An Interdisciplinary Approach to Safe Opioid Treatment · Diplomate, Academy of Integrative Pain Management (AIPM) ... low risk, moderate ... Chronic Back Pain Venlafaxine (Effexor®)

March 8, 2017

Dr. Jeffrey Fudin 1

An Interdisciplinary Approach to Safe Opioid Treatment

Reducing Potential for Opioid Mishaps

Presented at CBI’s 3rd Abuse Deterrent Formulations Summit

Jeffrey Fudin, B.S., Pharm.D., FCCP, FASHPDiplomate, Academy of Integrative Pain Management (AIPM)

President and Director, Scientific and Clinical Affairs, REMITIGATE LLCClinical Pharmacy Specialist & PGY2 Pain Residency Director; Stratton VA Medical Center (WOC)

Adjunct Affiliations;Albany College of Pharmacy & Health Sciences,

Western New England University College of Pharmacy, UCONN School of Pharmacy

www.paindr.com

Dr. Fudin’s Disclosures

•Astra Zeneca (Speakers Bureau)

•Clarity (Consultant)

•Daiichi Sankyo (Advisory Board)

•DepoMed (Advisory Board, Speakers Bureau)

•Endo (Consultant, Speakers Bureau)

•Iroko Pharmaceuticals (Speakers Bureau)

•Kaléo (Speakers Bureau, Advisory Board)

• Kashiv Pharma (Advisory Board)

• KemPharm (Consultant)

• Millennium Health, LLC (Speaker)

• Pernix Therapeutics (Speaker)

• Remitigate, LLC (Owner)

• Scilex Pharmaceuticals (Consultant)

Objectives

• Describe the impact of the opioid overdose problem and how pharmacist as clinicians can effectively collaborate with the healthcare team to prevent unforeseen risks

• Discuss roles for pharmacists to become more active on the pain management interdisciplinary team citing specific examples in an advanced practice

• Illustrate weaknesses and potentials harms of a universally accepted MEDD as outlined in the CDC Guidelines and describe the pseudoscience on which they are based

• Recognize new software technologies that integrate comprehensive risk assessments into the patient record to evaluate and mitigate risks, including quantification of OIRD, urine monitoring interpretation, and naloxone access

But first, how has opioid OD problemimpacted OUR profession?

Something for everyone…

Practical Daily Issues• New Limitations

– MEDD and the pseudoscience• Aid team members in calculating dose

– Maximum tablet / capsule units per RX fill– Maximum days supply

• Logistical and Time Constraints (Community Setting)– Counseling patients on regulation / 3rd party pay changes– Paperwork (Schedule II vs III)– Qualifying patients for in‐home naloxone & documentation

• Patient Hardships– Multiple copays– Repetitive dispensing fees– PBM conflicts of interest1

– Patient travel to clinics and pharmacies

1. Fudin J. Problems Associated with the Rising Costs of Naloxone and Plausible Solutions. Pharmacy Times. December 15, 2016. Available at http://www.pharmacytimes.com/contributor/jeffrey‐fudin/2016/12/problems‐associated‐with‐the‐rising‐costs‐of‐naloxone‐and‐plausible‐solutions

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Dr. Jeffrey Fudin 2

Product Development

• Abuse Deterrent Formulations

– Physical barrier

– Viscosity management

– Sequestered opioid antagonist

– Aversive agent

• Who will pay for these?

– Prior authorizations

– No accountability for third party payers

Incorporating Pharmacists into an Advanced Practice Setting

Provider Status vs Reimbursement

What could PHARMACISTS do?What do I do?

What should CONGRESS do?

Risk Assessment Tools

Question Formats

Indications Advantages Disadvantages

Scoring Validated

SOAPP1 5, 14, 24 1° Care, Assess for high abuse risk, suitability for long term opioid tx, preferable to ORT in high‐risk populations

Best psychometrics, less susceptible to deception, 5‐10 minutes

Dependent on patient reporting, Copyrighted

Numeric, simple to interpret

Yes, 14 quest ion studied in 396 pts

SOAPP‐R2 24 Primary Care 5 minutes, Cross‐validated, Less susceptible to overt deception c/t SOAPP

Less sensitive and less specific than SOAPP


Yes, 283 pts

ORT3 5 Categorizes patients as low risk, moderate risk, and high risk

Less than 1 minute, simple scoring, high sensitivity & specificity when stratifying patients

1 question in the ORT is limited by patient’s knowledge of family history of substance abuse


Yes, (male and female), Preliminary Validation in 185 patients at 1 pain clinic, high degree of sensitivity and specificity

DIRE4 7, by ptinterview

risk of opioid abuse and suitability of candidates for long term opioid therapy

2 minutes, score correlates well with patient’s compliance& efficacy of long term opioid therapy

