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1、Opiate Dependent Patients:Management Strategies in the United States Michelle Rainka, Pharm.D., CCRPDent InstituteUniversity at BCopyright : Reproduction of these slides is prohibited without permission of the authorOpiate dependent management objectivesKnow the following substanc

2、e abuse vocabulary: opiate agonist, opiate antagonist, partial agonist, withdrawal, tolerance, addiction, drug abuse, dependenceIdentify effects of abuse, including signs and symptoms of toxicity/withdrawalDiscuss treatment options for patientsRecommend treatments for overdose, dependence, withdrawa

3、l, and maintenance.Substance Use Disorder Facts & Figures - United States22.2 million people 12 or older (8.5% of the population) live with substance dependence or abuse 2.1 million Americans live with pain reliever opioid addiction disease, while 467,000 Americans live with heroin opioid addict

4、ion diseaseNearly 100 Americans die each day from opioid overdose- 60% men and 40% women About 3,000 Americans die annually from heroin overdose About 75% of opioid addiction disease patients switch to heroin as a cheaper opioid source /docs/default-source/advocacy/asam-opioid-addi

5、ction-disease-facts-figures-2014.pdf?sfvrsn=0VocabularyAddiction: a primary, chronic, neurobiological disease or behavioral syndrome, with genetic, psychosocial, and environmental factors influencing its development and manifestationsChronicity, impaired Control over drug use, Compulsive use, Contin

6、ued use despite harm, CravingDrug Abuse maladaptive pattern of substance use characterized by repeated adverse consequences related to the repeated use of the substanceVocabularyDiagnostic and Statistical Manual of Mental Disorders defines Dependence as - at least 3 of the following:ToleranceWithdra

7、walLarger amounts or longer period of time than was intendedPersistent desire or unsuccessful effort to cut down or controlTime spent in activities necessary to obtain, use, or recoverSocial, occupational, or recreational activities given up or reducedContinued despite knowledge of having a persiste

8、nt or recurrent physical or psychological problem caused or exacerbated by substanceAmerican Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) June, 2000ToleranceTolerance a state of adaptation in which exposure to a drug induces ch

9、anges that result in a diminution of one or more of the drugs effect over timeShifting Dose Response Curve to the right2 typesMetabolic Liver enzymesCellular Receptor down-regulationAcute vs. ProtractedAcute is within a single administrationCross-toleranceTolerance to one drug leads to tolerance of

10、other drugs in the same class.DOSERESPONSEtolerancePhysical dependence is associated with, but separate from, tolerance.The patient needs the drug to function normally and to avoid withdrawal symptoms.Dependence/WithdrawalPhysiological DependenceBody adapts to presence of drug. Needs drug on board t

11、o maintain homeostasisspecific withdrawal symptoms can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of a drug and/or administration of an antagonistWithdrawal symptomsBehaviors displayed by a user when drug use endsTypically the opposite of the drug effectRepeated Se

12、lf-AdministrationMesolimbic dopamine systemAbused drugs all tend to activate this system3 stagesPleasureAssociative learning through classical conditioningIncentive salienceCraving (wanting)Get DA release by cues/context alone Effects on Neural SystemsActivation of mesocorticolimbic systemReinforcem

13、ent: Neurochemical systemsEnkephalinInhibitoryNeuron REWARDGlutamate Excitatory InputEnkephalin orDynorphinInhibitory NeuronGABAInhibitoryNeuronGABA Inhibitory FeedbackDopamine NeuronGABANeuronVentral Tegmental Area(VTA)Nucleus Accumbens(NAc)Dopamine ReceptorsGABA-A ReceptorsPresynapticOpioidRecepto

14、rs(m, d?)m OpioidReceptorsk OpioidReceptorsTreatmentPharmacotherapyOutpatient/Inpatient (acute vs long term) addiction TreatmentCounselingGroups: Narcotics Anonymous Toxicology TestingIdentifying co-morbid conditions History, Physical Exam, Neurological exam, laboratory:Laboratory Vitamin D, B12, ir

15、on, folate, liver function tests, thyroid, Hematology, Metabolic Panel, HIV, Hepatitis CPsychiatric diagnosis Most common: other substances, PTSD, substance-induced psychiatric disorders, antisocial and borderline personality disorder Bipolar, schizophrenia, depression, anxietyOther health issues He

16、patitis, HIV/AIDS, Concerns with sharing needlesESAP programs Expanded syringe access programSexually Transmitted Diseases HIV/AIDSHepatitisTetanusAnaphylaxisNephrotic syndromeSepticemiaEndocarditis Abscesses “skin popping”VocabularyOpiate agonist: Drugs that activate opiate receptors on neuronsRepe

17、ated administration leads to physical dependence and toleranceOpiate antagonist opiates that bind to opiate receptors but block them rather than activating themOpiate partial agonists drugs that bind to opiate receptors, but not to the same degree as full agonists. ceiling effectOpiate agonistsMecha

