using suboxone and methadone to treat opiate dependence karen miotto, m.d. ucla addiction medicine...
TRANSCRIPT
Using Suboxone and Methadone to Treat Opiate
Dependence
Karen Miotto, M.D.UCLA Addiction Medicine Service
Scope of this Talk
• Epidemiology of heroin and prescription drug dependence
• Pharmacology, side effects and safety of methadone and buprenorphine (Suboxone® and Subutex®)
• Patient selection, monitoring and counseling
• The role of counseling in opioid treatment
Opioid addiction spread in last half of 19th century via:
• • Medical administration • Doctors injected morphine to treat casual
complaints as well as serious problems
• • Civil War • Morphine widely used for Civil War
injuries
• • Self-administration via patent medicines
No requirements for safety, efficacy
Anyone could produce, sell “medicines” – Unsafe– Ineffective– Made curative claims without benefit of
scientific proof
By early 1900s, medical consensus developed:
Opiates, other drugs overly prescribed Sold to unsuspecting customers & produced
addiction Worthless patent “medicines” being sold Harrison Act of 1914
Federal Pure Food and Drug Act of 1906
(& subsequent amendments)
Food, drugs pure Contents labeled Drugs must be safe and effective Food and Drug Administration
Harrison Act of 1914(& subsequent laws)
• • First law to control opiates, cocaine, other drugs• • Subsequent laws attempt to balance
– Use in medicine with potential for abuse
• • Marijuana Tax Act of 1937– Adds cannabis
The 1960 and 1970s
In 2005, for 12-17 year olds:
Current users of illicit drugs: 9.9%
Used Rx drugs non-medically: 3.3%
In 2005 for 18-25 year olds:
Current users of illicit drugs: 20.1%
Used Rx drugs non-medically: 6.3%
2005 National Survey on Drug Use and Health (NSDUH)
Prevalence of any illicit drug use
In 2005, for 12-17 year olds:
Ever used: 13.4%
Used in past year: 4.9%
In 2005, for 18-25 year olds:
Ever used: 25.5%
Used in past year: 12.4%
2005 National Survey on Drug Use and Health (NSDUH)
Prevalence of non-medical use of an Rx pain reliever
In 2005, for 12-17 year olds:
Past year Dependence or Abuse: 1.1% (275,000 persons)
In 2005, for 18-25 year olds:
Past year Dependence or Abuse: 1.7% (541,000 persons)
2005 National Survey on Drug Use and Health (NSDUH)
Prevalence of non-medical use of an Rx pain reliever
In 2005, for 12-17 year olds:
Past year use: 0.2% (60,000 persons)
Abuse or Dependence: 0.0% (9,000 persons)
In 2005, for 18-25 year olds:
Past year use: 1.5% (496,000 persons)
Abuse or Dependence: 0.3% (89,000 persons)
2005 National Survey on Drug Use and Health (NSDUH)
Prevalence of heroin use
Opioid Emergency Department Mentions 2004
0
20,000
40,000
60,000
80,000
100,000
120,000
140,000
160,000
180,000
Heroin Opioid Analgesics
Hydrocodone
Oxycodone
Seeking Detox
Trends In Emergency Department Mentions2004-2005
0 100,000 200,000
2004
2005
Heroin Rx Opioids
SOURCE: SAMHSA Drug Abuse Warning Network, 2007
Heroin Purity
Average Purity of Retail HeroinStreet Samples in U.S
0
5
10
15
20
25
30
35
40
1980's 1991 2000
Source: DEA, 2002
Smoking Heroinwww.thesun.co.uk/.../news/article1561831.ece
Types of Opioid Types of Opioid ReceptorsReceptors
-10 -9 -8 -7 -6 -5 -40
10
20
30
40
50
60
70
80
90
100
Intrinsic Activity
Log Dose of Opioid
Full Agonist(Methadone)
Partial Agonist(Buprenorphine)
Antagonist (Naloxone)
Intrinsic Activity: Full Agonist (Methadone), Partial Agonist (Buprenorphine), Antagonist (Naloxone)
OPIOID CNS EFFECTS
EFFECTS Analgesia Sedation Euphoria Body Temperature
Changes Miosis Respiratory
Depression
WITHDRAWAL Muscle Pain,
Cramping Insomnia Dysphoria Chills, Piloerection Mydriasis Yawning, Sneezing,
Rhinorrhea
THE BASICS: THE BASICS:
HOW IT HOW IT
WORKS WORKS 23
Opioid Maintenance Pharmacotherapy - A Course for Clinicians
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
24
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
Opioid Maintenance Pharmacotherapy - A Course for Clinicians
Source: MJ Kreek, Rationale for Maintenance Pharmacotherapy of Opiate Dependence, 1992
25
On/Off - Non-Tolerant Drug StatesOn/Off - Non-Tolerant Drug StatesM
oo
d/E
ffe
ct
Sc
ale “ON”
Drug Effect
“OFF”
No Drug Effect;
“Normal”
Overdose
Intoxication
Euphoria
“Normophoria”
Dysphoria
Opioid Maintenance Pharmacotherapy - A Course for Clinicians26
Opioid Maintenance Pharmacotherapy - A Course for Clinicians
Dru
g E
ffec
t S
cale
Time
“Loaded”
“High”
Normal Range“Comfort Zone”
“Sick”
Tolerant/Dependent Drug States
28
Do
se R
esp
on
se
Time
“Loaded” “High”
Normal Range“Comfort Zone”
“Sick”
Heroin Simulated 24 Hr. Dose/Response
With established heroin tolerance/dependence
0 hrs.