Prospective validation needed


?, Retrospective validation only of 61 pts over 38 months

1. J Pain Symptom Manage 2006;32:287–93 2. J Pain. 2008 April; 9 (4): 360‐3723. Pain Med 2005;6:432–424. J Pain 2006;7:671–81

Opioid Misuse Tools

Question Formats

Indications Advantages Disadvantages

Scoring Validated

PADT5

N/A To streamline the assessment of outcomes in patients with chronic pain, 2 sided chart note based on 4‐A’s*

5 minutes, Documents progress over time, Complements a comprehensive clinical evaluation

Not intended to be predictive of drug‐seeking behavior or predict positive or negative outcomes to opioid therapy

N/A Further studies needed to confirm the reliability and validity, Studied in 388 patients by 27 clinician

COMM6

17 To assess aberrant medication related behaviors of chronic pain patients

10 minutes, Useful in assessing & reassessing adherence to opioid RX(s)

Long term reliability is unknown

Numeric 222 pts, Long term reliability is unknown, Validated in small study, needs to be replicated

ABC7

20 questions Ongoing clinical assessment of chronic pain patients on opioid therapies

Concise and easy to scoreStudied in the VA setting

Needs validation in non‐VA setting.

Score of ≥3 indicates possible inappropriate opioid based on Y/N answers

Studied 136 veterans in a multidisciplinary VA Chronic Pain Clinic

5. Clin Ther 2004; 26:552–616. Pain. 2007 July; 130(1‐2):144‐156 7. J Pain Symptom Manage 2006;32:342‐351

Urine Drug Testing (UDM) Rationale

• Guidelines recommend UDM as standard of care when

prescribing chronic opioid therapy, especially for CNCP1‐5

• Helps to ensure compliance and mitigate risk1‐5

• Detects presence of illicit substances

• Detects absence of prescribed medication

• Helps to justify continual prescriptions

• Supports clinician decision to discontinue controlled substance

medication

References collectively on slide #15

Urine Drug Testing (UDM) Rationale

• Supports justification for closer monitoring

(more frequent visits / lab monitoring)

• Supports behavior modification and referral to psychologist

Potential Pitfalls6‐8

• Patient reliability to report compliance, use and misuse is

dubious and often poor

• Behavior alone is unreliable for identifying patients at risk non‐

compliance, abuse, misuse, and diversion


March 8, 2017

Dr. Jeffrey Fudin 3

• False or Unexpected Positive

– Discuss findings with patient

• Confirm false positive (as a true negative) to support and document patient’s integrity and compliance

– Confirm unexpected positive to justify

• ADT products, and or other RX adjustments

• substance abuse counseling

• Alternative and other behavior health intervention

• False Negative

– Confirm false negative (as a true positive) to support and document patient’s integrity and compliance

– DO NOT FALSELY ACUSE PATIENTS WITHOUT EVIDENCE!

Addressing Unexpected Results9


UDM References1. Gourlay DL, Heit HA, Caplan YH. Urine Drug Testing in Clinical Practice: the Art and Science of Patient

Care. 2010. Stamford, CT: PharmaCom Group, Inc.

2. Federation of State Medical Boards of the United States. Model Policy for the Use of Controlled Substances for the Treatment of Pain. J Pain & Palliative Care Pharmacotherapy. 2005; 19(2):73‐78.

3. Manchikanti L, Abdi S, Atluri S et al. American Society of Interventional Pain Physicians (ASIPP) Guidelines for Responsible Opioid Prescribing in Chronic Non‐Cancer Pain: Part 2‐Guidance. Pain Physician. 2012; 15:S67‐S116.

4. VA/DoD. Clinical Practice Guideline For Management of Opioid Therapy For Chronic Pain. 2010. [Online] Published May 2010. Accessed March 26, 2014. Available at http://www.va.gov/painmanagement/docs/cpg_opioidtherapy_fulltext.pdf

5. Fishbain DA, Cutler RB, Rosomoff HL, Rosomoff RS. Validity of self‐reported drug use in chronic pain patients. Clin J Pain 1999;15:184‐191.2.

6. Fishbain DA, Cutler RB, Rosomoff HL, Rosomoff RS. Validity of self‐reported drug use in chronic pain patients. Clin J Pain 1999;15:184‐191.2.

7. Berndt S, Maier C, Schultz HW. Polymedication and medication compliance in patients with chronic nonmalignant pain. Pain 1993;52:331‐339j.

8. Katz NP, Sherburne S, Beach M, et al. Behavioral monitoring and urine toxicology testing in patients receiving long‐term opioid therapy. Anesth Analg 2003;97:1097‐1102.

