Todd Korthuis, MD, MPHECHO-MAT ConferenceJanuary 17, 2017

Buprenorphine Overviewand Induction

Pharmacotherapy for Opioid Use

Disorder

no drug high dose

Drug Dose

low dose

%

Mu Receptor

Intrinsic

Activity

0

10

20

30

40

50

60

70

80

90

100

Full Agonist: Methadone

Partial Agonist: Buprenorphine

Antagonist : Naltrexone

(“How High”)

(“How Much”)

Buprenorphine/naloxone(4:1 combination)

• Partial opioid agonist

• Decreased overdose risk

• Naloxone inactive unless

injected –then

precipitates withdrawal

• Decreased abuse risk

• Sublingual, once daily

• Safe for flexible dosing

Buprenorphine Diversion

• Variable diversion in

RADARS1

• When diverted, mostly

used for self-treatment

of withdrawal

• Low overdose risk

decreases possibility

of harm if diverted

1Lavonas JSAT 2014

How Does Buprenorphine Work?

• Design: 17 week outpatient randomized,

double-blind clinical trial in heroin users

(n=220)

1. High dose methadone (60-100mg/day)

2. Buprenorphine (16-32mg 3x/week)

3. Low dose methadone (20mg/day)

• Outcomes

– Treatment retention

– Negative urine drug screens (%)

Buprenorphine vs. Methadone

Johnson NEMJ 2000

Buprenorphine vs. Methadone Treatment Retention

Perc

ent

Reta

ined

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

20% Low dose

methadone

58% Buprenorphine

73% High dose

methadone

Study Week Johnson NEMJ 2000

Buprenorphine vs. MethadoneOpioid Urine Results

Mean %

Negative

Study Week

40% Buprenorphine

80

1 3 5 7 9 11 13 15 17

0

20

40

60

100

Johnson NEMJ 2000

19% Low dose

methadone

39% High dose

methadone

Induction(Starting Buprenorphine)

Timing of Buprenorphine

Induction

• Schedule patient for induction soon after intake visit

• Must be in at least mild-to-moderate opioid

withdrawal in order to begin induction

• The more severe the withdrawal, the greater the relief

• Withdrawal symptoms typically begin

• 12-24 hours after last dose of a short-acting opioids like

heroin

• 2-4 days after last dose of long acting opioids like

methadone

Clinical Opioid Withdrawal

Scale (COWS)

• Measures withdrawal symptoms

• Guides timing of first dose of buprenorphine

Opioid Withdrawal SymptomsSigns and

Symptoms Description

Pulse rate Elevated pulse rate (above 100 bpm) may indicate withdrawal

Runny nose or

tearing

Nasal stuffiness, nose running

Lacrimation Moist/tearing eyes

Mydriasis Pupils appearing larger than normal for room light

Piloerection Piloerection of skin or hair standing up on arms

Diaphoresis Reports of chills and flushing, observable beads of moisture

or sweat

Chills Reports of chills

Anxiety/irritability Irritability or anxiousness observable or self-reported

Yawning Observed yawning during observation period

Tremulousness Tremor or muscle twitching

GI symptoms Stomach cramps, nausea, loose stools, vomiting or diarrhea

COWS AssessmentRates 11 items:

• Resting pulse rate

• Sweating

• Restlessness

• Pupil size

• Bone or joint aches

• Runny nose

• GI upset

• Tremor

• Yawning

• Anxiety or irritability

• Goose bumps

Criteria for Giving First Dose

Buprenorphine

• COWS ≥ 12, or…

• COWS < 12, and no self-reported opioid use

in the past 3 day and clinical UDS negative

for opioids

• Negative urine pregnancy on day of

induction, if female

Continue Observation if:

• COWS < 12, and…

• Self-reported opioid use in past 3 days,

and/or…

• UDS positive for opioids

• Repeat COWS periodically over the next few

hours until COWS ≥ 12, or ask patient to

return next day for induction

BUP/NX Dose Administration

• Directly observe all doses

placed under tongue

• Don’t swallow saliva

• Keep under tongue until

tablet completely dissolved

• Check to make sure tablet

dissolved

Induction & Stabilization

Dosing ScheduleSuggested Dosing* Maximum Dose

Day 1 2-4mg (wait 45 min)

+ 4mg if needed

8mg

Day 2 Day 1 dose + 4mg if needed

(single dose)

12mg

Day 3 Day 2 dose + 4mg if needed

(single dose)

16mg

Day 3-28 May increase dose 4mg per

week, if needed

(single dose)

24mg

Avoiding Precipitated Withdrawal

no drug high dose

Drug Dose

low dose

%

Mu Receptor

Intrinsic

Activity

0

10

20

30

40

50

60

70

80

90

100

Full Agonist: Methadone

Partial Agonist: Buprenorphine

Antagonist : Naltrexone

(“How High”)

(“How Much”)

Management of Precipitated

Withdrawal

• If a participant develops signs or

symptoms of opioid withdrawal after

dosing with buprenorphine, the medical

clinician can:

• Administer non-narcotic medications that

provide symptomatic relief

• Increase the dose of BUP/NX to overcome

withdrawal symptoms

Discussion

Detox vs. Maintenance: Which is Better?

• Multi-site trial of buprenorphine/nx for 653

prescription opioid-dependent patients in 10

primary care clinics

• Detox phase followed by maintenance phase for

those who relapse

• “Success” = minimal or no use on UDS & self-

report

Success at 12 Weeks:

Detox Phase: 6.6%

Maintenance Phase: 49.2%

1 Weiss Arch Gen Psych 2011

Buprenorphine for Chronic PainOff-Label Use

• 20% of pain specialists reported use for chronic pain1

• Ceiling effect for respiratory suppression

• Less of a ceiling for analgesia

• Analgesic effect 6-8 hours, so BID or TID dosing often helpful

• Partially blocks effect of other opioids

• DATA-2000 Waiver recommended

1 Rosen Clin J Pain 2014

• No large-scale randomized trials

• Systematic Review of 10 studies

(limited quality):• Increased efficacy in neuropathic pain

• Ease of use for the elderly

• Ceiling effect for respiratory depression

• Less effect on hypogonadism

• Antihyperalgesic effect

• All studies reported reduced pain intensity

Buprenorphine Effectiveness

for Chronic Pain

Cote Pain Med 2014

• Slow-release (6 month)

SQ implant

• 6 month RCT implant vs.

placebo

• Supplemental SL

buprenorphine allowed

Buprenorphine Implants

Probuphine

Bup Implant

(n=108)

Placebo Implant

(n=55) P-value

24-wk Retention 65.7% 30.9% <.001

% UDS Negative:

Weeks 1-16

Weeks 1-24

40.4%

36.6%

28.3%

22.4%

.04

.01

COWS 2.3 3.4 <.001

Subjective Withdrawal 4.1 6.5 .004

Opioid craving VAS 9.9 15.8 <.001

• 50% with mild implant irritation in both arms

• Conclusion: Improved retention & decreased opioid

use

Buprenorphine Implant RCT

Ling JAMA 2010

Injectable Long-Acting

BuprenorphineOn the way!

• Clinical trials in progress

• Once a month injection