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Look Alive, It’s Time to ReviveLook Alive, It’s Time to ReviveRuben Santiago, Pharm.D., BCPS, BCCCPEmergency Medicine Clinical PharmacistJackson Memorial Hospital, Miami, FLAugust 3, 2018

#FSHP2018Disclosure

• I do not have a vested interest nor am I affiliated with any corporate organization offering financial support or grant monies for this continuing education activity, or have any affiliation with an organization whose philosophy could potentially bias my presentation

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Pharmacist ObjectivesPharmacist Objectives• Discuss recent changes in law regarding naloxone

availability and use by non-medical personnel

• Review naloxone administration and dosing strategies

• Design a treatment algorithm for opioid overdose and identify appropriate use of naloxone that includes first responders and Emergency Medical Services

• Describe alternative pain management options in the emergency department to minimize opioid use

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Technician ObjectivesTechnician Objectives

• Discuss recent changes in law regarding naloxone availability and use by non-medical personnel

• Review naloxone administration and dosing strategies

• Identify appropriate use of naloxone that includes first responders or Emergency Medical Services

• Describe alternative pain management options in the emergency department to minimize opioid use

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Sobering Statistics

115 Americans die everyday from an opioid overdose

In 2016, 63,632 Americans died due to an overdose with ~2/3 involving an opioid

The number of deaths caused by overdose attributed to opioids is 5x higher in 2016 than it was in 1999

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Understanding the Epidemic. CDC.gov. August 2017.U.S. drug overdose deaths continue to rise; increase fueled by synthetic opioids. CDC.gov. March 2018

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Prescription opiates in the

(1990s)

Illicitly Manufactured

Fentanyl (2013)

Heroin (2010)

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Understanding the Epidemic. CDC.gov. August 2017.

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“Lotta drug dealin’ ’round me goin’ down in Dade county”

- Rick Ross, “Hustlin’”

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Opioid Epidemic in Florida

2016 •2,798 opioid related overdose deaths

1,566 •Synthetic opioid related deaths in 2016

2013 •200 synthetic opioid deaths

2015 •12.7 million prescriptions for opioids

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National Institute on Drug Abuse. Florida Opioid Summary. February 2018.

Florida Laws

911 Good Samaritan Act

Emergency Treatment and Recovery Act

HB 1241 –Pharmacists sell

naloxone without a prescription

2012 2015 2016

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2017: Florida State of Emergency

• Executive order 17-146: Opioid Epidemic Public Health Emergency

• Standing order for naloxone by State Surgeon General Dr. Celeste Philip

• Five essential steps for first responders by Substance Abuse and Mental Health Services Administration (SAMHSA)

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Florida Statute 381.887 – Emergency Treatment for Suspected Opioid Overdose• Caregivers• Emergency responders

• Law enforcement officers• Fire Fighters• Paramedics• Emergency medical technicians

• Crime laboratory personnel• Authorized health care practitioner

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Classification of OpioidsPhenanthrenes

• Naturally occurring alkaloids: morphine, codeine

• Semi-synthetic: buprenorphine, butorphanol, hydrocodone, hydromorphone, nalbuphine, oxycodone, oxymorphone, heroin

Phenylpiperidines

• Synthetic: alfentanil, fentanyl, meperidine, sufentanil

Diphenylheptanes

• Synthetic: methadone

Trescot A, et. al. Pain Physician. 2008; 11: S133 – S153. Ch. 38: Opioids. Goldfrank’s Toxicologic Emergencies.

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Pharmacology of Opioids

Mu

• Supraspinal analgesia, respiratory depression, euphoria, sedation, decreased gastrointestinal motility, physical dependence, pruritus, bradycardia

Kappa• Spinal analgesia, sedation, dyspnea, dependence, euphoria,

dysphoria, psychomimetic effects, respiratory depression, and miosis

Delta• Spinal analgesia, supraspinal analgesia, psychomimetic, and

dysphoric effects

Trescot A, et. al. Pain Physician. 2008; 11: S133 – S153.Ch. 38: Opioids. Goldfrank’s Toxicologic Emergencies.

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Respiratory Depression

Central Nervous System Depression

Miosis Depression of Autonomic Activity

Opioid Toxidrome

Ruha A. Emerg Med Clin N Am. 2014; 32: 205–221.Levine M. CHEST. 2011; 140(3): 795 – 806.