9. Reisfield GM,Goldberger, BA, Bertholf RL. False‐positive and false‐negative test results in clinical urine drug testing. Bioanalysis 2009. 1(5): 937‐52.

What do these results mean?

Case Study | Chronic Back Pain

Venlafaxine (Effexor®) 250mg PO QAMFentanyl (Duragesic®) 50mcg/hr changed Q72 hoursHydrocodone + APAP (Lortab®) 5/325, 1 PO Q4H PRNAlprazolam 0.5mg PO TID

IA In‐Office Results

Test Result

Opiate Negative

Benzodiazepines Negative

Benzoylecgonine

(cocaine metabolite)Positive

PCP Positive

Chromatography [send out]

Results

Test Result

Fentanyl Positive

Hydrocodone Negative

Alpha‐

hydroxyalprazolamPositive

Benzoylecgonine Positive

PCP Negative

Opioid Chemistry and Cross-sensitivity12

• Lack of hydrocodone PRN use

• Pharmacokinetics (when was urine collected?)

• Noncompliance (illegally obtained drugs)

• Test is not specific for the drug tested (opiate vs. synthetic, in this case fentanyl)

• False positive PCP

• Drug‐drug, drug‐disease, drug‐food/supplement interactions

• Genetic polymorphism

Unexpected Results

Negative for Prescribed MedicationsPositive for unprescribed and illicits

DO NOT FALSELY ACUSE PATIENTS WITHOUT EVIDENCE!

March 8, 2017

Dr. Jeffrey Fudin 4

Software Help!

1. Kirkwood J. Clinical Laboratory News. New Guidance on Pain Management Testing. July 2016;34‐38. (print version)Online version at https://www.aacc.org/publications/cln/articles/2016/july/new‐guidance‐on‐pain‐management‐testing2. Fudin J. Interview: New App Helps Interpret Urine Drug Test Results. Practical Pain Management. 2015 July/Aug; 15(6); 84‐87.3. Remitigate.com

March 8, 2017

Dr. Jeffrey Fudin 5

Generated Printout

http://www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose‐a.pdf

Recent CDC Guidelines:Who Should I Target for In‐Home Naloxone?

MME = morphine milligram equivalents

Fudin J, Pratt Cleary J, Schatman ME. The MEDD myth: the impact of pseudoscience on pain research and prescribing‐guideline development. Journal of Pain Research. 2016 March; 9:153‐156.

Variability in Opioid Equivalence Survey

• Sept 13 thru December 31, 2013.

• 411 Respondents, adjusted after stats to 319

• RPhs, MD/DOs, NPs, PAs

• Convert to Daily MEQ:

– Hydrocodone 80mg; Fentanyl 75mcg/hr; Methadone 40mg; Oxycodone 120mg; Hydromorphone 48mg

Rennick A, Atkinson TJ, Cimino NM, Strassels SA, McPherson ML, Fudin J. Variability in Opioid Equivalence Calculations. Pain Medicine. 2016;17: 892–898.

What Do You Think Were the Most Outrageous Conversions?

Rennick A, et al. Variability in opioid equivalence calculations. Pain Med. 2016;17:892‐898.

Morphine equivalent doses (mg) for each opioid medicationby specialty

Specialty Fentanyl Hydrocodone Hydromorphone Methadone Oxycodone

Pain Management(n=39)

166 ± 115(150)

85 ± 43(80)

191 ± 68(192)

162 ± 111(120)

167 ± 45(180)

Palliative Care(n=35)

168 ± 57(150)

84 ± 17(80)

188 ± 67(192)

251 ± 166(240)

154 ± 38(180)

None of the Above(n=247)

177 ± 124(150)

88 ± 43(80)

191 ± 50(192)

169 ± 115(160)

177 ± 37(180)

Available Online Opioid Conversion Calculators

• Med Calc

• WA State Agency

• Pain Research

• Pain Physicians

• Hopkins

• Palliative Care

• Global RPh

• Practical Pain Management (PPM)Ref. Shaw K, Fudin J. Evaluation and Comparison of Online Equianalgesic Opioid Dose Conversion Calculators. Practical Pain Management. 2013 August; 13(7):61‐66.

