Buprenorphine and the Office-Based Treatment of Opiate Dependence

• Matthew A. Torrington, MD AAFP ASAM• Medical Director Matrix Institute, Narcotic

Treatment Program

What are opiates?

• a.) Inducing sleep; somniferous; narcotic; hence, anodyne; causing rest, dullness, or inaction; as, the opiate rod of Hermes.

• (n.) Originally, a medicine of a thicker consistence than syrup, prepared with opium.

• (n.) Any medicine that contains opium, and has the quality of inducing sleep or repose; a narcotic.

• (n.) Anything which induces rest or inaction; that which quiets uneasiness.

Opiates• Oxycodone

– (oxycontin)• Propoxyphene

– (Darvon)• Hydrocodone

– (Vicodin)• Hydromorphone

– (Dilaudid)• Meperidine

– (Demerol), • Diphenoxylate (Lomotil)

• Codeine http://www.chemheritage.org/EducationalServices/pharm/asp/images/heroin.gif

Heroin• Heroin is processed

from morphine (diacetylmorphine)

• Morphine is a naturally occurring substance extracted from the seedpod of the Asian poppy plant.

• Heroin usually appears as a white or brown powder.

• Street names – "smack," "H,"

“horse,” "skag," and "junk" "Mexican black tar,” “China White”

• Originally produced by Bayer as a “non addictive” analgesic

www.thinkbigdesigns.com/ justin/Heroin.jpg

Opiate EFFECTS• Desirable

– Pain relief– Euphoria - heroin produces greater ‘rush’ than morphine due to lipophilicity

– Prolonged sense of contentment and well-being

• Undesirable– Nausea and vomiting – Respiratory depression – in sensitivity of respiratory center to PCO2

– Constipation - tone + motility in GI tract•DON’T RX OPIATES WITHOUT CONSIDERING THIS

– Pupillary constriction - stimulation of oculomotor nucleus

PATHOPHYSIOLOGY• Opiate metabolites act on receptors on GABA neurons to uninhibit the firing of dopaminergic neurons in VTA.

• This results in DE release in Nacc.

Tolerance, Addiction, and Withdrawal

• With regular opiate use, tolerance develops.

• As higher doses are used over time, physical dependence develops.

• Withdrawal, which in regular abusers may occur as early as a few hours after the last administration

• drug craving, restlessness, muscle and bone pain, insomnia, diarrhea and vomiting, cold flashes with goose bumps ("cold turkey"), kicking movements ("kicking the habit"), etc.

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Opiate withdrawal

• Major withdrawal symptoms peak between 48 and 72 hours after the last dose

• Duration and intensity dependent on quantity and half live of opiates being used

• Heroin WD usually subsides after about a week.

• Methadone WD can last weeks

• RX OPIATES CAUSE WITHDRAWAL TOO

http://www.heroinaddiction.com/Pictures/withdrawal.jpg

MOA Withdrawal• On cessation of heroin excessive cAMP production occurs causing withdrawal symptoms

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 period1. Desire or unsuccessful efforts to cut

down on opiate use2. 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

Substance Dependence A Multifactorial Brain

Disease

Genetic

BiologicalDysregulation

Social Cultural

Psychological Environmental

WHO. Neuroscience of Psychoactive Substance Use and Dependence. 2004.

Substance Dependence

Substance Dependence Is a Disease

Disease• An interruption, cessation, or disorder of bodily

function, system, or organ; When something is wrong with a bodily function.1

• Determinants include environment and genetics (nature and nurture).

Substance Dependence• A disorder of the normal biological regulation of brain

chemicals, specifically the GABA system in the brain. • Determinants include environment and genetics

1. Stedman’s Medical Dictionary. Baltimore, Md: Williams & Wilkins; 2000.

Substance-related disorders

• Intoxication – use of substance resulting in maladaptive behavior

Withdrawal negative reactions that occur when use is discontinued

or drastically reduced Delirium Dementia Psychosis Mood disorder Anxiety Sexual dysfunction Sleep disorder

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

RX Opiate Abuse

• The use of pain relievers for nonmedicinal purposes has been steadily increasing since the mid-1980s.

• The number of initiates leapt from an estimated 400,000 annually in the mid-1980s to two million by 2000 (SAMHSA, 2002a).

RX Opiate Abuse

• Abuse of prescription narcotics shows a concurrent increase in prevalence over the past decade, increasing 123% since 1994.

• In 1999, it was estimated that 2.9 million Americans had abused pain relievers in the past month (SAMHSA, 1999).

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

Treatment: Opiate Overdose

• Respiratory depression, CNS depression, Myosis, signs of drug abuse, history

• R/O hypoglycemia, acidemia, fluid and electrolyte abnormalities

• Support: airway, ventilation, cardiac function,

• Naloxone HCL 0.4-0.8mg initially;• repeat PRN

Treatment of opiate dependence

• Comprehensive treatment gives best chance of long lasting remission–Opiate replacement or pharmacologic support of withdraw symptoms

–Cognitive Behavioral Treatment: matrix, counseling, etc.

