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Know Pain, Know Gain
Pain Management
Preconference Speakers:
Dr. Cara Brock
Dr. Chris Herndon
Dr. Ayesha Khan
Dr. Lalita Prasad-Reddy
Moderator: Dr. Julie McGinley
Preconference Objectives
1. Describe the impact of acute and chronic pain on the public health of the US population.
2. Recommend opioid and non-opioid analgesics given a real or simulated case vignette.
3. Identify appropriate risk mitigation techniques when using opioids for chronic noncancer pain based on the Centers for Disease Control practice recommendations.
4. Recognize common adverse effects associated with chronic opioid use.
5. Explain the role of cannabis in the treatment of pain and associated disorders.
6. Review the signs of opioid use disorder and opioid overdose and discuss methods for addressing both.
Faculty
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Cara Brock
� Dr. Brock declares no conflicts of interest, real or apparent, and no financial
interests in any company, product, or service mentioned in this program,
including grants, employment, gifts, stock holdings and honoraria.
� Speaker contact information
Chris Herndon
� Dr. Herndon declares no conflicts of interest, real or apparent, and no
financial interests in any company, product, or service mentioned in this
program, including grants, employment, gifts, stock holdings and honoraria.
� Research support
� NIH # HHSN271201500056C
� SAMHSA # 1U79SM062499-01
� Speaker contact information
Ayesha Khan
� Dr. Khan declares no conflicts of interest, real or apparent, and no financial
interests in any company, product, or service mentioned in this program,
including grants, employment, gifts, stock holdings and honoraria.
� Speaker contact information
Lalita Prasad-Reddy
� Dr. Prasad-Reddy declares no conflicts of interest, real or apparent, and no
financial interests in any company, product, or service mentioned in this
program, including grants, employment, gifts, stock holdings and honoraria.
� Speaker contact information
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Session Overview
Time Topic Speaker(s)
1-1:30pm Pain 101: A Foundation for Pain Management Brock/Herndon
1:30-2pm This Won’t Hurt a Bit: Debating the CDC Pain Guidelines Brock/Herndon
2-2:30pm Adjuvant Analgesics and Co-Analgesics Prasad-Reddy
2:30-2:45pm Common Core Opioid Math Brock
2:45-3:00pm Break
3:00-3:30pm The Hard Truth: Opioid Adverse Effects Brock/Herndon
3:30-4pm Pharmacokinetic and Pharmacodynamic Considerations in Special Populations
Khan
4-4:30pm First Dance with Mary Jane: Medical Cannabis for Pain Brock/Herndon
4:30-4:45pm Drug Disposal and Takeback Programs Prasad-Reddy
4:45-5:15pm Opioid Use Disorder and Overdose Prevention/Treatment Herndon
5:15-5:45pm Q&A / Panel Panel
Pain 101: A Foundation
for Pain ManagementCara Brock, PharmD, BCGP
Roosevelt University
Chris Herndon, PharmD
Southern Illinois University Edwardsville
At the conclusion of the program, the pharmacists will be able to:
1. Review the incidence and prevalence of acute and chronic pain and
describe commonly encountered pain syndromes
2. Describe the taxonomy and classification of pain
Pharmacist Objectives
At the conclusion of this program, the pharmacy technician will be able
to:
1. Review the incidence and prevalence of acute and chronic pain and
describe commonly encountered pain syndromes
2. Describe the taxonomy and classification of pain
Pharmacy Technician Objectives
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Definition of pain
“An unpleasant sensory and emotional
experience associated with actual
or potential tissue damage”
International Association for the Study of Pain (IASP)
“whatever the experiencing person says it is, existing
whenever the experiencing person says it does”
(McCaffery)
International Association for the Study of Pain. Terminology. Accessed at: http://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698
McCaffery, M. (1968). Nursing practice theories related to cognition, bodily pain, and man- environment interactions. Los Angeles: University of California at Los Angeles Students’ Store.
Relief from pain is a human right
Von Korff M, Scher AI, Helmick C et al. United States National Pain Strategy for Population Research: Concepts,
Definitions, and Pilot Data. J Pain. 2016; 17(10):1068-80.
AK
HI
Weighing risk versus benefit
Centers for Disease Control. Injury prevention and control: Opioid Overdose. https//www.cdc.gov/drugoverdose/data/analysis.html. Accessed 7 February 2017.
Components of pain
Loeser JD, Ford WE. Chronic Pain. In: Carr JE, Dengerink HA, (eds). Behavioral Science in the Practice of Medicine. New York: Elsevier Biomedical:1983:331-345.
Pain Behavior
Pain Behavior
SufferingSuffering
PainPain
NociceptionNociception
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Potential barriers to effective pain
management
Provider Patient System
Knowledge
Poor assessment
Regulatory scrutiny
Fear of addiction
Concern of SE
Concern of tolerance
Reluctance to report
Low priority on list
Fear of what pain means
“Good patient” desire
Fear of addiction
Adherence
Funding priority
Low reimbursement
Insurance & cost
Regulatory issues
Availability & access
Pain Taxonomy
Term Description / Definition
Acute pain Expected physiologic experience to noxious stimuli. May become
pathologic. Normally sudden in onset, time limited, and motivates
avoidance behavior to avoid actual or potential tissue damage.
Chronic pain Occurs on at least half the days for six months or greater. May also be
described as pain that has outlived its protective usefulness.
High impact
pain
Pain resulting in substantial restriction of participation in work, social,
and self-care activities for six months or greater.
Integrative
pain care
Incorporates complementary approaches into the pain treatment plan.
Intractable pain
Pain not relieved by appropriate treatment.
Multimodal
pain
treatment
Addresses the full range of the patient’s biopsychosocial challenges with
multiple and different therapies including medical, surgical,
psychological, behavioral, and integrative.
International Association for the Study of Pain. Terminology. Available at: http://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698 Accessed June 16, 2018
National Pain Strategy: A Comprehensive Population Health-Klevel Strategy for Pain. Available at
https://iprcc.nih.gov/sites/default/files/HHSNational_Pain_Strategy_508C.pdf Accessed June 16, 2018.
Nociceptive Physiology Excitatory Presynaptic Potentials
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• Nociceptive nerve fibers are triggered/depolarized by noxious stimuli
Transduction
• Action potential along primary afferent neuron
Conduction
• Activation of postsynaptic receptors via presynaptic pro-nociceptive substances
Transmission
• Impact of descending inhibitory neurons
Modulation
• Emotional response, cognition, discreet sensory localization
Perception
5 Phases of Nociception Commonly Encountered Chronic Pain
Syndromes
� Chronic low back pain
� Nonspecific
� Osteoarthritis
� Hand
� Knee
� Hip
� Neurogenically-mediated pain
� Diabetic peripheral neuropathy
� Post herpetic neuralgia
� Phantom limb pain
� Central post-stroke pain
� Radicular low back pain
� Centrally-mediated pain
� Complex Regional Pain Syndrome
� Fibromyalgia
� Opioid induced hyperalgesia
� Inflammatory-mediated pain
� Rheumatoid arthritis
� Ankylosing spondylitis
� Psoriatic arthritis
� Systemic Lupus Erythematosus
Avoid opioids in Fibromyalgia syndrome and
Opioid Induced Hyperalgesia
Meet Richard
� 56 years old
� PMH
� Chronic low back pain (CLBP)
� Hypertension
� Generalized anxiety disorder (GAD)
� Bipolar Type 2
� Medications
� Morphine ER 30 mg 1 tab every 12 hours
� Lisinopril/HCTZ 20/25 mg 1 tab every morning
� Alprazolam 0.5 mg 1 tab every 8 hours
� Sertraline 100mg 1 tab every morning
� Lithium 300mg 1 cap every 8 hours
� SHx:
� Tobacco (+) (1 pack/day)
� Alcohol (-) denies
� Denies recreational drugs
� Consistently presents to your pharmacy requesting
early refills on morphine prescription
� Has been to the ED several times in the last 4-5
months for uncontrolled pain, received opioid Rx
� He states “the morphine just doesn’t work as well
as it used to”
� He has tried tramadol and cyclobenzaprine
previously without any relief
� His father also has CLBP and has been using opioids,
muscle relaxants, and benzodiazepines & past
history of alcohol abuse
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Questions for Richard? Additional Resources
� Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. MMWR Recomm Rep 2016;65(No. RR-1):1–49. DOI: http://dx.doi.org/10.15585/mmwr.rr6501e1
� APhA Opioid Use, Abuse, and Misuse Resource Center, www.pharmacist.com/opioid-use-abuse-and-misuse-resource-center
� National Pain Strategy, Interagency Pain Research Coordinating Committee, National Institutes of Health, https://iprcc.nih.gov/National_Pain_Strategy/NPS_Main.htm
� NIH Pain Consortium Centers of Excellence in Pain Education, https://painconsortium.nih.gov/nih_pain_programs/coepes.html
� Prescription Drug Monitoring Programs: A Guide for Healthcare Providers, Substance Abuse and Mental Health Services Administration, www.store.samhsa.gov
� Hooten WM, Timming R, Belgrade M, Gaul J, Goertz M, Haake B, Myers C, Noonan MP, Owens J, Saeger L, Schweim K, Shteyman G, Walker N. Institute for Clinical Systems Improvement. Assessment and Management of Chronic Pain. Updated November 2013.
Additional Resources (continued)
� Substance Abuse and Mental Health Services Administration. Managing Chronic Pain in Adults With or
in Recovery From Substance Use Disorders. Treatment Improvement Protocol (TIP) Series 54. HHS
Publication No. (SMA) 12-4671. Rockville, MD: Substance Abuse and Mental Health Services
Administration, 2011.
� U.S. Department of Health and Human Services (HHS), Office of the Surgeon General, Facing
Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health. Washington, DC:
HHS, November 2016.
� Chou R, et al. Guidelines for the management of postoperative pain. J Pain 2016;17(2):131-157.
http://dx.doi.org/10.1016/j.jpain.2015.12.008
� www.prescribetoprevent.org
� Opioid Use Disorders: Interventions for Community Pharmacists, College of Psychiatric and
Neurologic Pharmacists, URL: https://cpnp.org/_sdocs/guideline/opioid/opioid-intervention.pdf
This Won’t Hurt a Bit:
Debating the CDC Pain
Guidelines
Cara Brock, PharmD, BCGP
Roosevelt University
Chris Herndon, PharmD
Southern Illinois University Edwardsville
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1. Review clinical guidelines and evidence findings regarding chronic opioid
therapy in chronic pain management.
2. Apply the CDC guidelines for prescribing opioids for chronic pain to health-
system pharmacy practice.
3. Discuss strategies that enhance safe use of chronic opioid therapy in chronic
pain management.
Pharmacist Objectives
1. Review clinical guidelines and evidence findings regarding chronic opioid
therapy in chronic pain management.
2. Apply the CDC guidelines for prescribing opioids for chronic pain to health-
system pharmacy practice.
3. Discuss strategies that enhance safe use of chronic opioid therapy in chronic
pain management.