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Dr. Jeffrey Fudin 6

(+/‐) % Variation (Compared to Manual Calculation)

‐33%

‐55%

+100%

+242%

VARIOUSOPIOIDS

FENTA

NYL

METH

ADONE

0%

RISKS:Underdose &Withdrawal

RISKS:Overdose & Death

Shaw K, Fudin J. Evaluation and Comparison of Online Equianalgesic Opioid Dose Conversion Calculators. Practical Pain Management. 2013 August; 13(7):61-66. PPM 2013

Comparison of Proposed Morphineto Methadone Equivalents

Ripamonti et al, 1998Morphine dose(mg/day)

30-90 91-300 301+

Morphine:MethadoneEDR

3.70:1 7.75:1 12.25:1

Ayonrinde et al, 2000Morphine dose(mg/day)

˂100 101-300 301-600 601-800 801-1000 ˃1001


3:1 5:1 10:1 12:1 15:1 20:1

Mercadante et al, 2001Morphine dose(mg/day)

30-90 91-300 301+


4:1 8:1 12:1

Fudin et al, 2012

X=morphine (mg) | EDR=equianalgesic dose rationFudin J, Marcoux MD, Fudin JA. Mathematical Model For Methadone Conversion Examined. Practical Pain Management. 2012 September; 12(8): 46-51.

2% of prescriptions for opioid analgesics are for methadone

Methadone accounts for nearly 1 in 3 prescription opioid overdose deaths in the U.S., 6X times the number in 2009

Ref: Methadone Statistics (CDC2012)http://www.cdc.gov/features/vitalsigns/methadoneoverdoses/

The higher the dose of morphine (or “equivalent”), the less methadone is needed to replace it.

Met

had

on

e (m

g)

Morphine (mg)

Equianalgesic Dose of Morphine to Methadone

300mg Morphine = 60mg Methadone

302.5mg Morphine = 30mg Methadone

CDC Calculator is Grossly Flawed!

https://www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose‐a.pdf

https://www.cdc.gov/drugoverdose/prescribing/app.html

https://www.cdc.gov/drugoverdose/prescribing/app.html

An Actual Example from CDC Smart Phone App

Guideline Resources: CDC Opioid Guideline Mobile App

“Morphine Equivalent” (mg) Methadone Daily Dose (mg)

80 20

168 21

320 40

410 41

March 8, 2017

Dr. Jeffrey Fudin 7

Comparison of Proposed Morphineto Methadone Equivalents

Ripamonti et al, 1998Morphine dose(mg/day)

30-90 91-300 301+


3.70:1 7.75:1 12.25:1

Ayonrinde et al, 2000Morphine dose(mg/day)

˂100 101-300 301-600 601-800 801-1000 ˃1001


3:1 5:1 10:1 12:1 15:1 20:1

Mercadante et al, 2001Morphine dose(mg/day)

30-90 91-300 301+


4:1 8:1 12:1

Fudin et al, 2012

X=morphine (mg) | EDR=equianalgesic dose rationFudin J, Marcoux MD, Fudin JA. Mathematical Model For Methadone Conversion Examined. Practical Pain Management. 2012 September; 12(8): 46-51.

2% of prescriptions for opioid analgesics are for methadone

Methadone accounts for nearly 1 in 3 prescription opioid overdose deaths in the U.S., 6X times the number in 2009

Ref: Methadone Statistics (CDC2012)http://www.cdc.gov/features/vitalsigns/methadoneoverdoses/

Met

had

on

e (m

g)

Morphine (mg)

Equianalgesic Dose of Morphine to Methadone

Serum Fentanyl Concentrations Following Multiple Applications of DURAGESIC® 100mcg/h (n=10)

https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=49245

Fentanyl TD

Unanticipated Risks of Opioid‐induced Respiratory Depression

Hypothetical Case:Patient Profile (SR): Pain Clinic Patient

• SR 47‐year‐old female patient with 3 failed back surgeries and DM type 2 – 5’ 6” tall and weighs 200 lbs

• Medication regimen at pain clinic (for last 2 years):– Oxycodone ER 30 mg PO q12h and oxycodone IR 10 mg PO q4h

PRN

• Do you think this patient is at elevated risk (Low, Med, High)?– Medications prescribed by psychiatrist:

• Lorazepam 0.5 mg q8h for anxiety

– What if the patient:• Is placed on pregabalin 75 mg PO TID (Endocrine for DPN)• Goes on a grapefruit diet? (Self)• Is an ultra‐rapid 2D6 metabolizer? (Ohhhh Nooo!)• Develops an URTI?• Takes OTC meds?

– She has obstructive sleep apnea

http://www.arupconsult.com/assets/graphics/OpiatesAndOpiodMetabolism.jpg

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Dr. Jeffrey Fudin 8

43

American Medical Association, Arizona Center for Education and Research on Therapeutics, Critical Path Institute. Pharmacogenomics: increasing the safety and effectiveness of drug therapy. Chicago, IL: American Medical Association; 2011. Report 10-0290:5/11:jt. http://www.ama-assn.org/resources/doc/genetics/pgx-brochure-2011.pdf. Accessed August 16, 2012.

