1. 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

2. 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

3. Phases of Opioid Withdrawal 1. Anticipatory withdrawal (3-4 hrs) Fear of withdrawal Anxiety Drug seeking 2. Early Withdrawal (8-10 hrs) Anxiety Restlessness Nausea Nasal stuffiness Abdominal cramps Drug seeking Hypertension Tachycardia Yawning Sweating Rhinorrhea Lacrimation Dilated pupils 3. Fully Developed Withdrawal 3. Fully Developed Withdrawal (1-3 days) Severe anxiety Restlessness Muscle spasm Elevated BP Fever/Chills Drug seeking Tremor Piloerection Vomiting Diarrhea Tachycardia 4. Protracted Abstinence 4. Protracted Abstinence (up to 6 mos.) Hypotension Bradycardia Insomnia Loss of appetite Loss of energy Cue induced craving

4. 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

5. 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

6. 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”

7. Clonidine for Opioid Withdrawal  -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 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

8. 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)

9. 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)

10. 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

11. Methadone Pharmacokinetics Good oral bioavailability; fast and complete absorption Peak plasma concentration 2 1/2 hrs (liquid), 3 1/2 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

12. 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

13. 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

15. 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

16. Phases of Treatment: 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 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 “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

17. Methadone Maintenance 47%47% 23%23% 17%17% 12.5 % 6%6% 0% 10% 20% 30% 40% 50% Not in Tx Currently in Tx In Tx 5 years C&D No needle use since admission to Tx ABCD HIV Rates

18. 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

19. Buprenorphine: Pharmacological Characteristics Partial Agonist (ceiling effect) high safety profile low dependence Tight Receptor Binding long duration of action slow onset mild abstinence

20. Study # 999A: Buprenorphine’s Effect on Opiate Use Dose change option in effect Percent Patients on Initial Dose Johnson et al., 1998 Study 1008: Suboxone 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.

21. Buprenorphine and Methadone dose responses from four studies using “Joint Probability” N remaining in treatment X Total N of subjects N giving clean urinesN remaining in treatment Joint Probability

22. Opiate Agonist Measures Bup MS4.1 8:1 2:1 Plac Adding Naloxone to Buprenorphine Value of a Dose in Dollars Dollars Minutes 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

23. Suboxone vs Clonidine Percent Present and Clean CTN 0001 (Inpatient) Percent Present and Clean 0002 (Outpatient) 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 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

24. 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

25. Thank you