Opioid Abuse and Dependence Maritza Lagos, M.D. Michigan State University Kalamazoo Center for Medical Studies

Why Important? Non-medical use of Rx opioids: ↑ in US 12th graders: 1991  1% 2006  4 % Lack of education (< 40 % of MDs trained) MTF DATA IN CONTRAST, ---2005 SURVEYS OF THE NATIONAL CTR ON ADDICTION AND SUBSATNCE ABUSE @ COLUMBIA UNIVERSITY REPORT….. © AMSP

Opioids: Double-edged sword Cornerstone of pain management Mood altering properties SUBJECTED SERIOUS SIDE EFFECTS: SEDATION, RESP Dep, tolerance, OD LEADING TO INC Physi liability

Physicians’ Dilemma and Challenge To prescribe Not to prescribe Opiophobia vs generous prescriber HOW TO BALANCE SO BENEFITS OUTWEIGH HARMS Know, monitor, and balance use © AMSP

This Lecture Will Cover: Classifications Pharmacology Use of Opioids Assessment & Treatment © AMSP

History Morphine: early 1800’s Heroin: late 1800’s Sumerians and Egyptians Medicinal value Morphine: early 1800’s Heroin: late 1800’s Methadone: prior to WW II ISOLATED DEVELOPED IN GERMANY AND BY DRS DOLE & NYSWANDER © AMSP

Opiates Semi- synthetics morphine heroin codeine oxycodone hydrocodone thebaine buprenorphine naloxone Natural alkaloids Semi- synthetics DERIVED FROM EXTRACTS OF THE JUICE OF THE POPPY PLANT PREPARATIONS OF THESE NATURAL ALCALOIDS OR SEMI SYN DERIVATIVES © AMSP

Bind to opioid receptors OPIOIDS fully synthetic OPIATES Bind to opioid receptors Morphine-like action DSM-IV: OPIOIDS FULLY SYNTHETIC CHEMICALS © AMSP

Opioid Classification Full agonists: morphine oxycodone Partial agonist: butorphanol CMATOSE PT WITH DEPRESSED RESPIRATION: ESTABLISH A PATENT AIRWAY AND VENTILATE Antagonists: naloxone naltrexone © AMSP

Opioids FULL Pure agonists Antagonists Mixed agonists/ antagonists morphine oxycodone fentanyl PARTIAL butorphanol pentazocine Antagonists PURE naloxone naltrexone Mixed agonists/ antagonists buprenorphine nalbuphine others tramadol THIS IS JUST TO EXPAND ON THE PREVIOUS CLASSIFICATION © AMSP

Opioid Abuse/Dependence Classifications Pharmacology Use of Opioids Assessment & Treatment © AMSP

Opioid Receptors µ (mu): Activated by morphine: analgesia Primary action site of all opioids Distribution: CNS and GI Linked to abuse/dependence κ (kappa): analgesia, endocrine changes and dysphoria δ (delta): for endogenous peptides OUT OF 17 RECEP DESCRIBED IN THE LITERATURE MU: ANALGESIA BECAUSE EUPHORIC EFFECTS AND + REINF © AMSP

Binding Sites © AMSP Localization of opiate binding sites When a person injects heroin or morphine travels quickly to the brain and concentrate in: VTA, nucleus accumbens, caudate nucleus and thalamus are highlighted. The opiates bind to opiate receptors that are concentrated in areas within the reward system. The action of opiates in the thalamus contributes to their ability to produce analgesia. © AMSP

opiate binding in nucleus accumbens and activation of the reward pathway The big picture: As a result of opiate actions in the nucleus accumbens (the sprinkles of opiates), there are increased impulses leaving the nucleus accumbens to activate the reward system (the frontal cortex). As with cocaine, continued use of opiates makes the body rely on the presence of the drug to maintain rewarding feelings and other normal behaviors. The person is no longer able to feel the benefits of natural rewards (food, water, sex) and can't function normally without the drug present. © AMSP

Pharmacodynamics: CNS Desirable: Analgesia Cough suppression Undesirable: Euphoria Respiration Sedation Endocrine effects EUPHORIA & REWARD CONDUCIVE TO ABUSE AND DEPENDENCE RESPIR: DOSE DEPENDENT AND MOST SERIOUS © AMSP

Pharmacodynamics: GI Desirable: Undesirable: Nausea, vomiting Antidiarrheal Inhibit peristalsis NAUSEA & VOMITING: CHMORECEPTOR TRIGGER ZONE Undesirable: Nausea, vomiting Constipation © AMSP

Pharmacokinetics Absorption: GI tract Distribution: protein binding Biotransformation: liver Excretion: kidney and GI (bile) Differs by age, gender LIPID SOLUBLE: NASAL AND BUCCAL MUCOSA AND THE SKIN FIRST-PASS RATE © AMSP

