Opioid Dependence: Treatment Options

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 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

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 • 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

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 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

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: • 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

17. 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

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 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.

21. 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

22. 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

23. 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

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 Thank you Thank you