Understanding Opioids A primer in MAT, detox, overdose, and prevention 9/9/2016 Robert Levy MD, University of Minnesota North Memorial Medical Center Wi-fi Information: NETWORK: EC-CTR PASSWORD: westgate252 Add Event Logo if exists Disclosure Robert Levy reports no actual or potential conflicts of interest associated with this presentation. 1
Learning Objectives Upon successful completion of this activity, pharmacists should be able to: 1. Learn how to identify withdrawal and triage it's severity 2. Understand that substance use disorder is a brain disease with behavioral elements 3. Understand Medication Assisted Therapy (MAT) basics and the different modes and legal issues that arise. 4. Know and learn to apply best practices for withdrawal from opioids and to a lesser extent benzodiazepines and alcohol, including warning signs of severe disease. 9-11 2996 Deaths 2014 18893 Overdose Pain Prescriptions Deaths Center for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System, Mortality File. (2015). Number and Age-Adjusted Rates of Drug-poisoning Deaths Involving Opioid Analgesics and Heroin: United States, 2000 2014. Atlanta, GA: Center for Disease Control and Prevention. Available at http:// www.cdc.gov/nchs/data/health_policy/ AADR_drug_poisoning_involving_OA_Heroin_US_2000-2014.pdf. 2
2014 29467 Overdose Deaths Pain Prescriptions Heroin Overdose Death Rates Parallel Sales of Pain Prescriptions 1999 -> 2008 4x increase in rate of overdose deaths related to prescriptions pain pills 1999 -> 2010 4x increase in sales of prescription pain pills Paulozzi MD, Jones PharmD, Mack PhD, Rudd MSPH. Vital Signs: Overdoses of Prescription Opioid Pain Relievers United State, 1999-2008. Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Center for Disease Control and Prevention. 2011:60:5. 259 Million opioid Prescriptions 2012 Enough for every adult in the U.S. to have one bottle Centers for Disease Control and Prevention. (2014). Opioid Painkiller Prescribing, Where You Live Makes a Difference. Atlanta, GA: Centers for Disease Control and Prevention. Available at http://www.cdc.gov/vitalsigns/opioid-prescribing/. 3
Opioid Prescriptions and Heroin Use 4 of 5 heroin users started out misusing prescription pain pills Hedegaard MD MSPH, Chen MS PhD, Warner PhD. Drug-Poisoning Deaths Involving Heroin: United States, 2000-2013. National Center for Health Statistics Data Brief. 2015:190:1-8. Addiction (SUD) as a disease Myths: Moral Failing Trauma in Childhood Poverty Lack of Education Truth It s a chronic relapsing disease No History of Drug Use Risk Genotypes Unknown Ini,a,on of Use Genetic Factors Regular Use Addic,on/Dependence Environmental Factors Relapse Recovery Death 4
ASAM Long Definition of Addiction Addiction is a primary, chronic disease of brain reward, motivation, memory and related circuitry. The neurobiology of addiction encompasses more than the neurochemistry of reward. Genetic factors account for about half of the likelihood that an individual will develop addiction. Other factors that can contribute to the appearance of addiction, leading to its characteristic bio-psycho-socio-spiritual manifestations. Addiction is characterized by an inability to abstain, impairment in behavioral control, craving, diminished recognition of associated problems, and a dysfunctional emotional response. ASAM August 15, 2011 Koob definition Addiction is a chronic relapsing syndrome that moves from an impulse control disorder involving positive reinforcement to a compulsive disorder involving negative reinforcement. Establishment of Addiction 1) Many of the patterns of addiction are related to the reward system. 2) The reward system is modulated by dopamine. 3) Models illustrate that animals will self administer a drug or electrical stimulation in order to maintain dopamine levels in the nucleus accumbens 5