24 hrs.
“Abnormal Normality”
Subjective w/d
Objective w/d
Opioid Maintenance Pharmacotherapy - A Course for Clinicians29
Do
se R
esp
on
se
Time
“Loaded” “High”
Normal Range“Comfort Zone”
“Sick”
Methadone Simulated 24 Hr. Dose/ResponseAt steady-state in tolerant patient
0 hrs.
24 hrs.
“Abnormal Normality”
Subjective w/d
Objective w/d
Opioid Maintenance Pharmacotherapy - A Course for Clinicians
30
What Does Opioid What Does Opioid Maintenance Treatment Maintenance Treatment
DO?DO?
Impact of Impact of Treatment!Treatment! 31
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
function32
J. Thomas Payte, MD – Colonial Management Group, LP
Patients are 6.7 times more likely to die
during induction than untreated heroin
addicts (Caplehorn & Drummer, 1999).
42% of drug-related deaths occurred during
the first week of OMT (Zador & Sunjic, 2000).
10 OMT deaths are reported ― All 10 had
been in treatment less than 7 days
(Drummer, Opeskin, Syrjanen & Cordner,
1992). 33
SAFE SAFE
INDUCTION INDUCTION
TECHNIQUESTECHNIQUES34
Initial Dose
Degree of Tolerance
Dose Range
Non-Tolerant
10 mg +/- 5
Unknown Tolerance
20 mg +/- 5
Known Tolerance
20-40 mg
Payte
Opioid Maintenance Pharmacotherapy - A Course for Clinicians
35
Early Induction
Early dose adjustments to reach the “Therapeutic Window” as determined by established opioid tolerance.
-- The “Comfort Zone” –
Increase dose daily until pt. comfortable during methadone peak levels (3-5 hours after dose) then;
Hold dose for 3-5 days to reach steady-state before further dose adjustments.
REMEMBER STEADY-STATE PHARMACOLOGY!
Payte
Opioid Maintenance Pharmacotherapy - A Course for Clinicians 36
Induction Simulation – Low Dose/Low Tolerance with failure to reduce dose on day 2 or 3
0
50
100
150
200
250
300
350
400
450
1 2 3 4 5 6 7 8
ng/ml
mg/day
Time in DaysDose remains constant to steady-state in toxic
rangeOpioid Maintenance Pharmacotherapy - A Course for Clinicians
IntoxicationPotential OD
TherapeuticWindow
37
Induction Simulation – Low Dose/Low Tolerance with reduced dose on day 3 & 4
0
50
100
150
200
250
300
1 2 3 4 5 6 7 8
ng/ml
mg/day
Time in Days = Dose Reduction
Opioid Maintenance Pharmacotherapy - A Course for Clinicians
Intoxication,Potential OD
TherapeuticWindow
38
Induction Simulation – Low to Moderate Tolerance
050
100150200
250300350400
450500
1 2 3 4 5 6 7 8 9 10
ng/ml
mg/day
Days/Half-Lives =Dose Increase
Opioid Maintenance Pharmacotherapy - A Course for Clinicians
Therapeutic
Window
39
Issues in Issues in Maintenance:Maintenance:
HOW MUCH?HOW MUCH?
&&
HOW LONG?HOW LONG?Opioid Agonist Treatment of Addiction - Payte - 1998
40
. . . As long as patient desires and benefits from continued treatment
Opioid Agonist Treatment of Addiction - Payte - 1998
41
Recovery is a process, not an event!
P
ER
CE
NT
IV
US
ER
S
0
100
LA
ST
AD
DIC
TIO
N P
ER
IOD
AD
MIS
SIO
N
100%
81.4%
Pre- | 1st Year | 2nd Year | 3rd Year | 4th Year Admission
*
*
63.3%
41.7%
28.9%
Adapted from Ball & Ross - The Effectiveness of Methadone Maintenance Treatment, 1991 Opioid Agonist Treatment of Addiction - Payte - 1998
Opioid Maintenance Pharmacotherapy - A Course for Clinicians
OPTIMAL RESPONSE FROM OPIOID AGONIST IN MAINTENANCE
TREATMENT
Prevention of onset of withdrawal syndrome for 24 hours or more
Reduction or elimination of drug hunger or craving
“Blockade” of euphoric effects of illicit self-administered opioids
Kreek, 1987 – title change by Payte, 2001
Opioid Agonist Treatment of Addiction - 200144
Optimal Vs. Desired Response
The clinician and the patient must speak the same language to ensure realistic expectations and goals of OAT. A pattern of dose escalation in pursuit of the elusive state of “abnormal normality” must be recognized by the patient and the clinician.
