Prescribing Naloxone to Patients for Overdose Reversal Julie Kmiec, DO Assistant Professor of Psychiatry University of Pittsburgh School of Medicine
Disclosures • Financial – none • This presentation will discuss intranasal use of naloxone solution 1 mg/mL which is an off-label use of this product
Educational Objectives • At the conclusion of this activity participants should be able to: • Discuss how the opioid prescribing epidemic is associated with the overdose epidemic • Discuss opioid overdose risk factors • Describe the basic pharmacology of naloxone • Describe studies demonstrating the efficacy of naloxone in bystander overdose • Name the four different forms of naloxone available for bystander reversal of overdose and discuss to prescribe it
Overview • Opioid epidemic • Overdose epidemic • Overdose risk factors • Naloxone • Opioid overdose prevention programs • How you can prescribe naloxone
OPIOID EPIDEMIC
Opioid Epidemic • From 1999 to 2008, the number of opioids prescribed in the US quadrupled (CDC, 2011) • Consensus statement from American Pain Society and American Academy of Pain Medicine in 1997 • Little risk of addiction and overdose in pain patients • “Fewer than 1% of patients become addicted to opioids” (based on Letter to Editor to NEJM by Porter and Jick, 1980) • Greater emphasis in assessing and treating pain (TJC; Berry & Dahl, 2000), 5th vital sign (APS, VHA) • Purdue Pharma: OxyContin as safe and effective, funded >20,000 educational programs on pain, encouraged long-term opioid for pain, supported professional societies, FSMB, TJC (Kolodny et al., 2015)
New England Journal of Medicine ; 1/10/80
Total 608 citations Number and Type of Citations of the 1980 Letter, According to Year. 439 (72.2%) cited as addiction rare 491 (80.8%) did not cite that pts were hospitalized and given opiates Introduction of OxyContin Leung PT et al. N EnglJ Med 2017;376:2194-2195.
Opioid Misuse • Roughly 21- 29% of patients prescribed opioids for chronic pain misuse them • Between 8-12% develop an opioid use disorder • An estimated 4-6% who misuse prescription opioids transition to heroin • About 80% of people who use heroin first misused prescription opioids Vowles et al., 2015; Muhuri et al., 2013; Cicero et al., 2014; Carlson et al., 2016
Cicero et al., 2017
OVERDOSE EPIDEMIC
Overdose Deaths • From 2000-2014, there was a 200% increase in deaths involving opioids • Opioid overdoses increased 30% from July 2016 through September 2017 in 52 areas in 45 states Rudd et al., 2016; Vivolo-Kantor et al., 2017
Allegheny County Overdose Data 800 728 700 613 600 500 424 Fatal OD 400 Heroin 306 290 276 300 262 Fentanyl 234 227 225 200 100 0 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 Adapted from https://www.overdosefreepa.pitt.edu/
OVERDOSE RISK FACTORS
Overdose Risk Factors • Using >50 mg of oral morphine equivalents daily (Bohnert et al., 2011; Zedler et al., 2014; Liang and Turner, 2015; Yang et al., 2015) • Recent release from controlled environment • Incarceration (Binswanger et al., 2013; Binswanger et al., 2007) • Treatment (Strang et al., 2003) • Mixing opioids with benzos, alcohol, other drugs (Powis et al., 1999) • Medical conditions (renal, hepatic, pulmonary diseases, HIV)
Respiration • Respiration is principally controlled by medullary respiratory center with peripheral input from chemoreceptors • Control of respiration from dorsal respiratory group (DRG) likely produces breathing rhythm, has influence on ventral respiratory group (VRG) which has efferent fibers that innervate muscles of respiration • Respiration involves phasic activation (excitatory amino acids like glutamate) and inhibtion (GABA mediated) • GABA receptors (A and B) have high density in DRG and VRG • Chemoreceptors are located in carotid and aortic bodies, respond to changes in blood gases; they are stimulated by decreases in oxygen, and also, but to lesser extent by increase in CO2 or decrease in pH White & Irvine, 1999
Opioids and Respiration • Opioid peptides can modulate respiration, depress respiration through reduction in glutamate induced excitation • Agonist activity at medullary mu or delta receptors causes respiratory depression • Opioids may affect tidal volume and respiratory frequency • Agonist activity at kappa receptor has either no effect on respiration or may stimulate respiration slightly • At chemoreceptors, inhibition is mediated by mu opioid receptor binding, resulting in decreased sensitivity to changes in oxygen and CO2, particularly the response to increased CO2 White & Irvine, 1999
