Drugs to Watch: Tramadol, Hydrocodone and Naloxone

1. Drugs to Watch: Tramadol,
Hydrocodone and Naloxone
Presenters:
• Nathan Painter, PharmD, Associate Clinical Professor, University of California San
Diego Skaggs School of Pharmacy and Pharmaceutical Science
• Roneet Lev, MD, Director of Operations, Scripps Mercy Hospital Emergency
Department, and Chair, San Diego County (CA) Rx Drug Abuse Medical Task Force
• Traci Green, PhD, MSC, Deputy Director, Boston Medical Center Injury Prevention
Center, and Associate Professor of Emergency Medicine, Boston University
Pharmacy Track
Moderator: Anne L. Burns, RPh, Vice President, Professional Affairs,
American Pharmacists Association, & Member, Rx & Heroin Summit
National Advisory Board

2. Disclosures
Traci Green, PhD, MSC; Roneet Lev, MD; Nathan
Painter, PharmD; and Anne L. Burns, RPh, have
disclosed no relevant, real, or apparent personal
or professional financial relationships with
proprietary entities that produce healthcare
goods and services.

3. Disclosures
• All planners/managers hereby state that they or their
spouse/life partner do not have any financial
relationships or relationships to products or devices
with any commercial interest related to the content of
this activity of any amount during the past 12 months.
• The following planners/managers have the following to
disclose:
– John J. Dreyzehner, MD, MPH, FACOEM – Ownership
interest: Starfish Health (spouse)
– Robert DuPont – Employment: Bensinger, DuPont &
Associates-Prescription Drug Research Center

4. Learning Objectives
1. Analyze the impact of tramadol and hydrocodone
schedule changes on the number of prescriptions and
deaths related to these medications in California.
2. Describe reasons physicians and patients need a
better education about tramadol and its potential
dangers.
3. Evaluate pharmacists’ perspectives on pharmacy-
based naloxone based on a nationally representative
survey.
4. Provide accurate and appropriate counsel as part of
the treatment team.

5. Roneet Lev, MD FACEP
Nathan Painter, Pharm D, CDE

6.  Morphine
 from opium poppy
 Semi-SyntheticOpioid - Hydrocodone
 Fully SyntheticOpioid -Tramadol
Morphine Hydrocodone Tramadol

7. Opioid ME (mg) Daily dose (mg)
Morphine 5 30
Hydrocodone 5 30 – 45
Tramadol 5-10* 150-300
Oxycodone 7.5 15 – 20
*Washington State, CMS table, cures

8. “…less potential for abuse than other opioid agonists…”
“narcotic-like because it is a synthetic drug with a slightly different
chemical structure than other narcotics…”

10.  Adverse Drug Reactions : seizures
 Higher incidence when combined with alcohol, illicit drugs,
antipsychotics, or antidepressants
 Withdrawal can cause seizures
 Not reduced with naloxone
Caspian J Intern Med. 2012 Summer; 3(3): 484–487
Int J Prev Med. 2014 Mar; 5(3): 302–307

11.  Development of cravings when not using the drug
 Development of tolerance effects or requiring more and more of the
drug to achieve the same effects
 Use for nonmedical purposes
 Inability to control use
 Continually taking the drug regardless of the harm it causes, physically or
psychologically
 "Drug seeking" behavior such as constantly "losing" prescriptions,
arriving at clinics at the end of business hours, refusing examinations, or
tampering with medical records or prescriptions
 "Doctor shopping"
 Failing to perform as expected at work or school due to drug-related
impairments
 Neglecting friends and family in order to use or obtain drugs
Pharmacoepidemiol Drug Saf. 2009 Dec;18(12):1192-8

12.  Hydrocodone III II
• October 6, 2014
 TramadolV IV
• August 18, 2014

13.  Less hydrocodone?
 More tramadol?
 Less overall opioids?

15. Jones CM, et.al. JAMA Intern Med. Published online January 25, 2016
Hydrocodone
Combination Product
Nonhydrocodone
Combination Product

16. Jones CM, et.al. JAMA Intern Med. Published online January 25, 2016
Hydrocodone
Combination Product
Nonhydrocodone
Combination Product

17. 0
500,000
1,000,000
1,500,000
2,000,000
2,500,000
August-13 November-13 March-14 June-14 September-14December-14 April-15 July-15 October-15
#Rx
Hydrocodone
Total Opioids
Tramadol

18. 0
20,000,000
40,000,000
60,000,000
80,000,000
100,000,000
120,000,000
140,000,000
160,000,000
180,000,000
August-13 November-13 March-14 June-14 September-14December-14 April-15 July-15 October-15
NumberTablets
Hydrocodone
Total Opiods
Tramadol

