ASAM Disclosure of Relevant Financial Relationships Content of Activity: ASAM Medical –Scientific Conference 2014

Name Commercial Relevant Relevant No Relevant Interests Financial Financial Financial Relationships: Relationships: Relationships What Was For What Role with Any Received Commercial Interests Edwin Salsitz Reckitt Honoraria Treatment Benckiser Advocate Edwin A. Salsitz, MD, FASAM Attending Physician Mount Sinai Beth Israel New York, New York

Opioids‐Outline Heroin vs. Prescription Opioids • Complicated Overlap • Botany • More similarities than differences • Epidemiology • Neurobiology • Some topics covered in Pain and — Fri. • Metabolism &UDS • Overdose • Focus on Heroin today • Withdrawal • Opioids of Note • Treatment

Opium Alkaloids

• Morphine, 9‐14%, opiate , named after Morpheus, the Greek God of dreams • Codeine, 0.5%, opiate analgesic • Thebaine, 1.5‐0.3%. Important intermediate for the synthesis of semisynthetic opioids e.g. • Papaverine 1%, smooth muscle relaxant • (Poppy Seeds) UDS‐‐Opiate, Morphine, Codeine

1 Past Month and Past Year Heroin Use Prescription Drug Abuse Among Persons Age >12, 2002‐2012

Source: National Survey on Drug Use and Health: Summary of National Findings, 2012

Drug Overdose Deaths by Major Drug Type, The Changing Face of Heroin Use in the United States: A United States, 1999–2010 Retrospective Analysis of the Past 50 years JAMA Psych 5/28/14 Opioids Heroin Cocaine Benzodiazepines 18,000

16,000

14,000

12,000

10,000

8,000

Number of Deaths 6,000

4,000

2,000

0 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Year

CDC, National Center for Health Statistics, National Vital Statistics System, CDC Wonder. Updated with 2010 mortality data.

Endogenous Opioids and their Receptors

 H2 Receptor N Endogenous Ligand Extracellular S Types fluid AA identical in S 3 receptors βEndorphins Mu AA identical in 2 receptors Conclusion and Relevance Our data show that the demographic AA different in Enkephalins Delta 3 receptors composition of heroin users entering treatment has shifted over the last cell membrane 50 years such that heroin use has changed from an inner‐city, minority‐ Dynorphins Kappa cell interior Nociceptin/OrphaninF/Q centered problem to one that has a more widespread geographical ORL-1 HOOC distribution, involving primarily white men and women in their late 20s living outside of large urban areas. G-Protein Coupled Receptor LaForge, Yuferov and Kreek, 2000 JAMA Psych 5/14

2 The Reward Pathway

PreProOpiomelanocortin

Opioids

• Acutely:  Adenyl Cyclase cAMP PKA • Leads to hyperpolarization of neurons • opening Ca channels, inward K channels

• Chronically:  Adenyl Cyclase cAMP PKA • Tolerance and Physical Dependence • Internalization of Receptor

Full, Partial Agonist, Antagonist Activity

100 Levels Full Agonist (e.g. heroin) 90 80 70 At higher doses, even when Do Not Administer Partial or Mixed Opioid partial agonist drug completely 60 binds all mu receptors Agonists/Antagonists to Patients Currently % Maximum opioid agonist effect is Mu Receptor 50 Physically Dependent on Full Opioid Agonists Intrinsic Bupe + Benzo ≠  never achieved 40 Activity 30 Partial Agonist (e.g. buprenorphine) 20 e.g. A maintained patient given Like full agonists, partial agonist drugs 10 produce increasing mu Nalorphine(Nubain) mu ‐ k+ during labor 0 specific activity at lower doses no druglow dose ANTAGONIST high dose DRUG DOSE

3 Opioids

Opiates Morphine Heroin Morphine Codeine

Natural (opiates) & Semisynthetic

Synthetic D ia c e t y l m o r p h in e

HEROIN, CODEINE, MORPHINE METABOLISM & UDS Heroin=Pro‐Drug Codeine Lipophilic

6‐MAM, NAM • Natural Opium Alkaloid Potent Analgesic T1/2 in mins. • Low affinity for opioid receptors + Heroin Use • Pro‐Drug • Antitussive ? Non mu mechanism M6G M3G Potent Analgesic Weak Analgesic • ~10% metabolized to morphine via Long T1/2 Neuroexcitation Renal Excretion CYP2D6—accounts for analgesia • Wide variability in 2D6 activity across populations Poppy Seeds & UDS= Morphine > Codeine, Morphine Metabolites