Most Drugs of Abuse Affect Dopamine Drug Characteristics Very few chemicals (about 322 out of 34 million in CAS) are addicting Fairly broad range of chemical structures d-amphetamine diacetylmorphine striatum caudate putamen cingulate cortex medial orbitofrontal cortex amygdala hippocampus parahipocampus prefrontal cortex mesostriatal mesolimbic mesocortical Thalamus Nucleus Accumbens ABN VTA 6
Frontal Cortex Acc Amygdala Amphetamine Cocaine Opioids Cannabinoids Phencyclidine Ketamine VTA VP ABN Median Forebrain Bundle Opioids Ethanol Benzodiazepines Barbiturates Nicotine Cannabinoids Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nat Rev Neurosci. 2013 Sep;14(9):609-25. doi: 10.1038/nrn3381. Addiction leads to impaired learning and impaired function of the frontal cortex Addiction affects the previous functions: 1. Value of the reward is overestimated. 2. Negative consequences are not recognized. 3. Summed risk/benefit decisions are biased in the direction of continued substance abuse. 4. Drive states are reprioritized. Fuster JM. The Prefrontal Cortex, 4 th ed. Addiction. London, Academic Press, 2008. 7
So Addiction is a disease but how did we get here? Rich history of addiction in the US International Opium Convention - 1919 Before: Tonics Treatment for alcoholism Hypodermic Needle and Morphine American civil war History of prescribed opioids Heroin Bayer Demerol Farben Oxycodone Purdue Tramadol Watson Many others Pressure to Prescribe Pain as the 5 th vital sign Patient Satisfaction scores and $$$ Porter and Jick JAMA in 1980 8
Medical Providers as Source of the Problem Physician s Dilemma Direct Marketing Pressure to prescribe 259 Million opioid Prescriptions 2012 Enough for every adult in the U.S. to have one bottle Centers for Disease Control and Prevention. (2014). Opioid Painkiller Prescribing, Where You Live Makes a Difference. Atlanta, GA: Centers for Disease Control and Prevention. Available at http://www.cdc.gov/vitalsigns/opioid-prescribing/. Physicians Quandary About Pain and Addiction We have little training in addiction We have little training in pain. Yet pain is the most common reason for a primary care visit, and addiction is one of the most common illnesses seen in primary care. 9
Lack of Education and Pressure Data varies but 50% diversion Valuable and pure Oxycontin switch Increase in price Rise of Heroin & Cartels Drug Trafficing influence Poppies difficult to grow Super labs Meth Fentanyl Carfentanil Krokodil Risks of OD Dose of opioids VA study Follow-up analysis Long vs. short acting Other factors Role of Naloxone 10
Overdose Risk and Opioid Dose Percent of Person Years 100 90 80 70 60 50 40 30 20 10 0 10 78.3 9 8 7 6 5 4 3 13.1 2 5.0 3.5 1 0 1-19 20-49 50-99 100+ Opioid Dosage (mg/d) Percent Use Odds Ratio Narcan Who Benefits? In short, anyone with a history of opioid IV use Any patient on more than 100mg equivalents of Morphine daily Anyone with a history of opioid overdose Patients on 50-99mg equivalents of Morphine daily and a benzo or benzo like sleeping medication How to Distribute Narcan Comes in three forms IM injection Auto-injector Costly Intranasal Kits Difficult to find Equally effective Consider ease of use and cost Don t forget about ½ life! 11
Recognition of intoxication Mild - Moderate Apathy, dysphoria or euphoria, psychomotor retardation, drowsiness, dysarthria, impaired attention, pinpoint pupils Severe Respiratory depression Bradycardia Stupor or Coma Opioid Withdrawal Not lethal right??? Jean L How to recognize it? Opioid Withdrawal Diagnose via Clinical Opioid Withdrawal Scale (COWS) Timeline depends on the opioid of abuse Mild Dysphoric mood -N/V Muscle aches - Lacrimation or rhinorrhea Pupillary dilation - Piloerection or sweating Diarrhea/yawning - Insomnia Moderate to severe Hypertension - Tachycardia Seizures (especially Tramadol) Fever 12
