suboxone salsitz slides

Buprenorphine andOffice-Based Treatment of

Opioid Dependence

Stacy E. Seikel, MDBoard Certified Addiction Medicine

Board Certified Anesthesiology

Learning Objectives

• Understand pharmacology of buprenorphine

• Understand significance of drug Addiction Treatment Act of 2000

• Explain induction process for buprenorphine

Prescription Opioids

• Abuse of prescription opioids has risen rapidly in the US:– OxyContin, Vicodin, Demerol– Dramatic press coverage fueled demand

• Prescription opioids causing Emergency Department visits 1994–2001:– 41,68790,232 (117% increase)

• Significant diversion and abuse of methadone prescribed for pain

Opioid Dependence• $20 billion per year total cost of heroin abuse

(Harwood et al, 1998) • The economic cost of drug use and dependence

estimated to be $98 billion (Harwood et al, 1998) • Figures do not take into account social impact of

drug addiction– Crime / legal costs

– Absenteeism from work / unemployment

– Welfare / medical costs

Opioid Dependence (DSM-IV)(3 or more within one year)

• Tolerance• Withdrawal• Larger amounts/longer period than intended• Inability to/persistent desire to cut down or control• Increased amount of time spent in activities necessary

to obtain opioids• Social, occupational and recreational activities given up

or reduced• Opioid use is continued despite adverse consequences

Opioid Dependence

• Opioid dependence is a chronic, progressive, relapsing medical condition

• Profound neurobiologic changes accompany the transition from opioid use to opioid addiction

• Pharmacologic treatments are effective in normalizing the neurobiologic status, decreasing illicit opioid use, medical and social complications

Opiate Dependence

• Estimated 800,000 heroin users in the U.S.• About 25% of these users currently in treatment

– Methadone, LAAM; Clonidine; Naltrexone– Drug-free programming

• Present treatment system not meeting the need• When viewed as the medical problem that it is,

opioid dependency has been one of the poorest treated disorders.

Changes in Neurobiology• Repeated exposure to short acting opioids leads to

neuronal adaptations– Mesolimbic dopaminergic system

• adaptations in G protein-coupled receptors• up regulation of CAMP second messenger pathway

• Changes– Mediate tolerance, withdrawal, craving, self-administration– Insight into the chronic and relapsing nature of opioid

dependence

– Basis of specific pharmacotherapies to stabilize neuronal circuits

Opioid Agonist Treatment Rationale

• Cross-tolerance• prevent withdrawal • relieve craving for opioids

• Narcotic blockade• block or attenuate euphoric

effect of exogenous opioids

Buprenorphine: Why was it needed?

• Federal law prohibits physicians from prescribing methadone (or other DEA Schedule II medications) for detoxification from opiate addiction EXCEPT in a federally licensed opiate treatment program (OTP) (this includes methadone maintenance).

Buprenorphine: What is it?

• Synthetic opiod developed by NIDA researchers

• Prior use for pain management

• Recent FDA approval for treatment of heroin and other opiod dependence


• Related to morphine• Functions on the same brain receptors

as morphine, but does not produce the same high, dependence, or withdrawal syndrome (partial agonist)

• Long lasting• Less likely to cause respiratory

depression


• Partial u-opioid agonist– Ceiling effect at higher doses

– Lower level of physical dependence and potential for abuse

– High affinity for and slow dissociation from receptor (long lasting)

• Safe and effective for opioid maintenance and detoxification treatment


• Available as injectable solution (for pain management)

• Also available as sublingual tablet (for opioid dependence treatment)

• Marketed as single agent (buprenorphine only) or compound buprenorphine/nalozone tablet


• Buprenorphine joined methadone, LAAM, and Naltrexone as the fourth medication for treating opiate addiction

Legislation: DATA 2000

• Permits qualified physicians to obtain a waiver to treat opioid addiction with Schedule III, IV, and V opioid medications (or combinations of such medications)

– Medications must be approved by the FDA for that indication

– Medications may be prescribed or dispensed

Legislation: DATA 2000

• Medications Approved by FDA 10/8/02 for use in the treatment of Opioid Addiction are:– Subutex® CIII 2mg, 8mg sublingual tablet

• Buprenorphine

– Suboxone® CIII 2/.5mg, 8/2mg sublingual tablet• Buprenorphine and Naloxone (4:1 ratio)

• No other opioid agonist or partial agonist medications have been approved

• Methadone is Schedule II• Buprenorphine is Schedule III

Who will be qualified to prescribe Buprenorphine?

The Drug Addiction Treatment Act of 2000 defines who is qualified to prescribe buprenorphine (“qualifying physician”): Licensed physician who meets particular criteria.


