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Pharmacodynamics

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					Florida Alcohol & Drug Abuse Association

       2005 Annual Conference
       Pre-conference Workshop
     Medication-Assisted Treatment:
        New Tools for Recovery
               Stacey Seikel, MD
          J. Thomas Payte, MD, CMA
       August 23, 2005 – Orlando, Florida
            Early History of Opium
                C.3400 BC – Opium poppy cultivated in lower
                 Mesopotamia
                C.1300 BC – Egyptians begin cultivation
                AD 400 – Opium introduced to China by Arab
                 traders
                1600s – Persia & India recreational eating
                 and drinking of opium mixtures
                1803 – Morphine extracted from opium
                1843 – Injection technique for morphine
Source: http://opioids.com/timeline
                                      FADAA - 2005 Annual Conference   2
                             Sumerian crown
      “POPPY ART”             decorated with
Nix – the Greek goddess of    incised poppy
           night             plants, 3000 B.C.
Harvesting the Opium crop
   BRIEF OPIATE HISTORY
•1898 – Heroin introduced
•1900 – Estimated 250,000 opiate addicts in USA)
•1914 – Harrison Narcotics Act , control of domestic trade
•1918 – Opiate maintenance programs in estimated 40 programs in 14
cities
•Late 1920s – Maintenance programs closed by U.S. Treasury
Department
•WW II – Methadone synthesized by German chemists
•1947 – Methadone introduced in USA (Lexington KY)
•1963 – Dole & Nyswander start search for pharmacological treatment
•1965 – First reports on MM published
•1969 – 2000 MM patients in NYC, 1970 – 20,000 MM patients
•1972 – FDA/DEA introduce strict regulation of MM treatment defining
treatment and all aspects of treatment
•Mid 1990s – 250,000 MM patients world wide.
•2004 – Approx. 230,000 MM patients in US.
                                                                       5
Heroin – The strongest you can buy without a prescription   6
METHADONE:

   …What you always
    wanted to know but
    were afraid to ask:

           FADAA - 2005 Annual Conference   7
    Methadone is:
   A Synthetic mu agonist
   A Schedule II Controlled Substance
   Orally effective (80-90% bio-availability)
   Slow onset of effect (2-4 hours)
   Long duration desired effect (3-36+ hrs.)
   Half-life = 15-55 hours; (significance?)


                  FADAA - 2005 Annual Conference   8
Opioid Pharmacology
Drug Classes

   Agonist naturally occurring
   Agonist semi-synthetic
   Agonist synthetic
   Partial agonist
   Antagonist


                FADAA - 2005 Annual Conference   9
    OPIOID PHARMACOLOGY
   AGONISTS – Binds to the receptor and
    mimics the effects of endogenous ligands
   ANTAGONISTS – Devoid of intrinsic activity
    but, when bound to the receptor, inhibit or
    interfere with the binding of agonists
   PARTIAL AGONISTS – Bind to the receptor,
    but are not as active as agonists
                    FADAA - 2005 Annual Conference   10
Opioid Receptors
     MU

     Kappa

     Delta

              FADAA - 2005 Annual Conference   11
Pharmacodynamics
   Receptors
       Normal function is to receive endogenously
        produced ligands, such as hormones and
        neurotransmitters
       “Ligand” is a substance that produces a
        pharmacological effect when it attaches to
        a receptor, specialized cellular
        macromolecule

                   FADAA - 2005 Annual Conference   12
Receptors and Ligands
   The Ligand, neurotransmitter, specific drug
    molecule is very specific “Key”
   The Receptor is the “ignition switch” into
    which the Key (Ligand) fits and when turned,
    causes a pharmacological effect
   An antagonist will occupy the lock but will not
    cause the pharmacological effect. It blocks
    the receptor so that no agonist can attach
    thus preventing any effect or action.

                  FADAA - 2005 Annual Conference   13
Opioid Receptors
   Drugs and medications that activate mu
    receptors other than methadone include:
       Morphine
       Heroin
       Oxycodone (Oxycontin)
       Hydrocodone,
       Hydromorphone
       Buprenorphine
       Codeine
       Fentanyl

                   FADAA - 2005 Annual Conference   14
Pharmacodynamics
   Effects of drugs on the body and the
    mechanism by which drugs produce
    their effects
   Operationally viewed as what a drug
    does to the body
   Alter cellular function; enzymes, cell
    membranes, receptors

                FADAA - 2005 Annual Conference   15
Mu Receptor Effects
   Analgesia
   Euphoria
   Respiratory Depression
   Miosis
   Decreased Gastrointestinal Motility
   Physical Dependence & Tolerance
   Cough suppression, hypotension, & nausea
    and vomiting
                FADAA - 2005 Annual Conference   16
Methadone Side-Effects
   Amenorrhea
   Constipation
   Diaphoresis
   Libido decrease
   Pruritis
   QT prolongation
   Xerostomia
               FADAA - 2005 Annual Conference   17
Methadone - Medical Indications

