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Long Acting Opioids: Challenges in Pharmacotherapy

Long Acting Opioids: Challenges in Pharmacotherapy. Mary Jeanne Kreek, M.D. The Laboratory of the Biology of Addictive Diseases The Rockefeller University September 10, 2003 Anesthetic Life Support Drugs Advisory Committee Food and Drug Administration Bethesda, MD

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Long Acting Opioids: Challenges in Pharmacotherapy

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  1. Long Acting Opioids:Challenges in Pharmacotherapy Mary Jeanne Kreek, M.D. The Laboratory of the Biology of Addictive Diseases The Rockefeller University September 10, 2003 Anesthetic Life Support Drugs Advisory Committee Food and Drug Administration Bethesda, MD funded primarily by NIH-NIDA, NIHCRR and NYS OASAS

  2. Major Issues/ Problems Related to Physician Use/Prescribing of Long-Acting Mu Opioid Receptor Agonists in Humans A. Lack of adequate or updated medical education concerning pharmacokinetics and pharmacodynamics of long-acting (intrinsic or by formulation) mu opioid receptor agonists and partial agonists. • Decrease in formal medical education in classical pharmacology and lack of continuing medical education in pharmacology. 2) Discovery (synthesis) and development of intrinsically long-acting mu opioid agonists for treatment of opioid addiction and for treatment of chronic pain (1964 onward). 3) Increase in numbers of short-acting mu opioid agonists now formulated to be long-acting opioids for use in management of pain. Kreek, 2003

  3. Major Issues/ Problems Related to Physician Use/Prescribing of Long-Acting Mu Opioid Receptor Agonists in Humans (continued) B. Lack of adequate (or any) medical school education conerning any of the specific addictions and also medical approaches to assessing persons with ongoing misuse, abuse, or addiction to drugs. • Lack of awareness of prevalence of specific additions (10% to 20% in all US population with one or more addiction). 2) Lack of knowledge concerning, e.g., genetic vulnerabilities; predictable chronic drug use induced changes in brain; environmental (e.g., set and setting, peer pressure, availability) and host factors (e.g., psychiatric comorbidity, medical comorbidity, chronic pain) contributing to the vulnerability to develop an addiction. Kreek, 2003

  4. Major Issues/ Problems Related to Physician Use/Prescribing of Long-Acting Mu Opioid Receptor Agonists in Humans (continued) C. Secondary physician/healthcare worker and related enforcement issues. • Physicians (and related healthcare workers) with inadequate knowledge (and possibly inadequate access to information). • Physicians with inadequate time (due to HMO and related current healthcare system) to evaluate each patient carefully and to individualize care • Physicians desiring to (for profit) or willing to (for diverse reasons) become “prescription writers,” i.e., illicit practice of medicine. • Similar constraints of specific education and knowledge and time constraints often lead to inappropriate enforcement. *majority of problems probably lay within these two realms* Kreek, 2003

  5. Prevalence of Specific Drug Abuse and Vulnerability to Develop Addictions National Household Survey and Related Surveys – 1996 – 1999 Alcohol Use – ever ~ 177 millionAlcoholism ~ 15 million Cocaine Use – ever ~ 26 millionCocaine Addiction ~ 1 to 2 million Heroin Use – ever ~ 2.5 to 3 millionHeroin Addiction ~ 0.5 to 1 million Development of Addiction After Self Exposure Alcoholism ~ 1 in 10 to 1 in 20Cocaine Addiction ~ 1 in 10 to 1 in 20Heroin Addiction ~ 1 in 3 to 1 in 5 NIDA, SAMHSA Reports

  6. Factors Contributing to Vulnerability to Develop a Specific Addiction use of the drug of abuse essential (100%) Genetic(25-50%) • DNA • SNPs • other polymorphisms Environmental(very high) • prenatal • postnatal • contemporary • cues • comorbidity • neurochemistry • behaviors • mRNA levels • peptides • proteomics Drug-Induced Effects(very high) Kreek et al., 2000

  7. Endogenous Opioidsand Their Receptors Opioid ClassesOpioid Receptor Types Endorphins Mu Enkephalins Delta Dynorphins Kappa Endomorphins (?) Kreek, 2001