19. 15667302
0
23562191
15204104
4151099
29292835
25141736
0
5000000
10000000
15000000
20000000
25000000
30000000
35000000
Hydrocodone Tramadol Total Opioids
Before Change
After Change
After (Less Tramadol)
Total Opioids
6.7%
excluding
Tramadol
Hydrocodone
3%

20. IMS Health National Prescription
Audit
JAMA Internal Medicine
36 months
BEFORE schedule
change
12 months AFTER schedule
change
Hydrocodone Rx andTablets 8.4%, 6% 22%, 16% (refills 73.7% of decline)
Non-Hydrocodone Rx andTablets 0.2%, 0.5% 4.9%,1.2%
California Prescription Drug
Monitoring System
12 months AFTER schedule
change
Hydrocodone Rx andTablets 3%, 1.7%
Total Opioid Rx andTablets
(excludingTramadol)
6.7%,5.3%

21. 0
5
10
15
20
25
30
35
40
45
50
August-13 November-13 March-14 June-14 September-14December-14 April-15 July-15 October-15
Deaths
Hydrocodone
Total Opiods
Tramadol

22. 42
22
338
33
18
367
0
50
100
150
200
250
300
350
400
Hydrocodone Tramadol Total Opioids
Before Change
After Change
Hydrocodone
21.4
Tramadol
 0.2%
Total Opioids
 3.3 Deaths from
Tramadol per
Total Rx Tramadol
are 2x
Deaths from
Hydrocodone per
Total Rx

23.  Non-Narcotic Synthetic opioid
 Less-Addicting Than what?
 Less Potent 50Tramadol > 5/325 Hydrocodone
 Safer 2 x deaths?
Seizures: contraindication/withdrawal
False
False
False
False

24.  Decreased Rx
 3% California, 22% US
 ? Less refills in California
 IncreaseTotal Opioids Rx
 6.7% California, 5% US

25. Traci C. Green, PhD, MSc
Deputy Director, Boston Medical Center Injury Prevention Center
Boston Medical School, Department of Emergency Medicine, Boston, MA
Associate Professor of Emergency Medicine & Epidemiology
The Warren Alpert School of Medicine at Brown University, Rhode Island Hospital
Perspectives on
Pharmacy Based Naloxone:
A Nationally Representative Survey of
Pharmacists

26. Disclosures-Traci C. Green
• No conflicts to disclose
• Funding: Research reported in this presentation was funded
through the following federal grants: AHRQ R18 HS024021-01
Green (PI: Green), NIDA R01 DA034634(PIs: Friedmann/Rich)

27. Learning Objectives
• Evaluate pharmacists’ perspectives on
pharmacy-based naloxone (PBN) based on a
nationally representative survey

28. Effective Interventions for Opioid
Overdose
• Naloxone (Narcan), an
intranasal or intramuscular-
administered opioid antagonist
used to reverse respiratory
depression caused by opioids
– 26%-47% reduction in overdose
mortality
• Call or TEXT 911
• Rescue breathing

29. • An ANTIDOTE for OPIOID overdose
• Naloxone is an opioid receptor antagonist at mu,
kappa, and delta receptors
• Works at the opioid receptor to displace opioid
agonists
• Shows little to no agonist activity
• Shows little to no pharmacological effect in patients
who have not received opioids
Naloxone

30. How Naloxone Reverses Opioid Poisoning
Naloxone has a stronger
affinity to the opioid
receptors than the heroin, so
it knocks the heroin off the
receptors for a short time
and lets the person breathe
again
Opioid
receptor
Naloxone
Heroin

31. Rationale for Overdose Education and
Naloxone Rescue Kits
• Most opioid users do not use alone
• Known risk factors:
– High dose opioids, co-prescription
benzodiazepine+opioid, mixing substances,
abstinence, using alone, chronic medical illness
• Opportunity window:
– Opioid overdoses take minutes to hours
– Reversible with naloxone
• Bystanders are trainable to
recognize and respond to overdoses
• Fear of public safety
31

32. Endorsement for naloxone rescue kits
32
“The AMA has been a
longtime supporter of
increasing the availability of
Naloxone for patients, first
responders and bystanders
who can help save lives and
has provided resources to
bolster legislative efforts to
increase access to this
medication in several states.”
www.ama-
assn.org/ama/pub/news/news/2014/2014-04-07-
naxolene-product-approval.page
“APhA supports the
pharmacist’s role in selecting
appropriate therapy and
dosing and initiating and
providing education about
the proper use of opioid
reversal agents to prevent
opioid-related deaths due to
overdose”
www.pharmacist.com/policy/controlled-
substances-and-other-medications-potential-
abuse-and-use-opioid-reversal-agents-2
ASAM Board of Directors
April 2010
“Naloxone has been proven to be an
effective, fast-acting, inexpensive
and non-addictive opioid
antagonist with minimal side
effects... Naloxone can be
administered quickly and
effectively by trained professional
and lay individuals who observe the
initial signs of an opioid overdose
reaction.”
www.asam.org/docs/publicy-policy-
statements/1naloxone-1-10.pdf