   Severe pain

   Opioid agonist dependence

   Opioid agonist withdrawal



              FADAA - 2005 Annual Conference   18
Methadone Dosage
   Pain:

       2.5 – 10 mg every 4-12 hours

   Addiction:

       80-120 majority, up to 300 not unusual,
        rare cases in excess of 500 (QT concerns)


                   FADAA - 2005 Annual Conference   19
Methadone Drug Interactions
   Enzymes - cytochrome P450 (CYP) 3A4
    metabolize methadone.
   Some drugs increase this metabolism
    reducing effect of methadone– barbs,
    Dilantin, carbamazepine, etc.
   Some drus inhibit metabolism
    prolonging the effect of methadone –
    Tagamet, Cipro, Diflucan, grapefruit
    See Addiction Treatmen Forum Methadopne-Drug Interactions, in CMG reader


                             FADAA - 2005 Annual Conference                    20
Opioid Addiction is…

     Defined as a chronic,
     progressive,
     relapsing,
     incurable,
     often fatal, but
     Treatable disease.

              FADAA - 2005 Annual Conference   21
“Opioid Addiction is a
chronic brain disease”




      FADAA - 2005 Annual Conference   22
“Addiction is more than just a brain
              disease”
 Alan Leshner, PhD, Director NIDA




          FADAA - 2005 Annual Conference   23
Factors Contributing to Vulnerability
  to Develop a Specific Addiction
           Use of the drug of abuse essential (100%)




Genetic                                            Environmental
(25-50%)                                           (very high)




                                                   • neurochemistry
                                                   • behaviors
                   Drug-Induced Effects
                                                                    24
                        (very high)
                                                       Kreek et al., 2000
Important Distinctions


      Tolerance

      Dependence

      Addiction

            FADAA - 2005 Annual Conference   25
  Tolerance
A state in which an organism no
longer responds to a drug


A higher dose is required to achieve
the same effect

              FADAA - 2005 Annual Conference   26
   Dependence

A state in which an organism functions
normally only in the presence of a drug


Manifested as a physical disturbance
when the drug is removed (withdrawal)

                 FADAA - 2005 Annual Conference   27
Addiction
A state in which an organisam engages in
  a compulsive behavior

Behavior is reinforcing (rewarding or
 pleasurable)

Loss of control in limiting intake

               FADAA - 2005 Annual Conference   28
        Goals for Pharmacotherapy
           Prevention or reduction of withdrawal
            symptoms
          Prevention or reduction of drug craving
          Prevention of relapse to use of addictive drug
          Restoration to or toward normalcy of any
           physiological function disrupted by drug abuse
Source: MJ Kreek, Rationale for Maintenance Pharmacotherapy of Opiate
Dependence, 1992
                                          FADAA - 2005 Annual Conference   29
    Early Efficacy & Outcome Studies
   Retention - VS. TC and Drug Free
       NYC, DARP, & TOPS (>40K patients)

   Retention relative to dose/placebo
       Newman, Strain, & Caplehorn

   Reincarceration and heroin use
       Dole, Newman & Whitehill (‘69 & ‘76)
                    FADAA - 2005 Annual Conference   30
        PROFILE FOR POTENTIAL
        PSYCHOTHERAPEUTIC AGENT
         Effective after oral administration
         Long biological half-life (>24 hours)
         Minimal side effects during chronic administration
         Safe, no true toxic or serious adverse effects
         Efficacious for a substantial % of persons with the
             disorder

Source: MJ Kreek, Rationale for Maintenance Pharmacotherapy of Opiate Dependence, 1992



                                           FADAA - 2005 Annual Conference                31
                    Tolerant/Dependent Drug States

                    “Loaded”
Drug Effect Scale



                          “High”

                                    Normal Range
                                    “Comfort Zone”


                                                                           “Sick”


                                            Time

                                                                                        33
                         Opioid Maintenance Pharmacotherapy - A Course for Clinicians
                       Heroin Simulated 24 Hr. Dose/Response
                       With established heroin tolerance/dependence



                  “Loaded”
                     “High”
Dose Response



                                                      “Abnormal Normality”

                                  Normal Range
                                  “Comfort Zone”

                                            Subjective
                                               w/d     “Sick”
                                                         Objective w/d

                0                          Time                                             24
                hrs.                                                                        hrs.
                                                                                                   34
                             Opioid Maintenance Pharmacotherapy - A Course for Clinicians
                 Methadone Simulated 24 Hr. Dose/Response
                      At steady-state in tolerant patient

                  “Loaded”
                     “High”
Dose Response




                                                    “Abnormal Normality”


                                Normal Range
                                “Comfort Zone”
                                    Subjective
                                       w/d     “Sick”
                                                 Objective w/d

                0                        Time                                                24
                hrs.                                                                         hrs.
                                                                                                    35
                              Opioid Maintenance Pharmacotherapy - A Course for Clinicians
Steady-State Pharmacology
   The next slides are based on the
    accumulation and buildup that occurs
    when methadone treatment in initiated.
   Understanding this process can help to
    avoid potential methadone related
    problems.
   Half-life is the time required to
    eliminate ½ of a dose of medication.