18、nism of Action Binds to opiate receptors in the Central Nervous System, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depressionHeroin, morphine, codeine, hydrocodone, hydromorphone, fentanyl, oxycodone, tramadol, tapentadol,

19、 meperidineBy mouth, intravenous, insufflation, subcutaneously, Intramuscularly Mechanism of Action:Full opioid agonist The opioid receptor is empty. As someone becomes more tolerant they become less sensitive to the medications. The patient is experiencing pain, this is when withdrawal happens. The

20、 opioid receptor is filled with full agonist. The receptor is fully active. Drugs such as heroin and painkillers can cause euphoria and stop withdrawal for some time. OpiatesEffectsEuphoriaDysphoriaApathyMotor retardationSedationSlurred speechAttention impairmentMiosisConstipationWithdrawal(not fata

21、l, not delirious)LacrimationRhinorrheaMydriasisPiloerectionDiaphoresisDiarrheaYawningFeverInsomnia Muscle ache/pain“kicking the habit”OverdoseOverdose: supportive, Naloxone 0.4-2 mg IV q 3 min if unconscious and respiratory depressedNaloxone: Mechanism of Action Pure opioid antagonist that competes

22、with and displaces narcotics at opioid receptor sites SKOOP Program - The Harm Reduction Coalitions SKOOP (Skills and Knowledge on Overdose Prevention) Provides education, needle exchange and emergency access to naloxoneOpiatesWithdrawal:Methadone since 1960sLAAM levo-alpha-acetylmethadol 2003 disco

23、ntinued in USBuprenorphine: 4 mg- 32 mg/day since 2002Clonidine.Maintenance:Methadone since 1960sLAAM levo-alpha-acetylmethadol- 2003 discontinued in USBuprenorphineAbstinenceNaltrexone - by mouth or intramuscularlyMethadoneDetox or Maintenance Mechanism of Action Binds to opiate receptors in the CN

24、S, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depressionSubstrate of CYP2C9 (minor), 2C19 (minor), 2D6 (minor), 3A4 (major); Inhibits CYP2D6 (moderate), 3A4 (weak) Half-life elimination: 4-91 hours; may be prolonged with a

25、lkaline pH, decreased during pregnancy QT prolongationMethadone detoxWithdrawal:Withdrawal - Methadone 20-80 mg, taper by 5-10 mg dailyMethadone maintenance3 objectives:Suppress signs and symptoms of opiate withdrawalExtinguish opiate cravingBlock the reinforcing effects of illicit opiatesMethadone

26、MaintenanceInduction (prior to steady state): Half of each days dose remains in the body and is added to the next days, increasing levels without increasing dose - start low, go slow Initial dose not greater than 30 mg or 40 mg in day 1No correlation between trough or peak levels at doses above 100

27、mg/dayPeak levels should be no more than twice the troughs/s can be most effective indicators Relieve withdrawal adequacy based on 3-8 h Reach tolerance, reduce craving Establish adequate dose Maintenace = preservation of desired effectsComplete physical exam and labs within 14 daysLeavitt SB Methad

28、one Dosing and Safety I the treatment of opiate addiction.Addiction Teatment Forum 2003Methadone MaintenanceTake home: Depends on longevity in program (2 days/week in 1st 90 days to 1 month after 2 years) Capable of handling and taking unsupervised Abstinence from unauthorized substances Regular att

29、endance Absence of behavioral or criminal issues Stable home and social environments Methadone can be safely storedLeavitt SB Methadone Dosing and Safety I the treatment of opiate addiction.Addiction Teatment Forum 2003BuprenorphineMechanism of Action Buprenorphine exerts its analgesic effect via hi

30、gh affinity binding to opiate receptors in the CNS; displays partial mu agonist and weak kappa antagonist activitySubstrate of CYP3A4 (major); Inhibits CYP1A2 (weak), 2A6 (weak), 2C19 (weak), 2D6 (weak)Active metabolite = norbuprenorphineMechanism of Action: Partial Opioid Agonist Buprenorphine repl

31、aced the full-opioid agonists. Buprenorphine competes with the full agonists for the receptors. Buprenorphine has higher affinity so it is able to displace full-agonists. It also has limited opioid effects to stop withdrawal symptoms. Over time 24-72hours, buprenorphine dissipates however it still h

32、as limited opioid effects and continues to block other opioids from attaching to the receptor. Buprenorphine managementCandidatesNot merely physically dependent, but also addictedNo contraindicationsInterestedExpected to be reasonably compliantWilling to follow safety precautionsWilling after review

33、 of txUnlikely candidatesComorbid dependence on other CNS depressantsSignificant untreated psychActive/chronic SI/HIMultiple tx/relapsesPoor response to suboxoneComplex medical Treatment Improved Protocol (TIP) 40: Clinical Guidelines for the use of Buprenorphine in the treatment of Opioid Addiction

