals and create a burden for the family and country (Daley, Smith, Balogh, & Toscaloni, 2018). The severe and negative impacts of OUD push policy actors to seek actions in easing this crisis. In recent years, several policy facilitators have attempted to address specific barriers to robust buprenorphine provision. Leaders from the federal executive and legislative branches, in particular from SAMHSA, National Institute on Drug Abuse (NADA), and HHS have sought strategies to encourage the provision of quality OAT treatment (Saloner & Sharfstein, 2016). HHS has invited interested groups to submit comments on all aspects of the recommended rule. The key solutions that adding buprenorphine prescriber education and qualification in the graduate process for qualified prescribers, and expanding methadone treatment in primary care without limitations can ensure delivering accessible and effective OAT. Some innovative medical schools and states, like Massachusetts, are undertaking steps to include OAT training into medical education (Haffajee et al., 2018). This step could increase provider capacity in rural and underserved areas, where has fewer physicians with waivers and addiction specialists. Methadone maintenance therapy in primary care is cost-effective and enhances outcomes for opiate-dependent patients (Zhang et al., 2018). Moreover, expanding opportunities for OAT can also translate to a financial opportunity for physicians and pharmaceutical manufacturers (Cunningham, 2019; Rosenblatt et al., 2015). The change of policies to increase OAT availability will be highly possible to be supported by the majority of policymakers.

Concerns

Without a transformation in the treatment system for people with OUD, it will be impossible to solve the opioid epidemic. Federal oversight on insurance company practices was ineffective as the crisis expanded (Reif et al., 2017). The private insurance companies have become a more prominent payer of OUD treatment services. Burdensome prior authorization standards and increased insurance premium continue to limit access to OAT. A recent analysis of private insurance data found that most privately insured patients do not get recommended care following an opioid-related hospitalization (Christie et al., 2017). It is critical to developing new investments and powerful leadership from a diverse set of decisionmakers. These legislative change and intensify of governmental power will be extremely complicated. Also, it is essential that key stakeholders identify the health disparities in reaching life-saving OAT to be effective advocates of change. Additional training and reimbursement support are needed to support OAT adoption and use.

Conclusion

The opioid epidemic is one of the largest health crises affecting Americans. OAT is evidence-based and cost-effective intervention used to treat OUD. The public does not reach the optimal health outcome due to current legislative restrictions of OAT. Thus, enhancing OAT approachability in the community has been a notable focus to address the OUD treatment gap in the United States. Policies changes can open the door to the outside treatment settings and covering more OAT. Further policy change needs to concentrate on diminishing long-term opioid overdose risk and improving the quality of life of the millions of individuals who already have OUD. The long-term goal of expanding OAT accessibility is keeping people alive and providing them the opportunity to experience recovery and well-being in the future. Given these critical challenges for clinical practice, more researches about increasing OAT accessibility and evaluate alternatives are urgently needed.

