COMMENTARY
Are opioid receptor antagonists adequate for “Opioid” overdose in a changing reality?
John F. Peppin DO, FACP,
Joseph V. Pergolizzi Jr. MD,
Albert Dahan MD, PhD,
Robert B. Raffa PhD,
Corresponding Author
John F. Peppin DO, FACP
Marian University College of Osteopathic Medicine (Clinical Adjunct Professor), Indianapolis, IN, USA
Clinical Professor Internal Medicine, Pikeville University, College of Osteopathic Medicine, Pikeville, USA
Correspondence
John F. Peppin, DO, FACP, Marian Clinical Professor Internal Medicine, Pikeville University, College of Osteopathic Medicine, Pikeville, USA
Email: [email protected]
Search for more papers by this authorJoseph V. Pergolizzi Jr. MD
Enalare Therapeutics Inc, Naples, FL, USA
Neumentum Inc., Summit, NJ, USA
NEMA Research Inc., Naples, FL, USA
Search for more papers by this authorAlbert Dahan MD, PhD
Leiden University Medical Center, Leiden, The Netherlands
Search for more papers by this authorRobert B. Raffa PhD
Enalare Therapeutics Inc, Naples, FL, USA
Neumentum Inc., Summit, NJ, USA
University of Arizona College of Pharmacy (Adjunct Professor), Tucson, AZ, USA
Temple University School of Pharmacy (Professor emeritus), Philadelphia, PA, USA
Search for more papers by this authorJohn F. Peppin DO, FACP,
Joseph V. Pergolizzi Jr. MD,
Albert Dahan MD, PhD,
Robert B. Raffa PhD,
Corresponding Author
John F. Peppin DO, FACP
Marian University College of Osteopathic Medicine (Clinical Adjunct Professor), Indianapolis, IN, USA
Clinical Professor Internal Medicine, Pikeville University, College of Osteopathic Medicine, Pikeville, USA
Correspondence
John F. Peppin, DO, FACP, Marian Clinical Professor Internal Medicine, Pikeville University, College of Osteopathic Medicine, Pikeville, USA
Email: [email protected]
Search for more papers by this authorJoseph V. Pergolizzi Jr. MD
Enalare Therapeutics Inc, Naples, FL, USA
Neumentum Inc., Summit, NJ, USA
NEMA Research Inc., Naples, FL, USA
Search for more papers by this authorAlbert Dahan MD, PhD
Leiden University Medical Center, Leiden, The Netherlands
Search for more papers by this authorRobert B. Raffa PhD
Enalare Therapeutics Inc, Naples, FL, USA
Neumentum Inc., Summit, NJ, USA
University of Arizona College of Pharmacy (Adjunct Professor), Tucson, AZ, USA
Temple University School of Pharmacy (Professor emeritus), Philadelphia, PA, USA
Search for more papers by this authorAbstract
What is known and Objective
Deaths due to opioid-induced respiratory depression (OIRD) continue to rise despite intense regulatory and professional actions. COVID-19 has only worsened this situation.1 An opioid receptor antagonist (ORA) such as naloxone is the most common intervention for OIRD. However, with increasing overdose from highly potent illicit opioids and polysubstance abuse, appraisal of the adequacy of ORA seems warranted and timely.
Comment
OIRD results from the binding of an excess number of agonist molecules to opioid receptors. Mechanistically, it makes sense to reverse this by displacing agonist molecules by administering an ORA. But realistically, the trend to higher-potency agonists and polysubstance abuse diminishes the effectiveness of this approach. We are left facing a crisis without a solution.
What is new and Conclusion
For the increasingly common OIRD from highly potent illicit agonists and polysubstance overdose, ORAs are correspondingly less effective. Alternatives are needed—soon.
CONFLICT OF INTEREST
Consultant Relmada Therapeutics, New York. Consultant Medical Monitor Relmada Therapeutics, New York.
REFERENCES
- 1Kamp J, Campo-Flores A. The Opioid Crisis, Already Serious, Has Intensified During Coronavirus Pandemic. Wall Street Journal. Accessed October 28, 2020.