COWS Graded on a 1-4(5) scale Resting pulse rate - Restlessness GI upset - Yawning Sweating - Pupil size Tremor - Anxiety or irritability Bone or joint aches - Gooseflesh skin Runny nose or tearing Score 5-12=mild - 13-24=moderate 25-36=moderately severe More than 36=severe withdrawal COWS vs. CIWA Many similarities make it difficult to determine alcohol vs. opioid withdrawal CIWA Visual, auditory, tactile disturbances is specific Much more headache and headfullness COWS Bone or joint aches - Gooseflesh skin Runny nose or tearing - Pupil size Yawning Opioid Withdrawal Treatment Why treat at all? Goals of treatment Risk of relapse & Death Changes in tolerance 13
Glutamate GABA System GABA Glutamate- NMDA + AMPA receptors Inhibition Excitation Unopposed excitation Chronic Use Opioid Withdrawal Treatment Comfort medications Naproxen for pain Hydroxyzine for anxiety Trazadone for sleep Dicyclomine for abdominal pain Methocarbamol for muscle spasms Clonidine for agitation Gabapentin for restless legs Substitution treatment Remember it is actually illegal to prescribe opioids for opioid withdrawal (well it s a grey area ) Buprenorphine Methadone 14
Buprenorphine Pain medication first Partial agonist DATA 2000 Waiver DEA vs FDA Legal and on label to use for withdrawal and pain Buprenorphine Suboxone vs Buprenorphine Naloxone Does it work? Different formulations Different routes SL vs. IM vs. IV Methadone First synthesized in German in 1939 Many drug-drug interactions Long half life Stacking QTc Many legal loop holes Only time can be perscribed out of clinic is known as the three day rule 15
What Happens After Withdrawal? Modalities of treatment for opioid dependence are many and outcome data is lacking Project Match Large national study funded by NIAAA Outpatient: 9 sites, N = 1726 Compared three methods Motivational Enhancement Cognitive Behavioral Twelve Step Facilitation Project Match variables Wide range of matching variables demographics severity personality Numerous outcome points and variables percent of drinking days drinks per drinking day 16
Project MATCH 1-year outcomes Few significant differences between the three treatments Can this even be extrapolated to opioid dependence? What about long term substitution treatment? agent action Agonist - Methadone receptor Partial Agonist Buprenorphine Antagonist - Naltrexone x 17
Phase 1 2 wk Bup/Nal, 2 wk taper, 8 wk f-up Phase 2 Phase 1 pts who relapsed - 12 wk Bup/Nal, 4 wk taper, 8 wk f-up Outcomes % no opioid use P value Phase 1 -end 7.4%.36 Phase 2 -end Rx 46.7.27 Phase 2-8 wk f- up End Rx vs 8wk f- up 7.2.22 <.001 Weiss et al. Arch Gen Psych 2011 Role of Naltrexone - Randomized, doubleblind, placebocontrolled, 24 wk trial. - 250 opioid-dependent adults 100 50 % Abstinent - 380 mg SR naltrexone every 4 wks. - Liver enzyme elevation in SR Naltrexone group but no diff. in discontinuation. 0 Placebo Naltrexone 5 0-5 -10-15 Cravings Placebo Naltrexone Krupitsky et al. Lancet 377: 1506, 2011. Krupitsky et al. Lancet 2011. 18
Management of pain on Naltrexone Oral naltrexone half-life 14 hrs. Stop 48 72 hrs before elective procedure. Sustained- release naltrexone 28 day duration of action 1. Non - opioid analgesics 2. Regional nerve block 5. Consult Addiction specialist 3. Ketamine? Clonidine? Precedex? 4. Careful reversal with high-dose opioids - consult anesthesiologist - airway monitoring - opioid tolerance hard to predict Different Schools of Thought Harm Reduction vs. Abstinence treatment AA/NA vs MAT Head to head studies difficult and basically nonexistent Psychodynamic/CBT/DBT/TFT Inpatient treatment vs. outpatient Desperate Measures: Ibogaine First commonly advertised as having antiaddictive properties in 1962 - Howard Lotsof Illegal in the US Thailand/Africa tribal settings Some research backs this up sigma-2 and nicotinic receptors 19