Poppy Seeds UDS Opioid Effects

• CNS Sedation, Analgesia, Euphoria • GI  Constipation, Nausea, CBDpr • EndoTestosterone, Prolactin FSH, LH • UrinaryRetention • CardiovascularVasodilatation, QTc • Tolerance Varies: MiosisConstipationSedation/Euphoria

4 Opiate Overdose Management of Opioid Overdose • Classic Triad Seen In Overdose • Ventilatory support if needed •MIOSIS Dilated With Prolonged  Po2 • Parenteral Naloxone – If IV access, bolus 0.1mg/min titrated to •Coma • RR>10/min • Respiratory Depression • Improved level of consciousness • Pulmonary Edema (Non‐cardiogenic) • No withdrawal • If needed ongoing IV infusion 2/3 of initial bolus dose/hr. •Seizures – If no IV access, 0.4‐0.8mg sub q or IM and observe • Meperidine(demerol), Propoxyphene(darvon) – Naloxone Kits discussed in Talk Pentazocine(talwin), Tramadol(ultram) – (case report—s.l. buprenorphine)

Opioid Withdrawal Assessment

Pitfalls Opioid Analgesic ODs Hours Grade Symptoms / Signs after use Anxiety, Drug Craving • Need for repeated naloxone Rx with longer acting 4‐6 Yawning, Sweating, Runny nose, Tearing eyes, Restlessness opioids Insomnia • Check for Fentanyl Patch under clothing 6‐8 Dilated pupils, Gooseflesh, Muscle twitching & shaking, Muscle & Joint aches, Loss of appetite • Short period of observation in ED for Heroin OD 8‐12 Nausea, extreme restlessness, elevated blood pressure, Heart rate • Alert to possible acetominophen OD > 100, Fever 12‐72 Vomiting / dehydration, Diarrhea, Abdominal cramps, Curled‐up • Consider altered pharmacokinetics in the elderly body position and the young Clinical Opiate Withdrawal Scale (COWS): pulse, sweating, restlessness & • Bezoarsdelayed absorption IRER anxiety, pupil size, aches, runny nose & tearing, GI sx, tremor, yawning, gooseflesh (score 5‐ 12 mild, 13‐24 mod, 25‐36 mod sev, 36‐48 severe) Noradrenergic Hyperactivity, NE Output In Locus Coeruleus (α2 agonist—clonidine Boyer EW. N Engl J Med 2012;367:146‐155 inhibits) Seizures NOT Common

Severity of Opioid-Withdrawal Symptoms after Abrupt Discontinuation of Clinical Opiate Withdrawal Scale Equivalent Doses of Heroin, Buprenorphine, and Methadone (COWS) • Resting Pulse • GI Upset • Sweating • Tremor • Restlessness • Yawning • Pupil Size • Anxiety or Irritability • Bone or Joint Aches • Gooseflesh • Runny Nose or Tearing Items are scored 1 to 5 Total Score: 5‐12 mild 25‐36 moderately severe 13‐24 moderate over 36 severe Kosten, T. R. et al. N Engl J Med 2003;348:1786-1795

5 Medication Treatment for

This image cannot currently be displayed. Opioid Detoxification Outcomes

Methadone— Hospitalized, OTP, other Licensed OP • Low rates of retention in treatment Clonidine Bupe---Hospitalized, α-2 agonist Waivered MD/DO, • High rates of relapse post‐treatment L.C.N.E. OTP, . Autonomic Other Licensed OPD < 50% abstinent at 6 months 0Myalgia/Arth . < 15% abstinent at 12 months  BP, HR 72 Hour Rule . Increased rates of overdose due to decreased Symptomatic Meds, tolerance e.g.NSAIDS, Imodium . Walter Ling “Quote”

O’Connor PG JAMA 2005 Mattick RP, Hall WD. Lancet 1996 Stimmel B et al. JAMA 1977 Kosten, T. R. et al. N Engl J Med 2003;348:1786-1795

Opioids of Note Treatment of Opioid Addiction SUD • Medication Assisted: Therapy, Treatment, • Meperidine(Demerol)Normeperidine Recovery Neuroexcitation, MAO interactions Serotonin • Opioid Agonist Therapy: Methadone, Syndrome Buprenorphine, (LAAM) • Fentanyl TempSkin Absorption • Opioid Antagonist Therapy: Naltrexone Tablets • Tramadol Pro‐Drug M1 metabolite Weak and Depot Injection mu, 5HT, NE, Seizures, (Sched.) • Pro‐Drugs Heroin, Codeine, Tramadol • “Drug‐Free” Recovery, Treatment • Opioids/Seizures Tramadol, Meperidine, (Propoxyphene)

