Keeping Up With Clinical Advances: Opioid Use Disorder

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CNS SPECTRUMSCME Review ArticleKeeping Up with Clinical Advances: Opioid Use DisorderThis activity is provided by the Neuroscience Education Institute.Additionally provided by the American Society for the Advancement of Pharmacotherapy.Downloaded from Cambridge University Press, on 10 Sep 2019 at 14:03:43, subject to the Cambridge Core terms of use, available at

CME InformationPeer ReviewReleased: August 1, 2019CME credit expires: July 31, 2022Learning ObjectivesAfter completing this activity, you should be better able to: Differentiate the options available for medicationassisted treatment (MAT) of opioid use disorder(OUD)Increase adherence to MAT by optimizing strategiesto reduce withdrawal symptomsReduce relapse by applying maintenance treatmentstrategies for opioid use disorderAccreditation and Credit DesignationStatementsThe Neuroscience Education Institute (NEI) is accredited by the Accreditation Council for ContinuingMedical Education (ACCME) to provide continuingmedical education for physicians.NEI designates this enduring material for a maximumof 1.0 AMA PRA Category 1 Credit TM. Physicians shouldclaim only the credit commensurate with the extent oftheir participation in the activity. A posttest score of70% or higher is required to earn CME credits.The American Society for the Advancement ofPharmacotherapy (ASAP), Division 55 of the AmericanPsychological Association, is approved by the AmericanPsychological Association to sponsor continuing education for psychologists. ASAP maintains responsibilityfor this program and its content.The American Society for the Advancement ofPharmacotherapy designates this program for 1.0 CEcredit for psychologists.Nurses and Physician Assistants: for all of your CErequirements for recertification, the ANCC and NCCPAwill accept AMA PRA Category 1 Credits from organizations accredited by the ACCME. The content of this activity pertains to pharmacology and is worth 1.0 continuingeducation hour of pharmacotherapeutics.Optional Posttest and CME Credit Instructions1.2.3.Read the articleComplete the posttest and evaluation, available onlyonline at (under “CNSSpectrums”)Print your certificate (passing score 70% or [email protected] content has been peer reviewed by an MD specializingin psychiatry to ensure the scientific accuracy and medicalrelevance of information presented and its independencefrom commercial bias. NEI takes responsibility for the content, quality, and scientific integrity of this CME activity.DisclosuresAll individuals in a position to influence or control content are required to disclose all industry financial relationships. Although potential conflicts of interest areidentified and resolved prior to the activity being presented, it remains for the participant to determinewhether outside interests reflect a possible bias in eitherthe exposition or the conclusions presented.AuthorsThomas R.Kosten,MD, is a professor in the Departmentsof Psychiatry, Neuroscience, Pharmacology, Immunologyand Rheumatology; the JH Waggoner Endowed Chair;the Vice-Chair of Psychiatry for Research; the Director ofthe Division of Alcohol and Addiction Psychiatry; andCo-Director of the Institute for Clinical & TranslationalResearch; all at Baylor College of Medicine in Houston,TX. Dr. Kosten is a consultant/advisor to Alkermes,Gerson Lehman, Guidepoint Global, Indivior,MEDACorp/Leerink Swann, Novartis, and Opiant.Biren P. Patel, MD, is a psychiatrist in the Departmentof Psychiatry and Behavioral Sciences at the University ofTexas Medical Branch in Galveston, Texas; is affiliated withShriners Hospital For Children in the Texas MedicalCenter and with St Joseph Medical Center in Houston,Texas; and has a private practice in Galveston, Texas.Dr. Patel has no financial relationships to disclose.No writing assistance was utilized in the production ofthis article.CNS Spectrums Peer ReviewAll CME articles are peer reviewed in accordance with thestrict standards of CNS Spectrums and in accordance withrequirements and recommendations of the InternationalCommittee of Medical Journal Editors. The Editorial policies of the journal CNS Spectrums and peer review of allarticles that appear in the journal is managed independently by Cambridge University Press and no financialrelationship exists between the CME provider andCambridge for this service.The Content Editor, an NEI Peer Reviewer, and thePlanning Committee have no financial relationshipsto disclose.Downloaded from Cambridge University Press, on 10 Sep 2019 at 14:03:43, subject to the Cambridge Core terms of use, available at

