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Academic Excellence Showcase Proceedings Student Scholarship

2018-06-01

Naloxone: The Surgeon General's Answer to theOpioid CrisisJamie RebmanWestern Oregon University, jrebman16@mail.wou.edu

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Recommended CitationRebman, Jamie, "Naloxone: The Surgeon General's Answer to the Opioid Crisis" (2018). Academic Excellence Showcase Proceedings.134.https://digitalcommons.wou.edu/aes/134

Naloxone:THE SURGEON GENERAL’S ANSWER TO THE OPIOID CRISIS

by Jamie M. Rebman, Department of Chemistry

The Epidemic

Every day 115 Americans overdose

1 every 12.5 minutes

42,249 US drug fatalities -- 66% of the total

~1,000 more than breast cancer deaths (also more than car accidents)

More than half of deaths occur at home, before first responders arrive or victims can get to facility

Who is being affected?

77% die outside medical facility.

Demographics:

Rx painkillers → addiction (→ $$ → Heroin)

Demographics:

http://nprillinois.org/post/illinois-issues-saving-lives-fight-against-heroin#stream/0

What is considered an Opioid?Opioids:

HeroinMorphineCodeineHydrocodoneOxycodoneMethadone*FentanylTramadolDemerol

Opium from Poppy plantOpiates – Naturally DerivedOpioids - synthetic

100x more potent than morphine

http://speciosa.org/this-should-scare-you-more-than-terrorism-the-opioid-epidemic/

Mitigating the EpidemicTHE SURGEON GENERAL’S PLAN

The Advisory

April 5, 2018

Last Surgeon General issued Advisory -- February 2005.

Surgeon General’s Vison

Needs to be as commonplace as CPR

Foresees the day when drug is as widespread as fire extinguishers

Naloxone into as many hands as possible

https://www.tennessean.com/story/money/industries/health-care/2018/05/18/surgeon-general-vanderbilt-naloxone-jerome-adams-tennessee-opioid-epidemic/622920002/https://www.adweek.com/wp-content/uploads/2017/12/opiod-memorial-hed-2017.jpg

Recognizing an Opioid Overdose

▪Symptoms:▪ Pinpoint Pupils

▪ Blue Skin, Nail Beds

▪ Drowsiness

▪ Reduced Heart Rate

▪ Confusion, Lessened Alertness

▪ Slowed, Depressed, Shallow Breathing

→ Unconsciousness

→ Respiratory Failure

Elevated Risk

• Misusing prescription opioids (like oxycodone) or having an opioid use disorder

• Recent discharge from hospital or recovering from illness, recent released from incarceration or

rehabilitation (lower tolerance)

• Combining medications

• Using illicit drugs with unknown purity, such as heroin

• Injecting prescription or illicit opioids

• Using substances while alone

What is Naloxone?The Chemistry

C19H21NO4

Alkaloid (Organic Nitrogenous Base)

 Thebaine derivateMelting Point: 178-205 °C

http://www.hmdb.ca/spectra/

LC-MS/MS

GC-MS Physical Properties

Soluble in Water, Chloroform

Heat decomposition emits toxic fumes

Aromatic heteropolycyclic

Lipophilic 

Phenanthrenes and Derivatives

Two Methods

Oxymorphone demethylated → 4,5alpha-epoxy-3,14-dihydroxymorphinan-6-one

+ Ethanol + Allyl Bromide + NaHCO3 Naloxone n-allylated

+ Ethanolic hydrochloride → Naloxone hydrochloride

Naloxone:

14-Hydroxydihydronormorphinone + allyl bromide

ORN-alkylated

Naloxone Synthesis

http://pubs.rsc.org/en/content/articlehtml/2012/ra/c2ra21693k

Naloxone

1st FDA approval - 1971

Other names and Info

• Not to be confused with Naltrexone • Used for opioid dependence. • Chemical structures are very similar• Both can be made through same process.

NarcanNaloneEvzioPrenoxad Injection Narcotan

How Naloxone WorksThe Biochemistry

Opioid Antagonist

No agonist activity

Competitive antagonist at mu and

kappa opioid receptors

http://physioknowledgebd.blogspot.com

/2016/02/agonist-and-antagonist.html

Naloxone:

http://www-personal.umich.edu/~timaster/biopsych/pharm.html

https://www.scoop.it/t/krishan-maggon-knols/p/4050550660/2015/09/01/trevena-g-protein-biased-mu-opioid-receptor-modulator-trv130-effective-in-phase-ii-pain-study

https://encrypted-tbn0.gstaticfcE0ngWykDT.com/images?q=tbn:ANd9GcQKqHtgOJDbq4TKqEsi__VhuzIu27h0dQSXnvH7fOw

https://www.practicalrecovery.com/prblog/naloxone-everything-you-need-to-know/

• Opiate Antagonist – prevents or quickly reverses effects of opioids, such as: • Respiratory Depression• Sedation• Hypotension