- 2Niles JK, Gudin J, Radcliff J, Kaufman HW. The Opioid Epidemic Within the COVID-19 Pandemic: Drug Testing in 2020. Popul Health Manag. 2021; 24(S1): S-43.
- 3Azzam AAH, McDonald J, Lambert DG. Hot topics in opioid pharmacology: mixed and biased opioids. Br J Anaesth. 2019; 122(6): e136-e145.
- 4Boyer EW. Management of opioid analgesic overdose. N Engl J Med. 2012; 367(2): 146-155.
- 5Valentino RJ, Volkow ND. Untangling the complexity of opioid receptor function. Neuropsychopharmacology. 2018; 43(13): 2514-2520.
- 6Shenoy S, Lui F. Biochemistry, Endogenous Opioids. In: StatPearls [Internet] Treasure Island (FL): StatPearls Publishing; 2020 Jan-. 2018 [Updated 2020 Jul 26];2018.
- 7Corder G, Castro DC, Bruchas MR, Scherrer G. Endogenous and exogenous opioids in pain. Annu Rev Neurosci. 2018; 07(41): 453-473.
- 8Toubia T, Khalife T. The Endogenous Opioid System: Role and Dysfunction Caused by Opioid Therapy. Clin Obstet Gynecol. 2019; 62(1): 3-10.
- 9Kenichi N, Yamamoto S, Yamaga T, Horigome N, Hanaoka M. Peripherally acting μ-opioid antagonist for the treatment of opioid-induced constipation: Systematic review and meta-analysis. J Gastroenterol Hepatol. 2019; 30(5): 818-829.
- 10Labroo R, Paine M, Thummel K, Kharasch E. Fentanyl metabolism by human hepatic and intestinal cytochrome P 450 3A4: Implications for interindividual variability in diposition, efficacy and drug interactions. Drug Metab Dispos. 1997; 25(9): 1072-1080.
- 11Wilde M, Pichini S, Pacifici R, et al. Metabolic Pathways and Potencies of New Fentanyl Analogs. Front Pharmacol. 2019; 10: 238.
- 12Leen JLS, Juurlink DN. Carfentanil: a narrative review of its pharmacology and public health concerns. Can J Anaesth. 2019; 66(4): 414-421.
- 13Gill H, Kelly E, Henderson G. How the complex pharmacology of the fentanyls contributes to their lethality. Addiction. 2019; 114(9): 1524-1525.
- 14Comer SD, Cahill CM. Fentanyl: Receptor pharmacology, abuse potential, and implications for treatment. Neurosci Biobehav Rev. 2019; 11(106): 49-57.
- 15 Counterfeit Prescription Pills Containing Fentanyls: A Global Threat. DEA-DCT-DIB-021-16.
- 16Burns G, DeRienz RT, Baker DD, Casavant M, Spiller HA. Could chest wall rigidity be a factor in rapid death from illicit fentanyl abuse? Clin Toxicol (Phila). 2016; 54(5): 420-423.
- 17Trujillo C, Rudd D, Ogutcu H, Dong F, Wong D, Neeki M. Objective Characterization of Opiate-Induced Chest Wall Rigidity. Cureus. 2020; 12(6):e8459.
- 18 SB L. Opioid Antagonists in pain management. Practical Pain Management; 2009.
- 19Weijlard John, Erickson AE. N-Allylnormorphine. J Am Chem Soc. 1942; 64(4): 869-870.
- 20La W. The pharmacology of nalorphine (N-allylnormorphine. Pharmacol Rev. 1956; 175-198.
- 21 H B. Narcotic antagonist activity of naloxone. In: HB D, editor. Federation Proceedings; 1965. p. 676.
- 22Dixon R, Howes J, Gentile J, et al. Nalmefene: intravenous safety and kinetics of a new opioid antagonist. Clin Pharmacol Ther. 1986; 39(1): 49-53.
- 23Skolnick P. On the front lines of the opioid epidemic: Rescue by naloxone. Eur J Pharmacol. 2018; 835: 147-153.
- 24Shader RI. Antagonists, inverse agonists, and protagonists. J Clin Psychopharmacol. 2003; 23(4): 321-322.
- 25 YS C. Opioid antagonists: a review of their role in palliative care, focusing on use in opioid related constipation. In: JA B, editor.: J Pain Symptom Manage 2002; 2002.
