Download SAFE Opioid Prescribing: Strategies. Assessment. Fundamentals

American College of Physicians Internal Medicine Meeting 2016 Washington, DC SAFE Opioid Prescribing: Strategies. Assessment. Fundamentals. Education. Wednesday, May 4, 2016 CME ACCREDITATION The American College of Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The ACP designates this live activity for a maximum of 3.5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. MAINTENANCE OF CERTIFICATION POINTS Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 3.5 MOC points and patient safety credit in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC points. DISCLOSURE It is the policy of the American College of Physicians (ACP) to ensure balance, independence, objectivity, and scientific rigor in all its educational activities. To this end, and consistent with the policies of the ACP and the Accreditation Council of Continuing Medical Education (ACCME), faculty for all ACP continuing medical education activities are required to disclose all financial relationships they have with any entity producing, marketing, re‐
selling, or distributing health care goods or services consumed by, or used on, patients. Faculty are asked to use generic names only in the discussion of therapeutic options. If trade‐name products manufactured by companies with whom they have relationships are to be discussed, faculty are asked to provide evidence‐based citation in support of the discussion. The information is reviewed by the course director and, if necessary, adjustments to the topic or faculty are made to balance the discussion. Further, all participants are asked to evaluate each session for commercial bias so that future decisions about content and faculty are made in light of this information. Faculty disclosure information can be found at the beginning of this book. Faculty are required to inform the audience if they will be discussing unapproved or investigative use of a commercial product or device. This educational activity is supported by an independent educational grant from the ER/LA Opioid Analgesic REMS Program Companies. Please see http://ce.er‐la‐opioidrems.com/IwgCEUI/rems/pdf/List_of_RPC_Companies.pdf for a listing of the member companies. This activity is intended to be fully compliant with the ER/LA Opioid Analgesic REMS education requirements issued by the US Food & Drug Administration. EDUCATIONAL DISCLAIMER The primary purpose of this meeting is educational. Information presented, as well as publications, technologies, products, and/or services discussed, are intended to inform participants about the knowledge, techniques, and experiences of the faculty who are willing to share such information with colleagues. A diversity of professional opinion exists, and the views of the faculty are their own and not those of the ACP. The ACP disclaims any and liability for damages and claims, which may result from the use of information, publications, technologies, products, and/or services presented at this meeting or distributed in association with this meeting. NOTICE ©2016 American College of Physicians. All rights reserved. Reproduction of presentations, or print or electronic material associated with presentations, is prohibited without written permission from the ACP. Any use of program content, the name of a speaker and/or program title, or the name of ACP without the written consent of ACP is prohibited. For purposes of the preceding sentence, “program content” includes, but is not limited to, oral presentations, audiovisual materials used by speakers, program handouts, and/or summaries of the same. This rule applies before, after, and during the activity. American College of Physicians
Internal Medicine Meeting 2016
SAFE Opioid Prescribing: Strategies. Assessment. Fundamentals. Education.
May 4, 2016
Disclosure Information
Course Director:
Charles E. Argoff, MD, FABMP2
Professor of Neurology, Director, Comprehensive Pain Management Center, Department of Neurology,
Albany Medical College, Albany, NY
Faculty:
Michael J. Brennan, MD2
Medical Director, The Pain Center of Fairfield, Fairfield, CT
Steven Stanos, DO2
Medical Director, Swedish Pain Services, Swedish Health System, Seattle, WA
The following individuals were involved in curriculum development:
Daniel Chandler, MD1
Lyerka Miller, PhD1
Marc L. Mosier, MD1
NOTES:
1
Has no relationships with any proprietary entity producing health care goods or services consumed by
or used on patients.
2
Has disclosed a relationship with a proprietary entity(s) producing health care goods or services as
noted below:
Charles E. Argoff, MD, FABMP
Research Grants/Contracts: Grunenthal, Forest, Endo, Lilly
Royalties: Elsevier
Honoraria: Endo, Teva, Allergan, Purdue, Depomed
Speakers Bureau: AstraZeneca, Allergan, Teva
Michael J. Brennan, MD
Stock Options/Holdings: Cara
Consultantship: Purdue, Teva, Depomed, Insys, Endo, Cara, Kaleo
Speakers Bureau: Purdue, Teva, Depomed, Pernix, Insys, AstraZeneca, Endo, Cara, Kaleo
Steven Stanos, DO
Consultantship: Daiichi Sankyo, Endo, MyMatrixx, Pfizer, Purdue, Scilex, Teva
The ER/LA Opioid Analgesics REMS Program covers the following products produced by
companies with which faculty have disclosed relationships: Brand Name Products
Depomed
Nucynta® ER
(Tapentadol extended-release oral tablets)
Endo Pharmaceuticals
Opana® ER
(Oxymorphone hydrochloride extended-release tablets)
Purdue Pharma
Butrans®
(Buprenorphine transdermal system)
Hysingla™ ER (Hydrocodone bitartrate extended-release tablets)
MS Contin®
(Morphine sulfate extended-release tablets)
OxyContin®
(Oxycodone hydrochloride extended-release tablets)
®
Targiniq ER (Oxycodone hydrochloride and naloxone hydrochloride extended-release tablets)
Pfizer
Avinza®
Embeda®
(Morphine sulfate extended-release capsules)
(Morphine sulfate and naltrexone extended-release capsules)
Pernix Therapeutics
Zohydro® ER (Hydrocodone bitartrate extended-release capsules)
Generic Products
Endo Pharmaceuticals
Oxymorphone Hydrochloride
(Oxymorphone hydrochloride extended-release tablets)
Vintage Pharmaceuticals LLC, d/b/a Qualitest Pharmaceuticals and a subsidiary of Endo
Pharmaceuticals Inc.
Morphine Sulfate
(Morphine sulfate extended-release tablets)
American College of Physicians
ACP Internal Medicine Meeting 2016
Washington, DC
SAFE Opioid Prescribing:
Strategies. Assessment. Fundamentals. Education.
1:30-2:15 p.m.
Module 1: Evaluation is Essential for Safe and Effective Pain Management
Using ER/LA Opioids------------------------------------------------------- 9
2:15-2:45 p.m.
Module 2: Best Practices for How to Start Therapy with ER/LA Opioids,
How to Stop, and What to Do in Between ------------------------------- 23
2:45-3:15 p.m.
Module 3: Evidence-Based Tools for Screening for Patients at Risk and
Monitoring for Adherence to Prescribed ER/LA Opioids ------------- 37
3:15-3:30 p.m.
Break
3:30-4:00 p.m.
Module 4: Talk to Me: Proven Methods to Counsel Your Patients on
ER/LA Opioids and Achieve Positive Outcomes ----------------------- 49
4:00-4:30 p.m.
Module 5: Everything You Always Wanted to Know About ER/LA Opioids
as a Drug Class --------------------------------------------------------------- 61
4:30-5:00 p.m.
Module 6: Getting the Most Clinical Insights from Specific ER/LA Product
Information Sources --------------------------------------------------------- 75
5:00-5:15 p.m.
Q&A
SAFE Opioid Prescribing
Strategies. Assessment. Fundamentals. Education
Extended-Release and Long-Acting Opioid Analgesics
Risk Evaluation and Mitigation Strategy (REMS)
American College of Physicians
Internal Medicine Meeting 2016
Washington, DC
Wednesday, May 4, 2016
1
Faculty Information
Charles E. Argoff, MD, FABMP
Professor of Neurology, Director, Comprehensive Pain
Management Center, Department of Neurology, Albany
Medical College, Albany, NY
Michael J. Brennan, MD
Medical Director, The Pain Center of Fairfield, Fairfield, CT
Steven Stanos, DO
Medical Director, Swedish Pain Services, Swedish Health
System, Seattle, WA
2
1
Faculty Disclosure Information
Faculty are required to inform the audience if they will be
discussing unapproved or investigative use of a commercial
product or device. Also, in accordance with ACP policy,
faculty must disclose financial relationships that they have
with any entity that produces, markets, resells, or distributes
health care goods or services consumed by, or used on,
patients. The following relationships exist related to this
presentation.
3
Disclosure of Financial Relationships
Charles E. Argoff , MD, FABMP
Has disclosed relationships with an entity producing, marketing, reselling, or distributing health care goods or services consumed by,
or used on, patients.
Research Grants/Contracts: Grunenthal, Forest, Endo, Lilly
Royalties: Elsevier
Honoraria: Endo*, Teva, Allergan, Purdue*, Depomed*
Speakers Bureau: AstraZeneca, Allergan, Teva
* The ER/LA Opioid Analgesics REMS Program covers products produced by these companies. See the following list of products.
4
2
The ER/LA Opioid Analgesics REMS Program covers the following products produced by companies with which I have disclosed a relationship: Brand Name Products
Purdue Pharma
Butrans® Hysingla™
Buprenorphine transdermal system ER Hydrocodone bitartrate extended‐release tablets
MS Contin® Morphine sulfate extended‐release tablets
OxyContin® Oxycodone hydrochloride extended‐release tablets
Targiniq® ER Oxycodone hydrochloride and naloxone hydrochloride extended‐release tablets
Depomed
Nucynta® ER Tapentadol extended‐release oral tablets Endo Pharmaceuticals
Opana® ER Oxymorphone hydrochloride extended‐release tablets
5
The ER/LA Opioid Analgesics REMS Program covers the following products produced by companies with which I have disclosed a relationship: Generic Products
Vintage Pharmaceuticals LLC, d/b/a Qualitest Pharmaceuticals and a subsidiary of
Endo Pharmaceuticals Inc. Morphine Sulfate Morphine sulfate extended‐release tablets Endo Pharmaceuticals
Oxymorphone Hydrochloride Oxymorphone hydrochloride extended‐release
tablets
6
3
Disclosure of Financial Relationships
Michael J. Brennan, MD
Has disclosed relationships with an entity producing, marketing, reselling, or distributing health care goods or services consumed by,
or used on, patients.
Consultant: Speaker’s Bureau: Stock Holder:
Purdue, Teva, Depomed, Insys, Endo, Cara, Kaleo
Purdue, Teva, Depomed, Pernix, Insys, AstraZeneca, Endo, Cara, Kaleo
Cara
* The ER/LA Opioid Analgesics REMS Program covers products produced by these companies. See the following list of products.
7
The ER/LA Opioid Analgesics REMS Program covers the following products produced companies with which I have disclosed a relationship: Brand Name Products
Purdue Pharma
Butrans® Hysingla™
(Buprenorphine transdermal system) ER (Hydrocodone bitartrate extended‐release tablets)
MS Contin® (Morphine sulfate extended‐release tablets)
OxyContin® (Oxycodone hydrochloride extended‐release tablets)
Targiniq® ER (Oxycodone hydrochloride and naloxone hydrochloride extended‐release tablets)
Depomed
Nucynta®
(Tapentadol extended‐release oral tablets)
Pernix Therapeutics
Zohydro® ER (Hydrocodone bitartrate extended‐release capsules)
8
4
The ER/LA Opioid Analgesics REMS Program covers the following products produced by companies with which I have disclosed a relationship: Brand Name Products (continued)
Endo Pharmaceuticals
Opana® ER (Oxymorphone hydrochloride extended‐release tablets)
Generic Products
Vintage Pharmaceuticals LLC, d/b/a Qualitest Pharmaceuticals and a subsidiary of
Endo Pharmaceuticals Inc. Morphine Sulfate (Morphine sulfate extended‐release tablets) Endo Pharmaceuticals
Oxymorphone Hydrochloride (Oxymorphone hydrochloride extended‐release
tablets)
9
Disclosure of Financial Relationships
Steven Stanos, DO
Has disclosed relationships with an entity producing, marketing, reselling, or distributing health care goods or services consumed by,
or used on, patients.
Consultantship: Daiichi Sankyo, Endo, MyMatrixx, Pfizer, Purdue, Scilex, Teva
* The ER/LA Opioid Analgesics REMS Program covers products produced by these companies. See the following list of products.
10
5
The ER/LA Opioid Analgesics REMS Program covers the following products produced by companies with which I have disclosed a relationship: Brand Name Products
Purdue Pharma
Butrans® (Buprenorphine transdermal system) Hysingla™
ER (Hydrocodone bitartrate extended‐release tablets)
MS Contin® (Morphine sulfate extended‐release tablets)
OxyContin® (Oxycodone hydrochloride extended‐release tablets)
Targiniq®
(Oxycodone hydrochloride and naloxone hydrochloride extended‐release tablets)
ER Pfizer
Avinza®
(Morphine sulfate extended‐release capsules)
Embeda®
(Morphine sulfate and naltrexone extended‐release capsules)
Pernix Therapeutics
Zohydro® ER (Hydrocodone bitartrate extended‐release capsules)
11
The ER/LA Opioid Analgesics REMS Program covers the following products produced by companies with which I have disclosed a relationship: Brand Name Products (continued)
Endo Pharmaceuticals
Opana® ER (Oxymorphone hydrochloride extended‐release tablets)
Generic Products
Vintage Pharmaceuticals LLC, d/b/a Qualitest Pharmaceuticals and a subsidiary of
Endo Pharmaceuticals Inc. Morphine Sulfate (Morphine sulfate extended‐release tablets) Endo Pharmaceuticals
Oxymorphone Hydrochloride (Oxymorphone hydrochloride extended‐release
tablets)
12
6
Educational Grants in Support of this CME
Activity
This educational activity is supported by an independent
educational grant from the ER/LA Opioid Analgesic REMS
Program Companies (RPC). Please see http://ce.er-laopioidrems.com/IwgCEUI/rems/pdf/List_of_RPC_Companie
s.pdf for a listing of the member companies. This activity is
fully-compliant with the ER/LA Opioid Analgesics REMS
education requirements issued by the U.S. Food & Drug
Administration (FDA).
13
Overall Program Learning Objectives
Sessions I–VI
Upon completion of this initiative, the participants will
be better able to:





Implement patient assessment strategies, including tools to
assess risk of abuse, misuse, or addiction when prescribing
extended-release (ER/LA) opioids
Employ approaches to safely initiate therapy, modify dose,
and discontinue ER/LA opioids
Monitor patients by evaluating treatment goals and
implementing periodic urine drug testing (UDT)
Employ patient education strategies about the safe use of
ER/LA opioids
Identify similarities and differences among ER/LA opioids
14
7
Background:
Painkiller Overdoses = Public Health Epidemic

In 2014, 4.3 million people ≥12 years old reported current (past month)
nonmedical opioid use

Overdose deaths from opioid analgesics
•
•
•
•
•
•
18,893 in 2014; >4x # in 2000
Of opioid-analgesic deaths: Benzodiazepines involved in 31%; alcohol in 19%
Highest prescription painkiller overdose rates in middle-aged adults
Highest rates in rural counties
Highest rates in Whites and American Indians or Alaska Natives
Many more Rx opioid overdose deaths in men than women

In 2011, nearly 420,000 ED/ER visits involving nonmedical use of opioids

Direct health care costs of nonmedical prescription painkiller use:
$72.5 billion annually

In 2016, the CDC issued an Opioid Prescribing Guideline for primary care
While improper use of any opioid can result in serious side effects,
including overdose and death, risks may be greater with Rx ER/LA Opioids
SAMHSA 2015; Rudd RA et al. MMWR Morb Mortal Wkly Rep. 2016 Jan 1;64(50-51):1378-82. Chen LH, et al.
NCHS Data Brief, No. 166, September 2014; Opioids drive continued increase in drug overdose deaths. The
DAWN Report 2013.
15
Drug Overdose Rates by State – 2014
www.cdc.gov.
16
8
Amount of All Prescription Opioids Sold by State – 2012
www.cdc.gov.
17
The Prevalence of Chronic Pain in the
United States Is High