Pharmacy Technician Objectives
Back to RichardRichard rates his pain as follows:
Now – 8/10
Least – 5/10
Average – 7/10
Worst – 9/10
Relief from current modalities: ~20%
Descriptors: aching, shooting, radiating,
stabbing, burning (in legs)
It’s common sense, folks
Centers for Disease Control and Prevention. Annual Surveillance Report of Drug-Related Risks and Outcomes — United States,2017. Surveillance 1. Centers for Disease Control
and Prevention, U.S.Department of Health and Human Services. Published August 31,2017. Accessed Sept 5, 2017 from https://www.cdc.gov/drugoverdose/pdf/pubs/2017-
cdc-drug-surveillance-report. pdf
Incidence of opioid-related overdose deaths
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0
200
400
600
800
1000
1200
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
MME/Rx
0
2
4
6
8
10
12
14
16
18
20
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Days Supply
Making progress…Changes in prescribing
Centers for Disease Control and Prevention. Annual Surveillance Report of Drug-Related Risks and Outcomes — United States,2017. Surveillance 1. Centers for Disease
Control and Prevention, U.S.Department of Health and Human Services. Published August 31,2017. Accessed Sept 5, 2017 from
https://www.cdc.gov/drugoverdose/pdf/pubs/2017-cdc-drug-surveillance-report. pdf
0
10
20
30
40
50
60
70
80
90
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
All opioids
0
10
20
30
40
50
60
70
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
MME
0
100
200
300
400
500
600
700
800
900
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
MME/Capita
0
2
4
6
8
10
12
14
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
High dosage
CDC Recommendations In a Nutshell:1. Nonpharmacologic and non-opioid modalities preferred
2. Establish realistic treatment goals
3. Discuss known risks and realistic benefits
4. Immediate-release opioids preferred
5. Use lowest dose possible (50 mg and 90 mg MEDD thresholds)
6. Use for shortest duration possible (3 days and 7 days)
7. Evaluate benefits and harms regularly
8. Assess risk and offer naloxone (50 mg or concurrent benzodiazepine)
9. Prescription drug monitoring program use
10. Urine drug screen use
11. No benzodiazepines
12. Use medication-assisted therapy
Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. MMWR Recomm Rep 2016;65:1–49. DOI:
http://dx.doi.org/10.15585/mmwr.rr6501e1
IR vs. ER (Emergency Room)
Opioid Dose Level IR (PRN) % ER (time-contingent) % Significance
< 20 mg / day
20 to < 50 mg / day
50 to < 120 mg / day
120+mg / day
46.3
36.5
12.1
5.2
18.2
32.6
29.0
20.3 P < .0001
Average pain severity 5.9 5.8 P = .43
Von Korff M, et al. Pain. 2011;152:1256-1262.
� Use caution at any dose
� Use additional precautions with � 50 mg MEDD
� Avoid increasing dose � 90 mg MEDD
� The issues:
� Cutoffs are inconsistent with FDA approved therapeutic dosing
� Cutoffs are not supported by evidence
� Does not take in to account difference between opioids
CDC MEDD Recommendations
Stanton, M. and McClughen, D.C., 2017. The CDC Guideline and its Impact on Delivering Patient-Centered Care.
Wegrzyn, E.L., Chaghtai, A.M., Argoff, C.E. and Fudin, J., 2018. The CDC Opioid Guideline: proponent interpretation has led to misinformation. Clinical Pharmacology
& Therapeutics, 103(6), pp.950-953.
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The higher the dose…
11.88
4.63
7.18
0
2
4
6
8
1 < 20mg 20 < 50mg 50 < 100mg > 100mg
Death, HR
Bohnert AS, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA 2011;305(13):1315-1321.
Haza
rd R
ati
o
The longer the duration…
Shah A, Hayes CJ, Martin BC. Characteristics of Initial Prescription Episodes and Likelihood of Long-Term Opioid Use — United States, 2006–2015. MMWR Morb
Mortal Wkly Rep 2017;66:265–269. DOI: http://dx.doi.org/10.15585/mmwr.mm6610a1
� Intent vs. Application
� Voluntary vs. Standard of Practice
� Production limits
� Palliative
� Cancer
� Hospice
� 2/3 of pain patients reported reduced or stopped prescribing of
opioids
� CMS changing DUR criteria & formulary restrictions
� Implementation of non-patient centered policy
Impact of New CDC Recommendations
Anson, P. (2016). 5 Myths About the CDC Opioid Guidelines. Retrieved from. https://www.painnewsnetwork.org/ stories/2016/8/15/5-myths-about-the-cdc-opioid-guidelines.
Stanton, M. and McClughen, D.C., 2017. The CDC Guideline and its Impact on Delivering Patient-Centered Care.
Anson, P. (2016). Tennessee Pain Clinics to Stop Using Opioids. Retrieved from. https://www.painnewsnetwork.org/ stories/2016/4/27/tennessee-pain-clinics-to-stop-using-opioids.Wegrzyn, E.L., Chaghtai, A.M., Argoff, C.E. and Fudin, J., 2018. The CDC Opioid Guideline: proponent interpretation has led to misinformation. Clinical Pharmacology &
Therapeutics, 103(6), pp.950-953.
� IL Department of Public Health: Opioid Action Plan (Sept 2017)
1. Increase PMP use by prescribers
2. Reduce high-risk opioid prescribing through education & prescribing
guidelines
3. Increase accessibility of information and resources
4. Increase the impact of prevention programming
5. Strengthen data collection, analysis, and sharing
6. Increase access to care for individuals with opioid use disorder
7. Increase the capacity of deflection and diversion programs
8. Increase number of first responders and community members who
have access to and are trained to administer naloxone
IL Opioid Action Plan
IL Department of Public Health: State of Illinois Opioid Action Plan. Accessible at: http://dph.illinois.gov/sites/default/files/publications/Illinois-Opioid-Action-
Plan-Sept-6-2017-FINAL.pdf Accessed July 28, 2018.
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The Brushwood VIGIL System:A Proposed System for Community Pharmacists
Strickland JM, et al. Pharmacist-physician collaboration in pain management practice. J Opioid Manag 2007;3(6):295-301.
Tanzi MG. VIGIL helps pharmacists screen controlled substances. Pharmacy Today 2012;18(9):58.
Brushwood DB. Screening controlled substance prescriptions for legitimacy: The VIGIL system. Platform presentation at the 2010 Eastern Medicaid Pharmacy
Administrators Assocation Meeting. URL: http://www.empaa.org/downloads/EMPAA2010/presentation/BrushwoodDavid_VIGIL_EMPAA2010.pdf. Accessed 7
Feb 2017.
Red Flags Points
Male between ages of 16 – 45 years +2
Immediate family member also uses opioids +2
Not legal resident of this country +2
Opioid prescription from emergency department within past 6
months
+2
Opioid & benzodiazepine concurrently +4
Lost or stolen meds more than once in the past year +3
More than 20% too early, more than once in the past 6 months +2
More than 2 prescribers of opioids in the past 6 months +2
The Brushwood VIGIL Systema proposed system for community pharmacists
Strickland JM, et al. Pharmacist-physician collaboration in pain management practice. J Opioid Manag 2007;3(6):295-301.
Tanzi MG. VIGIL helps pharmacists screen controlled substances. Pharmacy Today 2012;18(9):58.
Brushwood DB. Screening controlled substance prescriptions for legitimacy: The VIGIL system. Platform presentation at the 2010 Eastern Medicaid Pharmacy
Administrators Assocation Meeting. URL: http://www.empaa.org/downloads/EMPAA2010/presentation/BrushwoodDavid_VIGIL_EMPAA2010.pdf. Accessed 7
Feb 2017.
Modified Risk Assessment Using VIGIL
Score Risk Care Level Approach
0-4 Low Standard Verify Rx, ID patient
5-9 Moderate Special Limit to 7 day supply,
communicate with
prescriber
10+ High Extra Communicate with
prescriber, hold Rx
until legitimate
medical purpose
verified
Unacceptable
risk
None Medication denied
Strickland JM, et al. Pharmacist-physician collaboration in pain management practice. J Opioid Manag 2007;3(6):295-301.
Tanzi MG. VIGIL helps pharmacists screen controlled substances. Pharmacy Today 2012;18(9):58.
Brushwood DB. Screening controlled substance prescriptions for legitimacy: The VIGIL system. Platform presentation at the 2010 Eastern Medicaid Pharmacy
Administrators Assocation Meeting. URL: http://www.empaa.org/downloads/EMPAA2010/presentation/BrushwoodDavid_VIGIL_EMPAA2010.pdf. Accessed 7
Feb 2017.
Red Flags Points
Male Age 56 +2
Immediate family member uses opioids (father) +2
Not legal resident +2
Emergency opioid Rx in the last 6 mos +2
Opioid + benzo + muscle relaxer +4
Lost/Stolen Rx more than once in the last year +2
More than 20% too early, more than once in past 6 months
+2
More than 2 prescribers of opioids in the last 6 months (ED)
+2
Red Flags Points
Non-problematic PDMP Report (early refills) -2
Written med agreement -2
Regular Rx from licensed mental health professional -2
At least one non-CS monthly x 6 mos -3
Willing to accept generics -2
Uses insurance only -2
Total 1
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Now that you know what the CDC
recommendations are, let’s talk about
how Richard fits into the CDC picture…
Additional Resources
� Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. MMWR Recomm Rep 2016;65(No. RR-1):1–49. DOI: http://dx.doi.org/10.15585/mmwr.rr6501e1
� APhA Opioid Use, Abuse, and Misuse Resource Center, www.pharmacist.com/opioid-use-abuse-and-misuse-resource-center
� National Pain Strategy, Interagency Pain Research Coordinating Committee, National Institutes of Health, https://iprcc.nih.gov/National_Pain_Strategy/NPS_Main.htm
� NIH Pain Consortium Centers of Excellence in Pain Education, https://painconsortium.nih.gov/nih_pain_programs/coepes.html
� Prescription Drug Monitoring Programs: A Guide for Healthcare Providers, Substance Abuse and Mental Health Services Administration, www.store.samhsa.gov
� Hooten WM, Timming R, Belgrade M, Gaul J, Goertz M, Haake B, Myers C, Noonan MP, Owens J, Saeger L, Schweim K, Shteyman G, Walker N. Institute for Clinical Systems Improvement. Assessment and Management of Chronic Pain. Updated November 2013.
Additional Resources (continued)
� Substance Abuse and Mental Health Services Administration. Managing Chronic Pain in Adults With or in Recovery From Substance Use Disorders. Treatment Improvement Protocol (TIP) Series 54. HHS Publication No. (SMA) 12-4671. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2011.
� U.S. Department of Health and Human Services (HHS), Office of the Surgeon General, Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health. Washington, DC: HHS, November 2016.
� Chou R, et al. Guidelines for the management of postoperative pain. J Pain 2016;17(2):131-157. http://dx.doi.org/10.1016/j.jpain.2015.12.008
� www.prescribetoprevent.org
� Opioid Use Disorders: Interventions for Community Pharmacists, College of Psychiatric and Neurologic Pharmacists, URL: https://cpnp.org/_sdocs/guideline/opioid/opioid-intervention.pdf
� Illinois Opioid Action Plan http://www.dph.illinois.gov/opioids/ilplan
� Illinois Opioid Crisis Response Advisory Council http://www.dhs.state.il.us/page.aspx?item=97186
Adjuvant Analgesics
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Pharmacist Objectives
1. Compare and contrast multimodal pain management strategies for common acute
and chronic pain conditions
2. Choose an adjuvant analgesic for a given patient, based on current guidelines and
/or evidence-based medicine
1. Compare and contrast multimodal pain management strategies for common
acute and chronic pain conditions
2. Choose an adjuvant analgesic for a given patient, based on current
guidelines and /or evidence-based medicine
Technician Objectives
Types of Nociceptive Pain
Somatic Pain Visceral Pain
Pain arising from skin, bone, joint, muscle,
connective tissuePain arising from internal organs
Typically presents as throbbing & well localized
Manifests as a “pain feeling” coming from other
structures (referred pain), or can be a localized
phenomenon
Tylenol, Opioids, NSAIDS Weak and strong opioids
Nicholson, B. Am J Manag Care. 2006;12:S256-S262
World Health Organization Analgesic Ladder
� Originally developed for the treatment of
cancer pain
� Stepwise approach to the treatment of pain
� “Administering the right drug at the right
time”
� 90% effective
http://www.who.int/cancer/palliative/painladder/en/
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Acetaminophen (APAP)
� Often considered drug of choice for mild - moderate pain
� Safety, efficacy, low incidence of adverse effects
� Mechanism of action
� Acts centrally to inhibit prostaglandin synthesis
� Does not provide anti-inflammatory effect
� Adverse Effects
� Considered one of the safest analgesics
� Hepatotoxicity
� Nephrotoxicity
Ennis et al. Basic & Clinical Pharmacology & Toxicology.2016;118:184–189
Acetaminophen and Liver Toxicity
� Mild increases in hepatic enzymes can be present at all doses of APAP
�Monitor liver function tests “periodically”
� At larger doses dizziness, excitement, disorientation may occur
� Severe hepatotoxicity (> 10 – 15 grams)
�Results in acute liver failure and often fatal
�Nausea, vomiting, diarrhea, abdominal pain
Lancaster et al. Arch Toxicol. 2015; 89:193–199
Acetaminophen Dosing
Patient Population Usual Dose Daily Maximum
Adult patients (Rx use) 325 – 650 mg q 4-6 hours 4 grams daily
Adult patients (OTC Use) 325 – 500 mg q 4 – 6
hours prn
3,250 mg daily
Hepatic Disease/Chronic
ETOH use
325-650 mg q 4-6 hours 2 grams daily
https://www.tylenol.com/safety-dosing/usage/dosage-for-adults
Nonsteroidal Antiinflammatory Drugs
(NSAIDS)
�Utilized in patients when APAP is ineffective
�Superior pain control when compared to APAP
�Mechanism of action
�Blocks prostaglandin synthesis by inhibiting cyclooxygenase enzymes (COX-1 & COX-2)
�Results in a decrease in prostaglandin synthesis
�Results in decreased pain sensations
Wongrakpanich et al. . Aging Dis. 2018 Feb; 9(1): 143–150.