–12 step work– Faith

“Supportive Detoxification”

• Alpha Blockers– clonidine

• Anxiolytics– Benzodiazepines, barbituates

• Analgesics– Ibuprofen, acetaminophen,

• Sleep Aids– Ambien, trazadone

• GI drugs– bentyl, compazine, phenergan

Receptor Binding at Mu receptor

AgonistOpens door

Partial Agonist

Opens door with safety chain

AntagonistsDummy key

Morphine like effect

Weak morphine like effects with strong receptor affinity

No effect in absence of an opiate or opiate dependence

Agonist Therapy

• Methadone is the gold standard– Must be administerd in setting of OTP, Opiate Treatment Program

– Highly regulated– Can be used for pain

• Legislation prevents the use of agonists specifically for the treatment of opiate dependence outside the setting of OTP

Agonist Therapy continued

• Methadone– Long acting opiate agonist– Combats withdraw and craving– must be dosed in NTPs, daily dosing mandatory until patient stable…months

– Outpatient treatment after patient considered very low risk….years

• LAAM even longer acting (dose 3 X a week)– potential for increased QT intervals– Of historical interest only, NO LONGER Available

Opiate Antagonist therapy

• Naltrexone, REVIA– Start 25mg po q d, repeat in 1 hour if no WD

– Must be opiate free 7-10 days and pass naloxone challenge test prior to dosing

– T/C Check LFTs @ baseline and q 3 months

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)

• Nalmefene• naloxone

Agonist

Partial Agonist

Antagonist

Buprenorphine

Buprenorphine for Opiate Dependence:

•Suppresses withdrawal•Substitutes for street opiates

•Blocks subsequently administered opiates

•Safety in long term use

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

Buprenorphine: Clinical Pharmacology

Partial Agonist• high safety profile/ceiling effect• low dependence• partial substitution for highly addicted

patients• precipitates withdrawal in highly dependent

patients

Tight Receptor Binding• long duration of action• slow onset mild abstinence

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/Naloxone combo SUBOXONE

4 part buprenorphine: 1 part naloxone

Sublingual: Opiate agonist effect from buprenorphine

Intravenous: Opiate antagonist effect from naloxone

Addition of Naloxone Reduces Abuse Potential

• Naloxone will block buprenorphine’s effects by the IV but not the sublingual route

• Sublingual absorption of buprenorphine @ 70%; naloxone @ 10%

• If injected, BUP/NX will precipitate withdrawal in a moderately to severely dependent addict

A Sequential Pharmacological Intervention Model for Opiate Dependence

StreetAddict

DailyBuprenorphine

Successful

Unsuccessful

Naltrexone

Buprenorphine 3 x/WeekMedication-free

Methadone

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• Mild CVS effect, mild G-I effect

• Ceiling effect on respiratory depression

• Analgesia not compromised by ceiling.

• Effective for long term use mos. to yrs.

Buprenorphine: Analgesic Profile

Rapid onset of actionLong duration of peak effect (60-120 min)Long half life (3.5 hrs)Analgesic action up to 8 hrs.No apparent analgesic ceiling effect at doses below 300 mg Ms equivalent; no inverted UCeiling effect on respiratory depressionLow physical dependence profile

Buprenorphine: Analgesic Use

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

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

Buprenorphine in Acute Pain

• 30 x potency of Ms by intramuscular injection

• 8-12 x by epidural route (effect: 12-24 hrs)

• Long duration of action (8-12 hrs)• Better analgesia cf. meperidine; comparable to morphine, hydromorphone, fentanyl

• Low incidence of respiratory depression (up to 7 mg iv given post-op)

• Nausea, vomiting, dizziness common

Buprenorphine for Chronic Pain

• Cancer and non-cancer pain• 0.15-0.8 mg/dose q 6-8 hrs• 0.3 mg=10 mg morphine• Given SL, epidural, subcut, subarachnoid

• Comparable to Ms; less resp dep• Given up to 12 wks.• Experience not extensive

Buprenorphine for Chronic Pain

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

• Transdermal patch (35-52.5 micro gm/hr)– Consistent delivery, desirable time course– Flexible dosing and compliance– Effective up to 7 days, used up to 18 mos

• Used in neuropathic pain (.3 mg=methadone 10 mg; usual dose 0.6 mg (20 mg methadone)

Thanks for your attention!

• DO NOT HESITIATE TO CONTACT ME WITH QUESTIONS

• matorringtonmd@yahoo.com• 310 207 4322 office• 310 207 6511 fax• 310 487 2488 mobile