Kendalyn Thompson presented on opioid substance use disorder and treatment options. The presentation covered the pathophysiology and risk factors of opioid use disorder, available pharmacological treatments including methadone, naltrexone, buprenorphine, and the new subdermal implant Probuphine. Clinical trials were discussed that evaluated the efficacy and safety of Probuphine over 6 months and its non-inferiority to sublingual buprenorphine/naloxone for treatment of opioid dependence. Probuphine may benefit patients with issues adhering to oral medications or those wanting extended release treatment.

1. Kendalyn Thompson
MCPHS University PharmD Candidate 2017
Community Pharmacy Rotation- Dr. Mistry
Opioids: Substance Use Disorder
and Treatment Options
http://www.multivu.com/players/English/7742951-braeburn-
fda-approval-probuphine/

2. Goals &
Objectives
1) Describe opioid substance use disorder
pathophysiology and risk factors.
2) Identify available treatment options and
determine an appropriate regimen for a
patient with an opiate/opioid substance use
disorder
3) Understand the new product, Probuphine®
including rationale of use, adverse effects, and
counseling information to educate patients.
4) Learn about the studies and clinical trials that
lead to the FDA approval of Probuphine®. 2

3. DEFINITIONS
Substance
Misuse
neurobehavioral syndrome characterized by the repeated,
comoulsive seeking or use of an opioid despite adverse
social, psychological, and/or physical consequences
often accompanied by physical ooooooooooo and tolerance1
neurobehavioral
adverse
consequences
compulsive
dependence
Addiction
primary, chronic, progressive, relapsing, fatal disease of
brain reward and motivation; behavioral aspect of
substance abuse disorder
chronic, disease
behavioralreward
3

4. Signs and Symptoms with Opiates 2
Substance Use Disorder Addiction
• A: Abstain
• B: Behavior
• C: Craving
• D: Diminished
• E: Emotional
• Drowsiness
• Confusion
• Slowed breathing
• Social withdrawal
• Constricted pupils
• Doctor shopping
• Mood changes
4

5. Etiology and
Pathophysiology
3
Risk Factors for
Substance Use
Disorder
1. Family or personal
history of drug/
alcohol misuse
2. History of abuse
3. Psychiatric
conditions² euphoria
² escape from reality
² treat other symptoms (anxiety, pain)
² treat withdrawal
GABA neuron
presynaptic
terminal somatodendritic
5
http://accesspharmacy.
mhmedical.com.ezproxymcp.flo.org/content.aspx?
bookid=1193& Sectionid=69108683

6. GOALS OF THERAPY
• Decrease frequency of substance use days
• Decrease amount of substance ingested
• Prevent social, psychological, or physical harm
• Prevent euphoria
6

7. Only1/10 people with substance
abuse disorder seek treatment
4
7

8. Barriers to treatment
5
negative social suppor
absence of problem
fear of treatment
time conflict
poor treatment
availability
admission difficulty
8
privacy concerns

9. Treatment Guidelines6
Specific
for
Opioids
Intoxication & withdrawal Pharmacological Psychosocial
Assessment Psychiatric Management Formulation of plan Implementation of plan
9

10. Patient centered
care: no treatment
plan is appropriate
for everyone
Legal services
Detoxification
Counseling
Family services
Non-Pharmacological
Treatment
Medical services
10

11. Pharmacological Treatment
full μ-opioid
agonist
partial μ-opioid
agonist
μ-opioid
antagonist
METHADONE
(Dolophine,
Methadose)
BUPRENORPHINE
(Belbuca, Butrans,
Probuphine, Subutex)
BUPRENORPHINE/
NALOXONE (Suboxone,
Bunavail)
NALTREXONE
(ReVia, Depade,
Vivitrol)
full activation partial activation no activation
http://antranik.org/the-proteins-in-cell-membranes/ 11

12. Methadone
Mechanism of action: bind to the µ-opiate receptors on the
surfaces of brain cells, mediating effects of opioids
Route: injection solution, oral solution, oral tablets, oral
tablet for suspension, diskettes
Starting dose: 20-30mg PO
Maximum dose: 30mg initially; 80-120mg/day maintenance
Drug-drug interactions: inhibitors and inducers of CYP3A4
Counseling points:
• Abusing other drugs that are depressants(EtOH, other
opioids, BDZs) may be fatal
• Be aware of symptoms of a serious heart problem such as
increased heart rate, dizziness or lightheadedness that
requires immediate attention
Monitoring parameters: ECG, withdrawal,
CNS and respiratory depression 12

13. Naltrexone
Mechanism of action: binds to mu opiate receptors tightly
with a higher affinity than other agonists thus displacing
other chemicals and blocking their effect
Route: IM powder for suspension, tablets
Starting dose: 25MG PO on day 1; may increase to 50mg if no
withdrawal signs occur– OR– 50mg on weekdays and 100mg
on Saturday– OR– 100mg Q2D– OR 150mg Q3D
Maximum dose: no maximum (if no withdrawal sx.)
Drug-drug interactions: OPIOIDS
Counseling points: report signs of opioid
withdrawal
Monitoring parameters: abstinence from opioids,
signs or symptoms of suicide
W A R N I N G
Patients should be opioid-free for
7-10days prior to initiating therapy! 13

14. Buprenorphine
Mechanism of action: partial agonist at the mu opiate
receptor and antagonist at the kappa receptor
Route: oral tablets
Starting dose: QD individualized on type and degree of
opioid dependence and time of last use Maximum dose
Drug-drug interactions: inhibitors and inducers of CYP3A4
Counseling points:
• Abusing other drugs that are depressants (EtOH, other
opioids, BDZs) may be fatal
Monitoring parameters: opioid dependence (negative urine
drug screening weekly x1month), compliance, liver function
tests baseline and periodically
14