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Naloxone (Narcan®)

Opioid antagonist

Initial dose: 0.4 – 2 mg

Onset:2 – 8 minutes

(varies)

Duration: 30 – 120 minutes (varies)

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Intranasal (IN) Naloxone

Prevent needlestick injuries

Nasal cavity ideal for systemic drug absorption

Naloxone drug properties

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Saved By the Nose – Denver Study

Design•Prospective evaluation of intranasal naloxone

Inclusion Criteria

•> 14 years of age •AMS, found down, suspected overdose

Protocol •IN naloxone via mucosal atomizer device, 1 mg per nare

Outcomes

•Patient response•Time to response post naloxone

Barton E. Journal of Emergency Medicine. 2005; 29(3): 265 – 271.

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Results

• 95 patients• 52 responded to IN or IV

naloxone• 43/52 (83%) responded to

IN naloxone• 36/43 (84%) required no

further naloxone• 9/52 (17%) only responded

to IV naloxone0

2

4

6

8

10

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Arrival to Clinical Response Drug Administration to ClinicalResponse

Min

utes

Response Times

IN Naloxone IV NaloxoneBarton E. J Emerg Med. 2005; 29(3): 265 – 271.

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IV versus IN Naloxone Prehospital

Study Design

• Retrospective review March 2003 – July 2004

Inclusion criteria

• Patients transported by EMS for suspected narcotic overdose

Protocol

• IN naloxone 1 mg per nostril via MAD if suspected narcotic intoxication and respiratory depression

Outcomes

• Time from naloxone administration to clinical response, time from patient contact to clinical response

Robertson T. Prehospital Emergency Care. 2009; 13: 512 – 515.

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ResultsIV versus IN Naloxone as First-line Therapy (n = 154)

Outcomes IV Naloxone ( n = 104) IN Naloxone (n = 50)Positive Clinical Response* 58 (56%) 33 (66%)Drug to Clinical Response Time (minutes) 8.1 12.9

Patient Contact to Clinical Response Time (minutes) 20.7 20.3

Second Dose 19 (18%) 17 (34%)Rescue Dose 0 (0%) 3 (6%)

*Positive clinical response defined as increase in respiratory rate of at least 6 breaths per minute or improvement of Glasgow Coma Scale (GCS) of at least 6 points

Robertson T. Prehospital Emergency Care. 2009; 13: 512 – 515.

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IM versus IN Naloxone

IM Naloxone 2 mg

Study Design: prospective, randomized,

unblinded trial

IN Naloxone 2 mg

Primary Outcome: proportion of patients with adequate response within 10 minutes

Kerr D. Addiction. 2009; 2067 – 2074.

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Results

IM versus IN naloxone (n = 172) Outcomes IM naloxone (n = 89) IN naloxone (n = 83)Adequate response ≤ 10 minutes 69 (77.5%) 60 (72.3%)

Mean response time (minutes) 7.9 8

Rescue naloxone 4 (4.5%) 15 (18.1%)

Kerr D. Addiction. 2009; 2067 – 2074.

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Nebulized Naloxone

Study Design• Convenience

sample of patients suspected of opioid intoxication

Objective• Describe

improvements in GCS and Richmond Agitation Sedation Scale (RASS) scores

Inclusion Criteria• > 18 years of age• No naloxone in the

prehospital setting• Received

nebulized naloxone for suspected opiate overdose

Protocol • > 6 breaths per

minute and suspected opioid intoxication

• 2 mg naloxone in 3 mL normal saline via nebulizer facemask

Baumann B. Am J Emerg Med. 2013; 585 – 588.

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Results Nebulized

naloxone (n = 26)

11 patients received repeat

doses (IV, n = 2; IN, n = 1; nebulizer, n = 8)

• Median time to second dose 33 minutes (range 15 –300 minutes)

3 patients received repeat doses

(IV, n = 2; IN, n = 1)

• Time to third dose ranged from 30 – 224 minutes

Outcomes Pre-naloxone Post-naloxoneGCS

(median) 11 13

RASS (median) -3 -2

Baumann B. Am J Emerg Med. 2013; 585 – 588.

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Overdose Prevention. Orange County Government Florida.

Accessed May 23, 2018.