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Pharmacological Effects of NSAIDS
� Analgesic (CNS and peripheral effect) may involve non-PG related effects
� Antipyretic (CNS effect)
� Anti-inflammatory (except acetaminophen) due mainly to PG inhibition.
� Some shown to inhibit activation, aggregation, adhesion of neutrophils & release of
lysosomal enzymes
� Some are Uricosuric
Zaeri, S. NSAIDS. Adapted from https://slideplayer.com/slide/10939925/.
NSAID Therapeutic Effects
Antithrombotic
(aspirin only)
Antipyretic,
Analgesic
Anti-inflammatory
0 1 2 3 4 5
Daily Dose of Aspirin
Zaeri, S. NSAIDS. Adapted from https://slideplayer.com/slide/10939925/.
COX – 1 ENZYME
Production of gastro-protective prostaglandins
Prostaglandins & thromboxane also participate in hemostasis &
renal blood flow
Expressed in gastric mucosa, vascular endothelial cells,
platelets, & renal collecting tubules
Constitutive - expressed everywhere
COX – 2 ENZYME
Production of prostaglandins that contribute to pain
sensation
Rapidly induced by inflammatory mediators
Production of prostacylin with a role in hemostasis, renal
blood flow, and reproduction
Inducible with inflammation
Wongrakpanich et al. . Aging Dis. 2018 Feb; 9(1): 143–150.
Membrane Phospholipids Arachidonic Acid
COX – 1 (Homeostatic)
COX – 2
(Inducible)
Prostaglandins
Thromboxane
Gastroprotection
Platelet aggregation
Renal function
Prostaglandins
Pain
Fever
Renal function
Tissue repair
Other???
Nonselective NSAIDS
Wongrakpanich et al. . Aging Dis. 2018 Feb; 9(1): 143–150.
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Membrane
Phospholipids
COX – 1 (Homeostatic)
COX – 2
(Inducible)
Prostaglandins
Thromboxane
Gastroprotection
Platelet aggregationRenal function
Prostaglandins
Pain
Fever
Renal function
Tissue repair
Other???
COX-2 Inhibitors
Wongrakpanich et al. . Aging Dis. 2018 Feb; 9(1): 143–150.
Nonspecific NSAIDS
& COX-2 Selective Inhibitors
Nonspecific NSAIDS
� Block COX-1 & COX-2
� Potential results
� GI ulcers
� ↑ bleeding risk
� Renal vasoconstriction
COX-2 Selective Inhibitors
� Block COX-2 ONLY
� Decreases inflammation
without blocking effects of
COX-1
� GI protective
� Decreases production of
prostacyclin
Wongrakpanich et al. . Aging Dis. 2018 Feb; 9(1): 143–150.
NSAID Dosing
Medication Dosage & Frequency MAX Dosage (mg/day)
Diclofenac 100-150 mg/day in divided doses 200
Indomethacin 25 mg 2-3 times/day; 75 mg SR once daily 200; 150
Nabumetone 500-1000 mg 1-2 times/day 2000
IBU 1200-3200 mg.day in 3-4 divided doses 3200
Naproxen 250-500 mg BID 1500
Oxaprozin 600-1200 mg daily 1800
Meloxicam 7.5 mg daily 15
Celecoxib 100 mg BID or 200 mg daily 200 (400 for RA)https://www.ncbi.nlm.nih.gov/books/NBK65641/
NSAID Adverse Effects
� Central nervous
system effects
� Exacerbations of
asthma
� Hypersensitivity
reactions
� Fluid retention
� Hypertension
� Drug-induced hepatitis
� Acute kidney injury
� Bleeding
� Irreversible with
aspirin
�Reversible with
nonspecific NSAIDS
Dipiro et al. Pharmacotherapy: A Pathophysiological Approach. 10th Edition.
9/25/2018
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Gastrointestinal Adverse Effects
� Can occur with any NSAID agent
MILD SEVERE
Nausea GI-Bleeding
Dyspepsia Perforations
Anorexia
Gastric outlet obstructionAbdominal pain
Flatulence
Diarrhea
Wongrakpanich et al. . Aging Dis. 2018 Feb; 9(1): 143–150.
Pro-thrombotic Imbalance with COX-2
COX-1↓
Prostaglandin I2(prostacyclin)
↓
Antithrombic
COX-2
↓
thromboxane
A2
↓
Prothrombic
Thromboxane A2 > Prostacyclin
• Potential increase in prothrombic events
• Unknown association with increased risk of CV
events in COX-2 inhibitors
Ong et al. Clinical Medicine and Research. 2007;5(1):19-34..
Types of Neuropathic pain
Neuropathic Pain Functional Pain
Result of nerve damage Abnormal operations of the nervous system
Postherpetic neuralgia, diabetic neuropathy
Fibromyalgia, irritable bowel syndrome,
sympathetic-induced pain, tension headaches,
non-cardiac chest pain
Antidepressants, anticonvulsants, capsaicin Everything!
• Nerve damage evokes changes in sensory transmission, nerve structure
reorganization, and loss of modulatory pain inhibition
• Pain circuits rewire themselves both anatomically and biochemically
• Mismatch between stimulation & inhibition results in an increase in the
discharge of neurons
http://www.iasp-pain.org/Taxonomy; http://www.slideshare.net/Painspecialist/understanding-pain-short
Definition of Neuropathic Pain
� “Pain caused by a lesion or disease of the peripheral or central
nervous system or damage to or dysfunction of nerve pathways”
� Typically resistant to conventional methods of pain management
http://www.iasp-pain.org/Taxonomy; http://www.slideshare.net/Painspecialist/understanding-pain-short
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Symptoms and Signs of Neuropathic Pain
Hyperalgesia- abnormally heightened sensitivity to pain
Allodynia
Paresthesia
Dysesthesias
Sensory deficits
Weakness
Reflex changes
Dysesthesia
Numbness
Imbalance
http://casemed.case.edu/clerkships/neurology/NeurLrngObjectives/PN.htm
Clinical Presentation
Signs/SymptomsSigns/Symptoms
• Unusual burning, tingling, electric shock, numbness, shooting
• Sensory deficit is characteristically present in the area of the patient’s pain
• Sensitiveness to cold or heat
• Minor stimuli � pain
• Worse at night
• Guarding/protecting extremities
Diagnostic TestsDiagnostic Tests
• Sudomotor changes – autonomic nerves that stimulate the sweat glands
• Neurologic deficits
• Allodynia
• Hyperalgesia
• Labs – evaluate underlying abnormalities
• EMG – electromyogram – records electrical activity of the muscles – measures response of muscle to nervous stimulation
http://neuropathology-web.org/chapter12/chapter12Neuropathy.html
Approach To Treatment
First Line Options
• TCA’s
• SNRI’s
• Gabapentin
• Pregabalin
Second Line Options
• Capsaicin
• Tramadol
• Lidocaine
Last Line Options
• Botulism
• Opioids
https://www.apsoc.org.au/PDF/Publications/Veterans_MATES_35_Neuropathic_Pain_TherBrief_JUN13.pdf
TCA – Adverse Effects and Precautions � Indications (not necessarily FDA approved)
� Diabetic neuropathy, post herpetic neuralgia, peripheral nerve injury, radiculopathy,
spinal cord injury pain, MS
� Considerations
� Tertiary TCA slightly more efficacious, but have more side effects
� Doses for PN treatment are lower than for management of depression
� Therapeutic effects occur sooner than for depression
� Adverse effects
� Sedation,, cardiac, weight gain, urinary retention, constipation,
orthostatic hypotension
� Caution in elderly and patients with cardiovascular riskMOA Comments
Tertiary TCA Imipramine Inhibit norepinephrine &
serotonin reuptake
• Maximum of 75 mg/day in > 65
y/o
• More effective than secondary
agents
Amitriptyline
Clomipramine
Secondary TCA Nortriptyline Inhibit norepinephrine
reuptake
• Typically first agents initiated
• Side effects less commonDesipramineBerget et al. Clin J Pain. 2007 Mar-Apr;23(3):251-8.
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Serotonin-Norephinephrine Reuptake Inhibitors
� Strong evidence that most SNRI’s have analgesic effects
� Duloxetine (Cymbalta®), Venlafaxine (Effexor®), Milnacaprin (Savella®), Desvenlafaxine (Pristiq®)
� Favorable side effect profile when compared to TCAs
� Considerations
� ADE: nausea, anorexia, constipation, dry mouth, HTN, insomnia
� Duloxetine Dosing
� Starting dose: 30 mg/day
� Titration: 30 mg weekly
� Target: 60-120 mg daily
Lee et al. Expert Opin Pharmacother. 2010 Dec;11(17):2813-25.
Anticonvulsants for Neuropathic Pain
Gabapentin (Neurontin®) Pregabalin (Lyrica®)
Indications Post herpetic neuralgia Neuropathic pain, Spinal Cord Injury, Diabetic Peripheral
Neuropathy, Post herpetic Neuralgia
Mechanism of action
Acts on supra-spinal region to stimulate noradrenaline mediated descending
inhibition, which contributes to its anti-
hypersensitivity action in neuropathic
pain
Inhibition of voltage gated Ca2+ channel which contributes to the reduction of excitatory neurotransmitters release and inhibition of
synaptic transmission
Dose 100 – 300 mg daily titrated to maximum
of 3600 mg daily in divided doses (doses >
1200 mg daily for effectiveness)
25 – 100 mg daily titrated to total dose of 600 mg daily in divided
doses
Side effects Sedation, weight gain, somnolence Sedation, dizziness, weight gain, blurred vision, edema, ataxia (all
dose dependent)
Comments • Elderly appear to be a higher risk of
adverse effects
• Not as effective in management of
pain
• Generally deemed more effective than Neurontin ®
• Useful in allydonia and hyperalgesia
• Exists dose dependent effects in attenuating pain
• Concerns with euphoria, abuse and dependence
https://www.cochrane.org/CD010567/SYMPT_antiepileptic-drugs-treat-neuropathic-pain-or-fibromyalgia-overview-cochrane-reviews
Capsaicin
� Extract of red pepper
� Depletes substance P from nociceptive nerve fibers
� Attenuate cutaneous hypersensitivity and reduce pain through ‘defunctionalization’ of
nociceptor fibers
� Useful for neuropathic, functional, and somatic pain
� Efficacy is dependent on use
� Should be applied to the affected area 2-4 times/day
� Takes several weeks for maximum effect
Anand et al. Br J Anaesth. 2011 Oct; 107(4): 490–502.
Which Opioids Would Be the Best
Options to Initiate in a Patient
With Neuropathic Pain Complaints?