  8. Human Opioid Receptors , , and     H2N extracellular fluid S AA identical in 3 receptors S AA identical in 2 receptors AA different in 3 receptors cell membrane cell interior HOOC LaForge, Yuferov and Kreek, 2000

  9. Hypothesis(1963–1964) Heroin (opiate) addiction is a disease – a “metabolic disease” – of the brain with resultant behaviors of “drug hunger” and drug self-administration, despite negative consequences to self and others. Heroin addiction is not simply a criminal behavior or due alone to antisocial personality or some other personality disorder. Dole, Nyswander and Kreek, 1966

  10. Heroin Addiction: Functional State of aTypical Addict "High" (overdose) Functional State "Straight" "Sick" (arrows indicate times of injection) AM PM AM PM AM Days Dole, Nyswander and Kreek, 1966

  11. Goals and Rationale for SpecificPharmacotherapy for an Addiction 1. Prevent withdrawal symptoms 2. Reduce drug craving 3. Normalize any physiological functions disruptedby drug use 4. Target treatment agent to specific site of action,receptor, or physiological system affected orderanged by drug of abuse Kreek, 1978; 1991; 1992; 2001

  12. Characteristics of an EffectivePharmacotherapeutic Agent forTreatment of an Addictive Disease • Orally effective • Slow onset of action • Long duration of action • Slow offset of action Kreek, 1978; 1991; 1992; 2001

  13. Methadone/Morphine/Heroin Chemical Structure Kreek Lectures: 1967 onward

  14. Methadone Maintenance: Functional State of a Former Addict Treated With Methadone Maintenance "High" "Straight" Functional State "Sick" H M M AM PM AM PM AM Days “Functional state of a patient blockaded with methadone (a single oral dose each morning). The effect of an intravenous injection of heroin in the blocked patient is shown in the second day. The dotted line (---) indicates the course if methadone is omitted.” Dole, Nyswander and Kreek

  15. Heroin versus Methadone* Heroin Methadone Route of administration intravenous oral Onset of action immediate 30 minutes Duration of action 3–6 hrs 24–36 hrs Euphoria first 1–2 hrs none Withdrawal symptoms after 3–4 hrs after 24 hrs * effects of high dosages in tolerant individuals Kreek, 1973; 1976; 1987

  16. Plasma Methadone Levels in anIndividual Maintained on 100 mg/day 500 400 300 Plasma levels (ng/ml) 200 100 0 0 2 4 6 8 24 Time (hours after dose) MJ Kreek, MD, 1994 (from Kreek, MJ, NY State J. Med. (73), 1973)

  17. Opioid Agonist Pharmacokinetics:Heroin Versus Methadone Compound Systemic Apparent Major Bioavailability Plasma Terminal Route of After Oral Half-life Biotrans- Administration (tBeta) formation 1/2 Heroin Limited 3 m Successive (<30%) (30 m for active deacetylation 6-actyl-morphine and morphine metabolite) glucuronidation (4-6 for active morphine metabolite) Methadone Essentially 24 h N-demethylation Complete (48 h for (>70%) active l-enantiomer) Kreek et al., 1973; 1976; 1977; 1979; 1982; Inturrisi, 1984

  18. [18F] Cyclofoxy (a Selective Opioid Antagonist) Binding in Human Brain: Normal Volunteer PET Study - NIH 116.25 82.50 48.75

  19. Plasma Methadone Levels in Long-Term, Methadone-Treatment Patients Sampled Across the 90-min PET Scan Session 500 400 300 Plasma MethadoneLevels (ng/ml) 200 100 n=12 0 0 10 20 30 40 50 60 70 80 90 Time (min) Kling et al., 2000

  20. Specific Binding of [18F] Cyclofoxy (mean + S.E.M.) in 13 Brain Regions of Normal Volunteers and Long-Term, Methadone Treated Former Heroin Addicts - PET Study normal volunteers n=14 16 MTP volunteers n=14 14 12 * 10 * Specific Binding (ml plasma/ml tissue) 8 * * 6 * 4 2 0 Thi Amy Caud Ins ACg Put MT MFr Par Crb IT Hip WMt Region of Interest Kling et al., 2000