- 26Fellows SE, Coppola AJ, Gandhi MA. Comparing methods of naloxone administration: a narrative review. J Opioid Manag. 2017; 13(4): 253-260.
- 27Weber JM, Tataris KL, Hoffman JD, Aks SE, Mycyk MB. Can nebulized naloxone be used safely and effectively by emergency medical services for suspected opioid overdose? Prehosp Emerg Care. 2012; 16(2): 289-292.
- 28Rzasa Lynn R, Galinkin JL. Naloxone dosage for opioid reversal: current evidence and clinical implications. Ther Adv Drug Saf. 2018; 9(1): 63-88.
- 29Smith K, Hopp M, Mundin G, et al. Low absolute bioavailability of oral naloxone in healthy subjects. Int J Clin Pharmacol Ther. 2012; 50(5): 360-367.
- 30Strickland D, Burson J. Sublingual absorption of naloxone in a large clinical population. J Drug Metab Toxicol. 2018; 9(2): 1-4.
10.4172/2157-7609.1000240 Google Scholar
- 31Krieter P, Chiang CN, Gyaw S, Skolnick P, Snyder R. Pharmacokinetic Interaction between Naloxone and Naltrexone Following Intranasal Administration to Healthy Subjects. Drug Metab Dispos. 2019; 47(7): 690-698.
- 32Lee MC, Wagner HN, Tanada S, Frost JJ, Bice AN, Dannals RF. Duration of occupancy of opiate receptors by naltrexone. J Nucl Med. 1988; 29(7): 1207-1211.
- 33Moss RB, Pryor MM, Baillie R, et al. Higher naloxone dosing in a quantitative systems pharmacology model that predicts naloxone-fentanyl competition at the opioid mu receptor level. PLoS One. 2020; 15(6):e0234683.
- 34Somerville NJ, O'Donnell J, Gladden RM, et al. Characteristics of Fentanyl Overdose - Massachusetts, 2014–2016. MMWR Morb Mortal Wkly Rep. 2017; 66(14): 382-386.
- 35Faul M, Lurie P, Kinsman JM, Dailey MW, Crabaugh C, Sasser SM. Multiple Naloxone Administrations Among Emergency Medical Service Providers is Increasing. Prehosp Emerg Care. 2017; 21(4): 411-419.
- 36Belz D, Lieb J, Rea T, Eisenberg MS. Naloxone use in a tiered-response emergency medical services system. Prehosp Emerg Care. 2006; 10(4): 468-471.
- 37Buajordet I, Naess AC, Jacobsen D, Brørs O. Adverse events after naloxone treatment of episodes of suspected acute opioid overdose. Eur J Emerg Med. 2004; 11(1): 19-23.
- 38 Administration FD. EVZIO® (naloxone hydrochloride injection) Auto-Injector for intramuscular or subcutaneous use: HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209862lbl.pdf. Accessed November 2, 2020.
- 39Dadpour B, Vahabzadeh M, Mostafazadeh B. Comparison of the efficacy of an infusion pump or standard IV push injection to deliver naloxone in treatment of opioid toxicity. Acute Crit Care. 2020; 35(1): 38-43.
- 40Tylleskar I, Skulberg AK, Nilsen T, Skarra S, Jansook P, Dale O. Pharmacokinetics of a new, nasal formulation of naloxone. Eur J Clin Pharmacol. 2017; 73(5): 555-562.
- 41Levy B, Spelke B, Paulozzi LJ, et al. Recognition and response to opioid overdose deaths-New Mexico, 2012. Drug Alcohol Depend. 2016; 167: 29-35.
- 42Algera MH, Kamp J, van der Schrier R, et al. Opioid-induced respiratory depression in humans: a review of pharmacokinetic-pharmacodynamic modelling of reversal. Br J Anaesth. 2019; 122(6): e168-e179.
- 43Peckham AM, Niculete ME, Steinberg H, Boggs DL. A Survey of Prescribers' Attitudes, Knowledge, Comfort, and Fear of Consequences Related to an Opioid Overdose Education and Naloxone Distribution Program. J Public Health Manag Pract. 2018; 24(4): 310-317.