Disclosure of Off-Label UseProvidersThis educational activity may include discussion of unlabeled and/or investigational uses of agents that are notcurrently labeled for such use by the FDA. Please consultthe product prescribing information for full disclosure oflabeled uses.This activity is provided by NEI. Additionally provided bythe ASAP.Cultural and Linguistic CompetencySupportThis activity is supported by an unrestricted educationalgrant from Alkermes.A variety of resources addressing cultural and linguisticcompetency can be found at this link: from Cambridge University Press, on 10 Sep 2019 at 14:03:43, subject to the Cambridge Core terms of use, available at

CNS Spectrums (2019), 24, 17–23. Cambridge University Press 2019doi:10.1017/S109285291900110XREVIEW ARTICLEKeeping Up with Clinical Advances: Opioid Use DisorderBiren Patel112and Thomas R. Kosten1,2*Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas, USAMichael E. DeBakey VA Medical Center, Houston, Texas, USAOpioid use disorder (OUD) is a disorder that can lead to several negative outcomes, including overdose and death. A variety of opioidscan be abused by individuals including both prescribed and non-prescribed opioids. Continued opioid use can be driven by negativeaffective states associated with opioid withdrawal. Several treatments exist in the field including medication assisted treatments such asmethadone, buprenorphine, and naltrexone. Treatments such as clonidine and lofexidine can also be used to assist with decreasingwithdrawal symptoms. Increasing adherence to treatment can further improve patient outcomes and promote continuation with treatment. A variety of methods to reduce relapse can also be utilized such as opioid agonists and maintenance therapy. According to theCenters for Disease Control, opioid overdoses contributed to 67.8% of overdose deaths in 2017.Received 12 March 2019; Accepted 29 April 2019IntroductionOpioid use disorder (OUD) is a complex disorder.According to the most recent data from the SubstanceAbuse and Mental Health Services Administration(SAMSHA), approximately 11.4 million individuals (4.2%of the total United States population) aged 12 or oldermisused opioids in 2017 with 11.1 million misusing prescription pain relievers.1 Among the 886,000 individualswho used heroin, 562,000 misused both prescriptionopioids and heroin. Prescription opioids include hydrocodone, morphine, oxycodone, codeine, tramadol, buprenorphine, methadone, and fentanyl. The abuse of opioids hasbeen well documented and can lead to increased emergencyroom (ER) visits,2 health complications such as HIV orhepatitis C,3 decreased social functioning,4 overdose, anddeath.5 While all of these conditions increase costs inhealth care and society, the opioid overdoses are themost concerning. Out of 63,632 overdose deaths in theUnited States in 2016, 66.4% of them involved opioids.6The misconception of opioids as being a safe treatmentfor pain and subsequent overprescribing of opioids led toincreased availability of prescription opioids. Opioid prescriptions increased in the United States from 76 million*Address correspondence to: Thomas R Kosten MD, WaggonerProfessor of Psychiatry, Pharmacology, Neuroscience and Immunology,1977 Butler Blvd – Suite E4.207, Houston, TX 77030, USA.(Email: [email protected]).This activity is supported by an unrestricted educational grant fromAlkermes.An addendum has been issued for this article, please see DOI: 1991 to roughly 215 million in 2016.7 Many individualswho had used prescription opioids in the early 2000’sbecame dependent, and by 2014 they started turning toheroin as it was cheaper and prescription opioids becameless available.8 An example of decreased availabilityinvolved hydrocodone, which due to its increased abuse,was reclassified from schedule III to II on October 6,2014. This lead to decreased prescribing of hydrocodonecontaining prescriptions particularly in Emergency Roomsettings.9 Thus, prescription opioids were more regulatedand less available, but another wave of opioid misusebegan with heroin abuse increasing from 2014 to 2017.10Continued opioid use is driven through a neurobiological process in which patients have a binge/ intoxication stage, withdrawal stage, and a preoccupation/anticipation stage.11 When used chronically, such as totreat chronic pain, tolerance will develop. This resultsin patients requiring higher doses in order to achievethe same effects. The chronic use of opioids can alsocause hyperalgesia, or the amplification of minor pain.12Thus, during the initiation phase of opioid misuse,intoxication is often desired to relieve pain and dysphoria. Other rewarding effects of intoxication can be driventhrough dopamine release in the nucleus accumbens,which has been detailed in other publications and willnot be elaborated in this review.5The withdrawal stage follows from physiologicaldependence, which can be another driving force for continued substance use. Dependence can occur withchronic use of opioids, and withdrawal symptoms beginDownloaded from Cambridge University Press, on 10 Sep 2019 at 14:03:43, subject to the Cambridge Core terms of use, available at