Opioid Agonist Treatment of Addiction - Payte - 2001
45
Edwin A. Salsitz, MD
Cytochrome P-450 Enzyme ActivityDrug Interactions - Methadone
Induction Rifampin Phenytoin Ethyl Alcohol Barbiturates Carbamazepine Nevirapine (Viramune)
Opioid Maintenance Pharmacotherapy - A Course for Clinicians
Cytochrome P-450 Enzyme ActivityDrug Interactions - Methadone
Inhibition
Fluconazole
Cimetidine
Erythromycin
Fluvoxamine (Luvox)
Ketoconazole
Nefazodone (Serzone)
Ritonavir (Norvir)
Opioid Maintenance Pharmacotherapy - A Course for Clinicians
Methadone Death
Overdose, overmedication or drug-drug interaction?
HARMDHelping America Reduce
Methadone Deaths
• “Helping America Reduce Methadone Deaths”• http://www.harmd.org/
Edwin A. Salsitz, MD
THE DOSING WINDOW
Edwin A. Salsitz, MD
Edwin A. Salsitz, MD
Edwin A. Salsitz, MD
Edwin A. Salsitz, MD
Subutex® and Suboxone®
• Two, schedule III, sublingual buprenorphine tablet formulations (2 mg and 8 mg) approved for US use:• Subutex® (buprenorphine alone)• Suboxone® (buprenorphine + naloxone)
• In contrast, methadone is a schedule II drug
• Partial mu-opioid agonists• Suboxone® is the focus of US
marketing efforts
Combination of Buprenorphineplus Naloxone
Addition of naloxone to buprenorphine may decrease the abuse potential of tablets
If an opioid/heroin user injects Suboxone the naloxone will be active and cause withdrawal
Buprenorphine plus naloxone = Suboxone
Buprenorphine without naloxone = Subutex
1/8/06, Anaheim, ASAM physician buprenorphine training
1/8/06, Anaheim, ASAM physician buprenorphine training
333333333333
Edwin A. Salsitz, MD
2005 Anaheim, ASAM buprenorphine training
Phone screening
Patient agreements
Monitor progress Referrals
MEDICATION/PSYCHOSOCIAL
1/8/06, Anaheim, ASAM physician buprenorphine training
DATA 2000 restrictions:number of patients
• Solo practice: 30 patients• Unless doctors request increase to 100 patients
2005 Anaheim, ASAM buprenorphine training
Examples of Patient agreements:
• To take the medication only as prescribed
• To notify the clinic immediately in case of lost or stolen medication
• To comply with the required pill counts and urine tests
• Enter counseling or a treatment program
2005 Anaheim, ASAM buprenorphine training
Elements of periodic
monitoring
• Tox screens
• Medication compliance
• Health and wellbeing
• Counseling
2005 Anaheim, ASAM buprenorphine training
Are you going to watch?
2005 Anaheim, ASAM buprenorphine training
Whizmaster KitWhizmaster Kit
2005 Anaheim, ASAM buprenorphine training
Example of tox screen protocol: Urine On -Site at each visit, discussed right away
- Send -away initial and yearly and any positives
- Random call twice a year - Temperature testing at each collection
Breathalyzer: initial, then individualized
2005 Anaheim, ASAM buprenorphine training
Medication compliance
• Observed dosing early on, potential for observed dosing at pharmacy or periodically.
• Pill counts with random callbacks.
• Use urine test for buprenorphine – they are available!
2005 Anaheim, ASAM buprenorphine training
THREATS TO STABILITY
Other drug abuse or positive screensMedical problemsLife changes: moves, divorce, new
jobDropping out of counseling, mutual
support meetings
2005 Anaheim, ASAM buprenorphine training
RED FLAGS CHECKLIST
• Missing appointments
• Running out of medication too soon
• Taking medication off schedule
• Not responding to phone calls
• Refusing urine or breath testing
• Neglecting to mention new medications or outside treatment
2005 Anaheim, ASAM buprenorphine training
RED FLAGS CHECKILST,cont.
• Appearing intoxicated or disheveled • Frequent or urgent inappropriate phone
calls• Neglecting to mention change in address,
work, or home situation• Inappropriate outbursts of anger• Lost or stolen medication• Frequent physical injuries or accidents
RESPONSE TO RED FLAGS
• Address red flags as soon as possible
• Ask for patient generated plan
• Coordinate care with the counselor or treatment program
• Increase the level of care or frequency of meetings
• Formalize the plan in the office
2005 Anaheim, ASAM buprenorphine training
MONITORING: SUMMARY
Regular follow-up visits
Regular and random testing and pill counts
Address red flag behavior promptly
Adjust structure according to progress
What you are doing should make sense
$ Cost $
Referral and discontinuation
• Cost may prohibit treatment – TAR possible
• Methadone treatment cost less –Drug MediCal
• Taper for administrative non-compliance
• (clear guidelines important)
• Higher level of care needed
• Immediate dismissal for behavior
Summary• Increasing rates of prescription drug
dependence
• Pharmacology, side effects and safety Methadone - risk of drug interaction and overdose
• Buprenorphine – compliance and diversion
• Patient selection, monitoring and counseling
• Essential role of counseling