Pharmacokinetics ~3 hr 24 hr ~5 hr ~6 hr Limited Significant 6/1 2/1 OPIOID MORPHINE METHADONE Plasma ½ life ~3 hr 24 hr Duration - analgesia ~5 hr ~6 hr Stored in body Limited Significant IM/oral potency 6/1 2/1 Elimination Kidney>>Gut Kidney=Gut Stored=accumulation © AMSP © AMSP 18

Opioid Abuse/Dependence Classifications Pharmacology Use of Opioids Assessment & Treatment © AMSP

Medical Use of Opioids Analgesia Severe diarrhea Cough suppressant Maintenance tx of opioid dependence Methadone & buprenorphine / naloxone Long-term administration Blocks effects of opioids  ↓illicit use BEFORE TALKING ABOUT ABUSE AND DEPENDENCE ANALGESIA; MORPHIN, POWERFUL, LOCAL, PCA , GENERAL ANESTHE METHDONE BLOCKS EFFECTS OF OPIOIDS AND REDUCES ILLICIT OPIOID USE © AMSP

Rx Opioids Incorrect use Mismanaged Illegal use Most commonly used Misuse Non-medical Incorrect use By patient Mismanaged By physicians D ated D uped D isabled D ishonest Illegal use Not prescribed Took for euphoria Most commonly used In US, age 12 +: Past month 2% Lifetime: 14% ELDERLY, ILLITERATE, CONFUSED PHYSICIANS MAY BE CLASSIFIED IN ONE OF THESE CATEGORIES OPIOIDS ARE THE MOST COMMON CLASS RESULTS OF THE 2006 NATIONAL SURVEY ON DRUG USE AND HEALTH © AMSP

Dependence 3+ in same 12 months Tolerance Withdrawal Larger & longer use than intended Can’t quit Much time obtaining, using, or recovering ↓ activities Continued use despite problems CATASTROPHIC © AMSP

Abuse Not if dependent 1 in 12 months: Failure to fulfill role Use in hazardous situations Legal problems Use despite problems PATTERN OF REPETITIVE AND MALADAPTIVE © AMSP

Abuse/Dependence Annual Prevalence NSDUH 2006 1.7% 0.7% 0.7% RESULTS OF THE 2006 NATIONAL SURVEY ON DRUG USE AND HEALTH 0.1% © AMSP

Opioid Tolerance With repeated use Need ↑ doses to maintain effect Can see in pain patients Adaptation of receptors Different rates for each effect PHENOMENON THAT DEVELOPS WITH CERTAIN SUBSTANCES EXAMPLE © AMSP

Opioid Withdrawal After quit or ↓chronic use or antagonist Opposite to agonist effects DSM-IV criteria: 3+ (minutes to days): Unhappy mood Muscle aches Tearing/runny nose Pupillary dilation Goose bumps or sweating Nausea/Vomiting Diarrhea – Fever - Yawning TOP TO BOTTOM © AMSP

Opioid Overdose Recent use Life threatening Constricted pupils 1+: Drowsiness or coma Slurred speech Poor attention and memory Can not allow yourself to take a break © AMSP

Opioid Abuse/Dependence Classifications Pharmacology Use of Opioids Assessment & Treatment © AMSP

Treatment Goals ↓ or eliminate use ↓ risks: Address: Overdose IV use Dependence Address: Co-morbid conditions Psychosocial outcomes Somatic needs © AMSP

Treatment Diagnosis: DSM-IV Lab tests Direct , empathic, non-judgmental Lab tests Urine, blood, others 12-36 hrs after use Targeted to morphine and most opiates Methadone: GC/MS © AMSP

Acute Intervention Overdose Withdrawal Emergency Support vital signs Naloxone: 0.4 mg q 2-3 min. SC/IV Withdrawal Rating scales: CINA, COWS Opioid substitution with gradual ↓ Symptomatic treatment CINA: Clinical Institute Narcotic Assessment. Adapted from Peachey, J.E., and Lei, H. Assessment of opioid dependence with naloxone. British Journal of Addiction 83(2):193–201, 1988. COWS - Clinical Opiate Withdrawal Scale. Wesson et al. 1999. ; 11 ITEMS RATED BY THE CLINICIAN 5-36 NOR ADRENERGIC HYPERACTIVITY IN THE LOC C © AMSP

Maintenance Treatment When chronic & relapsing condition Most studies for heroin dependence Goals: Achieve a stable dose that Suppresses withdrawal ↓ craving Block effects of illicit opioids Facilitate and promote rehabilitation © AMSP

Pharmacological Treatment Methadone Full µ agonists Once/day dosed 40-60 mg/d: sufficient to block withdrawal sx. Buprenorphine/Naloxone µ Receptor partial agonist Kappa receptor partial antagonist 12-16 mg/d Combination ↓ risk of diversion © AMSP

Psychosocial Treatment Specialized programs Cognitive behavioral therapy Behavioral therapy Psychodynamic/interpersonal Recovery-oriented therapies Group and Family therapy Self-help groups: NA, Al-Anon © AMSP

Summary Pain relief, but … misuse/dependence Can’t separate misuse & therapeutic use Tolerance, abuse and dependence Learn to use it Monitor effectiveness and side effects © AMSP