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Opioid Dependence: Treatment Options. Walter Ling MD Integrated Substance Abuse Programs(ISAP) UCLA Suboxone Advisory Board Meeting Kaohsiung, Taiwan November 4, 2007 lwalter@ucla.edu www.uclaisap.org. Treating Opioid Addiction: Aims. Getting off opioids: detoxification

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opioid dependence treatment options
Opioid Dependence: Treatment Options

Walter Ling MD

Integrated Substance Abuse Programs(ISAP)

UCLA

Suboxone Advisory Board Meeting

Kaohsiung, Taiwan

November 4, 2007

lwalter@ucla.edu

www.uclaisap.org

treating opioid addiction aims
Treating Opioid Addiction: Aims
  • Getting off opioids: detoxification
    • Agonist opioid based detoxification
    • Non-opioid based detoxification
    • Antagonist based detoxification
  • Staying of opioids: relapse prevention
    • Agonist maintenance: methadone/others
    • Antagonist maintenance: naltrexone
    • Partial agonist maintenance: buprenorphine
  • Changing life style
phases of opioid withdrawal
Phases of Opioid Withdrawal

3. Fully Developed Withdrawal(1-3 days)

Severe anxiety

Restlessness

Muscle spasm

Elevated BP

Fever/Chills

Drug seeking

Tremor Piloerection

Vomiting

Diarrhea

Tachycardia

1. Anticipatory withdrawal

(3-4 hrs)

Fear of withdrawal

Anxiety

Drug seeking

2. Early Withdrawal (8-10 hrs)

Hypertension

Tachycardia

Yawning

Sweating

Rhinorrhea

Lacrimation

Dilated pupils

Anxiety

Restlessness

Nausea

Nasal stuffiness

Abdominal cramps

Drug seeking

4. Protracted Abstinence(up to 6 mos.)

Hypotension

Bradycardia

Insomnia

Loss of appetite

Loss of energy

Cue induced craving

determinants of withdrawal severity
Determinants of Withdrawal Severity
  • Triggers and intensity of withdrawal
    • Amount and regularity of use
    • Rate of withdrawal
    • Patient physical & psychological condition and expectation
  • Settings and the severity of withdrawal
    • Presence of opiates vs absence
    • Treatment setting and environment
    • Physician confidence and attitude
    • Medications for symptom relief and

general nutrition

detoxification
Detoxification
  • Relieve Symptoms of withdrawal
  • Reverse neuro-adaptation from chronic heroin use
  • Reduce degree of physical dependence
  • Promote long term treatment leading to life style changes
  • Transitional treatment strategy

Methods and Medications

  • Methadone and buprenorphine
    • Opioids agonist and partial agonist
    • Short and long term
  • Clonidine and Lofexidine
    • Non-opioids; alpha adrenergic agonists
  • Antagonists assisted
    • Naloxone /Naltrexone
    • Rapid and ultra-rapid detoxifications
detoxification6
Detoxification
  • The most common outcome of detoxification, by whatever means and for however long, is relapse. “Detoxification may be good for a lot of things; staying off drugs is not one of them”
clonidine for opioid withdrawal
Clonidine for Opioid Withdrawal
  • Doses: 0.1 mg tid to 0.4 mg tid
  • Push dose until withdrawal sx abate or diastolic BP <60
  • Use adjunctive benzodiazepines, anti-emetics, anti-diarrheals
  • -2 adrenergic agonist binds to pre-synaptic autoreceptors on adrenergic neurons
    • In Locus Coeruleus
    • Possibly in A1 and A2 cell groups of the caudal medulla that project to BNST (extended amygdala)
  • FDA approved for hypertension
    • Limiting side effect: hypotension
  • Reduces W/D signs and sx:
    • Significantly better than placebo
    • Nearly comparable to slow methadone taper
rapid ultra rapid opioid withdrawal
Rapid &Ultra Rapid Opioid Withdrawal
  • Patient placed under deep sedation or general anesthesia
  • Administer opioid antagonists to provoke W/D
  • Manage emergent sx with:
    • Clonidine/ Lofexidine
    • Benzodiazepines
    • Antiemetics
    • Antidiarrheals
  • W/D essentially resolved in 12-24 hours (ultra rapid) or 2-3 days (rapid) with patient ± on full dose of antagonist (naltrexone)
opioid substitution or maintenance therapy
Opioid Substitution or Maintenance Therapy
  • Reduce symptoms & signs of withdrawal
  • Reduce or eliminate craving
  • Blocks effects of illicit opioids
  • Restored normal physiology
  • Promote psychosocial rehabilitation and non-drug life style

Maintenance Medications:

  • Methadone maintenance (agonist)
  • Naltrexone (antagonist)
  • Buprenorphine (partial agonist)
    • Buprenorphine (Subutex)
    • Buprenorphine-naloxone (Suboxone)
methadone clinical properties
Methadone: Clinical Properties

Orally active synthetic μ opioid agonist with morphine-like properties

Action—CNS depressant/ Analgesic

Quick absorption, slow elimination, long half-life

Effects last 24 hours; once daily dosing maintains constant blood level

Prevent withdrawal, reduce craving and use

Long term treatment normalize physiological function

Facilitates rehabilitation

slide11

Methadone Pharmacokinetics

  • Good oral bioavailability; fast and complete absorption
  • Peak plasma concentration 21/2 hrs (liquid), 31/2 hrs (tablet); mean half-life 24 hrs, steady state 3-10 days
  • 96% plasma protein bound
  • Variable bioavailability (40%-99%);genetic variations in protein binding, oxidative metabolism and GI (majority) and renal (minor) excretion, capacity limited clearance
  • Onset of analgesia 15-20 min; difficult to predict initial dose and dosing frequency.
  • Metabolism mediated via P450 cytochrome, primarily
    • CYP3A4, but also CYP2D6, CYP1A2, CYP2C9 CYP2C19
  • Clinically significant drug/drug interactions
methadone and cyp3a4 enzyme
Methadone and CYP3A4 Enzyme
  • CYP3A4: Inducible enzyme
    • Methadone induces its own metabolism; levels vary over time; 3.5 fold increase in clearance between induction and steady state
  • Increases metabolism of certain drugs:
    • Dilantin, Tegretol, Barbiturates, Rifampin, Cypro, Verapamil, Zidovudine, amitryptyline, spinololactone, and others
  • Decrease metabolism of certain other drugs:
    • Fluvoxamine, Nefazedone, Omeprazole, Indinavir,