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Tramadol Methadone
Analgesic with affinity for the µ-opioid receptor Analgesic with affinity for the µ-opioid receptor
Weak norepinephrine and serotonin
neurotransmitter inhibitor
Methadone has nonopioid actions, including
inhibition of the reuptake of monoamines (e.g.,
serotonin, norepinephrine) and inhibition of N-
methyl-D-aspartate (NMDA) receptors—
pharmacologic actions that result in additional
analgesia
Initiate at low dose 100 mg daily and titrate to
200 mg daily
2.5 mg q 8 hours (based upon patient and use
of opiods – Dosing is difficult due to
pharmacokinetic properties
Opioid-like adverse effects: Nausea, vomiting,
dizziness, constipation, headache, and
somnolence, seizures
Opioid adverse effects: Nausea, vomiting,
dizziness, constipation, headache, and
somnolence, respiratory depression
Opioids for Neuropathic Pain
Dipiro et al. Pharmacotherapy: A Pathophysiological Approach. 10th Edition.
Common Core Opioid Math
Cara Brock, PharmD, BCGP
Roosevelt University
1. Compare common opioid analgesics in terms of equianalgesic potency.
Pharmacist Objective
1. Compare common opioid analgesics in terms of equianalgesic potency.
Pharmacy Technician Objective
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� Lack of response
� Adverse effects
� Change in patient status
� Opioid rotation
� Cost/formulary changes
Reasons to Change Opioids
McPherson, ML. Demystifying opioid conversion calculations: a guide for effective dosing. Bethesda, MD: American Society of Health-System Pharmacists.
� Opioid responsiveness
� Acceptable level of analgesia
� Intolerable adverse effects
� Potency
� PK/PD
� Equipotency
� Equianalgesic
� Dosage forms
� Opioids
� Bioavailability
� Cross tolerance
� Total daily dose (TDD)
� Morphine equivalent daily dose (MEDD)
Opioid Conversion Vocabulary
McPherson, ML. Demystifying opioid conversion calculations: a guide for effective dosing. Bethesda, MD: American Society of Health-System Pharmacists.
Equianalgesic Doses (mg)
Drug Parenteral Oral
Morphine 10 30
Buprenorphine 0.3 0.4
Codeine 100 200
Fentanyl 0.1 NA
Hydrocodone NA 30
Hydromorphone 1.5 7.5
Meperidine 100 300
Oxycodone NA 20
Oxymorphone 1 10
Tramadol NA 120
Table adapted with permission from McPherson, Mary Lynn M. 2010. Demystifying opioid conversion calculations: a guide for effective dosing. Bethesda, MD:
American Society of Health-System Pharmacists.
Equianalgesic Dosing Conversion
G13Office [4]1Office [5]1
1. Assess pain
2. Determine total daily dose of current opioid
� Extended release
� Immediate release for breakthrough pain
3. Decide which opioid/dosage form to convert to
� Use table to convert
4. Individualize to patient
� Consider current pain
� Reduce for cross tolerance if switching opioid (lower by 25 – 50%)
� Ensure adequate access to breakthrough medication (10 – 15% of TDD)
5. Follow up and reassess
Conversion Steps
McPherson, ML. Demystifying opioid conversion calculations: a guide for effective dosing. Bethesda, MD: American Society of Health-System Pharmacists.
Slide 83
G13 Reference and permission needed.Gabby, 1/3/2017
Office [4]1 Reference addedMicrosoft Office User, 2/7/2017
Office [5]1 Permission requested (table adapted)Microsoft Office User, 2/7/2017
9/25/2018
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� Do not reduce for cross tolerance
� Fentanyl
� Methadone
� Unidirectional vs. Bidirectional conversion
� Fentanyl package insert
� Methadone
� Conversion is not linear
� Higher dose of opioid � Higher potency of methadone
� Many conversion factors
� Range from 3:1 – 20:1
� Phone a Phriend!
Exceptions to the Rule
Morphine Dose Recommended fentanyl dose
60 – 134 mg/d 25 mcg/h
135 – 224 mg/d 50 mcg/h
225 – 314 mg/d 75 mcg/h
315 – 404 mg/d 100 mcg/h
Duragesic package insert Janssen Pharmaceutica Products, L.P. Titusville, NJ 08560 2003
McPherson, ML. Demystifying opioid conversion calculations: a guide for effective dosing. Bethesda, MD: American Society of Health-System Pharmacists.
Simple Ratio
• Oral morphine : IV morphine = 30:10 = 3:1
• Divide or multiply by 3
Proportion Method 1
Xmg TDD Opioid B Equianalgesic factor Opioid B
---------------------- = ----------------------------------
TDD Opioid A Equianalgesic factor Opioid A
Proportion Method 2
Xmg TDD Opioid B Total mg TDD Opioid A
------------------------------------ = ----------------------------------
Equianalgesic factor Opioid B Equianalgesic factor Opioid A
Proportion Method 3
Equianalgesic factor Opioid B
mg TDD Opioid A x --------------------------------- = X mg TDD Opioid B
Equianalgesic factor Opioid A
Pharmacy Math Review
� Use your X to provide long acting opioid
� Around the clock IR, ER tablet, patch
� IV infusion (mg/hr)
� Provide short acting opioid for breakthrough pain
� IR tablet
� Offer 10 – 15% of new TDD q 1-2 hours
� IM/IV bolus
� Offer 10 – 15% of new TDD q 10 min
Conversion
McPherson, ML. Demystifying opioid conversion calculations: a guide for effective dosing. Bethesda, MD: American Society of Health-System Pharmacists.
Opioid (Cmax) Duration
Morphine IV Bolus 10 min 4 hours
Morphine IR PO 1 hour 4 hours
Oxycodone PO 1 hour 4 hours
Hydromorphone IV 10 min 4 hours
Hydromorphone PO 1 hour 4 hours
Back to Richard
Updated Medication List
Duloxetine 30 mg daily
Morphine ER 60 mg PO q12h
Morphine IR 10 mg PO q2h PRN (takes 6
doses/day)
Lisinopril/HCTZ 20/25 mg 1 tab every
morning
Alprazolam 0.5 mg 1 tab every 8 hours
Lithium 300 mg 1 cap every 8 hours
You know
you missed
me!
9/25/2018
23
Richard presents to the ED with
significant pain after playing basketball
with his sons. He needs an IV bolus dose
of morphine STAT!
First, we need to find his TDD of
morphine:
ER: 60 mg x 3 = 120 mg
IR: 10 mg x 5 = 60 mg
Total = 180 mg/d
� Convert PO to IV
� Morphine PO TDD = 180 mg/d
� Oral morphine 180 mg 30 mg oral morphine
------------------------- = ----------------------------
X mg IV morphine 10 mg IV morphine
� Solve for X to get equivalent TDD IV morphine
� 60 mg IV morphine TDD
� Dose for BTP = ~10-15% � 9 mg IV
� Would you round up?
Convert PO to IV
� Richard’s pain was controlled with a few boluses of morphine
in the ED and he was sent home. His morphine has been
adjusted by his physician to:
� Morphine ER 100 mg q12h
� Morphine IR 20 mg q2h prn for breakthrough pain (2 doses/day)
� His pain is controlled, but he has started to experience
intolerable ADR, you recommend a switch to oxycodone
� Calculate TDD:
� ER: 200 mg
� IR: 40 mg (20mg x 2 doses/day)
� Total: 240 mg TDD Morphine
Richard, Again� Morphine oral TDD = 240 mg/day
� Conversion:
� Morphine 30 mg oral = oxycodone 20 mg oral
� Math:
240 mg TDD morphine 30 mg oral morphine
--------------------------- = -----------------------------
X mg TDD oxycodone 20 mg oral oxycodone
� Cross multiply and solve for X
� 160 mg oral oxycodone/day
� Reduce for cross tolerance (-50%) = 80 mg oxycodone/day
� Provide IR for BTP: 8 – 12 mg
Let’s convert to oxycodone!
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The Hard Truth: Opioid
Adverse EffectsCara Brock, PharmD, BCGP
Roosevelt University
Chris Herndon, PharmD
Southern Illinois University Edwardsville
At the conclusion of the program, the pharmacists will be able to:
1. Compare current treatment options for the management of opioid-induced
constipation.
2. Evaluate patient cases and make clinical recommendations for patients with
opioid-induced constipation.
3. Recognize common adverse effects of opioids and provide
pharmacotherapeutic recommendations given a real or simulated patient
case.
Pharmacist Objectives
At the conclusion of this program, the pharmacy technician will be able to:
1. Compare current treatment options for the management of opioid-induced
constipation.
2. Evaluate patient cases and make clinical recommendations for patients with opioid-induced constipation.
3. Recognize common adverse effects of opioids and provide
pharmacotherapeutic recommendations given a real or simulated patient
case.
Pharmacy Technician Objectives Opioids� Mu-agonists
� Morphine, methadone, codeine, dihydrocodeine, hydrocodone, fentanyl, oxycodone, oxymorphone, levorphanol, hydromorphone, oxymorphone, diacetylmorphine
� Partial mu-agonists
� Buprenorphine
� Mixed agonist-antagonist (kappa agonist, mu antagonist)
� Nalbuphine, butorphanol, pentazocine
� Central (mu + NE / 5HT)
� Tramadol (5HT), tapentadol (NE)
� Peripheral agonists
� Loperamide, diphenoxylate
� Antagonists
� Naloxone, naltrexone, methylnaltrexone, alvimopan, naloxegol, naldemedine
NE: norepinephrine, 5HT: serotonin
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Adverse effects of opioids
Herndon. Exp Opin Pharm 2003.
LES: lower esophageal sphincter, ADH: antidiuretic hormone
Body System Adverse Effect
CNS Dependence, substance abuse, sedation,
psychotomimetic, vertigo, myoclonus,
resp. depression, neurocognitive
Gastrointestinal Constipation, nausea, spinchter of oddi
pressure changes, LES / cardiac spinchter
changes
Genito-urinary Urinary retention
Integumentary Flushing, urticaria, pruritus
Metabolic Stimulate ADH, prolactin, somatotropin,
loss of libido
Cardiovascular Hypotension and reflex tachycardia
Hepatic Rare
Renal Rare
Ocular Miosis
Immune Decrease in immune function with chronic
dosing
Opioid-induced pruritus - Incidence
Administration Route Incidence of Pruritus
Spinal / Epidural 30 – 100%
Intravenous 10 – 50%
Oral 2 – 20%
Gan TJ, et al. Anesthesiology 1997;87:1075-1081.
Woodhouse A, et al. Pain 1996;65:115-121.
Szarvas S, et al. J Clin Anesth 2003;15:234-239.
May be influenced by specific drug, dose, and condition (e.g., pregnancy)
Opioid Induced Pruritus
Which drugs cause mast cell activation?
• Yes• Morphine
• Codeine
• Meperidine
• No• Fentanyl
• Alfentanil
• Sufentanil
• Buprenorphine
Blunk JA, et al. Aneth Analg 2004;98:364-370.
� Hydroxyzine
� One study (n=40) in post-op epidural morphine
� Hydroxyzine > placebo (saline injection)
� Diphenhydramine
� No placebo controlled data
� Equally effective as ondansetron, with 50% requiring rescue naloxone for itch
� Cetirizine
� No data
� Loratadine
� No data
Juneja MM, et al. J Ky Med Assoc 1991;89:319-321.
Siddik-Sayyid SM, et al. Acta Anaesthesiol Scand 2010;54:764-769.
Opioid-induced pruritus - Antihistamines
� Hydroxyzine
� One study (n=40) in post-op epidural morphine
� Hydroxyzine > placebo (saline injection)
� Diphenhydramine
� No placebo controlled data
� Equally effective as ondansetron, with 50% requiring rescue naloxone for itch
� Cetirizine
� No data
� Loratadine
� No data
Juneja MM, et al. J Ky Med Assoc 1991;89:319-321.
Siddik-Sayyid SM, et al. Acta Anaesthesiol Scand 2010;54:764-769.
Opioid-induced pruritus - Antihistamines
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� Nalbuphine (kappa agonist, mu antagonist)
� 3 to 5 mg intravenous
� Naloxone
� 0.2 mg intravenous
� Propofol
� 20 mg intravenous
� Ondansetron
� 4 mg intravenous
� Opioid rotation (to hydromorphone or fentanyl)
� Oral first or second generation antihistamines?