Medication Assisted Addiction Opioid Agonist Therapy Treatment Addiction Regulatory “All Treatments Work For Some People/Patients” “No One Treatment Works for All Pharmacology Stigma People/Patients”

M>>>>B Alan I. Leshner, Ph.D Former Director NIDA Destitution Political

6 Acc VTA E. Gardner

Amphetamine Cocaine Opiates GLU HIPP Cannabinoids FCX Phencyclidine AMYG CRF Ketamine

GLU 5HT GABA OPIOID OPIOID ENK GABA GABA VP DYN 5HT OFT DA BNST GABA

ABN NE LC Opiates PAG HYPOTHAL NE END JAMA Classics: Celebrating 125 Years JAMA. 1965;193(8):646-650 LAT-TEG Methadone Maintenance 4 Decades Later To Thousands of Lives Saved But Still Controversial Opiates 5HT dorsal ICSS Ethanol Commentary by Herbert D. Kleber, MD Raphé horn JAMA. 2008;300(19):2303‐2305 MesoLimbic Dopaminergic Circuit Barbiturates Pleasure/Reward Center Benzodiazepines RETIC Nicotine H2O, Food, Sex, Parenting, Social Cannabinoids

39wk39 wk 137wk Cerebral phosphorus metabolite abnormalities in

opiate‐ Phosphorous MR Spectroscopy From these data, we conclude that polydrug abusers dependent in MMT have 31P‐MRS results consistent with polydrug abusers abnormal brain metabolism and phospholipid balance. in methadone Psychiatry Research: Neuroimaging The nearly normal metabolite profile in long‐term maintenance Volume 90, Issue 3, 30 June 1999, Pages MMT subjects suggests that prolonged MMT may be 143‐152 Kaufman,M associated with improved neurochemistry.

Fig. 3. Metabolite levels in control subjects (n=16) and in short‐ (n=7) and long‐term (n=8) methadone maintenance Psychiatry Research: Neuroimaging treatment (MMT) subgroups. Shown are means±S.D. of percent metabolite measures. Post hoc Scheffé test results: Volume 90, Issue 3 , 30 June 1999, Pages 143-152 *P<0.05 vs. control subjects; **P<0.01 vs. control subjects; ***P<0.0001 vs. control subjects ;†P<0.05 vs. long‐term MMT group

Impact of Methadone Opioid Agonist Therapy Maintenance Treatment

• Reduction death rates (Grondblah, ‘90) Euphoria • Reduction IVDU (Ball & Ross, ‘91) • Reduction crime days (Ball & Ross) • Reduction rate of HIV seroconversion (Bourne, ‘88; Novick ‘90,; Metzger ‘93) Medication Assisted • Reduction relapse to IVDU (Ball & Ross) Tolerance & Physical Therapy

Withdrawal Normal Dependence • Improved employment, health, & social function Acute use Chronic use

7 Steady‐State Simulation ‐ Maintenance Pharmacotherapy Rapid Metabolizer –Serum Levels at Peak and Attained after 4‐5 half‐times, 1 dose / half‐life Trough P/T <2 (not for dosing)

Indication for Trough and Peak Serum Levels

High

Normal ng / ml

Sick

Adapted from Goodman & Gilman Time (multiples of elimination half‐lives) Daily dose remains constant to steady‐state Hours

Start Low, Go Slow The Rate Of Overdose Deaths Involving Methadone In The United States In 2009 Was 5.5 Times The Rate In 1999.

*METHADONE FOR PAIN, not OTP Induction, Early/Late Stabilization, Maintenance MMWR, 7/6/12

Federal Opioid Treatment Standards OTP

. Administrative and . Record keeping and organizational structure patient confidentiality “Methadone Does Not Have a . Quality . Medication assurance/improvement administration, dispensing . Sense of Humor” Diversion Control Plan . Unsupervised use . Staff credentials . Interim maintenance . Patient admission criteria . Detoxification . Required services Doug Gourlay/Howard Heit (includes medical examinations)

8 Admission EKG QTc~ 600 msec. 50yoM 150mg Torsades de Pointes

Buprenorphine Methadone QTc Interval

• Mechanism—Blockade of the human cardiac ether a go‐go‐ • Thebaine derivative related gene(hERG), which encodes Ikr—Delayed Rectifier K ion • μ‐partial agonist κ‐antagonist currentdelayed repolarizationQTc • High affinity μ receptor >most agonists • Counterintuitively, S‐methadone  QTc  R‐Methadone • Slow dissociation long T1/2 at receptor • Opioid Class Effect‐‐Depends on clinically significant serum • CYP P450—3A4 minimal d/d interactions concentrations. • Norbuprenorphine—Active Metabolite • Multifactorial, K, Mg, 3A4 2D6 2B6 inhibitors, other QT med • Biliary (70%) and Urinary (30%) Excret. • Dose Related • Hemodialysis safe •  Buprenorphine Does Not QTc clinically significant • ~ 300K patients on Bupe. Maint. vs Detox

Buprenorphine Binding mu Receptor Precipitated Withdrawal . Buprenorphine will precipitate withdrawal only when it displaces a full agonist off the mu receptors. . Buprenorphine only partially activates the receptors, therefore a net decrease in activation occurs and withdrawal develops.