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Five Essential Steps for First Responders

1. •Call 911

2. •Check for signs of opioid overdose

3. •Support the person’s breathing

4. •Administer naloxone

5. •Monitor the person’s response SAMHSA Opioid Overdose Prevention Toolkit: Five Essential Steps for First Responders. Revised 2016.

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Executive Order Number 17-146Approved Options for Intranasal or Auto-Injector Administration

Intranasal Intranasal Auto-Injector

Naloxone 2 mg/2 mL prefilled syringe, # 2 syringesSIG: Spray one-half of the syringe into each nostril upon signs of opioid overdose.Call 911.May repeat x 1. Mucosal Atomization Device (MAD) # 2 SIG: Use as directed for naloxone administration. Kit must contain 2 prefilled syringes and 2 atomizers and instructions for administration.

Narcan Nasal Spray 4 mg, #2 SIG: Administer a single spray intranasally into one nostril. Call 911. Administer additional dose using a new nasal spray with each dose, if patient does not respond or responds and then relapses into respiratory depression. Additional doses may be given every 2 to 3 minutes until emergency medical assistance arrives.No kit is required.Product is commercially available.

Naloxone 0.4 mg/0.4 mL#1 twin packSIG: Use one auto-injector upon signs of opioid overdose. Call 911. May repeat x 1.Not kit is required.Product is commercially available.

Price: $135.99 Price: $4,500.00

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Trends in Opioid Prescribing• 2010, enough opioids were

prescribed in the US that every American adult could be provided with 5 mg hydrocodone every 4 hours for a month

• More than 1 in every 6 patients discharged from an emergency department (ED) are given a prescription for an opioid pain reliever

• Survey of 59 patients in the ED who self-reported heroin, or non-medical opioid use (heroin use n = 42, heroin overdose n = 12, non-medical prescription opioid use n = 5)

• 35/59 (59%) of patients initial exposure to opioids legitimate prescription from a medical provider, 10 exposed in the ED

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Butler M. Ann Emerg Med. 2016; 68(2): 202–208.

#FSHP2018

HB 21 signed into law March 19,

2018

> 16 years of age, a prescriber or dispenser must

consult E-FORSCE prior to prescribing

or dispensing a controlled substance

Prescription for a Schedule II opioid

for acute pain may not exceed a

3-day supply

7 – day supply of Schedule II opioid

may be prescribed for

certain indications

July 1, 2018

Scott, Jeff. Florida Medical Association.

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Alternatives to Pain Management in the Emergency Department

Pain most common presentation to the

EDOpioid shortages Opioid epidemic

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Non-Opioid Analgesics

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Acetaminophen

Nitrous Oxide

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Motov S. J Emerg Med. 2018; 54(5): 731 – 736. Todd K. Pain Ther. 2017; 6: 193 – 202.

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Local and Regional Nerve Blocks

Headache Back pain

Hip fractures Trauma

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Motov S. J Emerg Med. 2018; 54(5): 731 – 736. Todd K. Pain Ther. 2017; 6: 193 – 202.

Reisenauer S. Adv Emerg Nurs J. 2012. Roldan C. J Emerg Med. 2015; 49(6): 1004 – 1010.

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KETAMINE

NMDA receptor antagonist

Decreases in acute pain, opioid tolerance, opioid-induced

hyperalgesia, allodynia, and neuropathic pain

SDDK potent analgesic and amnestic effects and

preserves airway reflexes, spontaneous respiration, and

cardiopulmonary stability

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Ketamine for Acute Pain

Study Design

• Prospective, randomized, double-blind

Intervention

• 0.3 mg/kg ketamine versus 0.1 mg/kg morphine

Primary Outcome

• Pain reduction at 30 minutes

Patient Characteristics

• 18 – 55 years of age presenting to the ED for acute pain

Motov S. Ann Emerg Med. 2015; 66: 222 – 229.

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ResultsKetamine versus Morphine for Acute Pain in

the ED (n = 90)

Time Interval

(minutes)

Ketamine (n = 45) Pain NRS (median)

Morphine (n = 45)Pain NRS (median)

Baseline 8.6 8.515 3.2 4.230 4.1 3.960 4.8 3.4

Motov S. Ann Emerg Med. 2015; 66: 222 – 229.

Adverse events higher at 15 minutes in the ketamine

group versus the morphine group

Adverse event reached equivalence at 30 minutes

No significant difference between groups in rescue medication at 30 minutes

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Ketamine: To Push, or Not to Push?