References

• Andraka-Christou, B. (2016). America needs the treat act: Expanding access to effective medication for treating addiction. Health Matrix: Journal of Law-Medicine, 26, 309–362. Retrieved from http://dbproxy.lasalle.edu:2057/login.aspx?direct=true&db=asn&AN=115097208&site=ehost-live&scope=site
• Bachireddy, C., Weisberg, D. F., & Altice, F. L. (2015). Balancing access and safety in prescribing opioid agonist therapy to prevent HIV transmission. Addiction, 110, 1869-1871. doi:10.1111/add.13055
• Bäck, D. K., Tammaro, E., Lim, J. K., & Wakeman, S. E. (2018). Massachusetts medical students feel unprepared to treat patients with substance use disorder. Journal of general internal medicine, 33(3), 249-250.
• Berk, J. (2019). To help providers fight the opioid epidemic. Health Affairs, 11, 1-4. doi:10.1377/hblog20190301.79453/full/
• Carrieri, P. M., Michel, L., Lions, C., Cohen, J., Vray, M., Mora, M., . . . the Methaville Study Group. (2014). Methadone induction in primary care for opioid dependence: A pragmatic randomized trial. PloS One, 9, e112328-e112328. doi:10.1371/journal.pone.0112328
• Case, A., & Deaton, A. (2015). Rising morbidity and mortality in midlife among white non-hispanic Americans in the 21st century. Proceedings of the National Academy of Sciences of the United States of America, 112, 15078-15083. doi:10.1073/pnas.1518393112
• Christie, C., Baker, C., Cooper, R., Kennedy, P. J., Madras, B., & Bondi, P. (2017). The president’s commission on combating drug addiction and the opioid crisis: Origins and recommendations. Washington, DC: United States Government Printing Office.
• Congressional Research Service. (2018). Opioid treatment programs and related federal regulations. Retrieved from https://fas.org/sgp/crs/misc/IF10219.pdf
• Cousins, G., Boland, F., Courtney, B., Barry, J., Lyons, S., & Fahey, T. (2016). Risk of mortality on and off methadone substitution treatment in primary care: A national cohort study. Addiction, 111, 73-82. doi:10.1111/add.13087
• Cunningham, P. W. (2019). The health 202: Drug maker accuses FDA of hampering its medication for opioid treatment. Washington: WP Company LLC d/b/a The Washington Post.
• Daley, D. C., Smith, E., Balogh, D., & Toscaloni, J. (2018). Forgotten but not gone: The impact of the opioid epidemic and other substance use disorders on families and children. Commonwealth, 20(2-3).
• Day, E. (2018). Facing addiction in America: The surgeon general’s report on alcohol, drugs, and health. Drug and Alcohol Review, 37, 282-283. doi:10.1111/dar.12578
• DeFlavio, J. R., Rolin, S. A., Nordstrom, B. R., & Kazal, J. L. A. (2015). Analysis of barriers to adoption of buprenorphine maintenance therapy by family physicians. Rural & Remote Health, 15(1), 1–11. Retrieved from http://dbproxy.lasalle.edu:2057/login.aspx?direct=true&db=ccm&AN=103775949&site=ehost-live&scope=site
• Duber, H. C., Barata, I. A., Cioè-Peña, E., Liang, S. Y., Ketcham, E., Macias-Konstantopoulos, W., … & Whiteside, L. K. (2018). Identification, management, and transition of care for patients with opioid use disorder in the emergency department. Annals of emergency medicine, 72(4), 420-431.
• Fiscella, K., Wakeman, S. E., & Beletsky, L. (2018). Buprenorphine deregulation and mainstreaming treatment for opioid use disorder: X the x waiver. JAMA Psychiatry, 76, 229. doi:10.1001/jamapsychiatry.2018.3685
• Haffajee, R. L., Bohnert, A. S. B., & Lagisetty, P. A. (2018). Policy pathways to address provider workforce barriers to buprenorphine treatment. American Journal of Preventive Medicine, 54, S230–S242. doi:10.1016/j.amepre.2017.12.022
• Hagedorn, H., Kenny, M., Gordon, A. J., Ackland, P. E., Noorbaloochi, S., Yu, W., & Harris, A. H. S. (2018). Advancing pharmacological treatments for opioid use disorder (ADaPT-OUD): Protocol for testing a novel strategy to improve implementation of medication-assisted treatment for veterans with opioid use disorders in low-performing facilities. Addiction Science & Clinical Practice, 13, 25-9. doi:10.1186/s13722-018-0127-z
• Harper, J. (2018). Black market for suboxone gives opioid addicts a glimpse of recovery. Chicago: Tribune Interactive, LLC.
• Hugh, A., & Dunn, D. (2017). Why aren’t physicians prescribing more buprenorphine? Journal of Substance Abuse Treatment, 78, 1-7. doi:10.1016/j.jsat.2017.04.005
• Jones, C. M., Campopiano, M., Baldwin, G., & McCance-Katz, E. (2015). National and state treatment need and capacity for opioid agonist medication-assisted treatment. American Journal of Public Health, 105, e55-e63. doi:10.2105/AJPH.2015.302664
• Knopf, A. (2018). Calls for methadone in primary care: Leaders oppose. Alcoholism & Drug Abuse Weekly, 30, 1-4. doi:10.1002/adaw.32025
• Mattick RP, Kimber J, Breen C, & Davoli M. (2014). Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Retrieved from http://dbproxy.lasalle.edu:2057/login.aspx?direct=true&db=ccm&AN=105837515&site=ehost-live&scope=site