100 Full Agonist (e.g. heroin) 90 80 A Net Decrease in Receptor Activity if a 70 Partial Agonist displaces Full Agonist 60 % 50 Mu Receptor Intrinsic 40 Partial Agonist (e.g. buprenorphine) Activity 30 20 10 0 • Buprenorphine blocks opioid full mu agonist binding no druglow dose high dose • Zubieta et al [U Mich] Neuropsychopharmacology 23:326–334, 2000 DRUG DOSE

9 Mean Neonatal Morphine Dose, Length of Neonatal Buprenorphine Maintenance vs Detox Hospital Stay, and Duration of Treatment for Neonatal Abstinence Syndrome 20 (nr)

15 75% retention treatment

in 10 75% UTS negative 20% mortality in placebo group

Remaining 5 Control Buprenorphine

0 0 50 100 150 200 250 300 350

Treatment duration (days) Kakko J et al. Lancet 2003 Jones HE et al. N Engl J Med 2010;363:2320‐2331

Pregnancy and MAT Opioids Methadone/Buprenorphine Methadone Buprenorphine Safety—OD  • Methadone, Buprenorphine, NTX: All Cat. C Drug/Drug  • Methadone > 40 years, “Gold Standard” QTc/TdP  Dose and Divide Dose During Pregnancy Pain  • Buprenorphine: MOTHER STUDY Hepatic = START DAD =  • M & B in breast milk, small amts. Recommended Pregnancy Testosterone  • No develop. Sequelae in children. ??congenital Active Met.  • NTX: No studies. +breast milk Structure  Track Record  ?? Benzo/Sleep

Methadone/Bupe Adverse Effects Heroin Maintenance M only M & B • Harm Reduction . Minimal sedation once tolerance achieved • Positive outcome studies from Switzerland . Constipation, Excessive Sweating and Canada(Montreal and Vancouver) . 2º Hypoganadism: HPG axisTestosterone: M>B . Initial Peripheral Edema—not common . QTc prolongation . Exhaustively studied in all other organ systems with no evidence of chronic harm . Hemodialysis safe . “Rot teeth and bones”– Opioid Class Effect: Saliva ??osteoclast activity ? Clinical relevance

10 Methadone Buprenorphine Pain Naltrexone

Issues and Strategies • Effective in specialized populations; e.g. impaired professionals • Maintain Maintenance Dose: Not Analgesic • Low attraction in general in traditional OTPs • Divide Dose: Analgesic Effect 4‐6 hours • Early drop out is common: Hx. with po tabs • Utilize IR Full Agonist Opioids:  Doses Required • If NPO: ½ dose IM Methadone, parenteral Bupe • I.M. Naltrexone Depot—30 day duration, less overall exposure to NTX, no black box LFTs, • Bupe: Emerging Strategies for Anticipated Pain: Taper, D/C Bupe: or Continue and/or dose • Off opioids for 7—10 days, Naloxone challenge, • *Latest Evidence Favors Continuation of both peri‐operatively • Strategies to shorten “off opioid interval”* • Loss of Tolerance: OD Concerns

*The American Journal of Drug and Alcohol Abuse, 2012; 38(3): 187–199 Alford,Ann Intern Med. 2006 Jan 17;144(2):127‐34. Mcintyre, Anesth and Intensive Care March 2013

Naltrexone Adverse Effects • Nausea/Diarrhea • Headache • Insomnia • Dizziness • ?Dysphoria • Possible Hepatic toxicity at higher doses • Opioid will not be effective

Lancet. Vol.377 April 30, 2011, 1506‐13

What Is Addiction?

Does Physical Not Addiction Dependence Necessarily

Equal Actor Philip Seymour Hoffman, who was found dead February 2, 2014 on the bathroom floor of his New York apartment with a syringe in his left arm, died of acute mixed drug intoxication, including heroin, cocaine, benzodiazepines and amphetamine, the New York medical examiner's office said Friday e.g. (1) caffeine (2) nicotine (3) alcohol (4) opiates (5) cocaine (6) methadone

11