• No opioid, no effects • Binds strongest to mu receptor• Crosses Blood-Brain barrier

• Structured Indications:• Opioid Dependence• Opioid Overdose• Pruritis• Respiratory Depression• Moderate to Severe Pain• Septic Shock

• Off Label Uses*: • cardiogenic shock• high-altitude pulmonary edema• acute respiratory failure• senile dementia• ischemic neurologic deficits

*the safety and efficacy of naloxone in these conditions have not been established and further study is needed

Image: http://healthland.time.com/2012/02/17/lifesaving-overdose-antidote-should-be-made-more-widely-available/

Side Effects and Interactions

Hepatically metabolized, primarily via glucuronidation → naloxone-3-glucuronide

Elimination via urine (25%- 40% is excreted as metabolites within 6 hours)

The serum concentration or metabolism of Naloxone can be increased or decreased with certain medications (interacts with 107)

May immediately experience opioid withdrawal symptom: Nausea, vomiting, sweating, aches, tremors, rapid pulse, and diarrhea

Not life-threatening like alcohol withdrawals

Short duration of action

Monitor for responsiveness, potentially re-inject, or take to the hospital

Veterinarian Approved

For all ages

Use in ultra-rapid detoxification - controversial

Cytochromes P450 2C8 and 3A4

Forms of Naloxone

Available Forms

http://induced.info/?s=NARCAN+Nasal+Spray+4mg

Nasal Spray Improvised Nasal Spray*

Autoinjector Injectable

*Not FDA-approvedhttps://www.theoutpatienttreatmentcenter.com/blog/facts-about-naloxone/https://drugfree.org/wp-content/uploads/2017/02/giving-nasal-spray-naloxone4.jpg

Add a Slide Title - 3https://w

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.powerpak.com

/course/content/112666

What are the differences?

Combinations and Novel Forms

Buprenorphine 8 MG / Naloxone 2 MG Sublingual Tablet [Suboxone] – Prevents misuse and abuse of buprenorphine

Naloxone eye drop –Identification of opium dependency

Security -- personal morphine vaporization device

More Rx opioids are becoming mixed with naloxone Disintegrating Tablets*

Obtaining Naloxone

Naloxone Availability• Available in most States

• Becoming more easily obtainable

• Far in 5 years

• Some pharmacies offer in outpatient setting

http://pdaps.org/datasets/laws-regulating-administration-of-naloxone-1501695139

PDAPS.org – Naloxone Overdose Prevention LawsGetNaloxoneNow.org -- Information on obtaining Naloxone and Training

Improvised Nasal Spray: Prices doubled in 2014

Little competition, but increasing (4)

AffordabilitySurprisingly, First patented in 1961 FDA approved 1971

~$0.20 per dose in 1996↑ $15 per dose in 2016

Without government funding, organizations are having trouble providing services to growing number in need

2-pack Nasal Spray $139

Auto-injector list price $4100

For Consumers

Price regulation governed by politics and Big Pharma

Average cost: $10-$3500

Wise move from Surgeon General?

So far…

Italy – Harm reduction service distribution since early 1990s (doctor supported) – 4-fold reduction since ‘99

Indications point to yes!

Canadian survey of ER doctors found wide support.

Norway, 2014 – Multisite, government supported naloxone distribution program – Positive results

Source: United Nations International Narcotics Control Board

Costs pennies per dose in many countries

$2.40/dose

Only a temporary solution to much larger problem

Problems

Debate of possible “moral hazard” versus addressing root of epidemic

Opioid addiction is systemic problem, requiring years to decades to resolve

Large amounts of written prescriptions for Naloxone unfilled -- Stigma, cost

Price issue is not unique to Naloxonehttps://www.equities.com/news/naloxone-stocks-who-s-really-winning-the-battle-against-the-opioid-epidemic

Disclosures (fine print)

Naloxone exerts a biphasic effect on amphetamine induced dopamine release, with lower doses potentiating (↑) release and higher doses inhibiting (↓) release. May be due to the effect of low versus high doses of naloxone on intraterminal calcium influx

Naloxone dose-dependently protects against gastric mucosal damage (from Indomethacin- and HCl-, but not against ethanol-induced)

Pulmonary edema or ventricular fibrillation occasionally has occurred shortly after naloxone administration in opioid-intoxicated patients.

Rarely, severe cardiopulmonary effects resulting in death and coma have been reported in patients following postoperative administration of naloxone. No causal relationship has been established.

Both opioid receptor agonists and antagonists decrease gastric acid secretion.

Also– It has been found that Naloxone modulates endoplasmic reticulum-alpha activity directly and indirectly via Mu Opioid Receptors. This suggest that naloxone-like compounds may be developed as a novel treatment for breast cancer.