Approximately 100 million US adults experience chronic pain
(33%)
Numerous studies indicate undertreated pain: eg, cancer, older
adults, children, minorities
Goal: define most appropriate analgesic regimen for each person
in pain, which may include the use of ER/LA opioids
Ensure availability
of opioids
for patients with pain
AND
Establish systems
of control
to prevent abuse
IOM (Institute of Medicine). Relieving Pain in America: A Blueprint for Transforming Prevention, Care,
Education, and Research. 2011; www.painpolicy.wisc.edu.
18
9
Goals of Risk Evaluation and Mitigation Strategy
(REMS) CME on ER/LA Opioid Analgesics

In 2012, the US Food and Drug Administration (FDA) directed all
ER/LA opioid companies to provide independent CME grants to
educate prescribers and to provide information for patients to:
• Ensure that the benefits of ER/LA opioids outweigh the risks
• Help to reduce risk for ER/LA opioid analgesics misuse, abuse, and
overdose while ensuring access to pain medication
• Follow FDA “Blueprint” on ER/LA opioids CME to engage and educate
prescribers and be in compliance with standards for continuing education
for physicians and other health care professionals, including Accreditation
Council for Continuing Medical Education (ACCME)
This 6-Session Activity Is FDA REMS-Compliant CME
CME, continuing medical education.
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed Jan 4, 2016.
19
Goals of This REMS-Compliant Education for
ER/LA Opioid Analgesics

As clinicians, WE are best positioned to balance treatment of
pain against risks of serious adverse outcomes, including
addiction, unintentional overdose, and death

In this 6-session curriculum, we will review many best-practice
aspects of managing ER/LA opioid analgesic therapy
•
•
•
•
•
•
Patient assessment
Therapy initiation, dose modification, and discontinuation
Therapy management
Counseling of patients and caregivers
General drug information
Product-specific drug information
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed Jan 4, 2016
20
10
Session I
Evaluation is Essential for Safe
and Effective Pain Management
Using ER/LA Opioids
21
Learning Objectives for Session I
Upon completion of this module, the participants will
be better able to:

Identify risk factors for opioid-related
aberrant behavior

Differentiate among tolerance, physical dependence,
and addiction
22
11
Demographic Question 1
?
Do you have a DEA license for Schedule II and/or
Schedule III drugs?
1.
Yes
2.
No
23
Demographic Question 2
?
In the last 12 months, have you prescribed any ER/LA
opioid analgesics?
1.
Yes
2.
No
24
12
Pre-test Q1
?
Addiction is:
1.
A neurobiological disease characterized by compulsive
drug use despite harm
2.
Any use of an illegal drug
3.
A neuroadaptation in which an increasing dose is
required to maintain the same pharmacological effect
4.
Offering opioids to another person who is in pain
25
Pre-test Q2
?
You are assessing whether to prescribe an ER/LA-opioid to
a new patient and are assessing her for increased risk of
opioid-related aberrant behavior. If she is at risk, she will
present with which of the following:
1.
Personal history of treated substance abuse
2.
Significant family history of substance abuse
3.
Past/Comorbid psychological disorder
4.
Age > 45
5.
Answers 1 and 3
6.
Answers 1, 2, and 3
7.
All of the above
26
13
Opioid Therapy in Chronic Pain Management

Opioids ARE commonly prescribed for chronic pain
• Efficacious for many types of pain, though not necessarily for all
people who experience a certain type of pain
• Appropriate use is KEY to safety and success

Goals of chronic opioid therapy:
• Improve and/or stabilize pain intensity
• Improve function
• Improve quality of life (QOL)

However, significant gaps exist between guideline
recommendations for safe prescribing practices of ER/LA
opioids and how they are being used in practice
• Highlights need for further education
McCarberg BH. Postgrad Med. 2011;123(2):119-130.
27
Opioid Therapy –
Good Pain Management Principles

Evidence-based

Multidimensional

Based on appropriate assessment

A dynamic process
28
14
But There Are Also Risks

Opioid analgesics are among the most commonly misused or
abused pharmaceuticals
• Over- or under-concern by physicians, patients, and/or caregivers is
disruptive to physician-patient relationship as well as to effective care
• Other drugs also commonly abused, eg, stimulants, benzodiazepines

Misuse:
• Using a medication other than as directed or indicated, whether intentional or
not, and whether harm results or not
- eg, taking more than recommended dose of an opioid analgesic because pain is
poorly controlled
- eg, offering opioid analgesics to another person who is in pain

Abuse:
• Intentionally taking a medication for a nonmedical purpose
- eg, taking an opioid to get high

Both misuse and abuse are of concern
• Can lead to an overdose
• Common misconception that because opioid is a prescription drug it is safe
Chou R, et al. J Pain. 2009;10(2):113-130.
29
Risk Factors Associated With ER/LA Opioids

Overdose with ER/LA formulations

Life-threatening respiratory depression

Abuse by patient or household contacts

Misuse and addiction

Physical dependence and tolerance

Interactions with other medications and substances

Risk of neonatal opioid withdrawal syndrome with
prolonged use during pregnancy

Inadvertent exposure by household contacts,
especially children
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed Jan 4, 2016
30
15
Who Misuses/Abuses Opioids and Why?
Nonmedical
Use
Medical Use
• Recreational
abusers
• Pain patients
seeking more
pain relief
• Patients with
disease of
addiction
• Pain patients
escaping
emotional pain
31
Key Concepts
Term
Definition
Tolerance
State of adaptation. Exposure to a drug induces changes that result in
a diminution of 1 or more of the drug’s effects over time. Indicated by a
need for increasing doses to achieve the same effect. Commonly occurs
with opioids. Tolerance is not indicative of addiction.
Physical
Dependence
State of adaptation manifested by drug class-specific withdrawal
syndrome that can occur with abrupt cessation, rapid dose reduction,
decreasing blood level of the drug, and/or administration of an
antagonist. Physical dependence occurs in all patients using
opioids for a period of time. Physical dependence is not indicative
of addiction.
Addiction
A primary, chronic, neurobiologic disease with genetic,
psychosocial, and environmental components. Characteristic
behaviors include 1 or more of the following: impaired control over drug
use, compulsive use, continued use despite harm, craving.
Savage SR, et al. J Pain Symptom Manage. 2003;26(1):655-667; Jamison RN, et al. Clin Neuropsychol.
2013;27(1):60-80.
32
16
Tolerance, Dependence, and Addiction —
Critical Differences
What a patient who has developed tolerance to the analgesic effect of the
prescribed opioid would say to you:
“The fentanyl patch that you prescribed used to work really well, and now it
doesn’t seem to be easing as much of the pain as before. I am worried.”
What a patient who has become opioid-dependent will
typically say to you:
“I went up to the lake this weekend and forgot to take
along my long-acting morphine. I was without it for 2 days.
I got so sick that I went to the ER.”
33
Tolerance, Dependence and Addiction —
Critical Differences
Behavior that the addicted patient may display:
“ My husband used his entire month’s supply of that extended-release
opioid you gave him in 1 week. He seems like a totally different person.
I am very concerned.”
34
17
The FDA Definition of Opioid Tolerance

Opioid naïve vs opioid tolerant

Patients are considered opioid tolerant if they are taking,
for 1 week or longer, at least:
•
•
•
•
•
•
Oral morphine – 60 mg daily
Transdermal fentanyl – 25 mcg/h
Oral oxycodone – 30 mg daily
Oral hydromorphone – 8 mg daily
Oral oxymorphone – 25 mg daily
Equianalgesic daily dose of another opioid
www.fda.gov.
35
Key Concepts
Term
Definition
Abuse
Any use of an illegal drug, or the intentional self-administration of a
medication for a nonmedical purpose, such as altering one’s state of
consciousness—for example, getting high
Misuse
Use of a medication (for a medical purpose) other
than as directed or as indicated, whether willful or unintentional, and
whether harm results or not
Aberrant Drug-Related
Behavior
A behavior outside the boundaries of the agreed-on treatment plan
Chou R, et al. J Pain. 2009;10(2):113-130.
36
18
Examples of Misuse and Abuse
What patients will typically say to you:
“Sometimes in the morning I need to
take extra pills just to get going…”
“My friend was visiting this
weekend and had terrible back
pain. I gave her one of my
oxycodone pills. It really helped
her. That’s OK, right?”
“That hydrocodone you gave my wife—well,
it seems to make her feel a little too good
sometimes. I think she’s taking more than
you’ve prescribed and I’m worried about it…”
37
Prescribers Can Play an Active Role
in Reducing the Risks Associated With Opioids

Establish diagnosis
• History and physical
• Relevant diagnostic tests

When opioids are being considered as part of acute
or chronic pain treatment plan, complete an
appropriate risk assessment
• This is an active and ongoing process
McCarberg BH. Postgrad Med. 2011;123(2):119-130; Brennan MJ, et al. PM R. 2010;2(6):544-558.
38
19
Risk Factors for
Opioid-Related Aberrant Behaviors

Family history of substance abuse
• Alcohol, illegal drugs, prescription drugs
- Prescription drug abuse history carries greater risk

Personal history of substance abuse
• Alcohol, illegal drugs, prescription drugs
- Prescription drug abuse history carries greater risk

Age 16 to 45 years
History of preadolescent sexual abuse

Psychological disease

• Increases risk for women
• Attention deficit disorder (ADD) or depression
- ADD carries higher risk
Use of Risk Stratification Tools and Ongoing Monitoring
KEY to Safe and Effective Opioid Use
Webster LR, et al. Pain Med. 2005;6(6):432-442.
39
Risk Stratification and Monitoring Tools
Risk Stratification Tool
(used before opioids are prescribed)
Screener and Opioid Assessment for Patients with Pain
(SOAPP)
Opioid Risk Tool (ORT)
Available
www.painEDU.org
www.partnersagainstpain.com
40
20
Opioid Risk Tool (ORT)
Category
Risk Factor
Score if
Female
Score if
Male
Family History of
Substance Abuse
Alcohol
Illegal Drugs
Prescription Drugs
1
2
4
3
3
4
Personal History of Substance Abuse
Alcohol
Illegal Drugs
Prescription Drugs
3
4
5
3
4
5
Age
Age 16-45 years
1
1
3
0
2
2
1
1
History of Preadolescent Sexual Abuse
Psychological Disease
ADD, OCD, Bipolar
Disorder, Schizophrenia
Depression
Total Risk Score
Total Score Risk Category
Low Risk 0–3
Moderate Risk 4–7
High Risk ≥8
OCD, obsessive compulsive disorder.
Webster LR, et al. Pain Med. 2005;6(6):432-442.
Opioid Risk Tool. www.partnersagainstpain.com/printouts/Opioid_Risk_Tool.pdf.
Accessed January 8, 2013. Reprinted with permission: Lynn Webster, MD.
41
SOAPP — Sample Questions
Please answer the questions below, using the following scale:
0 = Never, 1 = Seldom, 2 = Sometimes, 3 = Often, 4 = Very Often
1.
How often do you have mood swings?
01234
2.
How often do you smoke a cigarette within an hour after you wake up?
01234
3.
How often have you taken medication other than the way that it was prescribed?
01234
4.
How often have you used illegal drugs (for example, marijuana, cocaine, etc)
in the past five years?
01234
5.
How often, in your lifetime, have you had legal problems or been arrested?
01234
42
21
Stratify Risk
Moderate Risk
• History of treated
substance abuse
• Significant family
history of
substance abuse
• Past/Comorbid
psychological
disorder
Consider referring high-risk patients or any patient you have concerns about to a pain specialist
Webster LR, et al. Pain Med. 2005;6(6):432-442.
43
Meet Peter




45-year-old white male, railroad worker for line maintenance and
reconstruction
S/p lumbar fusion with chronic back and leg pain
Hx of back pain prior to injury that led to surgery,
otherwise healthy
Still experiencing pain despite multiple treatments described below
History
Injured at work; pain on lower right side, radiating down
right leg to outside of foot

• Pain described as aching and throbbing
• Pain severity 6/10 at rest and 7-9/10 when bending, coughing,
or straining with a bowel movement


NSAIDs, muscle relaxant, and light work duty attempted
Patient struggled on job; complaints of severe pain
NSAID, nonsteroidal anti-inflammatory drug.
44
22
Peter
History (cont)
• Physical therapy (PT), Xray, MRI (L5-S1 disc w impingement of
S1 nerve root)
• Failed steroid taper, hydrocodone, epidural steroid, more PT
• Sleep deprived, anxious, withdrawn, financially stressed
• Surgery and rehabilitation – no improvement
• Pain specialist prescribed:

Oxycodone CR tablets 40 mg every 12 hours
Hydrocodone/acetaminophen 5/300 8/day for breakthrough pain
Gabapentin 300 mg/ 2 tablets TID
Zolpidem 10 mg/HS
Returns to your office for ongoing pain management
CR, controlled-release; MRI, magnetic resonance imaging.
45
Next Steps: Make No Assumptions

Even though the prescriber of the CR oxycodone and
hydrocodone/acetaminophen has evaluated Peter’s risk
for opioid misuse before initiating these drugs, should
you re-assess his level of risk now that the patient is
back in your care?
Yes, because the risk level can change and you want to
document you have performed a risk assessment
CR, controlled-release
46
23
Peter’s Score on ORT
Category
Risk Factor
Score if
Female
Score if
Male
Family History of
Substance Abuse
Alcohol
Illegal Drugs
Prescription Drugs
1
2
4
3
3
4
Personal History of Substance Abuse
Alcohol
Illegal Drugs
Prescription Drugs
3
4
5
3
4
5
Age
Age 16-45 years
1
1
3
0
2
2
1
1
History of Preadolescent Sexual Abuse
Psychological Disease
ADD, OCD, Bipolar Disorder,
Schizophrenia
Depression
Total Risk Score
4
Total Score Risk Category
Low Risk 0–3
Moderate Risk 4–7
High Risk ≥8
Webster LR, et al. Pain Med. 2005;6(6):432-442.
Opioid Risk Tool. www.partnersagainstpain.com/printouts/Opioid_Risk_Tool.pdf.
Accessed January 8, 2013. Reprinted with permission: Lynn Webster, MD.
47
Peter – Next Steps: Make No Assumptions


Complete history and physical
Ask Peter about his goals for treatment:
• Explain that complete pain relief is rarely achieved
• Focus on functional goals, eg, return to work, work part-time, able to
play golf on weekends, able to walk the dog daily