Patient Response Variability

Same DiagnosisSame Medications

No Efficacy and Toxicity

Efficacy and No Toxicity

No Efficacy and No Toxicity

Efficacy, but Toxicity

Patient Group

44

Argoff CE. Clinical implications of opioid pharmacogenetics. Clin J Pain. 2010;26(1):S16‐S20.Belle DJ, Singh H. Genetic factors in drug metabolism. Am Fam Physician. 2008;77(11):1553‐1560.

Individual Response to Treatment

Pharmacogenetics

How the drug affects the

body

How the body alters the drug

The science of how genetic variability impactsindividual responses to medications

PGY Variability & Response

• General population has 40‐60% phenotype variability

• CYP450 enzymes most frequently involved

– CYP2D6, CYP2C19, CYP2C9, CYP3A4, CYP1A2, CYP2E1

• Genetic differences impact 25% of all drugs

45

1. Cavallari LH, Limdi NA. Warfarin pharmacogenomics. Curr Opin Mol Ther. 2009 Jun;11(3):243‐51. 2. Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions and adverse effects. Am Fam

Physician. 2007; 76(3):391‐6.3. Ma JD, Lee KC, Kuo GM. Clinical application of pharmacogenomics. J Pharm Pract. 2012 Aug;25(4):417–27.

Phenotypes & Variants• Allele Variations

– wild:wild vs variant:wild vs wild:variant

46

Poor Metabolizer (PM)DDDD → M

Intermediate Metabolizer (IM)DDDD → MMm

Extensive Metabolizer (EM)DDDD → MMM

Ultra Rapid Metabolizer (UM)DDDD → MMMMmmm

Real CaseSally is a 42 year old female with history of depression, anxiety, chronic moderate back pain, mood disorder, and panic attacks

• Venlafaxine XR 225mg PO QAM– minimal response + side effects

• Citalopram 60mg PO QAM– minimal response

• Tramadol 100mg PO QID– minimal benefit

• constipation but no other SEs

• Carbamazepine 200mg PO BID• Consider PGT

Case: Sally

Gene Reported Phenotype Medication

CYP2C19 Ultrarapid metabolizer citalopram

CYP2D6 Poor metabolizervenlafaxinetramadol

MTHFR Reduced activity

CYP3A4 Extensive metabolizer ????

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Dr. Jeffrey Fudin 9

Case: Amy

Citalopram Desmethyl‐citalopram

Desmethyl‐citalopram



Desmethyl‐citalopram2C19

Folate Metabolism

Dietary Folate

MTHFR

L‐methylfolate

(not usable) (5‐HT, NE, DA)

COMT

X

50‐60% of individuals have reduced or greatly reduced activity

1. Papakostas GI, Shelton RC, Zajecka JM, et al. L‐Methylfolate as Adjunctive Therapy for SSRI‐Resistant Major Depression: Results of Two Randomized, Double‐Blind, Parallel‐Sequential Trials. Am J Psychiatry. 2012;169:1267‐1274.

2. Botto LD, Yang Q. 5,10‐Methylenetetrahydrofolate Reductase Gene Variants and Congenital Anomalies: A HuGE Review. Am J Epidemiol. 2000;151(9):862‐877.

Tramadol

O‐desmethyl‐Tramadol

2D6 3A4, 2B6

inactive metabolites

Raffa RB, Buschmann H, Christoph T, EichenbaumG, EnglbergerW, Flores CM, et al. Mechanistic and functional differentiation of tapentadol and tramadol. Expert opinion on pharmacotherapy. 2012;13(10):1437‐49.

Sally – what to do…

• Change SSRI / SNRI– Examples: O‐desmethy‐venlafaxine, milnicipran, fluvoxamine

• Supplement with L‐methylfolate• Switch tramadol to tapentadol• Is morphine a possibility?

– Which opioids don’t depend on CYP metabolism?

What could you do for Sally?

• Change tramadol to tapentadol

• Change carbamazepine to oxcarbazepine

NASR, SUHAYL. "Oxcarbazepine for mood disorders." American Journal of Psychiatry 159.10 (2002): 1793‐1793.

ARE YOU READY TO SCREAM YET?Let’s take a break…

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Dr. Jeffrey Fudin 10

NOW WHAT?

Do you think maybe in‐home naloxone is a good idea due to unanticipated or unpredictable risks?

Naloxone: Antidote for Life‐Threatening Opioid‐induced Respiratory Depression (OIRD)

• Non‐scheduled opioid antagonist proven to rapidly reverse life‐threatening OIRD and other CNS depressant effects

• Displaces opioid agonists at the mu receptor binding site

• Higher affinity for mu‐receptors than traditional opioids, except buprenorphine

Straus MM, et al. Subst Abuse Rehabil. 2013;2013(4):65‐72.

