Buprenorphine in the treatment of addiction

Matthew A. Torrington MDClinical Research Physician

UCLA: Integrated Substance Abuse ProgramsMatrix Institute on Addictions

Addiction Medicine ClinicNovember 4, 2004

Scope of this Talk

• What are we talking about? Addiction then buprenorphine….

• Buprenorphine: For the treatment of opioid dependence

• Buprenorphine: As an analgesic• Buprenorphine: On the horizon

AAPainMed,APainS, ASAMdefined ADDICTON in 2001

• Addiction is a primary, chronic, neurobiologic

disease, with genetic, psychosocial, and

environmental factors influencing its

development and manifestations. It is

characterized by behaviors that include one

or more of the following: impaired control

over drug use, compulsive use, continued use

despite harm, and craving

• Savage et al., 2001

DSM 4 criteria for opiate abuse

• Significant impairment or distress resulting

from use

• Failure to fulfill roles at work, home, or school

• Persistent use in physically hazardous

situations

• Recurrent legal problems related to use

• Continued use despite interpersonal problems

DSM 4 criteria for Opiate Depend.≥ 3 of the following occurring in the same 12- month period

1. Desire or unsuccessful efforts to cut down on opiate use

2. Large amount of time spent obtaining opiates, using opiates, or recovering from opiate effects

3. Social, occupational, or recreational activities reduced because of opiate use

4. Opiate use continued despite knowledge that a physical or psychological problem is being caused or exacerbated by use

5. Tolerance

• Need for increased amounts of opiates to achieve desired effect; or

• Diminished effect with continued use of the same amount of opiate– Tolerance develops normally with repeated

use– Tolerance to sedating effect develops quickly– Tolerance to respiratory depression can be

marked

6. Withdrawal

withdrawal syndrome with cessation of use, reduction of use, or use of opiate antagonist

Opiates or related

substance taken to relieve or avoid withdrawal symptoms

Pseudoaddiction

• operationally defined as aberrant drug-related behaviors that make patients with chronic pain look like addicts.

• these behaviors stop if opioid doses are increased and pain improves (Weissman and Haddox, 1989).

• This indicates that the aberrant drug-related behaviors were actually a search for relief

• Little data on the subject, but evidence in rats

Magnitude of the Problem

• There are ~ 1,110 licensed OTPs in the U.S.

• ~225,000 patients in methadone treatment• 800,000+ persons addicted to heroin• 4.7 million prescription opioid users• First time users are on the increase

Treatment Admissions

Schematic of Opiate Receptor

Source: Goodman and Gillman 9th ed, p. 526

Effect of Common Opiates at mu receptor

• Heroin, morphine,

methadone

• Buprenorphine

• Naltrexone (Revia, Vixo)

• Naloxone (Narcan)

• Nalmefene

Agonist

Partial Agonist

Antagonist

Receptor Binding at Mu receptor

Agonist:Opens door

Partial Agonist

Opens door with

safety chain

Antagonists

Dummy key

Morphine like effect

Weak morphine like effects with strong receptor affinity

• No effect in absence of an opiate or opiate dependence

Buprenorphine

Buprenorphine pharmacology contd.

• “Less bounce to the ounce”

• Ceiling effect on respiratory depression

• Less physical dependence capacity

• Blocks withdrawal in mildly dependent people

• Precipitates withdrawal in moderate to severely dependent people

Good Effect

0

20

40

60

80

100

p 0.5 2 8 16 32

Buprenorphine (mg)

Peak Score

3.75 15 60

Methadone (mg)

Respiration

02468

1012141618

p 1 2 4 8 16 32

Buprenorphine (mg)

Breaths/minute

Intensity of abstinence

60

50

40

30

20

10

0

Him

mel

sbac

h s

core

s

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Buprenorphine

Morphine

Days after drug withdrawal

Buprenorphine for Opiate Dependence:

• Suppresses withdrawal• Substitutes for street opiates• Blocks subsequently administered

opiates• Safety in long term use

Overview to theDrug Addiction Treatment Act

of 2000 – An Amendment

to the Controlled Substances Act

(October, 2000)

Narcotic drug:

Approved by the FDA for use in maintenance or detoxification treatment of opioid dependence

Schedule III, IV, or V

Drugs or combinations of drugs

Amended Controlled Substances Act

Practitioner requirements:“Qualifying physician”Has capacity to refer patients for

appropriate counseling and ancillary services

No more than 30 patients (individual or group practice)

Amended Controlled Substances Act

“Qualifying physician”:

A licensed physician who meets one or more of the following:

1. Board certified in Addiction Psychiatry

2. Certified in Addiction Medicine by ASAM

3. Certified in Addiction Medicine by AOA

4. Investigator in buprenorphine clinical trials

Amended Controlled Substances Act

“Qualifying physician” (continued):

Meets one or more of the following:

5. Has completed 8 hours training provided by ASAM, AAAP, AMA, AOA, APA (or other organizations which may be designated by HHS)

6. Training/experience as determined by state medical licensing board

7. Other criteria established through regulation by the Secretary of Health and Human Services

Amended Controlled Substances Act

Buprenorphine: Potent Analgesic

• 20-50 times potency of morphine• Available worldwide for pain treatment• Injectable formulation available in U.S.• Usual analgesic dose: .2-.4 mg sl• Higher dose for opiate dependence

Buprenorphine and Pain

• Animal data don’t predict human data• Good potent analgesic• No ceiling effect or inverted U curve• Mild CVS effect, mild G-I effect• Limited dependence, slow mild

withdrawal• Ceiling on respiratory depression • Analgesia not compromised by ceiling.• Effective for long term use mos. to yrs.

Buprenorphine: Analgesic Profile

Rapid onset of action

Long duration of peak effect (60-120 min)

Long half life (3.5 hrs)

Analgesic action up to 8 hrs.

Ceiling effect on respiratory depression

Low physical dependence profile

Buprenorphine – Clinical Analgesic Use

• Surgical pain– Intra-operative, peri-operative, post-

operative

• Labor pain• Back pain• Phantom pain• Post-herpetic neuralgia• Cancer pain

Buprenorphine for Pain

• Good for trans-dermal application– Lipophilic– High level analgesia– Low adverse effects

• Patch – Consistent delivery, desirable time course– Flexible dosing and compliance

Myths about buprenorphine and pain

• Partial agonist, limited clinical effects• Not reversible by naloxone• Can’t be given after other opioids.• Reality

• High affinity, mod intrinsic activity, slow dissociation from mu, highly lipophilic

Treating Acute pain in buprenorphine patients

• Keep on buprenorphine– Increase buprenorphine dose– Add high potency opioid—fentanyl– Add or switch to methadone (Caution)

• Regional analgesia• PCA• Non-opioids

Treating Chronic pain in buprenorphine patients

• Keep on sublingual buprenorphine• Consider buprenorphine patches (when

available) • Switch to morphine• Switch to methadone (CAUTION)• Use opioid rotation• High potency opioids for “break thru” pain• Non-opioid analgesics• Adjunct medications and local anesthetics• Non-pharmacological treatments

Issues on the horizon:

• Buprenorphine access: 30 pt rule, inability of NTPs to use buprenorphine, cost

• Buprenorphine abuse liability• Studies underway:

– Bup 3, CTN, outpatient detox schedules