Risk for aberrant drug behavior – Moderate (4 on ORT)
Evaluate mental health status
Peter’s Rx: oxycodone CR, hydrocodone/APAP, gabapentin,
zolpidem – any other Rx? OTC? Drug-drug interactions?
Re-establish care with new treatment agreement and UDT
Peter’s household – What is the possibility of inadvertent
exposure to the opioids you are prescribing by household
contacts, especially children? Have you discussed safe
storage?
48
24
Opioid Therapy – Ongoing Monitoring
ANALGESIA
ADVERSE EFFECTS
The 4 A’s
ACTIVITIES OF
ABERRANT DRUG-TAKING
DAILY LIVING
BEHAVIORS
Important to remember two other “A’s”: Assessment and Action (treatment plan)
Passik SD, et al. Adv Ther. 2000;17(2):70-83.
49
Additional Tools for Ongoing Monitoring
Current Opioid Misuse Measure (COMM) – Sample Questions
In the past 30 days, how often have you taken your medications differently than how they are
prescribed?
In the past 30 days, how much of your time was spent thinking about opioid medications (having
enough, taking them, dosing schedule, etc)?
In the past 30 days, how often have you had to visit the Emergency Room?
Available at www.painEDU.org
Pain Assessment and Documentation Tool (PADT) – Sample Questions
Is the patient’s functioning with the current pain reliever(s) better, the same, or worse since last
assessment?
Is patient experiencing any side effects from current pain reliever(s)?
Check-list of potential aberrant drug-related behavior
Available at www.ucdenver.edu
50
25
Post-test Q1
?
Addiction is:
1.
A neurobiological disease characterized by compulsive
drug use despite harm
2.
Any use of an illegal drug
3.
A neuroadaptation in which an increasing dose is
required to maintain the same pharmacological effect
4.
Offering opioids to another person who is in pain
51
Post-test Q2
?
You are assessing whether to prescribe an ER/LA-opioid to
a new patient and are assessing her for increased risk of
opioid-related aberrant behavior. If she is at risk, she will
present with which of the following:
1.
Personal history of treated substance abuse
2.
Significant family history of substance abuse
3.
Past/Comorbid psychological disorder
4.
Age > 45
5.
Answers 1 and 3
6.
Answers 1, 2, and 3
7.
All of the above
52
26
Session II
Best Practices for How to Start Therapy
with ER/LA Opioids, How to Stop, and What
to Do in Between
53
Learning Objectives for Session II
Upon completion of this module, the participants will
be better able to:

Convert patients from immediate-release to ER/LA
opioids as well as from one ER/LA opioid to another

Identify predisposing risk factors for significant
respiratory depression
54
27
Pre-test Q1
?
Patients are considered opioid tolerant if they are
taking:
1.
Oral morphine 60 mg daily for 3 days or more
2.
Oral oxycodone 30 mg daily for 1 week or more
3.
Oral hydromorphone 4 mg daily for 1 week or more
4.
Oral morphine 30 mg daily for 1 week or more
55
Pre-test Q2
?
Which of the following ER/LA opioid agents should be
prescribed only to opioid tolerant patients regardless
of dose?
1.
Avinza (morphine sulfate ER) and
MS Contin (morphine sulfate CR)
2.
Duragesic (fentanyl transdermal system) and
Exalgo (hydromorphone HCl ER)
3.
Oxycontin (oxycodone CR) and
Opana ER (oxymorphone ER)
4.
Nucynta ER (tapentadol ER) and
Butrans (buprenorphine)
56
28
Key Principles of Safe Prescribing

Know how to:
• Identify the ER/LA opioid and dosage to use in the appropriate
patient
• Supplement pain management with immediate-release opioids
and non-opioids
• Convert patients from immediate-release to ER/LA opioids and
from one ER/LA opioid to another
• Identify the warning signs and symptoms AND PREDISPOSING
RISK FACTORS for significant respiratory depression
• Safely taper an opioid dose when therapy is no longer needed

Keep current with regulations for opioid prescribing, both
federal and those in your own state
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 23,
2013.
57
Benefits and Limitations of ER/LA Opioids
Potential Benefits

Provide more consistent plasma
concentrations of drug compared
with short-acting agents
 This minimizes serum level
fluctuations that could contribute to
end-of-dose breakthrough pain
More consistent nighttime pain
control
 Less clock-watching by patients
 Possible improved compliance/
adherence due to a lower pill
volume

Not for
Not for as needed or “prn” use
Not for mild pain
 Not for pain that is not expected
to persist for an extended
duration
 Not for acute pain
 Not for routine use in headache
disorders or post-operative pain


ER/LA opioids are indicated for the management of pain severe enough
to require daily, around-the-clock, long-term opioid treatment and for
which alternative treatment options are inadequate.
Nicholson B. Pain Pract. 2009;9(1):71-81; www.fda.gov.
58
29
ER/LA Opioids – Contraindications

Significant respiratory depression

Acute or severe asthma in an unmonitored setting or in
absence of resuscitative equipment

Known or suspected paralytic ileus

Hypersensitivity
See individual product information for additional
contraindications
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1,
2016.
59
Opioid-Naïve vs. Opioid-Tolerant

Tolerance is a function of both time and dose
• Patients who have not taken an opioid recently are considered
opioid naïve
• THESE patients are at greater risk for respiratory depression and
sedation
60
30
Know The Risk Factors for Respiratory
Depression

Generally preceded by sedation and decreased
respiratory rate

Risk factors for respiratory depression include:
Sleep apnea or a sleep disorder
diagnosis
Morbid obesity with a high risk
of sleep apnea
Snoring
Risk increases with age
No recent opioid use
Post-surgery (particularly upper
abdominal or thoracic)
Preexisting pulmonary or
cardiac disease or dysfunction
or major organ failure
Smoking
(>60)
Use of other sedating drugs
(CNS depressants)
The Joint Commission. Sentinel Event Alert. August 8, 2012;49. www.jointcommission.org.
Accessed February 22, 2013.
61
The FDA Definition of Opioid Tolerance

Opioid naïve vs opioid tolerant

Patients are considered opioid tolerant if they are taking,
for 1 week or longer, at least:
•
•
•
•
•
•
Oral morphine – 60 mg daily
Transdermal fentanyl – 25 mcg/h
Oral oxycodone – 30 mg daily
Oral hydromorphone – 8 mg daily
Oral oxymorphone – 25 mg daily
Equianalgesic daily dose of another opioid
www.fda.gov.
62
31
Be Aware

Certain ER/LA-opioid medications should ONLY be
initiated in patients who have become opioid tolerant
as a result of ongoing therapy
www.fda.gov.
63
Be Aware


Some agents should never be prescribed unless a patient is opioid tolerant
• Duragesic (fentanyl transdermal system)
• Exalgo (hydromorphone hydrochloride ER)
Some agents can be prescribed to opioid-naïve patients, but not at higher doses
-- some ER/LA opioid doses can ONLY be used in opioid-tolerant patients
ER/LA Opioid
Doses that can be used in opioidtolerant patients ONLY
Avinza (morphine sulfate ER)
90 mg and 120 mg
Belbuca (buprenorphine buccal film)
600 mcg, 750 mcg, and 900 mcg
Butrans (buprenorphine transdermal system
10 mcg/h, 15 mcg/h and 20 mcg/h
Embeda (morphine sulfate ER-naltrexone)
100 mg/4 mg
Kadian (morphine sulfate ER)
100 mg and 200 mg
Morphabond (morphine sulfate ER)
100 mg
MS Contin (morphine sulfate controlled-release [CR])
100 mg and 200 mg
Oxycontin (oxycodone hydrochloride CR)
>40 mg single dose or >80 mg daily
Dolophine (methadone hydrochloride)
>2.5 mg to 10 mg every 8 to 12 hrs
Targiniq ER (oxycodone HCl / naloxone HCl)
>40 mg/20 mg single dose or >80 mg/40 mg daily
Zohydro (hydrocodone bitartrate ER)
>40 mg single dose or >80 mg daily
www.fda.gov.
64
32
Opioid Tolerance—Agents and Dosing
(Refer to full prescribing information)
Agent (Oral)
Selected Doses for Use in Opioid-Tolerant Patients Only
Avinza (morphine sulfate ER
capsules)
90 mg and 120 mg capsules for use in opioid-tolerant patients only
Embeda (morphine sulfate
ER-Naltrexone capsules)
100 mg/4 mg capsule for use in opioid-tolerant patients only
Hysingla (hydrocodone
bitartrate ER tablets)
Daily dose greater than or equal to 80 mg is for use in opioit-tolerant
patients only
Kadian (morphine sulfate ER
capsules)
100 mg and 200 mg capsules for use in opioid-tolerant patients only
MorphaBond (morphine
sulfate ER tablets)
100 mg tablets or a total daily dose >120 mg for use in opioid-tolerant
patients only
MS Contin (morphine sulfate
CR tablets)
100 mg and 200 mg tablets for use in opioid-tolerant patients only
OxyContin (oxycodone
hydrochloride CR tablets)
Single dose greater than 40 mg or total daily dose greater than 80
mg for use in opioid-tolerant patients only
Targiniq ER (oxycodone HCl/
naloxone HCl)
Single dose greater than 40 mg/20 mg or total daily dose of 80
mg/40 mg for use in opioid-tolerant patients only
Dolophine (methadone
hydrochloride tablets)
When used as first opioid analgesic, initiate therapy with small
doses, no more than 2.5 mg to 10 mg every 8 to 12 hours.
www.fda.gov.
65
Opioid Tolerance—Agents and Dosing
(Refer to full prescribing information)
Agent (transdermal)
Butrans (buprenorphine
transdermal system)
Agent
Selected Doses for Use in Opioid-Tolerant Patients Only
10 mcg/hr, 15 mcg/hr, and 20 mcg/hr transdermal systems are for use in opioidtolerant patients only
Use in Opioid-Tolerant Patients Only – All Doses
Duragesic (fentanyl
transdermal system)
All doses indicated for use in opioid-tolerant patients only
Exalgo (hydromorphone
hydrochloride ER tablets)
All doses indicated for use in opioid-tolerant patients only
Agent
Use in Opioid-Naive Patients
Belbuca (buprenorphine
buccal film)
In opioid-naïve patients or patients taking less than 30 mg oral morphine sulfate
equivalents, initiate treatment with 75 mcg buccal film daily or every 12 hrs
Hysingla ER (hydrocodone
bitartrate ER tablets)
In opioid-naïve patients, initiate treatment with 20 mg tablets every 24 hrs
Nucynta ER (tapentadol ER
tablets)
In opioid-naïve patients, the initial dose is 50 mg twice a day
Opana ER (oxymorphone
hydrochloride ER tablets)
In opioid-naïve patients, initiate treatment with 5 mg every 12 hours
Zohydro ER (hydrocodone
bitartrate ER capsules)
In opioid-naïve patients, initiate treatment with 10 mg every 12 hours
www.fda.gov.
66
33
Initiating Therapy:
Dose Selection and Titration
Individually titrate all opioids to a dosage that provides adequate analgesia
and minimizes adverse reactions
Drug
Initial Dosing
Avinza (morphine
sulfate ER capsules)
• Once daily
• Initial dose as first analgesic (opioid-naive patients) is 30 mg once daily
• Titrate using a minimum of 3-day intervals (4-day intervals for opioid-naïve
patients)
• Maximum daily dose 1600 mg (due to risk of renal toxicity)
Butrans
(buprenorphine
transdermal system)
• One transdermal system applied every 7 days
• Initial dose as first analgesic (opioid-naïve patients) is 5 mcg/hour
• Initial dose if prior total daily dose <30 mg oral morphine equivalents/day – 5
mcg/hour
• When converting from 30-mg to 80-mg morphine equivalents – first taper to
30-mg morphine equivalent, then initiate with 10 mcg/hour dose
• The minimum Butrans titration interval is 72 hours
• Maximum daily dose: 20 mcg/hour (due to risk of QTc interval
prolongation)
www.fda.gov.
67
Initiating Therapy:
Dose Selection and Titration
Drug
Initial Dosing
Dolophine
(methadone HCl
tablets)
• Every 8 to 12 hours
• Initial dose as first opioid analgesic (opioid-naïve patients) is 2.5 mg to 10 mg
• Conversion of opioid-tolerant patients using equianalgesic tables can result in
overdose and death. Use low doses according to the table in the full
prescribing information
• Special considerations: Methadone is characterized by complicated and
variable pharmacokinetics and pharmacodynamics and should be
initiated and titrated cautiously by clinicians familiar with its use and
risks (Refer to Module VI)
Duragesic (fentanyl
transdermal
system)
•
•
•
•
•
Embeda (morphine
sulfate and
naltrexone HCl) ER
• Once a day or every 12 hours
• Initial dose as first opioid is 20 mg/0.8mg
• Dosage adjustments may be done every 1 to 2 days
www.fda.gov.
Every 72 hours (3 days)
Duragesic is contraindicated in opioid non-tolerant patients
Use product-specific information for dose conversion from prior opioid
Use 50% usual dosage in mild or moderate hepatic or renal impairment
Titrate using no less than 72-hour intervals
68
34
Initiating Therapy:
Dose Selection and Titration
Drug
Initial Dosing
Exalgo
(hydromorphone
HCl ER tablets)
• Once a day
• Not for use in opioid non-tolerant patients. Do not begin any patient on Exalgo
as the first opioid
• Use the conversion tables in the full prescribing information
• Start patients with moderate hepatic impairment on 25% usual dosage
• Start patients with moderate renal impairment on 50%, and patients with
severe renal impairment on 25% usual dosage
• Titrate using a minimum of 3- to 4-day intervals
Belbuca
(buprenorphine
buccal film)
• Every 12 hours
• For opioid-naïve patients and those taking less than 30 mg oral morphine
sulfate equivalents, initiate treatment with a 75 mcg buccal film once daily, or if
tolerated, every 12 hours
• Titrate to 150 mcg every 12 hrs no earlier than 4 days after initiation
• Titrate using a minimum of 4 day intervals and increments of 150 mcg
• Start patients with severe hepatic impairment on 50% initial dose
Hysingla ER
(hydrocodone
bitartrate ER
tablets)
•
•
•
•
•
Once a day
For opioid-naïve patients, initiate with 20 mg tablets
Dose titration may occur every 3 to 5 days in increments of 10 mg to 20 mg
Daily doses greater than or equal to 80 mg are for opioid tolerant patients only
Start patients with severe hepatic or renal impairment on 50% initial dose
www.fda.gov.
69
Initiating Therapy:
Dose Selection and Titration
Drug
Initial Dosing
Nucynta ER
(tapentadol HCl
ER tablets)
•
•
•
•
Kadian
(morphine sulfate
ER capsules)
• Once a day or every 12 hours
• Not recommended as a first opioid
• Titrate using a minimum of 2-day intervals
MorphaBond
(morphine sulfate
ER tablets)
• Every 8 hours or every 12 hours
• Not recommended as first opioid
• Titrate using a minimum of 1 to 2-day intervals
MS Contin
(morphine sulfate
CR tablets)
• Every 8 hours or every 12 hours
• Not recommended as a first opioid
• Titrate using a minimum of 2-day intervals
Opana ER
(oxymorphone
HCl ER tablets)
•
•
•
•
www.fda.gov.
Every 12 hours
Use 50 mg every 12 hours as initial dose in opioid non-tolerant patients
Titrate by 50 mg increments using a minimum of 3-day intervals
Maximum total daily dose is 500 mg
Every 12 hrs; some may benefit from asymmetric dosing (higher in the AM than PM)
Use 5 mg every 12 hours as initial dose in opioid non-tolerant patients
Titrate dose at increments of 5-10 mg every 12 hours, at 3-7 day intervals
Start with lowest dose in patients with mild hepatic impairment and renal impairment
(creatinine clearance <50 mL/min) and in patients older than 65 years of age
70
35
Initiating Therapy:
Dose Selection and Titration
Drug
Initial Dosing
OxyContin
(oxycodone HCl CR
tablets)
•
•
•
•
•
Every 12 hours
Initiate treatment with 10 mg every 12 hours in opioid non-tolerant patients
Titrate using a minimum of 1- to 2-day intervals
Hepatic impairment: start with one-third to one-half usual dosage
Renal impairment (creatinine clearance <60 mL/min): start with one-half
usual dosage
Targiniq ER
(oxycodone
hydrocloride /
naloxone
hydrochloride
tablets)
•
•
•
•
Every 12 hours
For opioid-naïve patients, initiate with 10 mg/5 mg tablet every 12 hours
Titrate using a minimum of 1 to 2 day intervals
Contraindicated in moderate and severe hepatic impairment. Start with onethird to one-half dose in mild hepatic impairment. Start with one-half dose in
renal impairment
Zohydro ER
(hydrocodone
bitartrate ER
capsules)
•
•
•
•
Every 12 hours
For opioid-naïve patients, initiate with 10 mg capsule every 12 hours
Titrate dose at increments of 10 mg every 12 hours, at 3-7 day intervals
Start with low initial dose in patients with renal impairment and severe hepatic
impairment
www.fda.gov.
71
Supplementing ER/LA Opioids
Patients who are on
ER/LA opioids for
chronic pain may need
supplemental
analgesia
Increase dose
of
ER/LA opioid
No treatmentlimiting effects—
continue with
higher dose
Treatment-limiting
adverse effects
occur—reduce
dose
Treat with
non-opioid
analgesics
Acetaminophen
or NSAIDs
Antidepressants
and
anticonvulsants
Treat with
short-acting
opioids
Initial and
ongoing analysis
of therapeutic
benefit vs risk
Zeppetella G. Curr Opin Support Palliat Care. 2009;3:1-6; Prommer E, et al. Patient Prefer Adherence.
2012;6:465-475; Chou R, et al. J Pain. 2009;10(2):113-130; Burton AW. Medscape. June 15, 2005.
www.medscape.org/viewarticle/506124. Accessed September 7, 2012; Rhiner MI, et al. J Support Oncol.
2010;8:232-238.
72
36
Peter