Opioid-induced pruritus – Treatment Opioid-Induced Hyperalgesia
� Hyperalgesia is an enhanced response to a noxious stimulus
� Opioid induced hyperalgesia is a paradoxical response in
patients who become more sensitive to pain in response to
opioid therapy
Factor Opioid Tolerance Opioid Hyperalgesia
Duration of exposure Long Long or short
Dose escalation Slow Slow or fast
Nature of pain Unaltered from baseline More diffuse compared
to baseline
Location Unaltered from baseline May extend to locations
elsewhere
Quality Unaltered from baseline Allodynia may be
present
Sensitivity Unaltered from baseline Increase
Mitra S. J Opioid Manage 2008;4:123-130..
Opioid Induced Hypogonadism
� Hormones affected
� Gonadotropin releasing hormone
� Follicle Stimulating Hormone > Leutinizing hormone
� Testosterone
� Symptoms
� Loss of libido, impotence (men)
� Infertility
� Fatigue, depression, anxiety
� Loss of muscle strength
� Menstrual irregularities, galactorrhea (women)
Katz N, et al. Clin J Pain 2009;25:170-175.
Opioid Induced Respiratory Depression -
Opioids +
Drug(s) Deaths Adjusted Hazard RatioHR (95% CI)
Benzodiazepines 106 7.5 (5.5 – 10)
Benzodiazepine +
Skeletal Muscle Relaxant
56 12.6 (8.9 – 17.9)
Skeletal Muscle Relaxant 30 2.8 (1.8 – 4.2)
Garg RK, et al. Med Care 2017;55:661-668.
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Walker JM, Farney RJ, Rhondeau SM et al. J Clin Sleep Med. 2007; 3(5):455-461.
Guilleminault C, Cao M, Yue HJ et al. Lung. 2010; 188:459-68.
0 100 200
1.0
1.8
Morphine Equivalents
Rate
Rati
o
CSA
OSA
Hypopnea
REM apnea/hypopnea
Opioid Induced Respiratory Depression –
Apneic Episodes and Dose
CSA: central sleep apnea
OSA: obstructive sleep apnea
REM: rapid eye movement
STOP-BANG
Snoring
Do you snore loudly?
Yes / No
Tired
Do you often feel tired or fatigued?
Yes / No
Observed apnea
Has anyone observed you stop breathing while asleep?
Yes / No
Blood Pressure
Do you have or are you treated for high blood pressure
Yes / No
BMI
> 35 kg/m2
Yes / No
Age
>50
Yes / No
Neck circumference
>40 cm
Yes / No
Gender (male?) Yes / No
High risk of OSA with 3 or more “Yes” answersWebster LR. Eight principles for safer opioid prescribing. Pain Med. 2013; 14(7):959-61.
Opioid Induced Respiratory Depression
OSA Screening
Opioid Induced Constipation – Definition
Change from baseline
Reduced frequency of spontaneous bowel movements
Development or worsening of straining
Incomplete evacuation
Harder stool consistency
Gaertner J, et al. J Clin Gastroenterol. 2015
Opioid Induced Constipation -
Pathophysiology
� Effect of opioids on GI tract mu receptors:
� Increases non-propulsive contractions
� Stimulates pyloric, ileocolonic, & anal sphincters
� Induces segmental contraction in the small bowel and colon
� Decreased ion & fluid secretion
� Increasing intestinal transit time
� Increased fluid absorption
� Tolerance does not develop
Dorn, S., Lembo, A. and Cremonini, F., 2014. Opioid-induced bowel dysfunction: epidemiology, pathophysiology, diagnosis, and initial therapeutic approach. The American
Journal of Gastroenterology Supplements, 2(1), pp.31-37.
https://www.dallaswellnesscenter.com/2017/
03/23/constant-constipation/
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Opioid Induced Constipation -
Prevalence & Severity
0
10
20
30
40
50
60
70
Prevalence (%)
No Opioid
PRN Opioid
ATC Opioid
ATC + PRNOpioid
Villars P, et al. Differences in the prevalence and severity of side effects based on the type of analgesic prescription in patients with chronic cancer pain. J Pain
Symptom Manage. 2007; 33: 67-77.
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Severity (0 - 4)
No Opioid
PRN Opioid
ATC Opioid
ATC + PRNOpioid
Opioid Induced Constipation - Treatment
� Stool softeners
� Stimulant laxatives
� Osmotic laxatives
� Chloride channel activators
� Peripherally acting mu-opioid receptor antagonists
(PAMORA)
� The best treatment is prophylaxis
Pharmacokinetic and Pharmacodynamic
Considerations in Special PopulationsAyesha M. Khan, PharmD, BCPS, CSU-COP/Rush University Medical Center
At the conclusion of the program, the pharmacists will be able to:
1. Discuss the role of personalized medicine in the treatment of acute and
chronic pain.
2. Describe the safe use of opioid and non-opioid analgesics given a real or simulated patient with acute or chronic kidney disease or liver disease
Pharmacist Objectives
9/25/2018
29
At the conclusion of the program, the pharmacists will be able to:
1. Discuss the role of personalized medicine in the treatment of acute and
chronic pain.
2. Describe the safe use of opioid and non-opioid analgesics given a real or
simulated patient with acute or chronic kidney disease or liver disease
Pharmacy Technician Objectives Pharmacokinetics (PK) &
Pharmacodynamics (PD) Defined
� Clinical PK applies PK concepts and principles in humans to
individualize dosing, optimize therapeutic response, and minimize
adverse drug reactions
� PK is the study of absorption, distribution, metabolism, and
excretion of drugs (ADME)
Applied Clinical Pharmacokinetics, 2014.
� Pharmacodynamics is the relationship between drug concentrations and
pharmacological response
� Change in drug effect is usually not proportional to the change in drug
dose/concentration
� Increase in drug effect observed as dose is increased is subject to the law of
diminishing return� eventually maxed
Effect produced by
forming drug
complex with
receptors.
Applied Clinical Pharmacokinetics, 2014.
Volume of distribution (Vd): a hypothetical volume that is proportionally
constant which relates the concentration of drug in the blood/serum and the
amount of drug in the body
C = dose/Vd
LD= (Css) (Vd)
Applied Clinical Pharmacokinetics, 2014.
9/25/2018
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Half-life (t1/2): the time it takes for serum concentrations to reduce by 50% in the elimination phase
• SS typically reached in 3-5 half-lives
• Determines dosing intervals
Elimination rate constant (ke):
• Denotes how quickly drug
serum concentrations decline
in a patient
• Measured as a reciprocal of
time (t-1)
• t1/2= 0.693/ke
• Both half-life and ke are
dependent on Vd and
clearance
Applied Clinical Pharmacokinetics, 2014.
Chronic Kidney Disease: Pain Burden
� About 58% of CKD patients experience pain (moderate-
severe intensity)
� Pain and overall symptom burden associated with lower
HRQL, great emotional distress, insomnia, depressive
symptoms
Woolf CJ. Ann Intern Med. 2004;140(6):441–5
Chronic Kidney Disease: Pain Burden� CKD with or without dialysis alters the PK/PD of many analgesics and opioids
profoundly
� Reduced GFR: Increased drug levels and associated adverse effects
� Hypoproteinemia/acidemia: Increased free drug levels
� Dialysis: Fluctuations with drug removal modalities
� Clinical data is limited and variable
� Management:
� Guided by etiology and severity of pain
� Non-pharm: exercise, heat therapy
� Pharm: WHO Analgesic Ladder for chronic, non-cancer pain
� Conservative dosing of opioids due to PK parameters
� Small dose titrations to analgesia and side effects
� No long-term studies of opioid therapies in CKD patients
Woolf CJ. Ann Intern Med. 2004;140(6):441–5
Modified WHO Analgesic Ladder
� Step 1 (Mild pain, Score 2-3): Non-opioid +/- Adjuvant
� Acetaminophen
� NSAIDs, Cox-2 inhibitors (short term)
� Carbamazepine, Gabapentin, Pregablin, TCAs
� Step 2 (Moderate Pain, Score 4-6): Non-opioid +/- Adjuvant +/- Weak opioid
� Tramadol
� Oxycodone with acetaminophen
� Step 3 (Severe pain; Score 7-10): Non-opioid +/- Adjuvant +/- Strong opioid
� Oxycodone
� Hydromorphine, Fentanly/alfentanil, Methadone, Buprenorphine
Davison SN. J Palliat Med. 2007;10(6):1277–87.
Woolf CJ. Ann Intern Med. 2004;140(6):441–5
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PK Data on Analgesic Medications in CKD
Medication % excreted in urine
T ½ (hours)
Dialyzable? Comments
Acetaminophen < 5 1-4 Yes -Accumulation of inactive metabolite-For mild-moderate pain
-No dose reduction required
Codeine 0-16 2.5-4 No -Metabolized to morphine derivatives, profound
hypotension & CNS depression
-Not recommended in CKD
Tramadol 90 (60% as
metabolites)
6 Yes -Renal dosing recommendations for eGFR <30
ml/min
-Give after each HD session
Koncicki HM, et al. AJKD. 2017;69(3). 451-460.
Parmer MS, Parmer KS. F1000Research. 2013;2(28).
PK Data on Analgesic Medications in CKD
Medication % excreted in urine
T ½ (hours)
Dialyzable? Comments
Morphine 10 2-3 -Yes, parent
&
metabolites
-Minimally
removed by
CVVH and
CVVHD
-Metabolized to M3G* and M6G+
-M6G contributes to analgesic effect
-M3G contributes to side effects
-Accumulation of parent & active metabolites
-Clinically significant opioid toxicities (sedation,
confusion, respiratory depression, myoclonus)
-In HD, effects may persist as M6G re-equilibrates
across the BBB-Not recommended in CKD
Koncicki HM, et al. AJKD. 2017;69(3).451-460.
Pham PC, et al. Clinical Kidney Journal. 2017;10(5).688-697.
Franken LG. Clin Pharmacokinet. 2015;55.697-709.
*morphine-3-glucuronide
+morphine-6-glucuronide
PK Data on Analgesic Medications in CKD
Medication % excreted in urine
T ½ (hours)
Dialyzable? Comments
Hydromorphone 6 2-5 Yes, active
metabolite
-Compared to morphine in CKD:
� Better tolerated & less toxic metabolites
�PD data shows less neuroexcitation, >65%
reduction in pain, no significant toxicity when given
in low doses
Fentanyl < 7 2-7 No -Inactive metabolites (IV and patch)-Patch: Absorption correlates to patch surface area
-High extravascular Vd (3-8 L/kg)
-Distributes widely to various organ systems
-T ½ after patch removal ~17 hours (13-22 hours)
�Elderly: prolonged t ½
Analgesic effects may continue for 12-24 hours
Transition slowly to an IR product for 2-4 daysLater transition to SR formulation
Koncicki HM, et al. AJKD. 2017;69(3).451-460.
Pham PC, et al. Clinical Kidney Journal. 2017;10(5).688-697.
PK Data on Analgesic Medications in CKD Medication % excreted
in urineT ½ (hours)
Dialyzable? Comments
Oxycodone < 10 2-4 Yes -Small % of active metabolite, does not accumulate
-Case reports of toxicity in CKD
-Consensus: safe to use with appropriate monitoring
Methadone 12-60 13-47 No -Primarily excreted in feces
-Plasma conc. similar in CKD and non-CKD patients
-Use with caution in CKD, 50-75% dose reduction
Gabapentin ~100 5-7 Yes -Freely crosses BBB. Dose post-HD
-Follow renal dosing for eGFR <80 ml/min
Duloxetine < 1 8-17 No -Starting dose no greater than 30mg
-Some recommend to avoid use in CrCl < 30 ml/min
Amitriptyline < 2 9-25 No -Low starting dose recommended
-Likelihood of dose-related anticholinergic adverse
effect
Koncicki HM, et al. AJKD. 2017;69(3).451-460.