• Mendoza, S., Rivera-Cabrero, A. S., & Hansen, H. (2016). Shifting blame: Buprenorphine prescribers, addiction treatment, and prescription monitoring in middle-class America. Transcultural Psychiatry, 53, 465-487. doi:10.1177/1363461516660884
• Modesto-Lowe, V., Swiezbin, K., Chaplin, M., & Hoefer, G. (2017). Use and misuse of opioid agonists in opioid addiction. Cleveland Clinic Journal of Medicine, 84, 377-384. doi:10.3949/ccjm.84a.16091
• Nilsen, E. (2018). America’s opioid crisis has become an “epidemic of epidemics”. Retrieved from https://www.vox.com/2018/3/6/16453530/america-opioid-crisisepidemic-bacterial-endocarditis-hepatitis-c
• O’Toole, J., Hambly, R., Cox, A., O’Shea, B., & Darker, C. (2014). Methadone-maintained patients in primary care have higher rates of chronic disease and multimorbidity, and use health services more intensively than matched controls. European Journal of General Practice, 20, 275-280. doi:10.3109/13814788.2014.905912
• Pacula, R. L., & Powell, D. (2018). A supply-side perspective on the opioid crisis. Journal of Policy Analysis and Management, 37, 438-446. doi:10.1002/pam.22049
• Pincus, H. A., Scholle, S. H., Spaeth-Rublee, B., Hepner, K. A., & Brown, J. (2016). Quality measures for mental health and substance use: Gaps, opportunities, and challenges. Health Affairs (Project Hope), 35, 1000-1008. doi:10.1377/hlthaff.2016.0027
• Reif, S., Creedon, T. B., Horgan, C. M., Stewart, M. T., & Garnick, D. W. (2017). Commercial health plan coverage of selected treatments for opioid use disorders from 2003 to 2014. Journal of Psychoactive Drugs, 49, 102-110. doi:10.1080/02791072.2017.1300360
• Rosenblatt, R., Andrilla, H., Catlin, M., & Larson, E., (2015). Geographic and specialty distribution of US physicians trained to treat opioid use disorder. Annals of Family Medicine, 13(1), 23-26.
• Rudd, R. A., Seth, P., David, F., & Scholl, L. (2016). Increases in drug and opioid-involved overdose deaths – united states, 2010-2015. Morbidity and Mortality Weekly Report, 65(50-51), 1445.
• Saloner, B., & Barry, C. L. (2018). Ending the opioid epidemic requires a historic investment in medication-assisted treatment. Journal of Policy Analysis and Management, 37, 431-438. doi:10.1002/pam.22047
• Saloner, B., Daubresse, M., & Alexander, G. (2017). Patterns of buprenorphine-naloxone treatment for opioid use disorder in a multistate population. Medical Care, 55, 669-676. doi:10.1097/MLR.0000000000000727
• Saloner, B., & Sharfstein, J. (2016). A stronger treatment system for opioid use disorders. Jama, 315, 2165-2166. doi:10.1001/jama.2016.3674
• Scholl, L., Seth, P., Kariisa, M., Wilson, N., & Baldwin, G. (2018). Drug and opioid-involved overdose deaths-united states, 2013-2017. Morbidity and Mortality Weekly Report, 67, 1419-1427. doi:10.15585/mmwr.mm675152e1
• Substance Abuse and Mental Health Services Administration. (2017). Apply to increase patient limits. Retrieved from https://www.samhsa.gov/medication-assisted-treatment/buprenorphine-waiver-management/increase-patient-limits.
• Substance Abuse and Mental Health Services Administration. (2018). Dramatic increases in maternal opioid use and neonatal abstinence. Retrieved from https://www.drugabuse.gov/related-topics/trends-statistics/infographics/dramatic-increases-in-maternal-opioid-use-neonatal-abstinence-
• Substance Abuse and Mental Health Services Administration. (2019). Statutes, regulations, and guidelines. Retrieved from https://www.samhsa.gov/medication-assisted-treatment/statutes-regulations-guidelines#DATA-2000
• Substance Abuse and Mental Health Services Administration, & U.S. Department of Health and Human Service. (2015). Federal guidelines for opioid treatment programs. Retrieved from https://store.samhsa.gov/system/files/pep15-fedguideotp.pdf
• U.S. Department of Health and Human Services. (2019). Use of medication-assisted treatment for opioid use disorders in employer-sponsored health insurance: final report. Retrieved from https://aspe.hhs.gov/basic-report/use-medication-assisted-treatment-opioid-use-disorders-employer-sponsored-health-insurance-final-report
• Vashishtha, D., Mittal, M., & Werb, D. (2017). The North American opioid epidemic: current challenges and a call for treatment as prevention. Harm Reduction Journal, 14, 2-6. doi:10.1186/s12954-017-0135-4
• Volkow, N., Frieden, T., Hyde, P., & Cha, S. (2014). Medication-assisted therapies-tackling the opioid overdose epidemic. The New England Journal of Medicine, 320, 2063-2066. doi:10.1056/NEJMp1402780
• White, K. A. (2018). Exploring the perspectives and experiences of physicians in WV who prescribe medication-assisted treatment (MAT) to patients with opioid use disorder (OUD). Retrieved from https://dbproxy.lasalle.edu:443/login?url=https://dbproxy.lasalle.edu:6033/docview/2197685273?accountid=11999
• Zhang, G., Yang, Y., Ye, R., Zhang, D., Shan, D., Hu, Y., . . . Liu, Z. (2018). Effect of community-based extension clinics of methadone maintenance therapy for opiate-dependent clients: A prospective cohort study in dehong prefecture, yunnan province of china. Medicine, 97, e13323. doi:10.1097/MD.0000000000013323