33. Naloxone Access Points for Active Drug Users,
Family, Friends in Rhode Island
• Long-standing program
• Located in one urban
setting, grassroots effort
• Distributes lowest cost
formulation, for free, to
highest risk individuals
Community based
program
Treatment
Programs &
Prison
Pharmacy
Emergency
Department
& Hospitals
1. Certified Recovery Coaches counsel nonfatal
overdose survivors at bedside, train in Nlx, connect
to treatment/recovery supports post discharge
2. Hospital service (trauma services, psychiatric
hospital) counsels and dispenses at discharge
Pharmacists provide naloxone
upon request, initiate
prescription
Programs train
clients & dispense
naloxone or
coordinate with
pharmacy to
dispense

34. Traditional Models of
Naloxone Prescribing
Prescribetoprevent.org
Prescriber co/prescribes to patient
Office-based setting
Drug treatment/MMT site
Patient fills at
Pharmacy

35. Models of
Pharmacy Based Naloxone
Collaborative
Pharmacy
Practice
Agreement
Standing
Order
Furnish upon
request
Pharmacist
prescribes
1
prescriber
Many
pharmacists/
Pharmacies
1 prescriber
1+ Pharmacies
Anyone can be patient
Rhode Island
Washington
Kentucky
Anyone obtaining Rx
from the pharmacy
Massachusetts
Rhode Island
Anyone can be patient
California
Anyone can be patient
New Mexico
Many Pharmacists Pharmacist writes script
Prescriber notified of
provision
Prescriber notified of
provision

38. Survey Collaboration

39. Survey Method
• Anonymous, email based survey
• Randomly selected sample of American Pharmacists
Association membership
– Expected response rate 5%
• Oversampled practice settings relevant for the topic (i.e.,
community pharmacists)
• Fielded survey over 3 week period: September 12 –
October 3, 2015
– weekly, motivational reminders
• Incentive: random drawing for $100 VISA giftcard for
completers
• BU Medical School IRB approved protocol

40. Survey Content & Analysis
• Content
– Items reviewed by all collaborators, pre-tested items (UKY
survey), harvested from prior surveys of pharmacists (Green et
al., 2010), and PrescribetoPrevent evaluation
– Demographics
– Attitudes and experiences with pharmacy based naloxone (PBN)
and related opioid safety measures
– Assess possible PBN implementation challenges
– Learn about barriers and facilitators of PBN
– Self efficacy to identify, counsel, and provide naloxone
• Analysis
– Descriptive, summary statistics
– Psychometrics of scales, intercorrelations

41. Survey Respondents
n=453/6,424
7% response
rate
•Nationally
representative
•Consistent
with
membership in
terms of
gender, years
of practice

42. Demographics
Sample Percent
Age
21-25
26-34
35-44
45-64
65+
2%
32%
18%
41%
6%
Terminal
degree
BSPharm
PharmD
MSPharm
Other
30%
62%
2%
7%
Male
Female
35%
63%
Years in
Practice
<10 years
>20 years
46%
39%
31%
22%9%
6%
2%
12%
2%
15%
Practice Setting Chain pharmacy
Independent pharmacy
Supermarket pharmacy
Clinic (outpatient)
pharmacy
Mass-merchant pharmacy
Hospital/institutional
Long-term care pharmacy
other

43. Extant Collaborations with
Patients/Settings at High Risk of Overdose
• 12% provide care for HIV infected individuals
directly or through active coordination with
HIV clinic
• 33% active collaborations with outside
entities working with high risk populations:
drug treatment provider, VA, harm reduction services, health
department, HIV clinic, AIDS service organization, FQHC,
homeless shelter

44. Opioid Safety
Percent
Frequency of checking state Prescription Monitoring Program
Daily, at every controlled substance prescription or at every
opioid prescription
Approximately weekly
Monthly or less frequently
Never
Other
44%
20%
9%
19%
7%
In store opioid safety measures
Have prescription drug disposal onsite
Syringe disposal program
Provide info on syringe disposal options
Sharps containers
9%
14%
48%
57%
Ever trained to discuss overdose prevention with patients 32%
Ever trained to discuss naloxone use and administration 22%

45. Overdose & Naloxone Experience
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
Ever responded to
suspected overdose
Have personally
administered
naloxone
Close acquaintance
has overdosed
Correctly identified
911 Good Samaritan
law