Parmer MS, Parmer KS. F1000Research. 2013;2(28).
Pham PC, et al. Clinical Kidney Journal. 2017;10(5).688-697.
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NSAIDs
� Most PK studies are small or case reports of patients fluctuating
renal function
� Few studies have provided information on analgesic effects or
adverse effects of NSAIDs in renal insufficiency
� Depressed thromboxane B2 levels
� Suggest increased risk of bleeding
� Not described clinically
� eGFR < 35 ml/min: Recommend against use to avoid further
deterioration in residual renal function and risk of bleeding. Avoid
chronic use.
Pham PC, et al. Clinical Kidney Journal. 2017;10(5).688-697.
Prostaglandin Inhibition and eGFR
https://www.youtube.com/watch?v=J2YaULhMx5g
Properties of Selected Opioids
Dean M. J Pain Symptom Manage. 2004;28:497-504
Dialyzable medications:• High molecular weight
• Low protein binding
• High water solubility
• Low volume of distribution
Drug Vd (L/kg) Protein Binding (%) Water Solubility Molecular Weight
Morphine sulfate 3.2 35 1:21 758.8
Hydromorphone
hydrochloride
1.22 N/A 1:3 321.8
Oxycodone
hydrochloride
2.6 45 1:6 405.9
Codeine
phosphate
2.6 7 1:4 406.4
Methadone
hydrochloride
3.8 89 1:12 345.9
Fentanyl citrate 4 80 1:40 528.6
Liver Failure and Pain Management
� In patients with end-stage liver disease, adverse effects from analgesics are frequent
� Complications from analgesia can range from hepatic encephalopathy, hepatorenal syndrome, to gastrointestinal bleeding
� The greater the liver dysfunction, the greater impairment in drug metabolism
� Oxidation, hydrolysis, conjugation, biliary excretion, etc
� Efficiency of drug removal (via liver) depends upon:
� Hepatic blood flow
� Hepatic enzyme capacity
� Plasma protein binding
� Altered accumulation of free drug in plasma� altered end-organ response
Chandok N, et al. Mayo Clin Proc. 2010;85(5):451-459.
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Liver Failure and Pain Management
� General PK Principles:
� Drugs with HIGH hepatic extraction (1st pass metabolism)
� Low bioavailability in healthy people
� Higher bioavailability in cirrhotic patients
� Example: morphine, fentanyl
� Drugs with LOW hepatic extraction
� Bioavailability not impacted in liver disease
� Hepatic clearance may be impacted (reduced)
� Example: methadone
� Reduced albumin concentrations
� Higher free concentrations of highly bound drugs
� Impaired renal function
� CrCl tends to overestimate GFR in cirrhotic patients � dose reduction
neededChandok N, et al. Mayo Clin Proc. 2010;85(5):451-459.
Delco F, et al. Drug Safety. 2005;28(6):529-545.
PK Data on Analgesic Medications in Liver
DiseaseMedication Route of
excretionMetabolites/ Conjugated?
Comments
Acetaminophen Renal --- -Most common cause of fulminant hepatic failure in the US
-Limit to 2-3 gm/day in liver patients
-Limit alcohol intake
Codeine Renal/Fecal --- -CYP2D6, glucuronidation
-Prodrug, metabolized to morphine derivatives in liver
� CYP2D6 ultra-metabolizers: higher pain relief --> morphine toxicities
� CYP2D6 poor-metabolizers: lower pain relief/lack of
efficacy
Clinical Pharmacogenetics Implementation Consortium
(CPIC) Recommend non-CYP2D6 dependent opioids (morphine,
hydromorphone)
Delco F, et al. Drug Safety. 2005;28(6):529-545.
Verbeeck R. Eur J Clin Pharmacol. 2008;64:1147-1161.
PK Data on Analgesic Medications in Liver
Disease
Medication Route of excretion
Metabolites/ Conjugated?
Comments
Fentanyl Renal/Fecal Yes -CYP3A4
-Lipid soluble-stores in fat and muscle
-IV continuous infusion: prolonged sedation
Metabolism of agent does not yield toxic metabolites
� Typically well tolerated
Hydromorphone Renal Yes -Glucuronidation
-Consider dose reduction in liver impairment
-Metabolism of agent does not yield toxic metabolites
� Typically well tolerated
Delco F, et al. Drug Safety. 2005;28(6):529-545.
Verbeeck R. Eur J Clin Pharmacol. 2008;64:1147-1161.
PK Data on Analgesic Medications
Medication Route of excretion
Metabolites/ Conjugated?
Comments
Meperidine Renal/saliva Yes -CYP2B6, 3A4-Increased bioavailability of CNS active metabolite in
liver disease
-Highly protein bound
-Avoid use
Methadone Biliary/Renal
/Fecal
Yes -CYP3A4, 2D6, others
-Metabolism of agent does not yield toxic metabolites
� Typically well tolerated
-Consider dose reduction
-Cautiously titrate dose
Delco F, et al. Drug Safety. 2005;28(6):529-545.
Verbeeck R. Eur J Clin Pharmacol. 2008;64:1147-1161.
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PK Data on Analgesic Medications Medication Route of
excretionMetabolites/ Conjugated?
Comments
Oxycodone Renal No -CYP3A4, 2D6
-Unpredictable metabolite levels-Reduce dose AND frequency in liver disease
Tramadol Renal Yes -CYP3A4, 2D6, glucuronidation
-In cirrhotic pts, analgesic properties may not be evident
-Reduce dose AND frequency in patients with liver disease
NSAIDs Renal/Fecal varies -Largely metabolized by CYPs, heavily protein bound
-Hepatorenal syndrome in cirrhotic patients
-Thrombocytopenia and coagulopathy
Delco F, et al. Drug Safety. 2005;28(6):529-545.
Verbeeck R. Eur J Clin Pharmacol. 2008;64:1147-1161.
Acetaminophen in Liver Disease
Chandok N, et al. Mayo Clin Proc. 2010;85(5):451-459.
• Providing safe and effective analgesia to patients with hepatic and renal insufficiency can be a clinical challenge.
• PK/PD alterations correlate to signification clinical consideration in pain management
• No evidence-based guidelines exist on the use of analgesics in these populations
• Renal Patients:
• The degree of renal failure should be determined in terms of the GFR (and/or creatinine clearance)
• As renal failure develops, excretion of the metabolites and/or parent drug would decrease, gradual accumulation would occur, with associated clinical effects.
• In general, analgesics should be adjusted to account for potential accumulation. Close monitoring of adverse effects is recommended.
• Liver Patients:
• Most drugs can be used safely in liver dysfunction, but lower doses or reduced dosing frequency is often recommended.
• NSAIDs should be avoided because of the risk of ARF caused by prostaglandin inhibition.
• Opioids should be avoided/used sparingly at low and infrequent doses to avoid the risk of precipitating hepatic encephalopathy.
TAKE HOME POINTSPK/PD In Special Populations:
� Applied Clinical Pharmacokinetics, 2014.
� Woolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140(6):441–5.
� Davison SN. The prevalence and management of chronic pain in end-stage renal disease. J PalliatMed. 2007;10(6):1277–87.
� Koncicki HM, et al. Pain Management in CKD: A Guide for Nephrology Providers. Am J Kidney Dis. 2017;69(3). 451-460.
� Parmer MS, Parmer KS. Management of acute and post-operative pain in chronic kidney diseae. F1000Research. 2013;2(28).
� Franken LG, et al. Pharmacokinetics of Morphine, Morphine-3-Glucuronide and Morphine-6-Glucouronid in Terminally Ill Adult Patients. Clin Pharmacokinet. 2016;55.697-709.
� Pham PC, et al. 2017 update on pain management in patients with chronic kidney disease. Clinical Kidney Journal. 2017;10(5).688-697.
� Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004;28:497-504
� Chandok N, et al. Pain management in the cirrhotic patient: the clinical challenge. Mayo ClinProc. 2010;85(5):451-459.
� Delco F, et al. Dose adjustment in patients with liver disease. Drug Safety. 2005;28(6):529-545.
� Verbeeck R. Pharmacokinetics and dosage adjustments in patients with hepatic dysfunction. EurJ Clin Pharmacol. 2008;64:1147-1161.
Resources & References
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First Dance with Mary Jane: The
Role of Medical Cannabis in Pain
Cara Brock, PharmD, BCGP
Roosevelt University
Chris Herndon, PharmD
Southern Illinois University Edwardsville
At the conclusion of the program, the pharmacists will be able to:
� Review Illinois law pertaining to medical cannabis
� Describe the clinical pharmacology of medical cannabis and its active
components
� Review various dosage formulations of medical cannabis available to patients
� Evaluate clinical studies available for common conditions to evaluate the evidence for medicinal marijuana
Pharmacist Objectives
At the conclusion of this program, the pharmacy technician will be able to:
� Review Illinois law pertaining to medical cannabis
� Describe the clinical pharmacology of medical cannabis and its active
components
� Review various dosage formulations of medical cannabis available to patients
� Evaluate clinical studies available for common conditions to evaluate the evidence for medicinal marijuana
Pharmacy Technician ObjectivesTypes of Cannabis
� Cannabis sativa
� native to Europe
� most versatile and easy to grow
� Cannabis indica
� native to India
� Cannabis ruderalis
� native to Siberia and central Asia
� Trichomes
https://sensiseeds.com/en/blog/everything-you-ever-needed-to-know-about-cannabis-leaves/
https://hightimes.com/grow/trichome-anatomy/
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It’s been around…
� Reports as early 10,000 years BCE / BC for various uses
� Named for Greek word for hemp, kannabis
� Appeared in Chinese pharmacopoeia 2800 BCE / BC
� Documented use for pain, dysentery, nausea / vomiting, spasms, and convulsions
� delta-9-tetrahydrocannabinol isolated 1964
� Cannabinoid receptor described in 1990
Russo EB. Chem Biodivers 2007;4(8):1614-48.
� Lipids
� Anandamide (AEA; full-agonist)
� 2 Arachidonoylglycerol (2-AG)
� Play a role in acute pain analgesia
� Elevated at various nociceptive pathways in chronic pain
� Degraded quickly by fatty acid amide hydrolase (FAAH)
� Monoacylglycerol lipase (MAGL) degrades 2-AG
Endocannabinoids
Woodhams et al. The cannabinoid system and pain. Neuropharmacology 124 (2017) 105 -120
Phytocannabinoids
� Over 400 constituents of the cannabis plant
� 66+ are of the cannabinoid structure
� Tetrahydrocannabinols (THC; partial agonists)
� Cannabidiols (CBD; inverse-agonists)
� Cannabigerols
� Cannabinol and cannabinodiol
� Cannabichromenes
Cascini F, Aiello C, Di Tanna G. Increasing delta-9-tetrahydrocannabinol (_-9-THC) content in herbal cannabis over time: systematic review and meta-analysis. Curr Drug Abuse
Rev. 2012 Mar;5(1): 32-40.
Guindon J, Beaulieu P, Hohmann AG. Pharmacology of the cannabinoid system. In: Beaulieu P, Lussier D, Porreca F, Dickenson AH, eds. Pharmacology of Pain. Seattle, WA: IASP
Press;2010.
Woodhams et al. Neuropharmacology 124 (2017) 105 -120
Commercially Available Cannabinoids
� Dronabinol (Marinol®) - THC
� Nabilone (Cesamet®) – THC analog
� Nabiximols (Sativex®) - THC / CBD
� Cannabidiol (Epidiolex®) - CBD
THC: tetrahydrocannabinol
CBD: cannabidiol
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Cannabinoid ReceptorsReceptor Primary
LocationPutative Function Ligands
CB1 CNS* Nociception
(transmission/modulation)
Cardiovascular
Neuronal plasticity
Anxiolysis / Euphoria
Gastrointestinal
THC > Cannabinol
~ Cannabidiol
Dronabinol
Nabilone
CB2 Periphery:
Immune Sys >
GI > CNS
Microglia
Intestinal inflammatory
response and immune
suppression
~ Cannabidiol
Dronabinol
Nabilone
TRPV1 PNS & CNS Nociception and regulation
of heat
THC
Capsaicin
GPR55 Brain & GI Unknown; no phenotypes
recognized with knockouts
Cannabidiol
Ryberg E et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 2007;152(7):1092-1101.