Adverse effects, thought

to be attributable to

IV push administration

Prospective, randomized, double-blind,

double dummy

Ketamine 0.3 mg/kg given

IVP over versus short infusion

(SI) prepared in 100 mL of

normal saline over 15 minutes

Evaluated the overall rate as

well as the specific severity

levels of side effects

Motov S. Am J Emerg Med. 2017; 35: 1095 – 1100.

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Results24 patients per group

Overall feeling of unreality was 91.7% in the IVP group vs. 54.2% in the SI group (p = 0.008)

Feeling of unreality score at five minutes: three for the IVP group versus zero for the SI group ( p = 0.001)

IVP group showed a significantly greater degree of sedation at five minutes (p = 0.01)

Start a DRIP, REDUCE the TRIP

Motov S. Am J Emerg Med. 2017; 35: 1095 – 1100.

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Lidocaine

Class 1b antiarrhythmic

Inhibits sodium channel

depolarization

Administered via various routes for

various pain syndromes

Complications -periorbital numbness,

dizziness, vertigo, dysarthria

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Golzari S. Anesth Pain Med. 2014; 4(1): e15444.

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Short half-life (60 – 120 minutes)

Analgesic, antihyperalgesic, anti-inflammatory

Predictable adverse effects

Studied for intravenous use for

pain in various settings

Lidocaine

Silva L. Ann Emerg Med. 2017. [Epub ahead of print].

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Case Report 1 • 58 year old male • Acute pain

secondary to rotator cuff injury

• Unresponsive to opiates and NSAIDs

• Lidocaine 120 mg IV

• Discharged from ED

Case Report 2 • 29 year old male• Left flank pain• Previous Rx for

oxycodone/apap for renal colic

• Lidocaine 150 mg IV

• Discharged from ED

Case Report 3• 17 year old male• Traumatic ankle

injury • Persistent pain

despite morphine• Lidocaine 100 mg

IV• Discharged home

after orthopedic manipulation

Systematic Review• Assess safety and

efficacy of IV lidocaine for pain management in the ED

• ≥ 18 years of age who received IV lidocaine for pain

• Pain Presentations• Difference in

dosing strategies among studies

• Limited evidence

LIDOCAINE 45

Sin B. J Pharm Pract. 2017: 1 – 4. Sin B. Ann Pharmacother. 2016; 50(3): 242.

Wiafe J. Ann Pharmacother. 2017; 5(10): 923. Silva L. Ann Emerg Med.

2017. [Epub ahead of print].

Conclusion

• Opioid epidemic continues to plague the United States• Majority of fatal overdoses involve opiates• In Florida, first responders may administer naloxone for

reversal of opioid overdose• Expanding naloxone administration, in conjunction with

limiting number of days of opiate therapy, hope to decrease the number of opiate related adverse events

• Alternatives to opioids for pain management in the ED include sub-dissociative dose ketamine and lidocaine

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47 References • Understanding the epidemic. Centers for Disease Control and Prevention. August 30, 2017.

https://www.cdc.gov/drugoverdose/epidemic/index.html. Accessed May 23, 2018. • U.S. drug overdose deaths continue to rise; increase fueled by synthetic opioids. Centers for Disease

Control and Prevention. March 29, 2018. https://www.cdc.gov/media/releases/2018/p0329-drug-overdose-deaths.html. Accessed May 23, 2018.

• Opioid-related overdose deaths. Florida Opioid Summary. National Institute on Drug Abuse. February 2018. https://www.drugabuse.gov/drugs-abuse/opioids/opioid-summaries-by-state/florida-opioid-summary. Accessed May 23, 2018.

• Florida Department of Health, Office of Communications. Gov. Scott Directs Statewide Public Health Emergency for Opioid Epidemic. Florida Health. May 3, 2017. http://www.floridahealth.gov/newsroom/2017/05/050317-health-emergency-opioid-epidemic.html. Accessed May 23, 2017.

• Chapter 38. Opioids. Goldfrank’s Toxicologic Emergencies. 8th ed. 2006. • Trescot A, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008; 11: S133 – S153.

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References • Ruha A, Levine M. Central nervous system toxicity. Emerg Med Clin N Am. 2014; 32: 205–221. • Levine M, Brooks D, Truitt C, et. al. Toxicology in the ICU – Part 1: general overview and approach to

treatment. CHEST. 2011; 140(3): 795 – 806. • Holstege C, Borek H. Toxidromes. Crit Care Clin. 2012; 28: 479 – 498. • Wermeling D. a response to the opioid overdose epidemic: naloxone nasal spray. Drug Deliv Transl Res.