B. Patel ET AL.when opioids are abruptly discontinued. These withdrawalsymptoms include nausea, vomiting, diarrhea, worseningpain, body aches, and worsening depressive and anxietysymptoms.11 Patients can experience negative reinforcement of withdrawal symptoms with the improvement ofwithdrawal symptoms with subsequent use of opioids.The preoccupation/anticipation stage occurs aftercompletion of acute physiological withdrawal and is oftencalled “protracted” withdrawal, which can be a triggerfor relapse. Cravings occur during this stage and are associated with neurochemical changes in the prefrontal cortex, orbitofrontal cortex, and hippocampus.11 Patientscan have cue induced relapse, drug induced relapse, orstress induced relapse during this stage. Examples of cuesthat can induce relapses include someone in recoveryfinding syringes or a previous dealer’s phone numberor visiting the place where they had purchased illicitopioids. Drug induced relapse can include beginningto use opioids again as well as inadvertent use by someone in recovery. An example can include someone who isprescribed opioid pain medication following an currentmedical or surgical procedure in which opioid medication would be warranted. Stress induced relapse can follow when the patient experiences psychosocial stress,which activates their hypothalamic-pituitary-adrenal(HPA) axis leading to relapse as a conditioned response.This review article has three learning objectives thatwill teach you how to; (1) differentiate the options available for medication-assisted treatment (MAT) of OUD;(2) increase adherence to MAT by optimizing strategiesto reduce withdrawal symptoms; and (3) reduce relapseto OUD by applying maintenance treatment strategies.In this article, the term OUD will be used in lieu of opioidabuse or dependence as a diagnostic criterion. This is inaccordance with the updated Diagnostic and StatisticalManual of Mental Disorders, 5th edition (DSM-V). AnOUD involves a problematic pattern of opioid use leadingto clinically significant impairment/distress, manifestedby at least 2 of 11 symptoms in a 12-month period. Thesymptoms discussed will include cravings, tolerance, andwithdrawal symptoms.Medication Assisted TreatmentsProviders in the United States have many options forMedication Assisted Treatment (MAT) for OUD. Thesemedications have various mechanisms of action. The fourFood and Drug Administration (FDA) approved treatments include methadone, which is a full mu-opioid agonist and NMDA receptor antagonist. Buprenorphine isanother option which is a partial mu-opioid agonist,kappa-opioid antagonist, and delta-opioid antagonist.The third is Naltrexone which is a mu-opioid antagonistand kappa-opioid antagonist. Lofexidine is a newlyapproved alpha-2 agonist, which is used to manage acutewithdrawal symptoms.13 These medications should beused along with a behavioral treatment program in orderto improve medication adherence and abstinence fromillicit opioids.The first step in helping patients with OUD is managing their withdrawal symptoms when they abruptly stopusing opioids. Several medications that have been usedextensively for withdrawal symptoms include clonidine,guanfacine, and lofexidine. These medications can be usedin a variety of settings for symptom relief. However, theappropriate level of care for using these medications variesbased on the severity of the patient’s opioid use and subsequent withdrawal severity. Settings include inpatientdetoxification and subsequent rehabilitation, partial hospitalization programs, and