• Naloxone is an alkaloid; naturally organic nitrogenous base; Thebaine derivative

• Opioid Antagonist; higher affinity for opioid receptors -- kicks off and takes over

• Deaths from opioid overdose can be prevented by prompt administration of naloxone

• 20 years since take-home naloxone provision was first proposed

• Efforts to improve knowledge of and participation in the take-home naloxone program contribute to reducing opioid overdose mortality

• Take-home naloxone kits are not only for patients with current opioid abuse

• Studies are still on-going – but research points towards it being safe

Conclusions

References

▪ Naloxone https://pubchem.ncbi.nlm.nih.gov/compound/naloxone#section=Drug-and-Medication-Information.

▪ http://www.getnaloxonenow.org/find.html.

▪ Karlin-Smith, S. Price spikes for life-saving drug https://www.politico.com/story/2016/05/drug-prices-addiction-223192.

▪ Babcock, C.; Capehart, K. Naloxone Regulation and Integration into the Pharmacy Curriculum http://slideplayer.com/slide/12836327/ (accessed May 2, 2018).

▪ Debreceni, A.; Debreceni, B.; Mózsik, G. Journal of Physiology-Paris 1997, 91(3-5), 189–197.

▪ Elzey, M. J.; Fudin, J.; Edwards, E. S. Expert Opinion on Drug Delivery 2016, 14(9), 1045–1058.

▪ Feigenbaum, J. J.; Howard, S. G. Life Sciences 1997, 60(19), 1659–1668.

▪ Fiore, K. Nasal Naloxone Price Set to Jump https://www.medpagetoday.com/psychiatry/addictions/48829?pop=0&ba=1&xid=tmd-md&hr=trendMD.

▪ Kelman, B. Surgeon general at Vanderbilt: Ask about Naloxone - you might save a life https://www.tennessean.com/story/money/industries/health-care/2018/05/18/surgeon-general-vanderbilt-naloxone-jerome-adams-tennessee-opioid-epidemic/622920002/.

▪ Krieter, P.; Chiang, N.; Gyaw, S.; Skolnick, P.; Crystal, R.; Keegan, F.; Aker, J.; Beck, M.; Harris, J. The Journal of Clinical Pharmacology 2016, 56(10), 1243–1253.

▪ Kumar, T.; Rosenberg, H. Canadian Medical Association Journal 2017, 189(37).

▪ Lacroix, L.; Stiell, I. G.; Thurgur, L.; Orkin, A. Cjem 2017, 18(S1).

▪ Lanzkowsky, D. METHOD, System and apparatus for controlled delivery of opioid and other medications .62411455 (application number)

References (continued)

▪ Lorenzi, P. European Journal of Anaesthesiology 1999, 16(10), 719–727.

▪ Lynn, R. R.; Galinkin, J. Therapeutic Advances in Drug Safety 2017, 9(1), 63–88.

▪ Madah-Amiri, D.; Clausen, T.; Lobmaier, P. Drug and Alcohol Dependence 2017, 173, 17–23.

▪ Mcdonald, R.; Campbell, N. D.; Strang, J. Drug and Alcohol Dependence 2017, 178, 176–187.

▪ Mundin, G.; Mcdonald, R.; Smith, K.; Harris, S.; Strang, J. Addiction 2017, 112(9), 1647–1652.

▪ Naloxone https://www.drugbank.ca/drugs/DB01183.

▪ Nolan, S.; Buxton, J.; Dobrer, S.; Dong, H.; Hayashi, K.; Milloy, M. J.; Kerr, T.; Montaner, J.; Wood, E. Public Health Reports 2017, 132(5), 563–569.

▪ Opioid Overdose Reversal with Naloxone (Narcan, Evzio) https://www.drugabuse.gov/related-topics/opioid-overdose-reversal-naloxone-narcan-evzio.

▪ Pharmacists, opioid safety, take-home naloxone, and preventing overdose https://www.powerpak.com/course/content/112666 (accessed May 10, 2018).

▪ Surgeon general urges Americans to carry antidote for opioid overdose http://www.oregonlive.com/politics/index.ssf/2018/04/surgeon_general_urges_american.html (accessed Apr 10, 2018).

▪ Surgeon General's Advisory on Naloxone and Opioid Overdose https://www.surgeongeneral.gov/priorities/opioid-overdose-prevention/naloxone-advisory.html (accessed Apr 7, 2018).

▪ U.S. Department of Health and Human Services. Surgeon General Releases Advisory on Naloxone, an Opioid Overdose-Reversing Drug https://www.hhs.gov/about/news/2018/04/05/surgeon-general-releases-advisory-on-naloxone-an-opioid-overdose-reversing-drug.html.

Thank you!

Questions?https://www.google.com/imgres?imgurl=https%3A%2F%2Fwww.drugs.com%2Fimages%2Fslideshow%2F1239-intro_image-1487109598.png&imgrefurl=https%3A%2F%2Fwww.drugs.com%2Fnaloxone.html&docid=PNiSx1LsYLSdRM&tbnid=_1Skwn4AcLxUKM%3A&vet=10ahUKEwifh5yh5K_bAhVkMH0KHceIBl0QMwiWASgBMAE..i&w=300&h=182&bih=1100&b

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