Naloxone Regulatory Considerations

• Good Samaritan

• Liability protection

• Collaborative practice agreement

Naloxone Access

Davis C. Legal Interventions to Reduce Overdose Mortality: Naloxone Access and Overdose Good Samaritan Laws. www.networkforphl.org/_asset/qz5pvn/network‐naloxone‐10‐4.pdf. Accessed February 18, 2016.

States with Naloxone Access and Drug Overdose Good Samaritan Laws

States with Drug Overdose Good Samaritan Laws Only

States with Naloxone Access Laws Only

NALOXONE CHOICES

Politics, Practicality, Professionalism, and Pricing

Intranasal (IN)

Naloxone Rescue Kit

Edwards ET, et al. Pain Ther. 2015;4:1‐17.

March 8, 2017


FDA Approved In‐Home Naloxone

Naloxone Kits and Naloxone Autoinjectors Recommendations for Issuing Naloxone Kits and Naloxone Autoinjectorsfor the VA Overdose Education and Naloxone Distribution (OEND) Program. VA Pharmacy Benefits Management Services. October 2015. www.pbm.va.gov/PBM/clinicalguidance/clinicalrecommendations/Naloxone_Kits_and_Autoinjector_Recommendations_for_Use_Rev_Oct_2015.pdf. Accessed February 17, 2016.

Naloxone HCl for injection

Auto‐injector

(FDA approved in 2014)

Intranasal naloxone

(FDA approved 11/18/2015)

$$10

$

Critical Naloxone Comparisons

1. Edwards ET, et al. Pain Ther. 2015;4:89‐105.2. Kelly A, et al. Med J Aust. 2005;182:24‐27. 3. Krieter P, et al. J Clin Pharmacol. 2016. DOI: 10.1002/jcph.759

NXN Auto‐injector NXN Intranasal (FDA

Approved)

NXN Intranasal

(Makeshift)

NXN IM

Traditional

COMPLEXITY Usability studies show

90% and 100% correct

adm c/t NXN makeshift.1

Usability studies show

>90% correct adm3

60‐100% failure

rates1,3No usability

studies

INSTRUCTIONS Audio stepwise direction

and written directions

Written directions No FDA approved

written directions

N/A for in‐home

use

CONSIDERATIONS May inject through seam

of jeans

Reduced Cmax due to

altered nasal mucosa

(DS, cong)

Requires sig

dexterity and

familiarity

Requires sig

dexterity and

familiarity

FDA APPROVED

for in‐home use

YES, Known or suspected

Op OD, EVEN IF NOT

TRAINED

YES, Known or suspected

Op OD, EVEN IF NOT

TRAINED

NO N/A

DOSE 0.4 mg/0.4 mL injection 4 mg/0.1 mL spray 0.5 mg/0.5 mL 1.0 mg/mL

Tmax (median) 0.25 hour

(0.4 mg dose)

0.33 hour (8 mg)

(2 x 4 mg doses)

*N/A, but consider

Kelly et al.20.38 hour

(0.4 mg dose)

COST 170x 10.75x 2x 1x

Private 3rd Party Pay Discussion…

*Note: 2 mg IM vs 2 mg IN

IM Naloxone Kit IN Naloxone Kit

(2) Naloxone 0.4 mg/mL (1 mL) vials (2) Naloxone 1 mg/mL (2 mL) prefilled needleless syringes

(2) Syringe, 3 mL with 25G 1‐inch needle (2) Mucosal Atomizer Device (MAD 300)

(2) Alcohol pads (1) Laerdal face shield CPR barrier or equivalent

(1) Laerdal face shield CPR barrier or equivalent (1) Pair of gloves

(1) Pair of gloves (1) Overdose Rescue instructions

(1) Overdose Rescue instructions (1) Opioid Safety brochure

(1) Opioid Safety brochure (1) Zippered pouch

(1) Zippered pouch

Naloxone Kits and Naloxone Autoinjectors: Recommendations for Issuing Naloxone Kits and Naloxone Autoinjectors for the VA Overdose Education and Naloxone Distribution (OEND) Program. May 2015. VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives in collaboration with the VA OEND National Support and Development Work Group.

NALOXONE KIT COMPARISONS

National Alliance of State Pharmacy Associations (NASPA) www.ncspae.orghttp://naspa.us/wp‐content/uploads/2016/02/Naloxone‐Feb‐2016‐MAP.jpg

How does one decide who is a candidate for in‐home naloxone if you need to be selective?

But more importantly,How do you convince third party payers to pay?

Results

Zedler B, et al. Pain Med. 2015;16:1566‐1579.

QuestionPoints for

YES Response

In the past 6 months, has the patient had a healthcare visit (outpatient, inpatient or ED) involving any of the following health conditions?