46. Do Pharmacies stock and are
Pharmacists dispensing naloxone?
• 45% stock naloxone
– 72% of pharmacies not stocking were interested in
doing so
• 12% ever dispensed naloxone to an individual
or family member to take home for overdose
prevention
– 39% of whom had done so 1+ times in past month
– Primarily to those with history of opioid
overdose (their family/friend), high dose opioid,
or received buprenorphine prescription

47. What happens at naloxone fill?
• 57% provide education on use of naloxone
• 36% provide info on safe storage/disposal of Rx opioid
medications (31% not at all)
• Majority (51%) do not provide education on local drug
treatment resources
• 74% interested in having patient education materials for
use when speaking with patients
• Willingness of PBN scale (alpha=0.91) >>Willingness of
pharmacy syringe access scale (alpha=0.75)
– Means: 4.71 PBN willingness vs. 3.71 pharmacy syringe access
– PBN willingness ranges at item level (how willing are you to proactively
identify individuals meeting criteria for naloxone under a protocol 4.63; willing to stock
5.32 and dispense 5.37 naloxone with a prescription)
– Willingness to provide syringes 4.63 or sharps disposal 4.65

48. Confidence related to PBN
Confidence scale (alpha=0.86)
1 (not confident) to 6 (extremely confident)
How confident are you that
you can:
1-not at all
confident
2 3 4 5
6-
extremely
confident
Mean
Identify signs and symptoms
of opioid overdose 7% 14% 25% 24% 21% 9% 3.65
Proactively identify
individuals who may be at
risk for opioid overdose and
would benefit from a
naloxone prescription
10% 14% 23% 26% 18% 9% 3.55
Educate patients to
recognize opioid overdose
and safely administer
naloxone when indicated
12% 19% 23% 21% 15% 9% 3.34

49. What are key barriers to PBN
(real, perceived)?
• 49%: Time to develop, implement, sustain program
• 38%: Knowledge regarding states’ laws and
regulations authorizing naloxone access
• 36%: Lack of training among pharmacy technician
staff to implement program
• 35%: Complications with billing and reimbursement
• 25%: Concerns about clientele that might frequent
the pharmacy if a program were in place

50. What are Attitudes about Naloxone, other
Pharmacy-Public Health Efforts?
Attitudes scale: injury prevention, prevention measures at pharmacy
(immunization, syringe access), naloxone provision (alpha=0.83; mean 5.15)
1 strongly disagree to 6 strongly agree
Pharmacists have a role to play in injury prevention, including overdose prevention 4.94
Pharmacists could have a significant public health impact by providing access to
syringes and needles for people who inject drugs 4.54
– Correlated with injury prevention role perception (rho=0.51), access to syringes
to prevent blood borne infections (rho=0.67)
Screening patients for immunizations is a waste of time 1.46
– Low, consistent correlation with other items (rho=0.21-0.38)
Do NOT perceive that overdose prevention encourages heroin use 1.90 or opioid misuse
2.26, is a waste of $/time 1.79, or sends message that misuse/heroin use is OK 2.25

51. Summary
• Nationally, pharmacist’s interest, willingness to stock and
provide naloxone are high
• Attitudes toward overdose prevention and naloxone align
with perceptions of pharmacist as preventing injury,
providers of other harm reduction supplies
• Naloxone dispensing experience is uncommon, infrequent
• Least confident in ability to proactively identify those at
risk/would benefit and to educate on naloxone use
– Clear policy/rubric for proactive offering of naloxone
– Trainings needed: pharmacy schools, online, in stores
• Experience with naloxone and discussing overdose
prevention needs practice
– Community based organizations, harm reduction groups can help

52. Acknowledgements
Thank you!
APhA
Nickolas Zaller
Patricia Freeman
Thomas Stopka
Suzanne Nielsen
Jefrey Bratberg
Peter Friedmann
Hudson Breaud

53. Drugs to Watch: Tramadol,
Hydrocodone and Naloxone
Presenters:
• Nathan Painter, PharmD, Associate Clinical Professor, University of California San
Diego Skaggs School of Pharmacy and Pharmaceutical Science
• Roneet Lev, MD, Director of Operations, Scripps Mercy Hospital Emergency
Department, and Chair, San Diego County (CA) Rx Drug Abuse Medical Task Force
• Traci Green, PhD, MSC, Deputy Director, Boston Medical Center Injury Prevention
Center, and Associate Professor of Emergency Medicine, Boston University
Pharmacy Track
Moderator: Anne L. Burns, RPh, Vice President, Professional Affairs,
American Pharmacists Association, & Member, Rx & Heroin Summit
National Advisory Board