(continued)

• Licensed physician who also is approved for a waiver from the law requiring the prescription of narcotics for opiate addiction treatment to take place only in a licensed OTP.

• Non-MDs may not prescribe this class of drug


(continued)

• Physicians are required to refer patients for the full spectrum of care for their psychological and social needs.

• Maximum number of patients per agency/practice is 30, unless affiliated with OTP.

Potential Impact of Buprenorphine on practice of addiction medicine, on access to substance abuse

treatment, and on public health

• Increased access to treatment into multiple settings– Community Treatment Programs– Private Practitioner Offices (Office-Based

Treatment)• Provides alternative to methadone, LAAM, and

abstinence-based models• Increased diagnosis of co-existing health

problems due to contact with MD for office-based treatment

Pharmacology: Opioid Receptors• Types of receptors

– Mu*– Kappa– Delta

• Mu receptor activators:– morphine - heroin– methadone - hydromorphone– codeine -fentanyl

Pharmacology: Full Opioid Agonists

• Occupy the receptor and activate that receptor

• Increasing doses of the drug produce increasing receptor-specific effects until a maximum effect achieved

• Most abused opioids are full agonists• Examples: heroin, hydrocodone,

methadone, morphine

Pharmacology: Partial Opioid Agonists

• Bind to and activate receptor• Increasing dose does not produce as

great an effect as does increasing the dose of a full agonist (less of a maximal effect is possible)

• “Ceiling effect” on respiratory depression• Example: buprenorphine

Pharmacology: Opioid Antagonists

• Bind to receptors but don’t activate the receptor

• Block the receptor from activation by full and partial agonists

• Examples: Naloxone, Naltrexone

-10 -9 -8 -7 -6 -5 -40

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20

30

40

50

60

70

80

90

100

Intrinsic Activity

Log Dose of Opioid

Full Agonist(Morphine)

Partial Agonist(Buprenorphine)

Antagonist (Naloxone)

Intrinsic Activity: Full Agonist (Morphine), Partial Agonist (Buprenorphine), Antagonist (Naloxone)

Repeated Use and Discontinuation

• Repeated administration of opioids that activate the mu receptor results in dose-dependent physical dependence and tolerance

• Physical dependence and tolerance manifest as characteristic withdrawal signs and symptoms upon reduction or cessation of opioid use/administration (the opioid withdrawal syndrome)

Withdrawal Signs and Symptoms

• Dysphoric mood• Sweating• Piloerection• Diarrhea• Yawning• Mildfever• Insomnia

• Craving• Distress/irritability• Nausea or vomiting• Muscle

aches/cramps• Lacrimation• Rhinorrhea• Pupillary dilitation

Buprenorphine

• Partial Opioid Agonist

• Semi-synthetic (thebaine derivative)

• Available as a parenteral analgesic (not FDA approved for the treatment of opioid addiction)

• Produces sufficient agonist effects to be detected by the patient

Affinity and Dissociation

• Affinity: – Strength with which a drug binds to its

receptor– (Strength of binding is not related to

activation or efficacy at the receptor)

• Dissociation: – Speed (slow or fast) of disengagement or

uncoupling of drug from the receptor

Bioavailability of Buprenorphine

• Good parenteral bioavailability

• Poor oral bioavailability (extensive first-pass metabolism)

• Fair sublingual bioavailability

• Onset of action: 30 – 60 minutes (after S/L administration)

• Peak effects: 1 – 4 hours

• Half-life ~24 to 36 hours (receptor levels vs serum levels)

Duration of Action

Abuse Potential

• Buprenorphine is abusable (epidemiological, human laboratory studies show)

• Diversion and illicit use of analgesic form (by injection)

• Relatively low abuse potential compared to other opioids

Physical Dependence Potential

• Repeated administration of buprenorphine produces or maintains physical dependence

• Degree of physical dependence is less than that produced by full agonist opioids

• Withdrawal syndrome should be less severe

Sublingual Naloxone

• Relatively poor bioavailability

• Doses of 1-2 mg sublingual do not precipitate withdrawal in opioid dependent volunteers

• Sublingual naloxone does have a bitter taste

Buprenorphine/Naloxone Combination (Suboxone®)

• Addition of naloxone to buprenorphine to decrease abuse potential of tablets

• If taken as medically directed (dissolve under tongue), predominant buprenorphine effect

• If opioid dependent person dissolves tablet and injects, predominant naloxone effect (and precipitated withdrawal)

Safety Overview• Highly safe medication (acute and chronic dosing)• Primary side effects: like other mu agonist opioids