S/p lumbar fusion with chronic back and leg pain
Returns to your primary care office for ongoing pain
management
Current medications:

Goals of therapy:

Opioid rotation may be considered if goals of therapy are not
met, adverse effects are intolerable, or to lower opioid dose


•
•
•
•
Oxycodone CR tablets 40 mg every 12 hours
Hydrocodone/acetaminophen 5/300; 8/day for breakthrough pain
Gabapentin 300 mg/2 tabs TID
Zolpidem 10 mg/HS
• Work a full day
• Sleep through the night
• Improve daytime somnolence
73
Rationale for Opioid Rotation

Opioid rotation is switching from one opioid to another

Rationale for opioid rotation
• Adverse effects or toxicity of initial opioid
• Lack of efficacy of initial opioid
• Lowering the dose

Rotation may work because of:
• Incomplete cross-tolerance among opioids
• Inter-patient variability of response based on opioid receptor
genetic polymorphisms
Note: Conservative dose-conversion ratios are advised
Fine PG, et al. J Pain Symptom Manage. 2009 Se;38(3):418-25; Chou R, et al. J Pain. 2009;10(2):113-130.
74
37
Equianalgesic Dose Table – An Example
Equianalgesic (mg)
Dose Oral
Opioid
Equianalgesic (mg)
Dose Other
Morphine
60 PO
10 IM/IV/SQ
Hydromorphone
7.5 PO
1.5 IM/IV/SQ
20-30 PO
No information available
Oxymorphone
15 PO
1 IM/IV/SQ; 10 PR
Levorphanol
4 PO
2 IM/IV/SQ
Methadone
20 PO
Oxycodone



10 IM/IV/SQ
50-100 mcg IV/SQ
Fentanyl
Hydrocodone potency ranges 1:1 to 1:2 with morphine, but safest
approach is 1:1
Be aware that individual responses may vary
Refer to individual full prescribing information (PI) for complete
information
Knotkova H, et al. J Pain Symptom Manage. 2009;38(3):426-439.
75
Another Example:
Duragesic (fentanyl transdermal system)

Recommended Initial Duragesic Dose Based Upon Daily Oral
Morphine Dose
Oral 24-hour Morphine
(mg/day)
DURAGESIC Dose
(mcg/hour)
60-134
25
135-224
50
225-314
75
315-404
100
405-494
125
495-584
150
585-674
175
675-764
200
765-854
225
855-944
250
945-1034
275
1035-1124
300
Duragesic Full Prescribing Information. Available at www.fda.gov.
76
38
Incomplete Cross-Tolerance

Pharmacologic phenomenon whereby tolerance
developed to the effects of one drug translates into
tolerance to other drugs from the same class
• Incomplete cross-tolerance: Failure to develop complete
cross-tolerance, increasing the likelihood of therapeutic
effects as well as adverse effects

It is known to occur among opioids
• Mechanism behind opioid rotation
• Also reason for caution in
converting from one opioid to another
2
1
3
Chou R, et al. J Pain. 2009;10(2):113-130.
77
Converting Patients From Immediate-Release
to ER/LA Opioids or to Another ER/LA Agent

Guidelines for select agents
• Belbuca (buprenorphine buccal film)
- Equipotency to oral morphine not established
• Butrans (buprenorphine transdermal system)
- Converting from 30‐mg to 80‐mg morphine equivalents:
 First taper to 30‐mg morphine equivalent per day
 Then initiate with 10‐mcg/hr dose
• Dolophine (methadone HCl tablets)
- Converting opioid‐tolerant patients using equianalgesic tables can result in overdose and death.
- To minimize risk, use low doses according to table in full PI - Note: Relative potency to oral morphine varies, depending on patient’s prior opioid experience
• Duragesic (fentanyl transdermal system)
- For relative potency to oral morphine, see individual product‐specific PI for conversion recommendations from prior opioid
www.fda.gov.
Always refer to full prescribing information (PI)
78
39
Converting Patients From Immediate-Release
to ER/LA Opioids or to Another ER/LA Agent
• Exalgo (hydromorphone HCl ER tablets)
- Use conversion ratios in individual product‐specific PI - Relative potency to oral morphine approximately 5:1 oral morphine to hydromorphone
oral dose ratio
• Hysingla ER (hydrocodone bitartrate)
- See individual product‐specific PI for conversion recommendations from prior opioid
• Nucynta ER (tapentadol HCl ER tablets)
- Equipotency to oral morphine not established
• Opana ER (oxymorphone HCl ER tablets)
- Relative potency to oral morphine approximately 3:1 oral morphine to oxymorphone
oral dose ratio
• OxyContin (oxycodone HCl CR tablets)
- Relative potency to oral morphine approximately 2:1 oral morphine to oxycodone oral dose ratio
• Targiniq ER (oxycodone HCl/naloxone HCl tablets)
- See individual product‐specific PI for conversion recommendations from prior opioid
• Zohydro ER (hydrocodone bitartrate)
- For relative potency to oral morphine, see individual product‐specific PI for conversion recommendations from prior opioid
Always refer to full prescribing information (PI)
www.fda.gov.
79
Tapering and Discontinuing
ER/LA Opioid Analgesics

When ER/LA opioid analgesic is no longer required, gradually titrate downward to prevent signs and symptoms of withdrawal in the physically dependent patient

Do not abruptly discontinue these products
• Decrease original dose by 10% per week

Abrupt discontinuation of chronic opioids may cause withdrawal characterized by: • Stomach cramps, diarrhea, rhinorrhea, sweating, elevated heart rate, increased blood pressure, irritability, dysphoria, hyperalgesia, and insomnia
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1,
2016; Manchikanti L et al. Pain Phys. 2012;15(3 suppl):S67-S116; Morgan MM, et al. Br J Pharmacol.
2011;164(4):1322-1334.
80
40
Federal DEA Controlled Substance Schedules:
ER/LA-Opioids are Schedule II
Sch Description
Examples
I
No currently accepted medical use in the U.S.; high potential for abuse
Heroin, LSD, marijuana, peyote, methaqualone, Ecstasy
II
High potential for abuse, which Hydromorphone, methadone, meperidine, may lead to severe psychological or oxycodone, fentanyl, morphine, opium, and codeine, physical dependence
amphetamine, methamphetamine, methylphenidate, hydrocodone combination products III
Potential for abuse, which may lead Products containing ≤ 90 mg codeine per dose, to moderate or low physical buprenorphine, benzphetamine, phendimetrazine, dependence or high psychological ketamine, anabolic steroids
dependence
IV
Low potential for abuse
Alprazolam, carisoprodol, clonazepm, clorazepate, diazepam, lorazepam, midazolam, temazepam, tramadol (as of 2014), triazolam
V
Low potential for abuse
Cough preparations containing ≤ 200 mg codeine per 100 ml or per 100 g, ezogabine
State Laws/Regulations Vary. KNOW YOUR OWN STATE Rx REQUIREMENTS
DEA Diversion Control. Available at www.deadiversion.usdoj.gov/schedules/index.htm. Accessed Jan, 2016
Post-test Q1
81
?
Patients are considered opioid tolerant if they are
taking:
1.
Oral morphine 60 mg daily for 3 days or more
2.
Oral oxycodone 30 mg daily for 1 week or more
3.
Oral hydromorphone 4 mg daily for 1 week or more
4.
Oral morphine 30 mg daily for 1 week or more
82
41
Post-test Q2
?
Which of the following ER/LA opioid agents should be
prescribed only to opioid tolerant patients regardless
of dose?
1.
Avinza (morphine sulfate ER) and
MS Contin (morphine sulfate CR)
2.
Duragesic (fentanyl transdermal system) and
Exalgo (hydromorphone HCl ER)
3.
Oxycontin (oxycodone CR) and
Opana ER (oxymorphone ER)
4.
Nucynta ER (tapentadol ER) and
Butrans (buprenorphine)
83
Session III
Evidence-Based Tools for
Screening for Patients at Risk
and Monitoring for Adherence
to Prescribed ER/LA Opioids
84
42
Learning Objectives for Session III
Upon completion of this module, the participants will
be better able to:

Evaluate and manage adverse effects of ER/LA opioids

Differentiate strategies for monitoring patient adherence
85
Pre-test Q1
?
Oxymorphone is a metabolite of:
1.
Hydrocodone
2.
Codeine
3.
Oxycodone
4.
Morphine
86
43
Pre-test Q2
?
Your patient reports no relief on codeine and UDT is
negative for morphine. Possible explanations include:
1.
Laboratory error
2.
Patient is not taking the codeine because she is
hoarding it
3.
Patient is not able to metabolize codeine
4.
Answers 1 and 2 are correct
5.
All of the above
87
Key Principles of Managing Therapy
With ER/LA Opioids
Use clinical evidence-based guidelines to:

Screen for risk, including assessment of psychiatric comorbidities

Establish analgesic and functional goals

Use Patient Prescriber Agreements (PPAs) and monitor patient
adherence

Anticipate/manage adverse effects and periodically assess benefits
and side effects

Reevaluate patient’s underlying medical condition if clinical
presentation changes over time

Use referral sources for the treatment of abuse and addiction
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1,
2016.
88
44
Realistic Individualized Goal-Setting

Reach agreement with patient on treatment goals

Patient-specific goals may include 1 or more of
the following
• Pain reduction: 30% considered clinically significant
- Explain to patient that complete pain relief rarely achieved
• Improvement in select functional areas:
- eg, ability to work full time at previous or modified job; play golf once a
week, walk the dog daily
• Improved mood
89
Patient Prescriber Agreement (PPA)

Clinical evidence and guidelines support use of
agreements

Any of following can be used as a PPA:
• Informed consent documents
• Treatment agreement documents
• PPA available for download at no cost*

Benefits
• Informed decision making with patient
• Enables clear and mutual understanding of goals and
expectations and respective responsibilities of patient and
clinician
• Can be jointly signed during patient visit
*eg, www.caresalliance.org.
Chou R, et al. J Pain. 2009;10(2):113-130.
90
45
What Is Typically in a Patient Prescriber
Agreement (PPA)

Understanding of risks and benefits of opioid therapy

Taking the opioid exactly as prescribed

One prescribing doctor and one designated pharmacy and whether
or not refills will be called into pharmacy without an office visit

Urine/serum drug testing when requested

Pill counts at each office visit

No early refills

How to safeguard their opioids medication

List of behaviors that may lead to discontinuation of opioids

Places for signature and dating
Chou R, et al. J Pain. 2009;10(2):113-130.
91
Monitoring Patient Adherence

Level of monitoring depends on risk stratification
level determined during initial screening
(using ORT or other tool)
•
•
•
•
State PDMPs (Prescription Drug Monitoring Programs)
Urine drug testing (UDT)
Pill counts
Behavioral assessment at each visit
- If indicated, refer for substance abuse treatment
Chou R, et al. J Pain. 2009;10(2):113-130.
92
46
Monitoring Patient Adherence
Prescription Drug Monitoring Programs (PDMPs)

State-run electronic databases that track dispensing of
controlled substances

Can provide clinicians with critical information about
patient prescription history and identify “doctor shoppers”

Currently available in almost all states

No national standards for guidance; implementation of
programs is variable

Real-time data access not yet available in all states
• Each state has its own rules and laws
• Follow state guidelines
Dahl J. J Pain. April 2012;13:Abstract 245; Dahl J, et al. J Pain. April 2012;13:Abstract 246.
93
PDMPs: 2015
Operational or Legislated in 49 States, 1 Territory
www.namsdl.org
94
47
A Sample PDMP Report:
West Virginia = Board Of Pharmacy – Patient Profile

Date 4/15/2012 Date of Birth 12-10-1966
Beginning Date: 04-01-11 =nbsp Ending Date: 04-15-12

First Name: MIKE
Last Name: =OWEN
First
Name
Address
Zip
Fill date
Rx
no.
Product
Name
Strength
Qty
Doctor
Name
Doctor
DEA
Pharm
Name
Pharm
DEA
Ph Zip
MIKE
319 LOWER
25526
4/2/2011
11222
APAP/HYDRO
500MG10MG
180
SMITH JOE
DH0267890
TOM’S
PHARM
GF1234567
25526
MIKE
319 LOWER
25526
5/3/2011
19976
APAP/HYDRO
500MG10MG
180
SMITH JOE
DH0267890
TOM’S
PHARM
GF1234567
25526
MIKE
319 LOWER
25526
5/27/2011
23466
APAP/HYDRO
500MG10MG
180
SMITH JOE
DH0267890
TOM’S
PHARM
GF1234567
25526
MIKE
319 LOWER
25526
6/4/2011
31111
APAP/HYDRO
500MG10MG
180
JOHN JOHN
DH0267890
BILL’S
PHARM
AF1245687
25526
95
Monitoring Patient Adherence:
Urine Drug Testing (UDT)

Recommended for all patients for reasons of safety
and to remove the stigma associated with UDTs

Testing does not imply a lack of trust; it is a
conversation starter

Self reports of drug use and behavioral monitoring
often fail to detect abuse problems

UDTs can identify use of prescribed opioids as well
as illicit drug use

Know limitations of UDT or laboratory that you use
Katz NP, et al. Anesth Analg. 2003;97(4):1097-1102; Heit HA, et al. J Pain Symptom Manage.
2004;27(3):260-267.
96
48
Urine Drug Testing – KEY POINTS

Know what to expect and how to interpret results

Parent compound and or metabolite should show up in
the urine
• Oxycodone → oxymorphone
• Hydrocodone → hydromorphone
• Codeine → morphine

Is the substance present that you expect?