Guindon J, Beaulieu P, Hohmann AG. Pharmacology of the cannabinoid system. In: Beaulieu P, Lussier D, Porreca F, Dickenson AH, eds. Pharmacology of Pain. Seattle,
WA: IASP Press;2010.
Endocannabinoid System & Pain
� N and P/Q VSCC blockade
� K-ir potentiation
� VSSC blockade
� mapKinase activation
� mast cell inhibition
� modulation of GABAergic, glycinergic, and glutamatergicneurotransmission
Manzanares J, et al. Role of the cannabinoid system in pain control and therapeutic implications for the
management of acute and chronic pain episodes. Curr Neuropharmacol 2006;4(3):239-257.
Guindon J, Beaulieu P, Hohmann AG. Pharmacology of the cannabinoid system. In: Beaulieu P, Lussier D,
Porreca F, Dickenson AH, eds. Pharmacology of Pain. Seattle, WA: IASP Press;2010.
Cannabinoid Effects of Physiologic Systems
System Effect
Central Nervous
System
Euphoria
Enhanced sensory perception
Disruption of intellectual and
psychomotor performance
Temporospatial disorientation
Impaired memory / ideation
Thermoregulatory disorder
Psychotic episodes
Analgesia
Antiemetic
Anxiolytic
Appetite stimulation
Anticonvulsant
Cardiovascular Tachycardia, vasodilation, hypotension
Respiratory Bronchodilatation, cough suppression
Gastrointestinal Intestinal transit inhibition, anti-inflammatory
Reproductive Implantation, enhanced hormonal secretion
Locomotor Hypomobility, antispasmodic
Ocular Decreased intra-ocular pressures
Other Inhibition of tumor growth, immunomodulation
Guindon J, Beaulieu P, Hohmann AG. Pharmacology of the cannabinoid system. In: Beaulieu P, Lussier D, Porreca F, Dickenson AH, eds. Pharmacology of Pain. Seattle,
WA: IASP Press;2010.
Cannabinoid Effects on Cyclooxygenase
Ruhaak R, et al. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull 2011;34(5):774-778.
THC: tetrahydrocannabinol, THCA: tetrahydrocannabinolic acid
CBD: cannabidiol, CBDA: cannabidiolic acid, CBG: cannabigerol
CBGA: cannabigerolic acid
(reference line represents indomethacin)
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� Inhaled
� Bioavailability 10 – 20%
� Onset: a few minutes
� Duration: 1 – 2 hours
� Edibles
� Cannabinoids are soluble in alcohol and lipids
� Bioavailability 30 – 50%
� Onset: 20 – 60 minutes
� Duration: unknown
� Topical
� Sublingual
Dosage Forms
� Moderate
� Neuropathic pain
� Spasticity
� Weak
� Nausea
� Weight gain (AIDS, cancer)
� Sleep
The Evidence
Whiting, P.F., Wolff, R.F., Deshpande, S., Di Nisio, M., Duffy, S., Hernandez, A.V., Keurentjes, J.C., Lang, S., Misso, K., Ryder, S. and Schmidlkofer, S., 2015. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA, 313(24), pp.2456-2473.
Comparing apples to tomatoes
Whiting PF, et al. J Am Med Assoc 2015;313(24):2456-2473.
Condition Findings Comments
Chronic pain (28) Studies generally show improvement in pain
measures associated with cannabinoids
Did not reach statistical significance
Average number of patients reporting reduction in
pain of at least 30% was greater with cannabinoid
vs. placebo
No difference in QoL
Spasticity due to MS
or paraplegia (14)
Studies generally showed improvement in
spasticity but did not reach statistical
significance
All included placebo
Anxiety disorder (1) CBD was associated with a greater improvement
compared with placebo
High risk of bias
Simulated public speaking test
Sleep (2) Greater benefit compared with placebo
Sleep in fibromyalgia vs. amitriptyline –
improvement in insomnia (amitriptyline –
improvement in restfulness)
High risk of bias
Low risk of bias
Cannabinoids for Medical Use
A Systematic Review and Meta-Analysis
Whiting, P.F., Wolff, R.F., Deshpande, S., Di Nisio, M., Duffy, S., Hernandez, A.V., Keurentjes, J.C., Lang, S., Misso, K., Ryder, S. and Schmidlkofer, S., 2015. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA, 313(24), pp.2456-2473.
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Opioid reduction (among others)
Boehnke KF, et al. J Pain 2016;17(6):739-744.
� Driving impairment
� Addiction
� Hyperemesis syndrome
� Psychotic episodes
� Long-term cognitive dysfunction
� MI
� Stroke
� Schizophrenia
� Minor PFT changes
� No evidence for cancer or lung disease
Risks of cannabis for medical purposes
Tashkin DP. Effects of marijuana smoking on the lung. Ann Am Thorac Soc. 2013;10(3):239-247. doi: https://doi.org/10.1513/AnnalsATS.201212-127FR
Hartman RL, Huestis MA. Cannabis effects on driving skills.Clin Chem. 2013;59(3):478-492. doi:10.1373/clinchem.2012.194381.
Hartman RL, Huestis MA. Cannabis effects on driving skills. Clin Chem. 2013;59(3):478-492. doi:10.1373/clinchem.2012.194381.
Borgelt L, Franson K, Nussbaum A, Wang G. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy [serial online]. February 2013;33(2):195-209.
Available from: MEDLINE Complete, Ipswich, MA. Accessed June 16, 2018.
� Schedule I controlled substance under the CSA
� High potential for dependency, no accepted medical use
� October 2009 – Obama memo
� August 2013 – U.S. Department of Justice updated enforcement
policy (Cole memorandum)
� 2014 – Rohrabacker-Blumenauer Amendment
� January 2018 – AJ Sessions issued a memorandum that rescinded
the Cole Memorandum
Federal Implications
National Conference of State Legislatures. State Medical Marijuana Laws. Accessed at: http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx
Accessed June 16, 2018.
Lopez G. Vox, May 30, 2014.
State Regulations
National Conference of State Legislatures. State Medical Marijuana Laws. Accessed at: http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx Accessed
June 16, 2018.
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Illinois Medical Cannabis Pilot Program
� Patient applies for approval through Division of Medical
Cannabis
� Receives written certification order from MD or DO mailed
directly to Dept. of Public Health (Not required for VA
patients)
� May legally possess / purchase 2.5 oz per 2 weeks
� Scheduled to be repealed July 1, 2020
Illinois General Assembly. (410 ILCS 130/) Compassionate Use of Medical Cannabis Pilot Program Act. Available
at:http://www.ilga.gov/legislation/ilcs/ilcs3.asp?ActID=3503&ChapterID=35 Accessed June 16, 2018
IL Approved Pain-Related Conditions
� HIV / AIDS
� Arnold-Chiari malformation
� Cancer
� Chronic Inflammatory Demyelinating Polyneuropathy
� Complex Regional Pain Syndrome Type II
� MS, MD
� Myoclonus
� Lupus, RA, Fibromyalgia, Sjogren’s
� Phantom Limb Pain
� Spinal cord injury
� Terminal illness with life expectancy less than 6 months
� *Alternatives to Opioids Act (SB 0336)
Illinois Department of Public Health. Medical Cannabis Debilitating Conditions. Accessed at: http://www.dph.illinois.gov/topics-services/prevention-wellness/medical-cannabis/debilitating-conditions
Illinois General Assembly. Bill Status of SB0336 Cannabis-Medical Conditions. Available at: http://www.ilga.gov/legislation/BillStatus.asp?GA=99&DocTypeID=SB&DocNum=336&GAID=14&SessionID=91&LegID=100276 accessed June 16,
2018
� Top pain-related conditions
� Severe fibromyalgia (2,407)
� Cancer (2,139)
� RA (786)
� MS (596)
� Residual limb pain (354)
� Complex Regional Pain Syndrome Type I (352)
� Complex Regional Pain Syndrome Type II (351)
Illinois Medical Cannabis Registry Pilot
Program Mid-Year Report 2017
Illinois Department of Public Health Illinois Annual Progress Report: Compassionate Use of Medial Cannabis Pilot Program Act. July 1, 2016 through June 30, 2017. Accessed at:
http://www.dph.illinois.gov/sites/default/files/publications/mid-year-data-report-january-2016-040616.pdf. Accessed June 16, 2018
0
5,000
10,000
15,000
20,000
25,000
Number of Registered Adult Qualifying Patients
30-Jun-1530-Jun-1630-Jun-17
“No currently accepted
medical use”-- US Drug Enforcement Agency
National Academies of Sciences, Engineering, and Medicine. 2017. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for
research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
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“There is substantial evidence that cannabis is an effective treatment for
chronic pain in adults”--- National Academy of Science
� Report commissioned by HHS with representation from CDC, numerous
NIH institutes, NHTSA, FDA
� Findings rated by strength of findings / evidence
� Conclusive
� Substantial
� Moderate
� Limited
� None / insufficient
National Academies of Sciences, Engineering, and Medicine. 2017. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for
research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
Image: https://westfaironline.com/100159/stamford-approves-medical-marijuana-dispensary/
� Does Richard qualify for medicinal
marijuana in Illinois?
Can I Get a Pot
Card?
Drug Disposal and
Takeback ProgramsLalita Prasad-Reddy, PharmD, MS, BCPS, BCACP, CDE
At the conclusion of the program, the pharmacists will be
able to:
1. Describe the purpose behind drug take back programs and
the data that supports their use
2. Identify methods in which to incorporate drug take
methods into your pharmacy practice.
Pharmacist Objectives
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At the conclusion of the program, the pharmacy technican
will be able to:
Pharmacy Technician Objectives
Health and Human Services: 5 Priorities
� Improving access to treatment and recovery services
� Promoting use of overdose-reversing drugs
� Strengthening understanding of the epidemic through
better public health surveillance
� Providing support for cutting edge research on pain and
addiction
� Advancing better practices for pain management.
https://www.hhs.gov/opioids/about-the-epidemic/hhs-response/index.html
Prescription Drug Monitoring Programs
https://www.cdc.gov/drugoverdose/pdmp/states.html
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Improper Drug Disposal Consequences
� Drug misuse and abuse
� Poisoning of humans and pets
� Medication errors
� Contamination of water
� Threat to wildlife
http://apps.who.int/medicinedocs/en/d/Jwhozip51e/2.8.html
Secure and Responsible Drug Disposal Act
� Goal: Encourage public and private entities to develop a variety of methods of collection and disposal in a secure, convenient, and responsible manner
� Allow ultimate users to deliver unused pharmaceutical controlled substances to appropriate entities for disposal in a safe and effective manner consistent with effective controls against diversion
� Does not limit the ways that ultimate users may dispose of pharmaceutical controlled substances – it expands them
� Traditional, appropriate methods for drug disposal are still valid
� Allows for disposal in mail-back packages
� Allows for disposal of substances by individuals who are in the household
� Allows for DEA sponsored drug take back events, and encourages private entities to partner with governmental organizations to encourage take back events
https://www.deadiversion.usdoj.gov/drug_disposal/non_registrant/s_3397.pdf
Drug Take Back – Becoming a Collector
� Collection
� To receive a controlled substance for the purpose of destruction
from an ultimate user
� Registered manufacturer, distributor, reverse distributor,
narcotic treatment program, hospital/clinic with an on-site
pharmacy, or retail pharmacy that is authorized to so receive a
controlled substance for the purpose of destruction
� Registration can be modified online
�Collection receptacles, mail-back packages
� Collectors are NOT authorized to individually sponsor drug take
back events
https://www.deadiversion.usdoj.gov/drug_disposal/non_registrant/s_3397.pdf
Critical Thought….
What’s the Role of the Pharmacist??