  21. Methadone Maintenance Treatment Allows Normalizationof Endogenous Opioid-Related Physiological FunctionsDisrupted During Chronic Heroin Use Neuroendocrine Function • Hypothalamic-Pituitary-Adrenal Axis – Stress Responsivitylevels and circadian rhythm of release of POMC peptides( Endorphin; ACTH and cortisol) • Hypothalamic-Pituitary-Gonadal Axis – Reproductive Biology levels and pulsatile release of LH and testosterone levels Immune Function • Natural Killer Cell Activity • Absolute Numbers of Cells — T cells; T cell subset levels;B cells; NK cells • Immunoglobin Levels (M and G) Kreek, 1972; 1973; 1978; 1987; 1992; 2001; Novick et al., 1989

  22. Methadone Maintenance Treatment for Opiate (Heroin) Addiction Number of patients in treatment: 179,000 Efficacy in “good” treatment programs using adequate doses: Voluntary retention in treatment (1 year or more) 60 – 80% Continuing use of illicit heroin 5 – 20% Actions of methadone treatment: • Prevents withdrawal symptoms and “drug hunger” • Blocks euphoric effects of short-acting narcotics • Allows normalization of disrupted physiology Mechanism of action: Long-acting narcotic provides steady levels of opioid at specific mu receptor sites (methadone found to be a full mu opioid receptor agonist which internalizes like endorphins and which also has modest NMDA receptor complex antagonism) Kreek, 1972; 1973; 2001; 2002; Inturrisi et al, in progress; Evans et al; in progress

  23. Reinforcing or “Reward” Effects of Drugs of Abuse Initial exposure to a drug of abuse may produce effects which are interpreted by the individual as “desirable” or “pleasurable”, i.e., “rewarding”. These effects may lead to “craving” or “hunger” for the drug, with resultant spontaneous activity or work for drug acquisition and self-administration. Primary sites of actions of drugs of abuse with respect to their reward or reinforcing effects have been identified as specific brain regions, rich in dopamine nerve terminals or cell bodies, the mesolimbic and mesocortical dopamine systems especially the nucleus accumbens, as well as the amygdala and the anterior cingulate. Kreek, 1987; 2001

  24. Relationship Between Blood (and Brain) Levels of Drugs of Abuse and Their Effects on Events Related to Addictions Rates of rise of blood (and presumable brain) levels of drugs of abuse are related positively to their reinforcing effects Rates of fall of blood (and presumably brain) levels of drugs of abuse are related positively to the onset of withdrawal symptoms and/or acute “craving” Kreek, 1978; 1991, 1992; 2001

  25. “On-Off” versus “Steady-State” Disruption versus Normalization • levels of gene expression • receptor mediated events • physiology • behaviors Kreek, 1987; 2001

  26. Pharmacokinetics of LAAM(l--acetyl-methadol) • Orally effective • Long-acting • Long duration of action due, in part, to two biologicallyactive metabolites • P450 related hepatic enzymes involved in metabolism • Apparent  terminal half-life in humans • LAAM :2.6 days • norLAAM :2 days • dinorLAAM :4 days

  27. HO HCl O N CH3O CH3 HO C(CH3)3 Buprenorphine Hydrochloride* *Buprenex

  28. Buprenorphine— Pharmacokinetics and Dynamics in Humans • Mu opioid receptor partial agonist. • No oral preparation— (ineffective: “first pass” rapid biotransformation by GI mucosa and by liver). • Sublingual preparation– (without, and with, naloxone to reduce intravenous abuse liability). • Approved by FDA– maximum 16mg/day for treatment of opiate addiction (only); no approval for management of pain yet. • Maximal dose effective in humans 24 to 32mg. • Sublingual liquid or tablet; tablet ~55% plasma levels of liquid. • Plasma β terminal half-life: “3 to 5 hours.” • Around 120 minutes to peak after sublingual dose. • Pharmacodynamic sustained mu opioid effect, 24 to 48 hours due to very long mu opioid receptor occupancy. • Mu opioid agonist effects NOT reversible with opioid antagonist naloxone (because of very high affinity to and quasi-irreversible binding at mu opioid receptor. Kreek, 2003