2013; 3(1): 63–74. • Barton E, Colwell C, Wolfe T, et. al. Efficacy of intranasal naloxone as a needleless alternative for

treatment of opioid overdose in the prehospital setting. Journal of Emergency Medicine. 2005; 29(3): 265 – 271.

• Robertson T, Hendey G, Stroh G, Shalit M. Intranasal naloxone is a viable alternative to intravenous naloxone for prehospital narcotic overdose. Prehospital Emergency Care. 2009; 13: 512 – 515.

• Kerr D, Kelly A, Dietze P, et. al. Randomized controlled trial comparing the effectiveness and safety of intranasal and intramuscular naloxone for the treatment of suspected heroin overdose. Addiction. 2009; 2067 – 2074.

• Baumann B, Patterson R, Parone D, et. al. Use and efficacy of nebulized naloxone in patients with suspected opioid intoxication. Am J Emerg Med. 2013; 585 – 588.

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References• Butler M, Ancona R, Beauchamp G. ED prescription opioids as an initial exposure preceding addiction.

Ann Emerg Med. 2016; 68(2): 202–208. • Scott, Jeff. Florida’s New Law on Controlled Substance Prescribing. Florida Medical Association. • Pourmand A, et. al. Low dose ketamine use in the emergency department, a new direction in pain

management. Am J Emerg Med. 2017; 35: 918 – 921. • Sin B, et. al. The use of subdissociative-dose ketamine for acute pain in the emergency department.

Academic Emergency Medicine. 2015; 22: 251 – 257. • Motov S, et. al. A prospective randomized, double-dummy trial comparing IV push low dose ketamine

to short infusion of low dose ketamine for treatment of pain in the ED. Am J Emerg Med. 2017; 35: 1095 – 1100.

• Motov S, et. al. Intravenous subdissociative-dose ketamine versus morphine for analgesia in the emergency department: a randomize controlled trial. Ann Emerg Med. 2015; 66: 222 – 229.

• Silva L, Scherber K, Cabrera D, et. al. Safety and efficacy of intravenous lidocaine for pain management in the emergency department: a systematic review. Ann Emerg Med. 2017. [Epub ahead of print].

• Golzari S, Soleimanpour H, Mahmoodpor A, Safari S, Ala A. Lidocaine and pain management in the emergency department: a review article. Anesth Pain Med. 2014; 4(1): e15444.

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References • Wiafe J, Sin B. use of intravenous lidocaine for the treatment of acute pain in the emergency

department. Ann Pharmacother. 2017; 5(10): 923.• Sin B, Effendi M, Bjork C, Punnapuza S. The use of intravenous lidocaine for renal colic in the

emergency department. Ann Pharmacother. 2016; 50(3): 242.• Sin B, Gritsenko D, Tam G, Koop K, Mok E. The use of intravenous lidocaine for the management of

acute pain secondary to traumatic ankle injury: a case report. J Pharm Pract. 2017: 1 – 4. • Motov S, Strayer R, Hayes B, Reiter M, Rosenbaum S, Richman M, et. al. The treatment of acute pain in

the emergency department: a white paper position statement prepared for the American academy of emergency medicine. J Emerg Med. 2018; 54(5): 731 – 736.

• Todd K. A review of current and emerging approaches to pain management in the emergency department. Pain Ther. 2017; 6: 193 – 202.

• Reisenauer S. A needle in the neck – trigger point injections as headache management in the emergency department. Adv Emerg Nurs J. 2012; 34(4): 350 – 356.

• Roldan C, Hu N. Myofasical pain syndromes in the emergency department: what are we missing? J Emerg Med. 2015; 49(6): 1004 – 1010.

• Nejat A, Teymourian H, Behrooz L, Mosheni G. Pain management via ultrasound guided nerve block in emergency department; a case series study. Emergency. 2017; 5(1): e12.

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Look Alive, It’s Time to ReviveLook Alive, It’s Time to ReviveRuben Santiago, Pharm.D., BCPS, BCCCPEmergency Medicine Clinical PharmacistJackson Memorial Hospital, Miami, FLAugust 3, 2018

#FSHP2018