Are there substances present that you do not expect?

Know what your laboratory does
97
Common UDT Scenarios

Peter undergoes UDT in office and the test is negative
for opioids
• UDTs do differ
• Certain drugs, including oxycodone, may not be detected by
certain laboratory techniques
• UDT is a conversation starter: “Why do you think your UDT
is negative?”
- Is diversion a possibility?
- Is he bingeing and then running out of opioids?
- Is he failing to take the prescribed drug
because symptoms have abated?
- Do you give him a 30-day Rx supply?
Heit HA, et al. J Pain Symptom Manage. 2004;27(3):260-267.
98
49
Common UDT Scenarios

Patient on LA morphine undergoes UDT. Test results
positive for morphine and hydromorphone

Possible explanations include:
• Patient using another opioid obtained from another physician
• Hydromorphone is a trace metabolite
of morphine found only when very
high morphine concentrations are
present
99
Common UDT Scenarios

Patient being treated with hydrocodone has UDT
positive for hydrocodone and hydromorphone

After hydrocodone use, urine may be positive for:
• Hydrocodone only
• Hydrocodone and hydromorphone (metabolite)
• Hydromorphone only
100
50
Common UDT Scenarios

Patient reports no relief on codeine and UDT is negative

Possible explanations include
• Laboratory error
• Diversion
• Patient is a slow metabolizer
of codeine
Heit HA, et al. J Pain Symptom Manage. 2004;27(3):260-267.
101
Screening vs Confirmatory UDTs
ANALYSIS TECHNIQUE
SENSITIVITY (POWER TO
DETECT A CLASS OF DRUGS)
SPECIFICITY (POWER TO
DETECT AN INDIVIDUAL DRUG)
TURNAROUND
OTHER
SCREENING
CONFIRMATORY
Immunoassay
GC-MS or HPLC
Low or none when testing for
semi-synthetic or synthetic
opioids
High
Varies (can result in
false-positives
or false-negatives)
High
Rapid
Slow
Intended for a drug-free
population. May not be useful in
pain medicine.
Legally defensible results
GC-MS, gas chromatograph mass spectrometer; HPLC, high performance liquid chromatography.
www.opioidrisk.com.
102
51
Anticipating and Managing Adverse Effects
Adverse Effect
Treatment
Nausea and vomiting
Anti-emetics;
Switch opioids*
Sedation
Lower dose (if possible);
Add nonsedating co-analgesic;
Add stimulant or attention enhancer
Constipation
Treat prophylactically with stool softeners, bowel
stimulants; Nonpharmacologic and pharmacologic
treatment
*Opioid switching is an option for any adverse effect.
Swegle JM, et al. Am Fam Physician. 2006;74(8):1347-1354. Chou R, et al. J Pain. 2009;10(2):113-130.
103
Anticipating and Managing Adverse Effects
Adverse Effect
Treatment
Itching
Antipruritic therapy (eg, antihistamines)
Endocrine dysfunction/Reduced libido/Loss of
menstrual period
Endocrine monitoring;
Testosterone replacement;
Endocrine consultation
Edema and sweating
Switch opioids*
Dizziness
Antivertigo agents
Confusion
Titrate dose
*Opioid switching is an option for any adverse effect.
Swegle JM, et al. Am Fam Physician. 2006;74(8):1347-1354; Chou R, et al. J Pain. 2009;10(2):113-130.
104
52
Anticipating and Managing Adverse Events

Emerging issues
• Hyperalgesia
- An increased response to a normally painful stimulus
- May occur at higher doses
• Sleep
- Central and obstructive sleep apnea
- Sleep architecture
Brush DE. J Med Toxicol. 2012 Dec;8(4):387-92; Dimsdale JE et al. J Clin Sleep Med. 2007 Feb 15;3(1):33-6
105
Respiratory Depression – The Most Serious
Adverse Effect


Most serious adverse effect associated with opioids
is RESPIRATORY DEPRESSION
Occurs when
•
•
•
•
Initial doses are too high
Therapy is titrated too rapidly
Drug-drug interactions
Opioids combined with other drugs that may potentiate
opioid-induced respiratory depression
- Benzodiazepines
- Herbals
- OTC preparations that contain diphenhydramine


More common in patients with sleep apnea
Respiratory depression may be fatal
OTC, over-the-counter.
Manchikanti L, et al. Pain Physician. 2012;15(3 suppl):S67-S116.
106
53
ER/LA Opioid Analgesics in Pregnancy

Be aware of the pregnancy status of your patient

There re no adequate and well-controlled studies of
ER/LA opioids in pregnant women

ER/LA opioids should be used in pregnancy only if the
potential benefit justifies the risk to the fetus

If opioid use is required, advise the patient of risk of
neonatal opioid withdrawal syndrome
107
Reevaluating the Patient’s Condition

Reevaluate if the presentation changes to determine if
opioid therapy continues to be effective or necessary

Reevaluate or refer if there is new pain

Continue opioid therapy if appropriate analgesia and
functional status improvements are maintained
Chou R, et al. J Pain. 2009;10(2):113-130.
108
54
What to Do if Your Patient Needs Treatment
for Abuse and Addiction

Know treatment centers in your area

Work out a plan with the center you are referring to

With a clear indication of abuse or addiction,
discontinue prescribing of opioids
109
Referral Sources for Abuse and
Addiction Treatment

Balancing Pain Management and Prescription Opioid Abuse Available at www.cdc.gov/primarycare/materials/opoidabuse/index.html

Find Substance Abuse and Mental Health Treatment Available at www.samhsa.gov/treatment

National Institute on Drug Abuse Available at www.nida.nih.gov

American Council for Drug Education Available at www.acde.org

American Academy of Addiction Psychiatry
• Providers’ Clinical Support System for Opioid Therapies: www.pcss‐o.org
• Providers’ Clinical Support System for Medication Assisted Treatment: www.pcssmat.org
110
55
Post-test Q1
?
Oxymorphone is a metabolite of:
1.
Hydrocodone
2.
Codeine
3.
Oxycodone
4.
Morphine
111
Post-test Q2
?
Your patient reports no relief on codeine and UDT is
negative for morphine. Possible explanations include:
1.
Laboratory error
2.
Patient is not taking the codeine because she is
hoarding it
3.
Patient is not able to metabolize codeine
4.
Answers 1 and 2 are correct
5.
All of the above
112
56
Questions?
11
3
Session IV
Talk to Me: Proven Methods to
Counsel Your Patients on ER/LA
Opioids and Achieve Positive
Outcomes
11
4
57
Learning Objectives for Session IV
Upon completion of this module, the participants will
be better able to:

Implement counseling strategies to ensure patients
know to take ER/LA opioids exactly as prescribed

Use counseling strategies to explain signs of ER/LA
opioid overdose to patients and caregivers
ER/LA, extended-release and long-acting.
115
Pre-test Q1
?
Patients and caregivers need to be counseled about
the signs of an opioid overdose, including:
1.
Shallow rapid breathing
2.
Stomach cramps
3.
Elevated heart beat
4.
Miosis
116
58
Pre-test Q2
?
Which of the following statements are TRUE:
1.
Sharing prescription opioids is legal in some states, but
should be avoided because opioid overdose can occur
2.
Opioids prescribed for one person should never be shared
with anyone else
3.
It is sometimes ok to open an ER/LA opioid capsule and
sprinkle contents on applesauce
4.
Unused opioids should never be flushed down the toilet
5.
1 and 2
6.
2 and 3
7.
All of the above
117
Patient Counseling Document
ER/LA Analgesics REMS. http://www.er-la-opioidrems.com/IwgUI/rems/pcd.action. Accessed February 1, 2016.
118
59
Counseling Patients and Caregivers
About ER/LA Opioids

Use Patient Counseling Document for ER/LA opioids to:
• Explain product-specific information
• Explain how to take and importance of adherence
• Tell patient and/or caregiver they will receive a Medication Guide
from the dispensing pharmacy
- Stress importance of reading the Guide and getting answers to any
questions they may have from the pharmacist or you
• Warn patients not to tamper with ER/LA formulation
• Caution patients about use of other CNS depressants, including
alcohol
CNS, central nervous system.
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1,
2016.
119
Counseling Patients and Caregivers (cont’d)
• Instruct patients to tell you about all medications they are taking
• Warn patients to never abruptly discontinue their ER/LA opioid
• Caution patients about all adverse effects
- Specifically about signs and symptoms of respiratory depression,
gastrointestinal obstruction, and allergic reactions
- Instruct them on when and how to call you about side effects they
experience so that you can work with them to manage
 Side effects can be reported to FDA at 1-800-FDA-1088
• Caution patients to never share their ER/LA opioid with ANYONE
• Counsel patients about the risk of falls, working with heavy
machinery and driving
• Advise patients to store their medication carefully and dispose of
safely when no longer needed
- Medication Guides typically include specific disposal information
120
60
Why is patient and caregiver education so important?
121
Patient Education and Counseling Works!

Utah Department of Health statewide program
demonstrated effectiveness of patient education to
reduce unintentional deaths from prescription opioids
• Media campaign “Use Only As Directed” from May 2008 to May
2009, including:
- Television and radio spots
- Distribution of opioid prescribing guidelines and copies of print
materials (bookmarks, patient information cards, educational posters)

Results:
• In 2008-2009, 14% decrease in unintentional overdose deaths
from prescription opioids compared with 2007
Johnson EM, et al. Pain Med. 2011;12 suppl 2:S66-S72.
122
61
How to Counsel Patients to
“Use Exactly as Prescribed”
THE “DOs”

Tell your patients:
•
•
•
•
•
Read Medication Guide from dispensing pharmacy
Take your medicine exactly as prescribed
Store your medicine away from children and in a safe place
Flush unused medicine down the toilet
Call your health care provider for medical advice about side
effects. You may report side effects to the FDA at
1-800-FDA-1088
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1,
2016.
123
How to Counsel Patients to
“Use Exactly as Prescribed”
THE “DON’Ts”

Tell your patients:
• Do not give your medicine to others
• Do not take medicine unless it was prescribed for you
• Do not stop taking your medicine without talking to your
health care provider
• Do not break, chew, crush, dissolve, or inject your medicine.
If you cannot swallow your medicine whole, talk to your
health care provider
• Do not drink alcohol while taking this medicine
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1,
2016.
124
62
Patient Counseling Document

Patient Counseling Document (PCD) on ER/LA opioid
analgesics is a tool designed to facilitate important
discussions with patients and:
• Clearly describes “Do’s” and “Don’ts” related to safe use
• Gives clinician area to write patient-specific issues and
instructions that can be taken by patient from the visit
• Helps to consolidate informed consent discussion

PCD should be provided to and reviewed with patient
and/or the caregiver at time of prescribing

PCD is available at no charge at
www.er-la-opioidrems.com/IwgUI/rems/pcd.action
ER/LA Analgesics REMS. http://www.er-la-opioidrems.com/IwgUI/rems/pcd.action. Accessed February 1, 2016.
125
Case — Joan




62-year-old female with severe right hip osteoarthritis
Has significant medical issues that prevent her from
undergoing total hip replacement
Started physical therapy, but stopped because of increase
in pain
Her pain is significantly affecting her quality of life
• Unable to take NSAIDs because of previous GI bleed
• Her PCP initiated a trial of Ultram (tramadol), 50 mg, 1-2 TID, with no
reported analgesia
• This was followed by a 2-week course of Nucynta (tapentadol),
50 mg, 1 PO Q 6 hrs
- Reported pain relief for only 3-4 hours, with VRS decreasing from 8 to 5/10
• Because of less than optimal duration of effect, PCP decides to
initiate a trial of Nucynta ER (tapentadol ER), 100 mg PO Q 12 hrs
GI, gastrointestinal; PCP, primary care physician; VRS, verbal rating scale
126
63
Ensure Patients Know to Take Opioids ONLY
As Prescribed
Instructions need to be product-specific:
• For instance, since Joan is taking Nucynta ER (tapentadol
ER); she should be advised to:
- Not crush or chew her medication
- Place tablet in mouth and take it with enough water to ensure complete
swallowing immediately afterward
- Take a dose every 12 hours at same time every day
• But, if you had prescribed Kadian to Joan, you would advise
her to
- Swallow capsule intact (whole); never to crush, dissolve or chew the
pellets
- If she cannot swallow the capsule whole, contents of the Kadian capsule
(pellets) can be sprinkled on applesauce and then swallowed without
chewing
www.fda.gov.
127
Patients Need to Know About Adherence to
Prescribed Opioid Regimen

Counsel patients and caregivers
• ER/LA opioid medication and dosage is based on their individual
needs.
• Doubling up on a dose or taking it sooner than prescribed risks
overdose with possible life-threatening consequences
• Taking more than prescribed constitutes misuse or abuse
• Missing a dose may result in inadequate pain relief
• What to do if a dose is missed
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1,
2016.
128
64
Explain the Dangers of Combining Opioids
With Other Substances

Caution patients and caregivers that overdose or death can
occur if ER/LA opioids are used with other CNS depressants,
including:
• Sedative-hypnotics: eg, zolpidem (Ambien); triazolam
(Halcion); temazepam (Restoril)
• Anxiolytics: eg, diazepam, clonazepam
• Illegal drugs: eg, heroin



Fatal opioid poisonings have been associated more often with
concomitant use of benzodiazepines or alcohol
Advise patients to use other CNS depressants, including
other opioids, only under instruction of their prescriber
Advise patients to tell all their health care providers about all
medications they are taking
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1,
2016.
129
Discuss the Dangers of Abruptly Discontinuing
Medication

Warn patients to not abruptly discontinue or reduce their
ER/LA opioid analgesic and to discuss with you, the
opioid prescriber, how to safely taper the dose if they
wish to discontinue

Abruptly discontinuing an opioid may lead to withdrawal
syndrome
• Stomach cramps, diarrhea, rhinorrhea, sweating, elevated heart
rate, increased blood pressure, irritability, dysphoria,
hyperalgesia, insomnia
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1,
2016; Morgan MM, et al. Br J Pharmacol. 2011;164(4):1322-1334.
130
65
Inform Patients of Seriousness of
Adverse Events Associated With Opioids

Caution patients and caregivers that opioids can cause
serious side effects that may lead to death

Discuss:
• Signs and symptoms of an overdose, such as:
lethargy and somnolence, cognitive impairment
• Opioid-induced respiratory depression
• Risk for severe constipation and gastrointestinal
obstruction
- Emphasize the importance of healthy bowel habits: keeping hydrated,
less sedentary
• Possibility of allergic reactions
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1,
2016.
131
Opioid Overdose

Fatal overdose is not instantaneous—there is usually
time for remedial action
• Naloxone can quickly reverse the effects


Both patients and caregivers need to know how to
identify opioid overdose, as signs of an overdose are
often missed
Opioid overdose signs include:
•
•
•
•
Mental depression
Hypoventilation (decreased respiration)
Reduced bowel motility
Miosis (contracted pupils)
Green TR, et al. Addiction. 2008;103(6):979-989; Williams RH, et al. Laboratory Med. 2000;31:334-342.
132
66
Update on Joan

Joan returns to office after 1 month

Reports better pain relief and improved quality of life

Tolerating Nucynta ER (tapentadol ER) 100 mg BID and
oxycodone 5 mg, 1-2 per day for breakthrough pain

Urine drug toxicology testing (UDT) is completed

She reports running out 2 days early and is requesting
early refill
• She states: “My daughter hurt her back, so I gave her a couple of
my pills. It helped her pain, too.”