Nelfinavir, Ritonavir, Fluoxetine, Saquinavir, other SSRI’s

pharmacodynamics
Pharmacodynamics
  • Full agonist; receptor affinity lower than Ms
    • Main action on mu receptors
      • inhibit adenyl cyclase =  cAMP
      •  potasium channel opening
      •  calcium channel opening
    • also inhibit serotonin reuptake
    • also non competitive antagonist NMDA receptor
  • No known active metabolites; limited toxicity
    • No significant cognitive impairment with chronic use
    • No organ toxicity with chronic use
equianalgesic dose references
Equianalgesic dose references
  • Pereira J et al Equianalgesic dose ratio for opioids: a critical review and proposals for long-term dosing. J. Pain Symptom Management 2001 22(2) p. 672-687
  • Anderson R, et al Accuracy in equianalgesic dosing conversion dilemmas J Pain Symptom Management 2001 21(5) p.397-406
phases of treatment
Phases of Treatment:
  • On going Management:
    • Co-occurring disorders
    • Smoking, alcohol & other drugs
    • Adequate pain management
    • Dose and duration of treatment
    • Ancillary services &social support
    • Quality of therapeutic relationship
  • Life Changes:
    • Experience creates memory
    • Memory leads to protein synthesis
    • Protein synthesis alters gene expression
    • Gene expression creates new behavior
    • New behavior leads to life changes
  • Assessments:
    • Agreed treatment goals
    • Level of tolerance and dependence
    • Use/dependence on other drugs
    • Co-existing conditions
    • What social support systems
  • Initial Treatment Phase
    • Adequacy of dosing; clinic visits & dose changes
    • S&S of withdrawal
    • Side effects and toxicity
    • Drug/drug interactions

“You can change a man’s life by altering his genes; but you can also do that by paying off his credit card”—James Watson

methadone maintenance

Not in Tx

50%

47%

40%

Currently in Tx

30%

No needle use since

admission to Tx

In Tx 5 years

23%

20%

17%

12.5%

10%

6%

0%

A

B

C

D

C&D

Methadone Maintenance

HIV Rates

naltrexone the perfect drug
Naltrexone: The Perfect Drug
  • Orally Effective
  • Rapid onset of action
  • Long duration of action
  • Safe
  • Few side effects
  • Blocks effects of heroin
  • Non-addicting One reason not to take
  • No tolerance naltrexone: can’t get high
  • No dependence “It’s like taking nothing”
  • No withdrawal
buprenorphine pharmacological characteristics
Buprenorphine: Pharmacological Characteristics

Partial Agonist (ceiling effect)

  • high safety profile
  • low dependence

Tight Receptor Binding

  • long duration of action
  • slow onset mild abstinence
study 999a buprenorphine s effect on opiate use

Study 1008: Suboxone

Study # 999A: Buprenorphine’sEffect on Opiate Use

Percent Patients on Initial DoseJohnson et al., 1998

Dose change option in effect

  • 16mg mono SL tablets (Subutex) and 16mg/4mg combo SL (Suboxone) are equally efficacious.
  • Most reported adverse effects were those commonly seen in patients treated with opioids.
buprenorphine and methadone dose responses from four studies using joint probability

N remaining in treatment

X

N giving clean urines

Total N of subjects

N remaining in treatment

Buprenorphine and Methadone dose responsesfrom four studies using “Joint Probability”

Joint Probability

opiate agonist measures

14

12

2:1

10

Plac

8

8:1

4.1

6

Bup

4

MS

2

0

60

0

5

10

15

20

25

30

35

40

45

50

55

Adding Naloxone to Buprenorphine

  • Naloxone not absorbed sufficiently to interfere with buprenorphine when the combination is taken sublingually
  • Sublingual absorption of buprenorphine

@ 70%; naloxone @ 10%

  • If injected, BUP/NX will precipitate withdrawal in a moderately to severely dependent addict
Opiate Agonist Measures

Value of a Dose in Dollars

Dollars

Minutes

suboxone vs clonidine
Suboxone vs Clonidine

Percent Present and CleanCTN 0001 (Inpatient)

Percent Present and Clean0002 (Outpatient)

NNT:

Number Needed to Treat

NNT for Bup/Nx: 157/46 = 3.4

NNT for Clonidine: 74/4 = 18.5

NNT Clonidine : Bup/Nx = 5.44

  • NNT:
  • Number Needed to Treat
  • NNT for Bup/Nx 77/59 = 1.31
  • NNT for Clonidine 36/8 = 4.5
  • NNT Clonidine : BupNx = 3.44
in conclusion
In Conclusion
  • Opioid addiction is a serious chronic relapsing but treatable disorder
  • Treatment must be sustained, detoxification alone insufficient for long term outcome
  • Treatment must address both disordered physiology and disrupted lives
  • There are no right or wrong medications, only the right and wrong ways to use them.
  • Medications can only change physiology, but new behavior can change lives
slide25
Thank you

Thank you

Thank you