� Improving access to treatment and recovery
services
� Promoting use of overdose-reversing drugs
� Strengthening understanding of the epidemic
through better public health surveillance
� Providing support for cutting edge research on pain
and addiction
� Advancing better practices for pain management.
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Opioid Use Disorder,
Treatment, and Risk
MitigationChris Herndon, PharmD
Southern Illinois University Edwardsville
At the conclusion of the program, the pharmacists will be able to:
1. Identify the diagnostic criteria for opioid use disorder
2. Describe naloxone’s role in attenuating death and disability
during a real or simulated opioid overdose.
3. Discuss the pharmacist’s role in the provision of at-home
naloxone.
4. Compare and contrast common medication assisted therapies
for opioid use disorder.
Pharmacist Objectives
At the conclusion of this program, the pharmacy technician will be
able to:
1. Identify the diagnostic criteria for opioid use disorder
2. Describe naloxone’s role in attenuating death and disability
during a real or simulated opioid overdose.
3. Discuss the pharmacist’s role in the provision of at-home
naloxone.
4. Compare and contrast common medication assisted therapies
for opioid use disorder.
Pharmacy Technician Objectives
Richard consistently presents to
your pharmacy requesting early
refills of his prescription for
morphine which he takes for
chronic low back pain.
You are concerned but are not sure
how to proceed. He tells you the
morphine “used to work for his pain
but are not effective any longer.”
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� Aberrant drug taking behaviors
� Any departure from prescription
� Misuse
� Departure with therapeutic intent
� Abuse
� Departure without therapeutic intent
� Addiction
� Now called substance use disorder
� Neurobiologic disease characterized by cravings,
compulsion, withdrawal syndrome, and loss of control
� Tolerance
� Requiring increasing doses to garner the same effect
� Hyperalgesia
� When noxious stimuli produces a heightened and non-
proportional nociceptive responseBrady KT, et al. Am J Psychiatry 2016;173(1):18-26.
U.S. Department of Health and Human Services (HHS), Office of the Surgeon General, Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs,
and Health. Washington, DC: HHS, November 2016.
Is Richard “Addicted?” Diagnosis of Substance Use Disorder
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA.
< 2 symptoms = no disorder, 2-3 = mild disorder, 4-5 = moderate disorder, > 6 = severe disorder
Wanting to cut down or stop using, but not managing to
Spending a lot of time to get, use, or recover from use
Craving
Inability to manage commitments due to use
Continuing to use, even when it causes problems in relationships
Giving up important activities because of use
Continuing to use, even when it puts the user in danger
Continuing to use, even when physical or psychological problems are worsened
Increasing tolerance
Withdrawal symptoms
Using in larger amounts or for longer than intended
The “Addiction” Cycle
U.S. Department of Health and Human Services (HHS), Office of the Surgeon General, Facing Addiction in America: The Surgeon General’s Report on Alcohol,
Drugs, and Health. Washington, DC: HHS, November 2016.
G3
Prescription Opioids and Heroin
� Quantitative questionnaire using street
outreach, venue-recruitment, and
needle-exchange advertisement (n = 123)
� Median age 29 yrs (75% male, 53% white,
28% Hispanic, 19% black or other)
� 39.8% reported problematic prescription
opioid use prior to first heroin use
� We are lacking data on true risk for first
time exposure to opioids for an indication
of pain
Pollini RA, et al. Subst Abuse Rehabil 2011;2:173-180.
0.755
0.694
0.347
0.204 0.2040.163 0.143
0.082 0.041
Prior Prescription Opioid Abuse, by Drug
Slide 179
G3 permission requestedGabby, 1/3/2017
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Risk Mitigation Strategies for Pharmacists
� Prescription drug monitoring programs
� Screening tools (prior to and during therapy)
� Random drug screening
� Opioid agreements
� Pill counts
� COMMUNICATION with prescribers, nurses, AND patients
�Early requests
�Erratic behaviors
Validated Risk Assessment Tools
Acronym of toolα Number of questions Completion Time to complete
SOAPP®-R 24 items Self-report < 10 minutes
DIRE 7 items Clinician administered < 5 minutes
ORT 5 items Clinician administered < 5 minutes
COMM 40 items Self-report < 10 minutes
CAGE 4 items Either < 5 minutes
PDUQ 42 items Clinician administered 20 minutes
STAR 14 items Self-report < 5 minutes
SISAP 5 items Clinician administered < 5 minutes
PMQ 26 items Self-report < 10 minutes
α - SOAPP®-R (Screener and Opioid Assessment for Patient’s in Pain-revised); DIRE (Diagnosis, Intractability, Risk, and Efficacy); ORT
(Webster’s Opioid Risk Tool); COMM (Current Opioid Misuse Measure); CAGE (Cut-down, Annoyed, Guilt, Eye-opener); PDUQ
(Prescription Drug Use Questionnaire); STAR (Screening Tool for Addiction Risk); SISAP (Screening Instrument for Substance Abuse
Potential); PMQ (Pain Medication Questionnaire)
Opioid Risk Tool
Low Risk 0 – 3 points, Moderate Risk 4 – 7 points, High Risk > 8 points
Webster LR, Webster RM. Pain Med 2005;6(6)432-42.
Is Richard Low Risk, Medium Risk, or
High Risk?
� 56 years old
� Father abused EtOH
� Past medical history of
Bipolar disorder
Low Risk 0 – 3 points, Moderate Risk 4 – 7 points, High Risk > 8 points
Webster LR, Webster R. Predicting aberrant behaviors in Opioid-treated patients: preliminary validation of the Opioid risk too. Pain Med. 2005; 6 (6) : 432
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Urine Drug Screening
� Immunoassay� Fast results
� Inexpensive
� High sensitivity, low specificity
� Gas chromatography / mass spectrometry� Slower results
� Expensive
� High sensitivity, high specificity
� Interpretation� Pharmacists ideally positioned to interpret presence or absence of metabolites
� What would you expect if patient is on hydrocodone? Oxycodone?
Herndon CM, Arnstein P, Darnall B, Hartrick C, Hecht K, Maleki J, Manworren R, Miaskowski C, Lyons M, Sehgal N, eds. Principles of Analgesic Use 7th ed. Chicago,
IL: American Pain Society Press.
Opioid Agreements
� No data to support their efficacy in reducing
misuse / abuse
� Standard of care
� Many include stipulations for patient conduct
� Should be used as informed consent
� Why aren’t pharmacists incorporating these?
Tobin DG, et al. Cleve Clin J Med 2016;83(11):827-835.
The Treatment of Opioid Substance Use
Disorder
• Treatment is a continuum involving
• Harm reduction: decrease the harm associated with the SUD
and encourage incremental increases in the intensity /
holistic range of treatment – MEDICATIONS (methadone /
bup), NEEDLE EXCHANGE, NALOXONE KITS, SAFE USE HOUSES
• Sobriety: counseling (residential, PHP, IOP, aftercare
continuum)/ self help (>3Xwk with sponsor and home group)
/ MAT / family education – counseling/monitoring.
The Treatment of Opioid SUD M/S –
quick overview
� Optimal treatment = MAT (Medication ASSISTED
Treatment) with naltrexone, buprenorphine, or
methadone assisting a treatment program
� Medications alone are NOT treatment but rather harm
reduction – and they can provide a tremendous amount
of harm reduction
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Criteria for legal controlled substance
prescribing
• Prescribing must take place:
• Within the usual course of medical practice
• For a legitimate medical purpose
• Consistent with State Law
• Consistent with licensure board rules
• Some Federal Courts have found that the “usual course”
and “legitimate medical purpose” are one in the same
US Department of Justice, Drug Enforcement Administration. Diversion Control Division: Practitioner’s Manual Section V. Available at:
https://www.deadiversion.usdoj.gov/pubs/manuals/pract/section5.htm
Indications for possible chronic opioids
THE FIVE QUESTIONS
1. Is there a clear diagnosis in your area of expertise?
2. Is there documentation of an adequate work-up?
3. Is there impairment of function?
4. Has non-opioid multi modal therapy failed?
5. Are contraindications to opioid therapy ruled out … and are contraindications respected when present?
• Begin opioid therapy…Document! Monitor!
• Avoid poly-pharmacy
SUMMARY: RX Controlled Drugs in Addiction
and Recovery
• Balancing indications and contraindications:
• Increase comfort with prescribing as only a small part of a multi-modal tx plan
• Assess for SUD M/S and avoid controlled drugs
• FIRST do no harm, THEN comfort always and cure sometimes.
• Target opioid prescribing towards low risk / away from high risk patient populations.
• High risk patients needing opioids = buprenorphine or methadone, and ALWAYS add “TX” for the SUD!
Who Should Get Naloxone?1. Prescribed long-term opioid therapy; doses > 50 mg of morphine
equivalent/day
2. Prescribed rotating opioid medication regimens
3. Prescribed methadone
4. Taking an opioid plus other CNS depressants (benzodiazepines,
alcohol)
5. Prescribed or taking an opioid with co-occurring renal/hepatic
dysfunction, cardiovascular disease, respiratory disorders (sleep
apnea), mental illness, or HIV/AIDS
6. Using heroin
7. Recently discharged from a substance abuse treatment facility or from
an acute medical center following opioid intoxication or poisoning
8. Recently released from jail and history of opioid abuse
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Identify the Overdose
• STEP 1: Identify if someone is experiencing an overdose-- No response upon yelling their name or
vigorously rubbing chest with knuckles
-- Blue lips or fingertips-- Slow breathing (< 8 breaths/minute)-- Limp body or choking/gurgling/snoring noise
• STEP 2: Call 911 for help• STEP 3: If breathing is shallow or non-existent,
perform mouth-to-mouth rescue breathing
Administer Naloxone and
Stay Until Help Arrives!
1. Administer naloxone via IM or IN delivery system2. Place the person in the recovery position.
A. On their side with their top leg and arm crossed over their body
3. Stay with the person- do not leave someone alone after giving
naloxone A. The effect of naloxone wears off in 30 to 90 minutes and patients can go
back into overdose if a long-acting opioid was taken (methadone, oxycodone)
B. Patients may want to take more opioids upon reversal due to feeling opioid withdrawal symptoms
C. Some patients may become agitated or combative during withdrawal
IM = intramuscular; IN = intranasal
Naloxone Product Information Key resources
• Facing addiction in America, 2016 US Surgeon General’s report.
https://addiction.surgeongeneral.gov/surgeon-generals-report.pdf
• CDC http://www.cdc.gov/drugoverdose/data/overdose.html,
http://www .cdc .gov/ vitalsigns/ opioidprescribing
• DOJ DEA 2016 National Drug Threat Assessment
• UNODC UNODC, World Drug Report 2012, NSDUH Series H-46, HHH
Publicaqtion No. (SMA) 13-4795
• CDC Guideline for Prescribing Opioids for Chronic Pain:
http://dx.doi.org/10.15585/mmwr.rr6501e1
• N Engl J Med 2016;375:357-68
• JAMA, June 5, 2013—Vol 309, No. 21, 2219-2220
• Annals of Internal Medicine • Vol. 164 No. 1 • 5 January 2016
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� Always maximize non-pharm options
� Utilize non-opioids and adjuvants
� Opioid benefits vs. risks
� Medical cannabis indications for use keep growing
� Consider patient-specific factors
� Understand differences between opioids
� Be proactive about risks
� Education is key
Deep Thoughts…Pain Management Points
to Ponder
Opioids: Recommendations for Pharmacists
� Talk to your patients first
� Quiet private location using open ended questions and avoiding stigmatizing
� Do not refuse to fill prescription without discussion with patient
� Verify the prescription
� Within the law
� Within the scope (of prescriber)
� For the correct patient
� Patient counseling & assessment
� Clarification of patient responsibilities
� As directed
� Safe storage and disposal (some require receipt for lock box)
� Behavior expectations / motivational interviewing
Opioid Use Disorders: Interventions for Community Pharmacists, College of Psychiatric and Neurologic Pharmacists, Available at:
https://cpnp.org/_sdocs/guideline/opioid/opioid-intervention.pdf. Accessed May 31, 2018.