What should you do?
133
Dangers of Sharing Medication:
Legal Responsibilities of the Patient

In our society, a commonly held belief among patients
and caregivers is that sharing prescription medications is
not dangerous or a problem because “prescription
medications are safe”.

Here’s what you should do:
• Counsel Joan about importance of not giving her medication to
or sharing it with others, even her daughter
• Advise her that drugs prescribed for one
patient can have serious or even fatal
consequences for another
• Tell her that sharing prescription
medications is illegal
Manchikanti L, et al. Pain Physician. 2012;15(3 suppl):S67-S116; SAMHSA (2010). 2009 National Survey
on Drug Use and Health. www.samhsa.gov/data/2k9/2k9Resultsweb/web/2k9results.htm. Accessed February 22,
2013.
134
67
Storing ER/LA Opioids Safely

Patients and caregivers must understand importance of
storing opioids carefully and protecting them from theft
• A secure place away from children, family members, household
visitors, and pets
- eg, a medication safe, which not only deters theft, but also inadvertent
use in children, which could be fatal
Manchikanti L, et al. Pain Physician. 2012;15(3 suppl):S67-S116; SAMHSA (2010). 2009 National Survey
on Drug Use and Health. www.samhsa.gov/data/2k9/2k9Resultsweb/web/2k9results.htm. Accessed February 22,
2013.
135
Disposing of ER/LA Opioids



Counsel patients to dispose of any ER/LA opioid
analgesics that are no longer needed
Encourage them to read product-specific disposal
information, including the Medication Guide
Safe disposal methods include:
• Dropping off medication at a DEA-designated drop box or
take-back program
• Removing medication from original bottles, mixing with used
coffee grounds or kitty litter, and throwing it in the garbage
• Flushing it down the toilet
- Many patients believe that medications should NOT be flushed into the
toilet or put into septic or sewer systems. Education can help them
understand this is an appropriate disposal
DEA, Drug Enforcement Administration.
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1,
2016; Practical Pain Management. Opioid Disposal: Dos and Don’ts.
www.practicalpainmanagement.com/opioid-disposal-dos-don-ts. Accessed January 8, 2013.
136
68
Post-test Q1
?
Patients and caregivers need to be counseled about
the signs of an opioid overdose, including:
1.
Shallow rapid breathing
2.
Stomach cramps
3.
Elevated heart beat
4.
Miosis
137
Post-test Q2
?
Which of the following statements are TRUE:
1.
Sharing prescription opioids is legal in some states, but
should be avoided because opioid overdose can occur
2.
Opioids prescribed for one person should never be shared
with anyone else
3.
It is sometimes ok to open an ER/LA opioid capsule and
sprinkle contents on applesauce
4.
Unused opioids should never be flushed down the toilet
5.
1 and 2
6.
2 and 3
7.
All of the above
138
69
Session V
Everything You Always Wanted
to Know About ER/LA-Opioids
as a Drug Class
13
9
Learning Objectives for Session V
Upon completion of this module, the participants will
be better able to:

Assess the differences in opioid metabolism and how
these impact appropriate ER/LA prescribing

Identify how opioid-drug interactions influence ER/LA
opioid prescribing
140
70
Pre-test Q1
?
The opioid with the greatest risk of prolongation of the
QTc interval is:
1.
Tapentadol
2.
Oxycodone
3.
Oxymorphone
4.
Methadone
141
Pre-test Q2
?
Of the following cytochrome P450 enzymes, which
one is particularly important in opioid metabolism?
1.
CYP2E1
2.
CYP2C19
3.
CYP3A4
4.
CYP1A2
142
71
Opioids As A Drug Class – General Information
ER/LA Opioid Analgesic Products Key Points
1.
ER/LA opioid analgesic products are scheduled under Federal
Controlled Substances Act
• Can be misused and abused
• Risk for diversion
2.
Most serious adverse effect: respiratory depression
3.
Most common long-term side effect: constipation
4.
Drug-drug interaction profiles: Vary among products
• Important to recognize and avoid clinically significant interactions
5.
Tolerance to sedating and respiratory-depressant effects
• Clinician and patient understanding of tolerance is fundamental for safe use
6.
Adherence to ER/LA opioid dosing instructions is critical
• Oral formulations must be taken as directed and patients instructed to not
tamper with the formulation
• For transdermal products, external heat, fever, or exertion can increase
absorption
143
Neurobiology of Opioids

Opioid receptors are ubiquitous
• Found throughout CNS and within GI tract
• Accounts for their numerous effects, including potent analgesia,
sedation, and reduced GI motility
• Are G-coupled receptors
• Both endogenous and exogenous opioids exert their effect by
acting as ligands on these receptors
.
Schäfer M. Opioids in Pain Medicine. In: Kopf A, et al, eds. Guide to Pain Management in Low-Resource Settings. Washington,
DC: International Association for the Study of Pain; 2010. http://www.iasppain.org/AM/Template.cfm?Section=Home&Template=/CM/ContentDisplay.cfm&ContentID=12166. Accessed March 2, 2013.
144
72
Opioid Receptors and Analgesia

Analgesic effects likely mediated through mu
opioid receptors
• Highly concentrated in the outer laminae of spine dorsal horn
• Two areas of brainstem—rostral ventromedial medulla (RVM)
and periaqueductal gray (PAG) area
145
Respiratory Depression

Most common serious adverse effect
• Can be immediately life-threatening

Factors that may increase risk for respiratory
depression include:
•
•
•
•
•
•
Sleep apnea or snoring
Morbid obesity
Older age
Opioid naïve
Concomitant use of other sedating drugs
Smoking
Schäfer M. Opioids in Pain Medicine. In: Kopf A, et al, eds. Guide to Pain Management in Low-Resource Settings. Washington,
DC: International Association for the Study of Pain; 2010. http://www.iasppain.org/AM/Template.cfm?Section=Home&Template=/CM/ContentDisplay.cfm&ContentID=12166. Accessed March 2, 2013.
146
73
Constipation

Most common long-term side effect
• Activation of GI peripheral opioid receptors decreases GI motility and increases
fluid absorption

Nausea and vomiting may develop as primary AE or over time as a
sign of chronic constipation

Constipation should be anticipated and managed prophylactically
• eg, increase fiber and water intake
• OTC agents include bulking, lubricants, stimulants
• Prescription agents include stimulants, chloride ion (CIC-2) activators
(eg, lubiprostone) and opiate antagonists (eg, methylnaltrexone, naloxegol)
• Opioid rotation may be warranted
AE, adverse event.
Schäfer M. Opioids in Pain Medicine. In: Kopf A, et al, eds. Guide to Pain Management in Low-Resource Settings. Washington, DC:
International Association for the Study of Pain; 2010. http://www.iasp
pain.org/AM/Template.cfm?Section=Home&Template=/CM/ContentDisplay.cfm&ContentID=12166. Accessed March 2, 2013; National
Comprehensive Cancer Network Guidelines Version 1.2012. Adult Cancer Pain.
http://www.nccn.org/professionals/physician_gls/pdf/pain.pdf. Accessed February 27, 2013; Chou R, et al. J Pain. 2009;10(2):113130.
147
Drug-Drug Interactions (DDI)
Are Common and Vary Among Opioids

Underlying mechanisms
• Pharmacodynamics (pD)
- Pharmacological effects
• Pharmacokinetics (pK)
- Drug absorption, metabolism and
clearance
• DDI may enhance or inhibit
either pK or pD, thus altering
intended and/or precipitating
unintended effects
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 23, 2013.
148
74
CNS Depressants May Potentiate
Opioid Effects

Pharmacodynamic (PD) interaction

Concomitant use increases risk of:
• Respiratory depression
• Hypotension
• Profound sedation, coma

Management includes reducing the initial dose of both
opioid and CNS depressant

Examples of CNS depressants
Sedatives
Hypnotics
Tricyclic Antidepressants
general anesthetics
antiemetics
phenothiazines
alcohol
marijuana
other tranquilizers
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016.
149
Alcohol and ER/LA Opioids
Pharmacodynamic (PD) Interactions

With some ER/LA opioid formulations, rapid release of
opioid may occur when exposed to alcohol
• Known as “dose dump”
• Can result in fatal toxicity

Alcohol may increase opioid drug levels and predispose
to adverse effects, including overdose

How to manage:
• Counsel patients to not consume alcohol when taking opioids
• See product-specific warnings
U.S. Food and Drug Administration. FDA Alert [7/2005]: Alcohol-Palladone Interaction.
www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/
ucm129288.htm. Accessed March 3, 2013.
150
75
MAOIs and ER/LA Opioids PD Interactions

Concomitant use of monoamine oxidase inhibitors (MAOIs)
and opioids may increase risk of respiratory depression

May also cause serotonin syndrome
Serotonin Syndrome Symptoms
•
•
•
•
•
•
•
•
•
•
•
Agitation or restlessness
Diarrhea
Fast heart beat and high blood pressure
Hallucinations
Increased body temperature
Loss of coordination
Nausea
Overactive reflexes
Rapid changes in blood pressure
Vomiting
Spontaneous or induced clonus
How to Manage
• Maintain hemodynamics
• Reduce/Discontinue offending agent
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016; Gillman PK. Br
J Anaesth. 2005;95(4):434-441.
151
Opioids and Other Drug Interactions

Opioids can induce release of antidiuretic hormone (ADH)
• Can reduce efficacy of diuretics

Avoid co-administration of opioids with partial agonists
or mixed agonist/antagonist analgesics
• May reduce the analgesic effect and can precipitate withdrawal
symptoms
- Buprenorphine (Butrans)
- Nalbuphine (Nubain)
- Butorphanol (Stadol)
Reisine T, et al. In: Goodman & Gilman’s: The Pharmacological Basis of Therapeutics (9th ed). McGraw-Hill; 1996. 521-555; FDA
Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016.
152
76
Opioids and Other Drug Interactions (cont’d)

Skeletal Muscle Relaxants
• Opioids may enhance neuromuscular blocking action
and increase risk of respiratory depression

Anticholinergics
• Increased risk of urinary retention
• Increased risk of severe constipation, which may lead
to paralytic ileus
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016.
153
Summary of Opioid-Drug Interactions
Concomitant Use of ER/LA Opioids With:
Potential Effects
Other CNS depressants (alcohol, sedatives, hypnotics, tranquilizers, tricyclic antidepressants)
Increased risk of respiratory depression, hypotension, profound sedation, or coma; reduce the initial dose of 1 or both agents
Partial agonists, mixed agonist/antagonist analgesics (buprenorphine, pentazocine, nalbuphine, butorphanol)
May reduce analgesic effect or precipitate withdrawal symptoms; avoid concurrent use
Skeletal muscle relaxants
Increased respiratory depression
Anticholinergic agents
Increased risk of urinary retention and severe constipation, which may lead to paralytic ileus
Drugs that act as inhibitors or inducers of various cytochrome P450 enzymes Higher or lower than expected blood levels of some opioids
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed August 2014.
154
77
Opioids and QTc Prolongation

Methadone and buprenorphine can prolong QTc
interval in some patients

Dose-related incidence in patients on long-term
methadone maintenance
• 9% at a dose >300 mg/d
• 83% at a dose >600 mg/d

Management:
• Monitor EKG
• Consider alternative drugs should any abnormality develop
www.fda.gov; Reddy S, et al. J Palliat Med. 2010;13(1):33-38.
155
Cytochrome P450 Enzymes

Account for almost 50% of overall elimination of
commonly used drugs, including:
•
•
•
•
•
•
•

Statins
SSRIs
Calcium channel blockers
Benzodiazepines
Beta Blockers
Opioids
Warfarin
CYP450 drug-drug interactions often clinically relevant
SSRI, selective serotonin reuptake inhibitor.
Indiana University School of Medicine. Drug Interactions. http://medicine.iupui.edu/flockhart/table.htm. Accessed November 6,
2012; Wilkinson GR. N Engl J Med. 2005;352(21):2211–2221.
156
78
Opioids and CYP450 Interactions

Pharmacokinetic drug-drug interactions can cause higher
or lower blood levels of opioid than expected and result
in:
• Excess opioid effects (including fatal toxicity)
• Loss of analgesia
• Misinterpretation of drug tests
Overholser BR, et al. Am J Manag Care. 2011;17 suppl 1:S276-S287.
157
ER/LA Opioids and CYP450 Enzyme
Interactions

Metabolism of several commonly used opioids occurs through enzyme
CYP3A4, but CYP2D6 is also important
• 3A4 is a potent inactivation enzyme
• 2D6 is an activating enzyme

Inhibition

Stimulation

However, if an agent is a pro-drug, an inhibitor can decrease drug
effects, while an inducer increases the rapidity with which the active
compound enters the bloodstream

Refer to product-specific information for specific opioid-DDIs before
prescribing
• Can increase drug plasma levels, resulting in greater drug-related effects
• Can decrease drug plasma levels and decrease drug-related effects
Overholser BR, et al. Am J Manag Care. 2011;17 suppl 1:S276-S287.
158
79
Peter’s Current Medication Regimen


Returns to your office complaining of serious foot fungus.
Current medications:
•
•
•
•


Oxycodone CR tablets 40 mg every 12 hours
Hydrocodone/acetaminophen 5/300 8/day for breakthrough pain
Gabapentin 300 mg/2 tablets TID
Zolpidem 10 mg/HS
When considering a medication to treat the fungus, should you
be concerned about possible drug-drug interactions?
YES – many commonly used antifungals have known CYP450
interactions
159
Overview of Opioid Metabolism
Active Components
Metabolism (CYP450)
Morphine
Not significantly metabolized by CYP450
Oxymorphone
Not significantly metabolized by CYP450
Tapentadol
Not significantly metabolized by CYP450
Hydromorphone
Not significantly metabolized by CYP450
Oxycodone
2D6, 3A4
Hydrocodone
3A4
Hydrocodone + Acetaminophen
2D6, 3A4
Tramadol
2D6, 3A4
Codeine
2D6
Fentanyl
3A4
Methadone
3A4, 2B6, 2D6, 2C9, 2C19
Oxycodone + Acetaminophen
2D6, 3A4
www.accessdata.fda.gov.
160
80
Interactions With Other Agents and Substances
Agent
Concomitant Use With:
Potential Effect on Opioid
Levels and Other Effects
Avinza (morphine
sulfate ER capsule)
• Alcohol
• PGP Inhibitors (quinidine)
 (potentially fatal dose)

Belbuca
(buprenorphine
buccal film)
•
•
•
•
CNS depressants and benzodiazepines
CYP3A4 inhibitors
CYP3A4 inducers
Class IA and III antiarrythmics, other
potentially arrhythmogenic agent
Respiratory depression 


QTc prolongation and torsade
de pointe risk 
Butrans
(buprenorphine
transdermal system)
•
•
•
•
CYP3A4 inhibitors
CYP3A4 inducers
Benzodiazepines
Class IA and III antiarrythmics, other
potentially arrhythmogenic agent


Respiratory depression 
QTc prolongation and torsade
de pointe risk 
Dolophine*
(methadone HCl
tablets)
•
•
•
•
•
CYP450 inhibitors
CYP450 inducers
Anti-retroviral agents
Benzodiazepines
Potentially arrhythmogenic agents