Chronic Pain and Addiction Large overlap clinically Chicken or the egg problem Pressure to treat patient satisfaction Altered Neuro Structure Chronic pain accompanied by cortical reorganization: Flor, Neurosci Lett, 1997 Chronic back pain is accompanied by brain atrophy: Apkarian, Neurosci, 2004 New Research Latest ASAM conference Dr. Ebkari Cronification of pain Chronic pain maladaptation occurs mostly in the limbic system Particularly the Nucleus Accumbens Some brain changes similar to that of chemical dependency Chronic, likely life long, disease model. 20
Tools To Screen For Substance Use Disorders (SAMHSA TIP 54, Exhibit 2-8) Tool Alcohol, Smoking, and Substance Involvement Screening Test Alcohol Use Disorders Identification Test (AUDIT) Format 1 item for lifetime use, 6 items for each of 10 sub-stances used, and 1 item on injection use 10-item screening questionnaire Administration/ Scoring Time Depends on number of substances used 2 minutes to administer/ 1 minute to score AUDIT-C 3-item screening questionnaire Less than 1 minute to administer and score CAGE Adapted To Include Drugs 4 yes/no questions Less than 1 minute/ not scored Drug Abuse Screening Test 20 yes/no questions 1 2 minutes to administer/ not scored Michigan Alcoholism Screening Test (MAST) (MAST-G for older adults) 24 yes/no questions 10 minutes to administer/ 5 minutes to score Training Required Yes Yes Yes No No No Aberrant Drug-Related Behaviors More Predictive Selling prescription drugs Prescription forgery Stealing or borrowing drugs from another patient Injecting oral formulations Less Predictive Aggressive complaining about the need for higher doses Drug hoarding during periods of reduced symptoms Requesting specific drugs Prescriptions from other physicians Obtaining prescription drugs from non-medical sources Unsanctioned dose escalation Concurrent abuse of related illicit drugs Multiple, unsanctioned dose escalations Repeated episodes of lost prescriptions Unapproved use of a drug Reporting psychic effects not intended by the physician Portenoy 1996 Role of Treatment Chronic pain and Addiction also share similar treatment modalities CBT/DBT found to be helpful Opioids Induced hyperalgesia 21
Co-Occurring Mental Health Depression/Anxiety ADHD Suicidal ideation Suicide Attempts Most dangerous time is right after intervention or detection AAAP vs. ASAM Role of pharmacotherapy Addicted Health Care Professionals Pharmacists/Physicians are no different Sorry Rate 22
Epidemiology The reasons for higher rates of opioid and benzodiazepine substance use disorders among physicians and nurses are multi-factorial Easier access Frequently used in line of work Stressful work environment Personality factors (perfectionism) Feelings of omnipotence (invulnerable to illness) Intellectualization (TMI) Evaluation and Treatment Occupation (January-July 2012) HCPs: Differences in Outcomes Success rates are disputed, but most agree that outcomes are excellent in >80% of physicians treated Five-year sustained abstinence rates (rated as a good outcome ) range from 75-92% compared to <50% at one year in the general population ~25% of physicians have at least one relapse 74% of those had only one episode of alcohol or drug use Outcomes are less impressive for nurses due to multiple factors (eg, less intense treatment, financial barriers, licensure problems, less aftercare support) Still unclear about the persistence of these outcomes 23
Summary Addiction is a chronic disease We are in the middle of a crisis Overdose is predictable and preventable Withdrawal can kill Treatment works No one is immune Questions? Robert Levy MD Levyx114@umn.edu 24