know pain know gain handout...avoid opioids in fibromyalgia syndrome and opioid induced hyperalgesia...

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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

� [email protected]

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



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.



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.



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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




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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.


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.


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





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





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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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


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


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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


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


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.

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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


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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18

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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20

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



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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21

� 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


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


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

22

� 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


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


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!

9/25/2018

24

The Hard Truth: Opioid

Adverse EffectsCara Brock, PharmD, BCGP





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.


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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25

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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26

� 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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27

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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28

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


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


9/25/2018

29


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.


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)


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30

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


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


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.


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31

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).



T ½ (hours)


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



T ½ (hours)


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



PK Data on Analgesic Medications in CKD Medication % excreted

in urineT ½ (hours)


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


Parmer MS, Parmer KS. F1000Research. 2013;2(28).


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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.


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)


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




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


-Consider dose reduction

-Cautiously titrate dose



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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



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






� 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


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.


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At the conclusion of the program, the pharmacy technican

will be able to:


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



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.


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.


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

G3 permission requestedGabby, 1/3/2017

9/25/2018

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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.

know pain know gain handout...avoid opioids in fibromyalgia syndrome and opioid induced hyperalgesia...

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