  29. Opiate Addiction Treatment Outcome* Methadone Maintenance 50 – 80% LAAM Maintenance 50–80% Buprenorphine-Naloxone Maintenance 40–50%** Naltrexone Maintenance 10 – 20% “Drug Free” (non-pharmacotherapeutic) 5 – 20% Short-term Detoxification (any mode) 5 – 20% (limited data) * One year retention in treatment and/or follow-up with significant reduction or elimination of illicit use of opiates ** Maximum effective dose (24mgsl) equal to 60 to 70 mg/d methadone. Data base on 6 month follow-up only. Kreek, 1996; 2001; 2003

  30. Continuing Urgent Medical Needs • To provide the most effective treatment for a major addictive disease, long term heroin (or other short-acting opiate) addiction, the use of long-acting mu opioid agonists or partial agonists is usually essential. • To provide the most effective treatment for chronic pain, neoplastic or other, the use of long-acting mu opioid agonists or partial agonists are often essential. Kreek, 2003

  31. Specific Critical Questions • Is this mu opioid agonist medication and/or this specific formulation short- or long-acting? • Is the patient opioid naïve, modestly exposed, or long-term exposed and, thus, tolerant? • Does this patient already have a problem with some type of drug abuse or addiction or other indicators suggesting risk of increased vulnerability to develop an addiction? Kreek, 2003

  32. H3CO OH O H-Cl- N CH3 O Oxycodone Hydrochloride* *OxyContin

  33. OH HCl H O H N CH3 CH2 O CH2 Hydromorphone Hydrochloride

  34. CH3 CH2 CON N CH2 CH2 Fentanyl

  35. *“Taken broken, chewed, crushed xxx (compound formulations 1, 2, or 3) could lead to rapid release… toxic dose.” Kreek, 2003

  36. Hypothesis Some of the individual genetic variability in susceptibility to the development and persistence of, or relapse to, opiate addiction may be due to polymorphism at the mu opioid receptor. Also, individual differences in responses to endogenous opioids (“physiogenetics”) or treatment pharmacotherapies (“pharmacogenetics”) may be mediated by variant forms of the mu opioid receptor.

  37. Role of Mu Opioid Receptor and Related EndorphinSystems in Normal Physiological Functions* • Neuroendocrine Functions • Stress responsive systems includinghypothalamic-pituitary-adrenal axis • Reproductive function includinghypothalamic-pituitary-gonadal axis • Response to Pain • Immunological Function • Gastrointestinal Function • Cardiovascular Function • Pulmonary Function • ? Mood, Affect; Cognition * All disrupted by chronic abuse of the short acting opiate, heroin Kreek, 2000

  38. SNP — a single nucleotide polymorphism, that is, one nucleotide or base of any base pair that is different from the “usual”, “prototypic”, (or first identified and recorded base) Coding region — that part of a gene which codes for a peptide (protein) Allelic Frequency: <1% low or rare 1–5% intermediate >5% high or frequent Human Gene Diversity: Single Nucleotide Polymorphisms (SNPs) in Genes: Definitions M.J. Kreek, 2000

  39. Single Nucleotide Polymorphisms inHuman Mu Opioid Receptor Gene Variant Exon Protein Corresponding Allele (nucleotide position) location domain amino acid change frequency A118G 1 N-terminus Asn 4 Asp (N40D) 10.5% (26 heterozygous; 3 homozygous) C17T 1 N-terminus Ala 6 Val (A6V) 6.6% (14 heterozygous; 3 homozygous) G24A 1 N-terminus Synonymous 2% mutation (6 heterozygous) G779A 3 CL3 Arg 260 His (R260H) <1% (1 heterozygous) G942A 3 EL3 Synonymous <1% mutation (1 heterozygous) * Nucleotide position 1 is first base of the start codon. Bond et al., 1998

  40. Allelic Frequency AssociationsOpioid Dependence – C17T and A118G C T A G Total 207 19 206 20 226 Dependent (0.916) (0.084) (0.912) (0.088) 77 1 66 12 78 Non-dependent (0.987) (0.013) (0.846) (0.154) c 3.70 (p = 0.054)* 1.98 (p = 0.159) Yate's corrected = † 2 (1) c = 4.1 [p=0.05] * This finding is similar to that obtained by Berrettini et al. (1997) 2 2 However, within the Hispanic study subjects groups (total n=67), the A118G variant allele was present in a significantly higher proportion of non-opioid dependent subjects compared to opioid dependent subjects. (Yates corrected Chi-square † c 2 = 8.22 [p=0.0041]) 2 (1) (1) Bond et al., 1998