Other Factors Influencing Overdose Risk • Glutamate and GABA mediate the control of respiration, explaining contribution of benzodiazepines and alcohol to overdose • Benzodiazepines and alcohol facilitate the inhibitory effect of GABA at GABA-A receptors • Alcohol decreases excitatory effect of glutamate at NMDA receptors • Individual differences in susceptibility to overdose may be mediated by an individual's metabolism • Glucuronidation • CYP 3A4 and 2D6 • Overdose may occur when there is loss of tolerance at cellular and/or pharmacokinetic level • High tolerance may also increase risk, as person will need to use higher doses to get an effect • Pulmonary edema is also consequence of opioid overdose and may contribute to death White & Irvine, 1999
Opioid Overdose • Decreased oxygenation of brain and heart leads to • Unresponsiveness • Anoxia, cyanosis • Death • Respiratory depression can last 1-3 hours, is reversible with naloxone Boyer, 2012
Possible Complications of Non-fatal Overdoses • Anoxic brain injury • Pulmonary edema • Acute respiratory distress syndrome • Hypothermia • Renal failure • Compartment syndrome • Liver failure • Seizures (depending on substance ingested) Boyer, 2012
NALOXONE
Naloxone • Naloxone is opioid antagonist • High affinity for mu receptor • Displaces bound agonist • Prevents other agonists from binding • Works within minutes • Lasts 20-90 mins • FDA approved for IV, SC, IM use • Recent FDA approved intranasal naloxone; also off-label intranasal use of naloxone for injection • Naloxone has been used for opioid reversal for 40 years in hospitals • Naloxone has been used for overdose in ED and by paramedics for years • Since mid-1990s, provision for use outside medical setting for people at risk of overdose Boyer, 2012
Possible Adverse Effects of Naloxone • If administered in usual dose to someone not using opioids, there are no adverse effects • Tachycardia • Hypertension • Hypotension • Seizure – due to anoxia • Nausea, vomiting • Diaphoresis • Other opioid withdrawal symptoms • Severe symptoms listed in prescribing info were seen in post-op reversals Naloxone prescribing information
Naloxone IM vs IN • Kerr et al. (2009) • Concentrated naloxone 2 mg/1 mL IM vs. IN randomized, controlled, open-label trial • 172 patients with suspected overdose treated by EMS • 83 received 1 mg/0.5 mL in each nostril • 89 received 2 mg/1 mL IM • 129 had adequate response within 10 mins (95% CI -18.2, 7.7%) • 60 in IN group (72.3%) • 69 in IM group (77.5%) • Adverse events were similar between groups • Mean response time was similar between groups, about 8 mins
Mueller et al., 2015
Rzasa et al., 2017
Naloxone and Fentanyl • Fentanyl is highly lipophilic and rapidly equilibrates between the plasma and the CSF, resulting in fast onset of analgesia and respiratory depression • Fentanyl may be extensivel redistributed to less highly perfused tissues • Large doses of fentanyl can prolong duration of action due to saturation of tissue • Fentanyl has been shown to be resistant to reversal with standard doses of naloxone • In 2015, almost 1/5 of patients receiving naloxone from EMS required more than one administration, up from 1/6 of patients in 2012 • Fentanyl overdoses may be unresponsive to IN naloxone and only transiently reversed with IV naloxone and required additional IV doses or continuous infusions to prevent recurrence of toxicity and respiratory depression Rzasa et al., 2017
Refusing Medical Treatment After Naloxone • Retrospective review of San Diego EMS database and medical examiner’s database • Looked at paramedic data, who received naloxone and who signed AMA form (n = 998) • Looked at ME data, who died of heroin OD (n=601) • Cross-referenced lists, no one released AMA had died of OD within 12 hours Vilke et al., 2003
OPIOID OVERDOSE PREVENTION PROGRAMS
Opioid Overdose Prevention Programs (OOPP) • Started 1996, first program in Chicago • Started in harm prevention programs • OOPP train people at risk for overdose how to prevent overdose as well as how to recognize and respond to overdose • Participants are trained to seek help (call 911), rescue breath, administer naloxone IN or IM, and stay with the person who has overdosed
OOPP Providing Naloxone, 2014 2010 2014 % increase Number of sites 188 644 243% providing naloxone Number of persons 53,032 152,283 187% provided kits Number of reversals 10,171 26,463 160% reported Number of states 16 30 94% with OOPP Wheeler et al., 2015
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