Mixed effects on levels
Respiratory depression 
QTc prolongation and torsade
de pointe risk 
* Pharmacokinetic drug-drug interactions with methadone are complex. Refer to package insert for additional information.
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed January 1, 2016.
161
Interactions With Other Agents and Substances
Agent
Concomitant Use With:
Potential Effects on Opioid
Levels and Other Effects
Duragesic (fentanyl
transdermal system)
• CYP3A4 inhibitors
• CYP3A4 inducers


Embeda (morphine sulfate
ER-naltrexone capsules)
• Alcohol
• PGP Inhibitors (quinidine)
 (potentially fatal dose)

Exalgo (hydromorphone
HCl ER tablets)
None
Hysingla ER (hydrocodone
bitartrate ER tablets)
• CYP3A4 inhibitors
• CYP3A4 inducers


Kadian
(morphine sulfate ER
capsules)
• Alcohol
• PGP Inhibitors (quinidine)
 (potentially fatal dose)

MorphaBond (morphine
sulfate ER tablets)
• PBP inhibitors (quinidine)

MS Contin
(morphine sulfate CR tablets)
• PGP Inhibitors (quinidine)

FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016.
162
81
Interactions With Other Agents and Substances
Agent
Concomitant Use With:
Potential Effects on Opioid
Levels and Other Effects
Nucynta ER (tapentadol HCl
ER tablets)
• Alcohol
• MAOIs
 (potentially fatal dose)
Contraindicated in patients
taking MAOIs
Opana ER (oxymorphone
HCl ER tablets)
• Alcohol
 (potentially fatal dose)
OxyContin (oxycodone HCl
CR tablets)
•
•
•
•
CYP3A4 inhibitors
CYP3A4 inducers
2D6 inhibitors
2D6 inducer


Targiniq ER (oxycodone HCl
/ naloxone HCl)
• CYP3A4 inhibitors
• CYP3A4 inducers


Zohydro ER (hydrocodone
bitartrate ER capsules)
• CYP3A4 inhibitors
• CYP3A4 inducers


Increased effect
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016.
163
Drug Interactions Between Methadone or
Buprenorphine and Select Medications
Medication
Methadone
Buprenorphine
AZT
Increase in AZT concentrations; possible
AZT toxicity
No clinical significant interaction
Lopinavir/Ritonavir
Opiate withdrawal may occur
No clinically significant interaction
Rifampin
Opiate withdrawal may occur
Opiate withdrawal may occur
Fluconazole
Increased methadone plasma concentrations
Ciprofloxacin
Increased methadone plasma concentrations
Sertraline
No associated adverse drug interactions
Duloxetine
Potentially increases duloxetine exposure
Dextromethorphan
Associated with delirium
No clinically significant interaction
Aripiprazole
No clinically significant interaciton
No clinically significant interaction
Carbamazepine
Associated with opiate withdrawal
Not studied
Methylphenidate
No clinically significant interaction
No clinically significant interaction
Diphenhydramine
May have synergistic depressant effect
Adapted from McCance-Katz EF, et al. Am J Addict. 2010;19(1):4-16.
164
82
Tolerance to Sedating and
Respiratory Depressant Side Effects

Opioid-naïve patients – no prior opioid exposure
• Especially prone to most serious adverse effects of opioids

Tolerance to sedating and respiratory-depressant effects
critical to safe use of certain opioid products, dosages,
and strengths
• Opioid-tolerant patient: at least 1 wk of tx = 60 mg morphine or
equivalent/day
• Patients must be opioid tolerant before using any strength of
transdermal fentanyl or ER hydromorphone
• With other ER/LA products, patients must be opioid tolerant
before using certain strengths or certain daily doses
FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016.
165
Other Important Opioid Safety Issues

Oral formulations of ER/LA opioids must be taken as
directed. Instruct patients to not tamper with the
formulation:
-

Swallow tablets whole
Swallow capsules whole/intact
If necessary, pellets from some capsules can be sprinkled on
applesauce and swallowed without chewing
For transdermal products, instruct patients on proper and
safe use
• External heat, fever, and exertion can increase absorption of the
opioid, leading to fatal overdose
• Transdermal products with metal foil backings are not safe for
use in MRIs
www.fda.gov
166
83
Post-test Q1
?
The opioid with the greatest risk of prolongation of the
QTc interval is:
1.
Tapentadol
2.
Oxycodone
3.
Oxymorphone
4.
Methadone
167
Post-test Q2
?
Of the following cytochrome P450 enzymes, which
one is particularly important in opioid metabolism?
1.
CYP2E1
2.
CYP2C19
3.
CYP3A4
4.
CYP1A2
168
84
Session VI
Getting the Most Clinical Insights
from Specific ER/LA Product
Information Sources
16
9
Learning Objectives for Session VI
Upon completion of this module, the participants will
be better able to:

Differentiate the prescribing information among
available ER/LA opioids

Identify ER/LA opioids and dosages indicated
for opioid-tolerant patients only
170
85
Pre-test Q1
?
Which of the following is TRUE about Exalgo
(hydromorphone HCl) Extended Release?
1.
If the patient is unable to swallow Exalgo, capsule can
be opened and pellets sprinkled on applesauce
2.
All doses are indicated for use in opioid-tolerant
patients only
3.
Its relative potency to oral morphine has not been
established
4.
Patients should rotate site of application
171
Pre-test Q2
?
Which of the following is TRUE about Opana ER
(oxymorphone HCl) Extended Release?
1.
If the patient is unable to swallow Opana ER, capsule
can be opened and pellets sprinkled on applesauce
2.
All doses are indicated for use in opioid-tolerant
patients only
3.
Its relative potency to oral morphine has not been
established
4.
Some patients may benefit from asymmetric dosing
(different dose given in AM than in PM)
172
86
Prescribers Must Be Knowledgeable

Before prescribing an opioid, each clinician needs to be
knowledgeable about specific characteristics of each
available ER/LA opioid, including:
•
•
•
•
•
Drug substance
Formulation
Strength
Dosing interval
Key instructions – reserve for use in patients for whom alternative
treatment options (eg, non-opioid analgesics or immediaterelease opioids) are ineffective, not tolerated, or would be
otherwise inadequate to provide sufficient management of pain
173
Prescribing Information