               FADAA - 2005 Annual Conference   36
        Methadone Buildup to Steady State

      450
      400
      350
      300
      250
ng/ml
      200
      150
      100
       50
        0
            1   2          3         4          5          6   7   8

                          Days/Half-Lives
        Dose constant at 30 mg/day to steady-state @ 5+days
                                                                       37
                    Opioid Maintenance Pharmacotherapy -
        Steady-State – Fluctuations Determined by Frequency of Dose


                 600

                                                                                            Over-
                 500
                                                                                            Medication

                 400

  Mean Plasma                                                                               Therapeutic
                 300                                                                        Window
  Level

                 200

                                                                                            Under-
                 100                                                                        Medication

                    0
                        0       1       2       3          4               5            6
                            100 mg qd       50 mg q 12 h       25 mg q 6 h Infusion
                                                Time in Days
WHO Guide to Good Prescribing: Essentials of Pharmacology in Daily Practice. Annex 1.
http://www.docnet.org.uk/who/ggp/homepage.htm                                                       38
Impact of Maintenance Treatment
    Reduction death rates (Grondblah, ‘90)
    Reduction IVDU (Ball & Ross, ‘91)
    Reduction crime days (Ball & Ross)
    Reduction rate of HIV seroconversion
     (Bourne,‘88; Novick ‘90,; Metzger ‘93)
    Reduction relapse to IVDU (Ball & Ross)
    Improved employment, health, & social
     function


                    FADAA - 2005 Annual Conference   39
               DEATH RATES IN TREATED AND
               UNTREATED HEROIN ADDICTS
                                                 MMT           VOL DTX         INVOL DTX     UN-
                                                                                           TREATED

                OBSERVED                         1.4              1.65              6.91     7.2


                 EXPECTED                        0.17             0.44              0.13    0.11


                OBSERVED                         8.4               3.8              53.1    65.4
                /EXPECTED


Slide data courtesy of Frank Vocci, MD, NIDA -
Reference: Grondblah, L. et al. ACTA PSCHIATR          FADAA - 2005 Annual Conference              40
SCAND, P. 223-227, 1990
MMT: Essential Elements

   Treat patients with compassion, dignity,
    & respect.
   Ensure that all patients receive an
    individualized and adequate dose
   Support the maintenance model of
    treatment

                FADAA - 2005 Annual Conference   41
                   Evidence-Based Practices:
               Elements to Maximize OAT Outcomes


    •   Adequate Methadone Dose

    •   Availability of counseling
    •   Maintenance versus abstinence/detoxification
        program orientation
    •   Contingency management with focus on positive
        and immediate reinforcement/rewards


Source: Opioid Agonist Therapy Monitoring System (OMS) Willenbring et al. 2003

                                    FADAA - 2005 Annual Conference               42
                                                                                  42
Final Issues:
   What is an adequate dose?
       The amount required to control craving
        and to prevent withdrawal.
   How long should MMT last?
       As long as patient needs, desires, benefits
        from treatment.
       Recent studies are in support of long-term
        MMT.

                   FADAA - 2005 Annual Conference   43
                                            Opioid Agonist Treatment Algorithm
                                             Application




                                                                       No          Refer to alternate
                                                CPD?                                  treatment

                                                       Yes



                                                1 year                 No            Detoxification
                                               history?

                                                       Yes

                                              Induction                                 STD or                          STD
                                                                                         LTD?



                                             Stabilization                                                              Brief
                                                                                         LTD                          Induction



                                             Maintenance                                                           Taper to "0 mg"
                                                                                       Induction                    within 30 days



                                               Periodic
                                             Assessment                              Stabilization            No        OK?



                                                                                                                              Yes
             MSW                      No      Continue           Yes                MSW - Taper to
                                               MMT?                                "0 mg" - 180 days                 Drug-free
                                                                                                                   continuing care

           Periodic                                                                    Periodic
         Assessment                                                                  Assessment




No            OK?                                                                        OK?            Yes           Continue
                                                                                                                       MSW

                      Yes                                                                        No

           Continue
            MSW                                                              Yes         MMT
                                                                                       Eligibile?

            MSW                                                                                  No
          completed

                                                     Refer to alternate     No         Continue         Yes
          Drug-free                                     treatment                       MSW ?
        continuing care
                                                                                                                       MSW
                                                                                                                     completed



                                                                                                                     Drug-free
                                                                                                                   continuing care
                            Legend
 CPD:     Current physical dependence
 STD:     Short-term detoxification
 LTD:     Long-term detoxification
 MMT:     Methadone maintenance treatment
J. Thomas Payte, MD, CMA
 Colonial Management Group
14050 Town Loop Blvd., Ste.204
     Orlando, FL 32837
        407-351-7080
 Email: jtpayte@jtpayte.com
   Web: www.jtpayte.com          1

                              45

				
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