15. KEYFACTS7
Indicated for patients stable on ≤8mg of Subutex or Suboxone for ≥3 months
Four implants inserted for 6 months by a trained healthcare professional
Utilizes REMS program for prescribing
2.5 mm
26 mm
15

16. Open-label dose-finding trial of buprenorphine implants (Probuphine)® for
treatment of heroin dependence8
Author’s Conclusions
1616
Design
Objectives
Outcomes
Author’s Conclusions
Open-label
dose-finding
(Phase 1
trial)
Conduct an
evaluation of the
safety,
pharmacokinetics
and efficacy of two doses of
Probuphine in subjects with
opioid dependence
maintained on sublingual
buprenorphine.
(1) all patients successfully switched from sublingual buprenorphine to Probuphine and
remained on treatment for the full 6 month period, (2) steady blood levels of buprenorphine were maintained for the full 6
months, (3) efficacy measures showed little evidence of withdrawal symptoms or craving, and (4) no safety concerns were
apparent, although minor injection site reactions were present in half of the patients.

17. Buprenorphine implants for treatment of opioid dependence: A randomized
control trial9
Author’s Conclusions
1717
Design
Objectives
Outcomes
Author’s Conclusions
Randomized,
placebo-
controlled,
multi-center
Percentage of
48 urine
samples that
were negative
for illicit
opioids during the 1-16th week
of trial.
2°: Percent of urine samples
negative weeks 17-24 (Also
treatment failure, withdrawal &
craving scales)
This study demonstrated that buprenorphine implants are effective in the treatment of opioid
dependence over a 24-week period following implantation.

18. Buprenorphine implants for treatment of opioid dependence: randomized
comparison to placebo and sublingual buprenorphine/naloxone10
Design
Objectives
Outcomes
Author’s Conclusions
18
Randomized,
double-blind,
placebo-
controlled,
multi-center
Confirm
efficacy of
buprenorphine
implants
relative to placebo implants
over 24 weeks for opioid
dependence.
2°: establish non-inferiority of
BI relative to buprenorphine/
naloxone weeks 1-24
Buprenorphine implants compared with placebo implants resulted in significantly less opioid use over 24 weeks,
replicating the efficacy observed in a previous randomized clinical trial. BI was found to be not inferior to BNX
comparing as an open-label treatment.

19. Conclusions
19
Possible individuals Probuphine® may
benefit include:
• Patients with young children in the
home
• Patients with inconsistent
adherence issues
• Patients with a tendency to lose or
misplace oral formulations
Concerns:
• Effectiveness of Probuphine®
compared to oral formulations in
a blinded study
• Studies conducted showed bias
when compared to placebo
• Long-term effects

20. Questions?
20

21. References1. Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Rockville (MD): Substance Abuse and Mental Health Services Administration (US);
2004. (Treatment Improvement Protocol (TIP) Series, No. 40.) 1 Introduction. Available from: http://www.ncbi.nlm.nih.gov/books/NBK64248/
2. Sober Media Group. (2016, August 11). Opiate Abuse. Retrieved September 12, 2016, from http://drugabuse.com/library/opiate-abuse/
3. Lüscher C (2015). Drugs of Abuse. In Katzung B.G., Trevor A.J. (Eds), Basic & Clinical Pharmacology, 13e. Retrieved September 12, 2016 from http://accesspharmacy.mhmedical.com.ezproxymcp.flo.org/
content.aspx?bookid=1193&Sectionid=69108683.
4. Johnson, R. (2016, February 1). Opioid Addiction Statistics – America’s Opioid Dependence Problem [Web log post]. Retrieved September 11, 2016, from https://www.opiate-freedom-center.com/getting-help/
5. Rapp, R. C., Xu, J., Carr, C. A., Lane, D. T., Wang, J., & Carlson, R. (2006). Treatment barriers identified by substance abusers assessed at a centralized intake unit. Journal of Substance Abuse Treatment, 30(3), 227–
235. http://doi.org/10.1016/j.jsat.2006.01.002
6. Herbert D. Kleber, Roger D. Weiss, Tony P. George, Thomas R. Kosten, et al.. "Treatment of patients with substance use disorders, second edition. American Psychiatric Association" Vol. 164 Iss. 4 Suppl (2007) .
http://www.ncbi.nlm.nih.gov/pubmed/17569411
7. Probuphine® [package insert]. Princeton, NJ: Braeburn Pharmaceuticals, Inc. 2016.
8. White, J., Bell, J., Saunders, J. B., Williamson, P., Makowska, M., Farquharson, A., & Beebe, K. L. (2009). Open-label dose-finding trial of buprenorphine implants (Probuphine)® for treatment of heroin dependence.
Drug and Alcohol Dependence, 103(1-2), 37-43. doi:10.1016/j.drugalcdep.2009.03.008
9. Ling, W., Casadonte, P., Bigelow, G., Kampman, K. M., Patkar, A., Bailey, G. L., . . . Beebe, K. L. (2010). Buprenorphine Implants for Treatment of Opioid Dependence. Jama, 304(14), 1576. doi:10.1001/jama.2010.1427
10. Rosenthal, R. N., Ling, W., Casadonte, P., Vocci, F., Bailey, G. L., Kampman, K., . . . Beebe, K. L. (2013). Buprenorphine implants for treatment of opioid dependence: Randomized comparison to placebo and
sublingual buprenorphine/naloxone. Addiction, 108(12), 2141-2149. doi:10.1111/add.12315
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