For detailed information, prescribers can refer to the
prescribing information available online:
• DailyMed at www.dailymed.nlm.nih.gov
• www.fda.gov/drugsatfda
174
87
Avinza—Morphine Sulfate ER
Morphine Sulfate ER
Capsules, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, and 120 mg
Avinza
Dosing Interval
Once a day
Initial dose in opioid non-tolerant patients: 30 mg
Maximum daily dose: 1600 mg
Key Instructions
• Initial dose in opioid non-tolerant patients: 30 mg
• Titrate using minimum of 3-day intervals (4-day intervals in opioid nontolerant patients)
Instruct patient:
- Swallow capsule whole (do not chew, crush, or dissolve)
- If unable to swallow, capsule can be opened and pellets sprinkled on
applesauce for patients
Specific Drug
Interactions
• Avoid alcoholic beverages or medications containing alcohol; may result in
“dose dump” and absorption of potentially fatal dose of morphine
• PGP inhibitors (eg, quinidine) may increase absorption/exposure of
morphine sulfate by approximately 2x
Use in Opioid-Tolerant
Patients
Use 90 mg and 120 mg capsules in opioid-tolerant patients ONLY
PGP, P-glycoprotein
www.fda.gov
175
Belbuca—Buprenorphine Buccal Film
Belbuca
Dosing Interval
Buprenorphine
Buccal Film, 75 mcg, 150 mcg, 300 mcg, 450 mcg, 600 mcg, 750
mcg, 900 mcg
Every 12 hours (or once every 24 hrs for initiation in opioid-naïve pts and
those taking <30 mg oral morphine equivalents)
• Maximum dose: 900 mcg every 12 hrs due to risk of QTc prolongation
Key Instructions
• Initiate treatment with a 75 mcg buccal film in opioid-naïve or if prior total daily dose of opioid
< 30 mg oral morphine equivalents/day
• Titrate in increments of 150 mcg q 12 hrs
• The minimum titration interval is 4 days
• In severe hepatic impairment and in oral mucositis, reduce dose by 50%
• Do not use if package seal is broken or film damaged in any way
Specific Drug
Interactions
•
•
•
•
Use in Opioid-Tolerant
Patients
• 600 mcg, 750 mcg and 900 mcg are for use following titration from lower doses
Product-Specific Safety
Concerns
• QTc prolongation ad torsade de pointes
• Hepatotoxicity
Relative Potency to Oral
Morphine
• Equipotency to oral morphine has not been established.
www.fda.gov
CYP3A4 inhibitors may increase buprenorphine levels
CYP3A4 inducers may decrease buprenorphine levels
Benzodiazepines may increase respirator depression
Class IA and III antiarrhythmics and other potentially arrhythmogenic agents may increase risk
for QTc prolongation and torsade de pointes
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Butrans—Buprenorphine
Butrans
Dosing Interval
Buprenorphine
Transdermal System, 5 mcg/hr, 7.5 mcg/hr, 10 mcg/hr,
15 mcg/hr, and 20 mcg/hr
One transdermal system every 7 days
• Initial dose: 5 mcg/hr.
• Maximum dose: 20 mcg/hr due to risk of QTc prolongation
Key Instructions
• When used as first opioid analgesic initiate treatment with 5 mcg/hr
• If prior total daily dose of opioid < 30 mg oral morphine equivalents per day, initiate
treatment with 5 mcg/hr dose
• If prior total daily dose of opioid between 30 mg to 80 mg of oral morphine equivalents,
taper patient’s opioid for up to 7 days to no more than 30 mg of morphine equivalents,
then initiate with 10 mcg/hr dose
• The minimum titration interval is 72 hours
Instruct patient
•
•
•
•
•
•
•
Apply only to sites indicated in full prescribing information
Apply to intact/non-irritated skin
Skin may be prepped by clipping hair, washing site with water only
Rotate site of application; allow a minimum of 3 weeks before reapplying to same site
Do not cut
Avoid exposure to heat
Dispose of used/unused patches by folding the adhesive side together and flushing
down toilet
www.fda.gov
177
Butrans—Buprenorphine (cont’d)
Butrans
Buprenorphine
Transdermal System, 5 mcg/hr, 7.5 mcg/hr, 10 mcg/hr,
15 mcg/hr and 20 mcg/hr
Specific Drug
Interactions
•
•
•
•
CYP3A4 inhibitors may increase buprenorphine levels
CYP3A4 inducers may decrease buprenorphine levels
Benzodiazepines may increase respiratory depression
Class IA and III antiarrythmics, other potentially arrhythmogenic agents,
may increase risk for QTc prolongation and torsade de pointe
Use in Opioid-Tolerant
Patients
Use 7.5 mcg/hr, 10 mcg/hr, 15 mcg/hr and 20 mcg/hr transdermal systems in
opioid-tolerant patients ONLY
Drug-Specific Safety
Concerns
• QTc prolongation and torsade de pointe
• Hepatotoxicity
• Application site skin reactions
Torsade de pointe (TdP) –a form of polymorphic ventricular tachycardia that may result in syncope or
cardiac arrest.
www.fda.gov
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89
Dolophine—Methadone Hydrochloride
Dolophine
Methadone Hydrochloride
Tablets, 5 mg and 10 mg
Dosing Interval
Every 8 to 12 hours
Initial dose in opioid non-tolerant patients: 2.5 mg to 10 mg slowly titrated to
effect
Key Instructions
• Conversion of opioid-tolerant patients using equianalgesic tables can result
in overdose and death; use low doses according to table in full prescribing
information (PI)
• High interpatient variability in absorption, metabolism, and relative
analgesic potency
• Opioid detoxification or maintenance treatment shall only be provided in a
federally certified opioid (addiction) treatment program
Specific Drug
Interactions
•
•
•
•
•
Complex pharmacokinetic drug-drug interactions with methadone
CYP450 inducers may increase methadone levels
CYP450 inhibitors may decrease methadone levels
Antiretroviral agents have mixed effects on methadone levels
Potentially arrhythmogenic agents may increase risk for QTc prolongation
and torsade de pointe
• Benzodiazepines may increase respiratory depression
www.fda.gov
179
Dolophine—Methadone Hydrochloride (cont’d)
Dolophine
Methadone Hydrochloride
Tablets, 5 mg and 10 mg
Use in Opioid-Tolerant
Patients
Refer to full prescribing information
Product-Specific
Safety Concerns
• QTc prolongation and torsade de pointe
• Peak respiratory depression occurs later and persists longer
than analgesic effect
• Clearance may increase during pregnancy
• False-positive urine drug screens possible
Relative Potency to
Oral Morphine
Varies depending on patient’s prior opioid experience
www.fda.gov
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90
Duragesic—Fentanyl Transdermal System
Duragesic
Fentanyl
Transdermal System, 12, 25, 37.5*, 50, 62.5*, 75, 87.5*, and 100
mcg/hr
(*these strengths available only in generic form)
Dosing Interval
Every 72 hours (3 days)
Key Instructions
• Use product-specific information in the full prescribing information for dose conversion from
prior opioid
• Use 50% of the dose in mild or moderate hepatic or renal impairment; avoid use in
severe hepatic or renal impairment
• Titrate generally using no less than 72-hour intervals; some patients may require 48 hour
titration if adequate analgesia not achieved at 72 hour dose
Instruct patient:
-
Apply to intact/non-irritated/non-irradiated skin on a flat surface
Skin may be prepped by clipping hair, washing site with water only
Rotate site of application
Do not cut
Avoid exposure to heat
Avoid accidental contact when holding or caring for children
Dispose used/unused patches by folding the adhesive side together and flushing down the toilet
Specific contraindications:
• Patients who are not opioid-tolerant
• Management of acute or intermittent pain, or in patients who require opioid analgesia
for a short period of time
• Management of postoperative pain, including use after outpatient or day surgery
• Management of mild pain
www.fda.gov
181
Duragesic—Fentanyl Transdermal System (cont’d)
Duragesic
Fentanyl
Transdermal System, 12, 25, 37.5*, 50, 62.5*, 75, 87.5*, and 100
mcg/hr
(*these strengths available only in generic form)
Specific Drug
Interactions
• CYP3A4 inhibitors may increase fentanyl drug levels and exposure
• CYP3A4 inducers may decrease fentanyl drug levels and exposure
• Discontinuation of a concomitantly used CYP3A4 inducer may result in an
increase in fentanyl plasma concentration
Use in Opioid-Tolerant
Patients
Indicated for use in opioid-tolerant patients ONLY
Product-Specific
Safety Concerns
• Accidental exposure due to secondary exposure to unwashed/unclothed
application site
• Increased drug exposure with increased core body temperature or fever
• Bradycardia
• Application site skin reactions
Relative Potency to
Oral Morphine
See full prescribing information for conversion recommendations from
prior opioid
www.fda.gov
182
91
Embeda—Morphine Sulfate ER-Naltrexone
Embeda
Morphine Sulfate ER-Naltrexone
Capsules, 20 mg/0.8 mg, 30 mg/1.2 mg, 50 mg/2 mg,
60 mg/2.4 mg, 80 mg/3.2 mg, and 100 mg/4 mg
Dosing Interval
Once a day or every 12 hours
Initial dose as first opioid: 20 mg/0.8 mg
Titrate using 1-2 day intervals
Key Instructions
• Swallow capsules whole (do not chew, crush, or dissolve)
• Instruct patient:
- Crushing or chewing will release morphine, possibly resulting in fatal
overdose, and naltrexone, possibly resulting in withdrawal symptoms
- If unable to swallow capsule whole, can open capsule and sprinkle
pellets on applesauce; use immediately
Specific Drug
Interactions
• Alcoholic beverages or medications containing alcohol may result in the
rapid release and absorption of a potentially fatal dose of morphine
• GP inhibitors (eg, quinidine) may increase the absorption/exposure of
morphine sulfate by approximately 2-fold
Use in Opioid-Tolerant
Patients
Use 100 mg/4mg capsule in opioid-tolerant patients ONLY
www.fda.gov
183
Exalgo—Hydromorphone Hydrochloride
Exalgo
Hydromorphone Hydrochloride
Extended-Release Tablets, 8 mg, 12 mg, 16 mg, and 32 mg
Dosing Interval
Once a day
Titrate using a minimum of 3- to 4-day intervals
Key Instructions
• Use conversion ratios in the full prescribing information
• Start patients with moderate hepatic impairment on 25% of the dose that would
be prescribed for a patient with normal hepatic function
• Start patients with moderate renal impairment on 50%, and patients with severe
renal impairment on 25% of the dose that would be prescribed for a patient with
normal renal function
• Do not use in patients with sulfa allergy
• Instruct patient to swallow tablets whole
- DO NOT chew, crush, or dissolve
Specific Drug
Interactions
None
Use in Opioid-Tolerant
Patients
Use in opioid-tolerant patients ONLY
Drug-Specific Adverse
Reactions
Allergic manifestations to sulfa component
Relative Potency to Oral
Morphine
Approximately 5:1 oral morphine to hydromorphone oral dose ratio, use
conversion recommendations in the full prescribing information
www.fda.gov
184
92
Hysingla ER—Hydrocodone Bitartrate
Hysingla ER
Hydrocodone Bitartrate
Extended-Release Tablets, 20, 30, 40, 60, 80, 100 mg
Dosing Interval
Once a day (every 24 hours)
Titrate in increments of 10 mg to 20 mg every 3-5 days
Key Instructions
•
•
•
•
•
•
In patients who are not opioid tolerant, initiate therapy with 20 mg
QTc prolongation has been observed with daily doses of 160 mg
Hepatic impairment: use half the initial dose
Renal impairment: use half the initial dose
Instruct patients to swallow tablets whole
Consider alternative analgesic in patients who have difficulty swallowing or
have underlying GI disorders that may predispose them to obstruction
Specific Drug
Interactions
•
•
•
•
CYP3A4 inhibitors may increase hydrocodone exposure
CYP3A4 inducers may decrease hydrocodone exposure
Concomitant use with strong laxatives may decrease hydrocodone absorption
Concomitant use of MAOIs or TCAs may increase the effect of either drug
Use in Opioid-Tolerant
Patients
Doses equal to or greater than 80 mg are for use in opioid tolerant patients only
Abuse Deterrence
This product is formulated with physicochemical properties intended to make the
tablet more difficult to manipulate for misuse and abuse.
www.fda.gov
185
Hysingla ER—Hydrocodone Bitartrate (cont’d)
Hysingla ER
Product-Specific Safety
Concerns
Hydrocodone Bitartrate
Extended-Release Tablets, 20, 30, 40, 60, 80, 100 mg
•
•
•
•
Relative Potency to Oral
Morphine
Use with caution in patients with difficulty swallowing or with underlying GI
disorders that may predispose them to obstruction
Esophageal obstruction, dysphagia, and choking have been reported with
Hysingla ER
In nursing mothers, discontinue nursing or discontinue drug
QTc prolongation has been observed with Hysingla ER following daily doses of
160 mg. Avoid use in patients with congenital long QTc syndrome. This
observation should be considered in making clinical decisions regarding patient
monitoring when prescribing Hysingla ER in patients with CHF,
bradyarrhythmias, electrolyte abnormalities, or if taking medications known to
prolong QTc interval. In patients who develop QTc prolongation, consider
reducing the dose.
See individual product information for conversion recommendations from prior
opioid.
www.fda.gov
186
93
Kadian—Morphine Sulfate
Kadian
Morphine Sulfate
Extended-Release Capsules, 10 mg, 20 mg, 30 mg, 50 mg,
60 mg, 70 mg, 80 mg, 100 mg, 130 mg, 150 mg, and 200 mg
Dosing Interval
Once a day or every 12 hours
Titrate using a minimum of 2-day intervals
Key Instructions
• Do not use as first/initial opioid (see PI)
• Instruct patient:
- Swallow capsules whole
• DO NOT chew, crush, or dissolve
- If unable to swallow capsule whole, can open capsule and sprinkle pellets
on applesauce; use immediately
Specific Drug
Interactions
• Do not use with alcoholic beverages or medications containing alcohol as
may result in the rapid release and absorption of a potentially fatal dose of
morphine
• PGP inhibitors (eg, quinidine) may increase the absorption/exposure of
morphine sulfate by approximately 2-fold
Use in Opioid-Tolerant
Patients
Kadian 100-mg, 130 mg, 150 mg and 200-mg capsules are for use in opioidtolerant patients ONLY
www.fda.gov
187
MorphaBond—Morphine Sulfate
MorphaBond
Morphine Sulfate
Extended-Release Tablets, 15 mg, 30 mg, 60 mg, 100 mg
Dosing Interval
Every 8 hours or every 12 hours
Titrate using a minimum of 1 to 2-day intervals
Key Instructions
• Do not use as first/initial opioid (see PI)
• Instruct patient to swallow tablets whole
- Do NOT chew, crush, or dissolve
Specific Drug
Interactions
PGP inhibitors (eg, quinidine) may increase the absorption/exposure of
morphine sulfate by approximately 2-fold
Use in Opioid-Tolerant
Patients
Use MorphaBond 100 mg tablet strengts in opioid-tolerant patients ONLY
www.fda.gov
188
94
MS Contin—Morphine Sulfate
MS Contin
Morphine Sulfate
Controlled-Release Tablets, 15 mg, 30 mg, 60 mg, 100 mg,
and 200 mg
Dosing Interval
Every 8 hours or every 12 hours
Titrate using a minimum of 2-day intervals
Key Instructions
• Do not use as first/initial opioid (see PI)
• Instruct patient to swallow tablets whole
- Do NOT chew, crush, or dissolve
Specific Drug
Interactions
PGP inhibitors (eg, quinidine) may increase the absorption/exposure of
morphine sulfate by approximately 2-fold
Use in Opioid-Tolerant
Patients
Use MS Contin 100-mg and 200-mg tablet strengths in opioid-tolerant
patients ONLY
www.fda.gov
189
Nucynta ER—Tapentadol
Nucynta ER
Tapentadol
Extended-Release Tablets, 50 mg, 100 mg, 150 mg, 200 mg,
and 250 mg
Dosing Interval
Every 12 hours
• Use 50 mg every 12 hours as initial dose in opioid non-tolerant patients
• Titrate by 50 mg increments using a minimum of 3-day intervals
• Maximum total daily dose is 500 mg
Key Instructions
• Dose once daily in moderate hepatic impairment with 100 mg per day
maximum
• Avoid use in severe hepatic and renal impairment
• Instruct patient :
- Swallow tablets whole
• Do not chew, crush, or dissolve
- Take 1 tablet at a time and with enough water to ensure complete
swallowing immediately after placing in the mouth
Specific Drug
Interactions
• Do not use with alcoholic beverages or medications containing alcohol as
may result in the rapid release and absorption of a potentially fatal dose of
tapentadol
• Contraindicated in patients taking MAOIs
www.fda.gov
190
95
Nucynta ER—Tapentadol (cont’d)
Tapentadol
Extended-Release Tablets, 50 mg, 100 mg, 150 mg, 200 mg,
and 250 mg
Nucynta ER
Use in Opioid-Tolerant
Patients
No product-specific considerations
Product-Specific
Safety Concerns
•
Risk of serotonin syndrome
•
Angioedema
Relative Potency to
Other Oral Opioids
•
•
Equipotency to oral morphine not established
Studies leading to its FDA approval use a dose ratio of 5:1 of Tapentadol
ER to Oxycodone CR
www.fda.gov
191
Opana ER—Oxymorphone Hydrochloride
Opana ER
Oxymorphone Hydrochloride
Extended-Release Tablets, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg,
30 mg, and 40 mg
Dosing Interval
Every-12-hours dosing; some benefit from asymmetric (different dose given in AM
than PM) dosing
Key Instructions
• Use 5 mg every 12 hours as initial dose in opioid non-tolerant patients and
patients with mild hepatic impairment and renal impairment (creatinine clearance
<50 mL/min) and in patients over 65 years of age
• Titrate using 3-7-day intervals
• Contraindicated in moderate and severe hepatic impairment
Instruct patient:
• Swallow tablets whole (do not chew, crush, or dissolve)
• Take 1 tablet at a time, with enough water to ensure complete swallowing
immediately after placing in the mouth
• Use with caution in patients who have difficulty swallowing or have underlying GI
disorders that may predispose them to obstruction
Specific Drug
Interactions
Do not use with alcoholic beverages or medications containing alcohol as may
result in absorption of a potentially fatal dose of oxymorphone
Use in OpioidTolerant Patients
No product specific considerations
Relative Potency
to Oral Morphine
Approximately 3:1 oral morphine to oxymorphone oral dose ratio
www.fda.gov
192
96
OxyContin—Oxycodone Hydrochloride
OxyContin
Oxycodone Hydrochloride
Controlled-Release Tablets, 10 mg, 15 mg, 20 mg, 30 mg,
40 mg, 60 mg, and 80 mg
Dosing Interval
Every 12 hours
Key Instructions
•
•
•
•
Specific Drug
Interactions
• CYP3A4 inhibitors may increase oxycodone exposure
• CYP3A4 inducers may decrease oxycodone exposure
Opioid-naïve patients: initiate treatment with 10 mg every 12 hours
Titrate using a minimum of 1- to 2-day intervals
Hepatic impairment: start with one-third to one-half usual dosage
Renal impairment (creatinine clearance <60 mL/min): start with one-half usual
dosage
• Consider use of other analgesics in patients who have difficulty
swallowing or have underlying GI disorders that may predispose them to
obstruction
• Instruct patient:
- Swallow tablets whole
• DO NOT chew, crush, or dissolve
- Take 1 tablet at a time, with enough water to ensure complete swallowing
immediately after placing in the mouth
www.fda.gov
193
OxyContin—Oxycodone Hydrochloride (cont’d)
OxyContin
Oxycodone Hydrochloride
Controlled-Release Tablets, 10 mg, 15 mg, 20 mg, 30 mg,
40 mg, 60 mg, and 80 mg
Use in Opioid-Tolerant
Patients
Single dose greater than 40 mg or total daily dose greater than 80 mg is for
use in opioid-tolerant patients ONLY
Product-Specific
Safety Concerns
• Choking, gagging, regurgitation, tablets stuck in the throat, difficulty
swallowing the tablet
• Contraindicated in patients with GI obstruction
Relative Potency to
Oral Morphine
Approximately 2:1 oral morphine to oxycodone oral dose ratio
New as of 4/16/2013
This product has abuse-deterrent properties. The tablet is more difficult to
crush, break, or dissolve. It forms a viscous hydrogel and cannot be easily
prepared for injection.
New as of 8/13/2015
Indicated for opioid-tolerant pediatric patients 11 years and older who are
already receiving and tolerate a minimum daily opioid dose of at least 20 mg
oxycodone orally or its equivalent
www.fda.gov
194
97
Targiniq ER—Oxycodone HCl / Naloxone HCl
Targiniq ER
Oxycodone Hydrochloride / Naloxone Hydrochloride
Extended-Release Tablets, 10 mg/5 mg, 20 mg/10 mg, and
40 mg/20 mg
Dosing Interval
Every 12 hours
Key Instructions
•
•
•
•
Specific Drug
Interactions
• CYP3A4 inhibitors may increase oxycodone exposure
• CYP3A4 inducers may decrease oxycodone exposure
Opioid-naïve patients: initiate treatment with 10 mg/5 mg every 12 hours
Titrate using a minimum of 1- to 2-day intervals
Do not exceed 80 mg/40 mg total daily dose
Hepatic impairment: contraindicated in moderate and severe hepatic impairment.
In mild hepatic impairment, start with one-third to one-half usual dosage
• Renal impairment (creatinine clearance <60 mL/min): start with one-half usual
dosage
• Instruct patient:
- Swallow tablets whole
• DO NOT chew, crush, split or dissolve as this will release oxycodone possibly
resulting in fatal overdose, and naloxone, possibly resulting in withdrawal
symptoms
- Take 1 tablet at a time, with enough water to ensure complete swallowing
immediately after placing in the mouth
www.fda.gov
195
Targiniq ER—Oxycodone HCl / Naloxone HCl
Targiniq ER
Oxycodone Hydrochloride / Naloxone Hydrochloride
Extended-Release Tablets, 10 mg/5 mg, 20 mg/10 mg, and
40 mg/20 mg
Use in opioid-tolerant
patients
Singe dose greater than 40 mg/20 mg or total daily dose of 80 mg/40 mg are
for use in opioid-tolerant patients only
Product-specific
safety concerns
• Contraindicated in moderate and severe hepatic impairment.
Relative potency to
oral morphine
• See individual product information for conversion recommendations from
prior opioid
www.fda.gov
196
98
Zohydro ER—Hydrocodone Bitartrate
Zohydro ER
Hydrocodone Bitartrate
Extended-release capsules 10 mg, 15 mg, 20 mg, 30 mg, 40 mg
and 50 mg
Dosing Interval
Every 12 hours
Key Instructions
•
•
•
•
Specific Drug
Interactions
• CYP3A4 inhibitors may increase hydrocodone exposure
• CYP3A4 inducers may decrease hydrocodone exposure
Use in Opioid-Tolerant
patients
• Single dose greater than 40 mg or total daily dose greater than 80 mg are
for use in opioid-tolerant patients only
Relative Potency to
Oral Morphine
• Approximately 1.5:1 oral morphine to hydrocodone oral dose ratio
Opioid-naïve patients: initiate treatment with 10 mg every 12 hours
Titrate using 3- to 7-day intervals
Renal impairment (creatinine clearance <60 mL/min): start with a low dose
Instruct patient:
- Swallow capsules whole
• DO NOT chew, crush, or dissolve
www.fda.gov
197
Post-test Q1
?
Which of the following is TRUE about Exalgo
(hydromorphone HCl) Extended Release?
1.
If the patient is unable to swallow Exalgo, capsule can
be opened and pellets sprinkled on applesauce
2.
All doses are indicated for use in opioid-tolerant
patients only
3.
Its relative potency to oral morphine has not been
established
4.
Patients should rotate site of application
198
99
?
Post-test Q2
Which of the following is TRUE about Opana ER
(oxymorphone HCl) Extended Release?
1.
If the patient is unable to swallow Opana ER, capsule
can be opened and pellets sprinkled on applesauce
2.
All doses are indicated for use in opioid-tolerant
patients only
3.
Its relative potency to oral morphine has not been
established
4.
Some patients may benefit from asymmetric dosing
(different dose given in AM than in PM)
199
Questions?
20
0
100