(e.g., nausea, constipation), but may be less severe

• No evidence of significant disruption in cognitive or psychomotor performance with buprenorphine maintenance

• No evidence of organ damage with chronic dosing

Safety

• Low risk of clinically significant problems• No reports of respiratory depression in clinical

trials comparing buprenorphine to methadone• Pre-clinical studies suggest high doses of

buprenorphine should not produce respiratory depression or other significant problems

• Overdose of buprenorphine combined with other drugs may cause problems (reviewed below)

Safety

• Reports of deaths when buprenorphine injected along with non-medical doses of benzodiazepines – Reported from France, where

buprenorphine-only tablets available: appears patients dissolve and inject tablets

• Probably possible for this to occur with other sedatives as well

Medication Interactions

• Benzodiazepines and other sedating drugs

• Medications metabolized by cytochrome P450 3A4

• Opioid antagonists

• Opioid agonists

SuboxoneInduction and Dosing

• Instruct patient to abstain from any opioid use so they are in mild withdrawal at time of first buprenorphine dose– Short-acting opioids: 12-24 hours

– Long-acting opioids: 24-48 hours

• Objective signs of mild-moderate withdrawal (use COWS)

• If not in withdrawal, consider having patient return another day or wait in the office until evidence of withdrawal seen

Buprenorphine Induction

•

Induction Example• Objective signs of withdrawal (use COWS)

• Day 1:– Initial dose 2/.5-4/1 mg

– Second dose of 2/.5-4/1 mg after assessing initial response

– Take home dose given prn

• Day 2– Continue to titrate dose to relieve withdrawal & cravings and

avoid sedation (generally aim to double Day 1 dose)

• Day 3– Continue to titrate according to patient’s response

OrDo A Home Induction

With Appropriate Client

Reviewing Dose Adequacy

• Sedation

• Adverse events– (headache, nausea, constipation, sweating)

• Cravings

• Continued use of illicit opioids

• Withdrawal

• Urine Toxicology

Objectives of Maintenance TreatmentObjectives of Maintenance Treatment

• To normalize and stabilize brain functionTo normalize and stabilize brain function

• To improve psychosocial functioningTo improve psychosocial functioning

• To reduce mortality from overdose and infectionTo reduce mortality from overdose and infection

• To reduce opioid and other illicit drug useTo reduce opioid and other illicit drug use

• To reduce transmission of HIV, HCV, HBVTo reduce transmission of HIV, HCV, HBV

Maintenance Treatment• Majority of patients respond to 4-24 mg daily• No maximum or minimum duration of treatment• Provides opportunity for health care providers to address all

aspects of needed care (e.g. psychosocial, medical, etc.)• Variability between patients (e.g., absorption,

metabolism,elimination) requires individualized dosing • No maximum recommended dose

– Use of illicit opioids and treatment retention improves with increasing dose (Ling, Addiction 1998)

• Recommend once daily dosing, two tablets at a time

Medical Withdrawal (Detox)

• Minimal rebound withdrawal following short courses of buprenorphine

• Minimal symptomatic medication needed

• Post-Medical Withdrawal (Detox) linkages– Medical Withdrawal is only the first step– Opioid Agonist Maintenance treatment– Antagonist treatment– Psycho-social interventions

Lintzeris et al, 2001

3-day schedule***Day

Buprenorphine dose (mg) – sublingual tablet 7-day schedule**10-day schedule*

1 2 3 4 5 6 7 8 9 10

8 6 4 4 4 2 2 2 2 0

8 6 4 4 2 2 0

4+8 8 8

* Adapted from Vignau, 1998

** Adapted from Zhi-Min et al., 1997

*** Adapted from Cheskin et al., 1994

Examples of 10 day inpatient medical withdrawal schedules

As seen in Drug and Alcohol Dependence Supplement, Volume 70, Issue 2, Supplement S1-S104

Withdrawal Using Buprenorphine

• Few studies of buprenorphine for such time periods

• Buprenorphine more effective than clonidine over this time period

• However, outcomes not as good as longer periods of buprenorphine withdrawal

Detoxification vs. Maintenance

Treatment duration (days)

0

5

10

15

20

0 50 100 150 200 250 300 350

Bup 6 day detox

Bup Maintenance

All Patients: Group CBT Relapse Prevention, Weekly Individual Counseling, Three times Weekly Urine Screens

Buprenorphine RCT A tragic appendix: Mortality

Heilig, Lancet 2003

2=5.9; p=0.015

0/20 (0%)4/20 (20%)Dead

Cox regression

BuprenorphineDetox

Thank you.

suboxone salsitz slides

Health & Medicine