  41. Human MOR Gene SNPs S4R A6V H2N N40D SNPvs with changed AA 50 Synonymous mutation extracellular fluid Putative Glycosylation site V234L S147C 300 N152D 150 200 250 cell membrane R260H R265P 350 100 cell interior S268P 400 HOOC Kreek, Yuferov and LaForge, 2000

  42. Binding and Coupling to G Protein-Activated, Inwardly Rectifying K+(GIRK) Channels by Endogenous Opioid Peptides to the Prototype and A118G Variant Mu Opioid Receptor 100 100 80 80 60 60 Percent Bound 40 40 20 20 0 0 -11 -10 -9 -8 -7 -11 -10 -9 -8 -7 Log [Endomorphin -1(M)] Log [ Endorphin (M)] A118G 1.0 1.0 Prototype Fraction Maximum Current Response 0.5 0.5 0 0 -10 -9 -8 -7 -6 -9 -8 -7 -6 Log [Endomorphin -1(M)] Log [ Endorphin (M)] Bond et al., 1998

  43. “Physiogenetics”—Cortisol Levels After Incremental Naloxone Administration:Mu Opioid Receptor A118G Heterozygote Individuals 24 A/A (n=29) N 22 N A/G (n=7) 20 18 Serum Cortisol (ug/dl) N 16 14 PI 12 N 10 8 0 50 100 150 200 50 Time(min) Kreek, 1999; Wand et al, 2002

  44. “Physiogenetics”?– Pharmacogenetics–ACTH and Cortisol Levels in Family History Positive (n=8) and Negative (n=7) Social Drinkers after 50mg Oral Naltrexone 60 60 Naltrexone Naltrexone FH- FH+ Placebo Placebo 50 50 40 40 ACTH (pg/ml) ACTH (pg/ml) 30 30 20 20 10 10 0 0 0 30 60 90 120 150 180 240 0 30 60 90 120 150 180 240 Time (min) Post Capsule Time (min) Post Capsule 25 Naltrexone Naltrexone 25 FH- FH+ Placebo Placebo 20 20 15 15 Cortisol (µg/dl) Cortisol (µg/dl) 10 10 5 5 0 0 0 30 60 90 120 150 180 240 Kreek 1999; King et al, 2002 0 30 60 90 120 150 180 240 Time (min) Post Capsule Time (min) Post Capsule

  45. Pharmacogenetics:Mu Opioid Receptor A118G Polymorphism—Naltrexone Treatment Response *All subjects consented for genetics studies either at the time of naltrexone study or at a later date Study 1: UPENN (Monterosso et al., 2001)*  183 alcohol dependent outpatient subjects  Randomized to 3 groups: a) 9 months of naltrexone (100mg/day) b) 12 weeks of naltrexone (100mg/day), followed by 6 months of placebo c) 9 months of placebo Study 2: UPENN (unpublished)*  240 alcohol dependent outpatient subjects  Randomized to 6 groups: a) either naltrexone (100mg/day) for 24 weeks or b) placebo for 24 weeks c) all subjects in (a) or (b) randomized to 3 different psychosocial interventions Study 3: University of Connecticut Health Center (Kranzler et al., 2000)*  183 alcohol dependent outpatient subjects  After Initial treatment of 1 week single-blind placebo, randomized to 3 groups: a) naltrexone (50mg/day) b) placebo c) nefazine (up to 600mg/day) Oslin, Berrettini, Volpicelli, Kranzler, O’Brien, et al., 2003

  46. 1.0 0.9 Naltrexone/ Asp40 Allele (A/G, G/G) (n=23) 0.8 0.7 Naltrexone/ Asn40 Allele (A/A) (n=48) 0.6 Placebo/ Asp40 Allele (A/G, G/G) (n=18) 0.5 Placebo/ Asn40 Allele (A/A) (n=41) 0.4 0.3 0.2 0.1 0.0 0 14 28 42 56 70 84 “Pharmacogenetics”—Naltrexone Treatment Response:Survival Analyses for Time to Relapse in Subjects With One or Two Copies of the Asp40 Allele vs. Those Homozygous for the Asp40 Allele by Medication Group Cumulative Survival (Time to Relapse) Days Oslin, Berrettini, Volpicelli, Kranzler, O’Brien, et al., 2003