Opioid dependence?Chronic hepatitis or cirrhosis?Bipolar disorder or schizophrenia?Chronic pulmonary disease (e.g., emphysema, chronic bronchitis, asthma, pneumoconiosis, asbestosis)?Chronic kidney disease with clinically significant renal impairment?An active traumatic injury, excluding burns (e.g., fracture, dislocation, contusion, laceration, wound)?Sleep apnea?

15975543

Does the patient consume:An extended‐release or long‐acting (ER/LA) formulation of any prescription opioid?

(e.g., OxyContin, Oramorph‐SR, methadone, fentanyl patch)Methadone? (Methadone is a long‐acting opioid so also check “ER/LA formulation” [9 points])Oxycodone? (If it has an ER/LA formulation [e.g., OxyContin] also check “ER/LA formulation” [9 points])A prescription antidepressant? (e.g., fluoxetine, citalopram, venlafaxine, amitriptyline)A prescription benzodiazepine? (e.g., diazepam, alprazolam)

9

9374

Is the patient’s current maximum prescribed opioid dose:≥100 mg morphine equivalents per day?50‐<100 mg morphine equivalents per day?20‐<50 mg morphine equivalents per day?

1695

In the past 6 months, has the patient:Had one or more emergency department (ED) visits?Been hospitalized for one or more days?

118

Total point score (maximum 115)

March 8, 2017


Results

Zedler B, et al. Pain Med. 2015;16(8):1566‐1579.

Overdose or Serious Opioid‐InducedRespiratory Depression(All patients, n=8,987)

RiskClass

Risk IndexScore(Points)

All Patients(N=8987),n (%)

Average PredictedProbability(95% CI)

ObservedIncidence

1 0‐24 7133 (79.4) 0.03 (0.03, 0.03) 0.03

2 25‐32 780 (8.7) 0.14 (0.14, 0.15) 0.14

3 33‐37 306 (4.5) 0.24 (0.24, 0.24) 0.23

4 38‐42 238 (2.7) 0.34 (0.34, 0.35) 0.37

5 43‐46 133 (1.5) 0.46 (0.45, 0.46) 0.51

6 47‐49 77 (0.9) 0.55 (0.54, 0.55) 0.55

7 50‐54 101 (1.1) 0.64 (0.64, 0.65) 0.60

8 55‐59 87 (1.0) 0.76 (0.75, 0.76) 0.79

9 60‐66 73 (0.8) 0.85 (0.84, 0.85) 0.75

10 ≥67 59 (0.7) 0.94 (0.93, 0.95) 0.86

Model PerformanceC‐statistic = 0.88Hosmer‐Lemeshow goodness‐of‐fit statistic = 10.8 (P>0.05)

NON‐VA POPULATION

• Retrospective case‐control study of 18,365,497 patients • IMS PharMetrics Plus integrated commercial health plan

opioid claims in the U.S.• 7,234 patients experience OSORD• OSORD found to be associated with:

– ER/LA opioid formulations– Daily morphine equivalence dose– Interacting medications– ED visits and hospital admissions– Coexisting health conditions

OSORD = Overdose or Serious Opioid‐induced Respiratory Depression Zedler B, Saunders W, Joyce A, Vick C, Murrelle L (Venebio Group) Validation of a Screening Risk Index for Overdose or Serious Prescription Opioid‐Induced Respiratory Depression. Courtesy of painmed.org Accessed: 2/9/2016.

RIOSORD Risk Index for Overdose or Serious Opioid‐induced Respiratory Depression

146 Zedler B, Saunders W, Joyce A, Vick C, Murrelle L (Venebio Group) Validation of a Screening Risk Index for Overdose orSerious Prescription Opioid‐Induced Respiratory Depression. Courtesy of painmed.org Accessed: 2/9/2016

NON‐VA POPULATION

Online Software App to Determine Risk for OIRD

https://www.remitigate.com/naloxotel/

https://www.remitigate.com

March 8, 2017


March 8, 2017


Documented: 10/05/16Provider:Dr. John Doolittle, PhysicianPatient:John Doe, 00/00/0000, ID 666

Prescribed drugsoxycodone 60 mg/dayhydrocodone 20 mg/day

Total Morphine Dose:110mg/dayThe following parameters were evaluated and identified to elevate risk for opioid‐induced respiratory depression in this patient:Within the past 6 months the patient has had a healthcare visit (outpatient, inpatient, or ED) involving the following:

‐ Bipolar disorder or schizophrenia

‐ Chronic pulmonary disease (e.g., emphazema, chronic bronchitis, asthma, pneumoconiosis, abestosis)

‐ Chronic headache (e.g., migraine)

Prescribed Drugs or Drug Classes Identified by RIOSORD:

An extended‐release or long‐acting (ER/LA) formulation of any prescription opioid, including the above

A prescription benzodiazepine (e.g., diazepam, alprazolam)

A prescription antidepressant (e.g., fluoxetine, citalopram, venlafaxine, amitriptyline)

The following parameters were evaluated and identified to elevate risk for opioid‐induced respiratory depression to this patient above that which is calculated for the validated RIOSORD: carisporidol, hydroxazine

Predicted Opioid Risk Assessment ‐ 83%This patient was evaluated for percent risk of opioid‐induced respiratory depression using the validated RIOSORD [1,2] analysis tool. This patient was determined to have a(n) 83% risk based on the unique criteria outlined herein.