34、 (2004). HHSBuprenorphine managementMaintenance tx with BuprenorphineInduction Switching patients from opiates to buprenorphine, finding the minimum dose at which the patient discontinues or markedly diminishes use of opiates, experiences no withdrawal, minimal or no side effects and no cravings.Sta

35、bilization Marked by the pt experiencing no withdrawal, minimal or no side effects, no longer uncontrolled cravings, pts seen weeklyMaintenance May be indefinite, attention to psychosocial issues, seen/toxed monthlyTreatment Improved Protocol (TIP) 40: Clinical Guidelines for the use of Buprenorphin

36、e in the treatment of Opioid Addiction (2004). HHSMedically supervised detox with BuprenorphineTo provide a transition for an opiate physically dependent state to an opiate free state.InductionDose reductionTreatment Improved Protocol (TIP) 40: Clinical Guidelines for the use of Buprenorphine in the

37、 treatment of Opioid Addiction (2004). HHSBuprenorphineDetox/Withdrawal OR Maintenance:Buprenorphine: 4 mg- 32 mg/daySubutex = Buprenorphine 2 mg or 8 mgSuboxone = buprenorphine/naloxone Suboxone 12/3mg sl Film Suboxone 8/2mg sl Tablets/Film Suboxone 4/1mg sl Film Suboxone 2/0.5mg sl tablets/FilmZub

38、solv = buprenorphine/naloxone Zubsolv 5.7/1.4mg sl Tablets Suboxone 1.4/0.36 mg sl tabletsBunavail = buprenorphine/naloxone Buccal Films 6.3mg buprenorphine-1 mg Naloxone 4.2mg-0.7mg 2.1mg-0.3mg Zubsolv & Suboxone Clinical Data: 758 patients were studied to look at transitioning patients from Su

39、boxone to Zubsolv Zubsolv showed comparable retention to Suboxone No statistical difference in cravings were noted between the two medications No statistical difference between adverse events associated between Suboxone and Zubsolv Fischer A, Jnsson M, Hjelmstrm P. Pharmaceutical and pharmacokinetic

40、 characterization of a novel sublingual buprenorphine/naloxone tablet formulation in healthy volunteers. Drug Dev Ind Pharm. 2013;1-6http:/ & Suboxone The bioavailability of Zubsolv compared to Suboxone Zubsolv contains less buprenorphine and naloxone compared to Suboxone The higher bioavailabil

41、ity of Zubsolv allows for a lower dose of buprenorphine and may help to reduce potential misuse and diversionThis graph indicates that both Zubsolv and Suboxone reach similar concentration in the body Zubsolv & Suboxone Dose conversion Suboxone Zubsolv 8mg/2mg 5.7mg/1/4mg2mg/0.5mg 1.4mg/0.36mgBu

42、navail & Suboxone 249 patients in a 12 week study studied the efficacy of transitioning patients from Suboxone to Bunavail Bunavail offers twice the bioavailability of buprenorphine compared to SuboxoneOnly 7.6% of patients had a positive urine test for nonprescribed opioidsVasisht N, Stark J, B

43、ai SA, Finn A. Buprenorphine/naloxone buccal film has a relative buprenorphine bioavailability approximately twice that of the buprenorphine/naloxone sublingual tablet. Poster presented at: 45th Annual American Society of Addiction Medicine (ASAM); April 10-13, 2014; Orlando, FL. Sullivan JG, Webste

44、r L, Warneke T, Finn A. Buprenorphine-naloxone buccal film is well tolerated in opioid-dependent patients converted from buprenorphine-naloxone sublingual tablet or film. Poster presented at: 45th Annual American Society of Addiction Medicine (ASAM); April 10-13, 2014; Orlando, FL. http:/ & Subo

45、xone Bunavail offers twice the bioavailability of Suboxone due to unidirectional flow and efficient absorption of buprenorphinePatients can be treated with half the dose of buprenorphine to reach a bioequivalent plasma concentration compared with Suboxone Bunavail & Suboxone Dose Conversion Conv

46、ersion Ratio: approximately 2:1 Suboxone Dose Bunavail Dose 4mg/1mg2.1mg/0.3mg8mg/2mg4.2mg/0.7mg12mg/3mg 6.3mg/1mgSuboxoneRainka et al unpublished dataIs buprenorphine abused/diverted?Is buprenorphine abused/diverted?Is buprenorphine abused/diverted?Is buprenorphine abused/diverted?Is buprenorphine

47、abused/diverted?ClonidineWithdrawal:Clonidine 2 mcg tid x 7 days, then taper (note: we use lower doses in outpatient setting)Mechanism of Action Stimulates alpha2-adrenoceptors in the brain stem, thus activating an inhibitory neuron, resulting in reduced sympathetic outflow from the CNS,Common Adverse effects : drowsiness, dizziness, dry mouth , HNaltrexoneAbstinence maintenance:Naltrexone 25mg po qd x 1 week, then 50 mg qd Mechanism of Action Naltrexone markedly attenuates or completely blocks, reversibly, the subjective effects of IV-administered opioids by competitive binding (ie, analog