  47. Alcohol Dependence For: Town, et al., 1999 No Evidence For: Bergen, et al., 1997; Kranzler et al., 1998; Sander et al., 1998; Gelernter et al., 1999; Gscheidel et al., 2000. Opioid Dependence For: Bond et al., 1998; Szeto et al., 2001; Shi et al., 2002; Tan et al., 2003; Bart et al., 2003 No Evidence For: Kranzler et al., 1998; Li et al.,2000; Franke et al., 2001. Mixed Drug Dependence For: Berrettini et al., 1997; Hoeho et al., 1997; Hoehe et al., 2000,Schinka et al., 2002; Luo et al, 2003 No Evidence for: Kranzler et al., 1998; Gelernter et al., 1999 Mu Opioid Receptor Gene: Evidence of Association or Linkage With Addictions adapted from K.S. LaForge, 2003

  48. Allelic Frequencies of the Variant Allele of the A118G Single Nucleotide Polymorphism of the Human -Opioid Receptor Gene in Diverse Populations Ethnicity or Bergen et al. Bond et al. Gelernter et al. Szeto et al Tan et al Bart et al population (1997) (1998) (1999) (2001) (2003) (2003) Asian Japanese 0.485 (34) Han Chinese 0.362 (297) Chinese 0.351 (208) Thai 0.438 (56) Malay 0.446 (156) Indian 0.442 (137) Southwest Native 0.163 (367)American Caucasian European American 0.105 (100) 0.115 (52) 0.141 (543)Finnish Caucasian 0.122 (324) Swedish Caucasian 0.107 (187) Hispanic 0.142 (67) 0.117 (47) African American 0.016 (31) 0.028 (144) Other (populations in Israel) Ethiopian 0.170 (49) Bedouin 0.080 (43) Ashkenazi 0.210 (93) Allele frequency for the variant allele is shown for various study populations. Numbers in parentheses are the number of subjects whose genotype was ascertained in each study. A study of Han Chinese found the 118G allele at a frequency of 0.321, and no occurrence of the 17T allele in 540 subjects (Li et al., 2000). LaForge, Yuferov and Kreek, 2003

  49. Human Gene Diversity – SNPs and OtherPolymorphisms in Coding Region ofOpioid Receptor Genes # Polymorphisms Identified by our Laboratory* # of Additional Polymorphisms Gene Total # Mu opioid receptor 11 6 17 Kappa opioid receptor 8 1 9 Delta opioid receptor 0 2 2 *Without or with prior identification or later verification by other groups LaForge, Yuferov and Kreek, 2000; LaForge and Kreek, 2002

  50. The Laboratory of the Biology of Addictive DiseasesMary Jeanne Kreek, M.D. – Professor and Head2003 Laboratory ScientistsClinical ScientistsAdministrative Staff Ann Ho Gavin Bart Kitt Lavoie K. Steven LaForge Lisa Borg Janesse Rojas Eduardo Butelman Scott Kellogg Susan Russo Vadim Yuferov Charles Lilly David NielsenAssistants for Research Yan Zhou Clinical Adjunct ScientistsJonathan Ball Alexis Bailey Paola Piccolo Lauren Bence Thomas Kroslak Joan Culpepper-Morgan Jason Choi Dmitri Proudnikov Lawrence Brown Wan-Xin Feng Brian Reed James Kocsis David Fussell Stefan Schlussman Mark Green Rob Gianotti Adena Svingos Lynette Benjamin Todd Harris Yong Zhang Elizabeth Khuri Lauren Hofmann Aaron Wells Elizabeth Oosterhuis Laboratory Adjunct Scientists Charles InturrisiResearch NursesLaboratory Worker Roberto Picetti Kathy Bell Laura Nunez Virginia Pickel Elizabeth Ducat Ellen Unterwald Dorothy Melia Vanya Quinones-Jenab

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