For this reason, naloxone for in‐home use is recommended for this patient. This recommendation is consistent with AMA, ASAM, FDA, CDC, SAMHSA and other professional organization recommendations or guidelines to provide in‐home naloxone for patients receiving opioids that are at risk for opioid induced respiratory depression.

hydrocodone 20mg/day and oxycodone 60mg/dayThis patient is on hydrocodone 20mg/day and oxycodone 60mg/day which are metabolized by CPY 2D6 to a more active metabolite and by 3A4 to an inactive metabolite. For this reason, a medication inducer or inhibitor may increase or decrease these levels and place the patient at higher risk of opioid induced respiratory depression.

Patient and caregiver was/were counseled on opioid risk factors, how to minimize such risks, and offered naloxone for in‐home use. Based on the overall assessment and understanding of patient and/or caregiver, it is determined that the best option for this patient is: Evzio auto‐injector. This is due to the following reason(s): Patient has medically documented seasonal or chronic sinusitis with nasal congestion,Patient has other nasal septal abnormalities, nasal trauma, epistaxis.

Patient agrees to fill prescription for naloxone as outlined above. Education about overdose prevention and instructions for use of Evzio auto‐injector for OPIOID OVERDOSE reversal were provided to this patient and/or caregiver. Method of contact was In‐person. Length of the session was 20 minutes.

1. Zedler, Barbara, et al. "Development of a Risk Index for Serious Prescription Opioid‐Induced Respiratory Depression or Overdose in Veterans' Health Administration Patients." Pain Medicine 16.8 (2015): 1566‐1579.

2. Zedler BK, Saunders W, Joyce A, Vick C, Murrelle L. Validation of a screening risk index for serious prescription opioid‐induced respiratory depression or overdose in a national commercial insurance claims database. Pain Medicine, 2015.

These recommendations were generated by Naloxotel, a product of Remitigate

Documented: 10/05/16 Provider:Dr. John Doolittle, Physician Patient:John Doe, 00/00/0000, ID 666

Prior Authorization for John Doe, DOB 00/00/0000, ID 666

By receipt of this fax, insurance provider is notified, understands and acknowledges that the medical provider or pharmacist on record has determined that Evzio auto‐injector is MEDICALLY NECESSARY in order to mitigate risk of mortality or morbidity.

The VALIDATED calculated percent risk of at least 83% for opioid induced respiratory depression exists for insured patient John Doe. If payment for all FDA approved products is denied with the presumption and advice from insurer and staff that the prescriber and dispenser of naloxone off‐label product with no usability studies, and insurer understands there are inherent risks for the insured patient. Patient, insurer, and the third party payer staff denying this request understand availability of FDA approved naloxone for in‐home use could prevent harm or death in case of intentional or unintentional opioid overdose emergency. This will become part of the patient's medical record for review in case of harm or death.

Prescribed drugs oxycodone 60 mg/day hydrocodone 20 mg/day Total Morphine Dose: 110mg/day The following parameters were evaluated and identified to elevate risk for opioid‐induced respiratory depression in this patient:continued…

Importance for Collaborating with Pharmacists by Practice Setting

• Community

• Inpatient Hospital

• Ambulatory Care

March 8, 2017


Access to Naloxone Varies From State to State

• Media, Governors:Naloxone in the state is now “OTC”

• Certain large chain pharmacies:“Our pharmacists provide naloxone”

– Dispensing pharmacist: What?!?!?

– Some payers require prior authorization

• Maine requires naltrexone failure

Patient: Why Should I Have Naloxone Now?

• Why all of a sudden is this an issue?

• Who will pay for it?

• Where should I keep it?

• Documentation in EMR or pharmacy record

• Software application for assessing OIRD risk

– Yet to come…

PANIC BUTTON & HOME ALONEPANIC BUTTON & HOME ALONE

OPEN ACCESS

NOverdose

HOME ALONE

Conclusion• Encourage the use of risk stratification tools (See painedu.org)

• Education for all prescribers & pharmacists

• Slow escalation of opioid doses upon conversion

• Recognize unique population variables

• Realize the value of a PHARMACIST “provider” to mitigate drug risks and encourage them to be part of YOUR team!

• And when all else fails…There’s an app for that!