- 44Rudolph SS, Jehu G, Nielsen SL, Nielsen K, Siersma V, Rasmussen LS. Prehospital treatment of opioid overdose in Copenhagen–is it safe to discharge on-scene? Resuscitation. 2011; 82(11): 1414-1418.
- 45Olfson M, Crystal S, Wall M, Wang S, Liu SM, Blanco C. Causes of death after nonfatal opioid overdose. JAMA Psychiatry. 2018; 75(8): 820-827.
- 46Dahan A, van der Schrier R, Smith T, Aarts L, van Velzen M, Niesters M. Averting opioid-induced respiratory depression without affecting analgesia. Anesthesiology. 2018; 128(5): 1027-1037.
- 47Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic. J Pharmacol Exp Ther. 1992; 260(1): 275-285.
- 48Marquardt KA, Alsop JA, Albertson TE. Tramadol exposures reported to statewide poison control system. Ann Pharmacother. 2005; 39(6): 1039-1044.
- 49Foster B, Twycross R, Mihalyo M, Wilcock A. Buprenorphine. J Pain Symptom Manage. 2013; 45(5): 939-949.
- 50Eizadi-Mood N, Ghandehari M, Mansourian M, Sabzghabaee AM, Samasamshariat S, Sadeghi E. Risk of seizure after naloxone therapy in acute tramadol poisoning: a systematic review with meta-analysis. Int J Prev Med. 2019; 10: 183.
- 51O'Malley GF, Seifert S, Heard K, Daly F, Dart RC. Olanzapine overdose mimicking opioid intoxication. Ann Emerg Med. 1999; 34(2): 279-281.
- 52 Abuse NIoD. Opioid Overdose Reversal with Naloxone (Narcan, Evzio). https://www.drugabuse.gov/drug-topics/opioids/opioid-overdose-reversal-naloxone-narcan-evzio. Accessed October 28, 2020.
- 53Volkow ND, Collins FS. The role of science in addressing the opioid crisis. N Engl J Med. 2017; 377(4): 391-394.
- 54Chou R, Korthuis PT, McCarty D, et al. Management of suspected opioid overdose with naloxone in out-of-hospital settings: a systematic review. Ann Intern Med. 2017; 167(12): 867-875.
- 55Lyons RM, Yule AM, Schiff D, Bagley SM, Wilens TE. Risk Factors for Drug Overdose in Young People: A Systematic Review of the Literature. J Child Adolesc Psychopharmacol. 2019; 29(7): 487-497.
- 56Golladay M, Donner K, Nechuta S. Using statewide death certificate data to understand trends and characteristics of polydrug overdose deaths in Tennessee, 2013–2017. Ann Epidemiol. 2020; 41: 43-48.e1.
- 57Cook S, Moeschler O, Michaud K, Yersin B. Acute opiate overdose: characteristics of 190 consecutive cases. Addiction. 1998; 93(10): 1559-1565.
- 58 Hygiene NYCDoHaM. Illicit drug use in New York City. NYC Vital Signs. 2010; 1-4.
- 59Andrews JY, Kinner SA. Understanding drug-related mortality in released prisoners: a review of national coronial records. BMC Public Health. 2012; 12: 270.
- 60Cone EJ, Fant RV, Rohay JM, et al. Oxycodone involvement in drug abuse deaths: a DAWN-based classification scheme applied to an oxycodone postmortem database containing over 1000 cases. J Anal Toxicol. 2003; 27(2): 57-67; discussion 67.
- 61Cone EJ, Fant RV, Rohay JM, et al. Oxycodone involvement in drug abuse deaths. II. Evidence for toxic multiple drug-drug interactions. J Anal Toxicol. 2004; 28(4): 217-225.
- 62Martins SS, Sampson L, Cerdá M, Galea S. Worldwide Prevalence and Trends in Unintentional Drug Overdose: A Systematic Review of the Literature. Am J Public Health. 2015; 105(11): e29-e49.
- 63Webster LR, Dasgupta N. Obtaining adequate data to determine causes of opioid-related overdose deaths. Pain Med. 2011; 12(Suppl 2): S86-S92.
- 64Priest J. One in 3 death certificates were wrong before coronavirus. It's about to get even worse USA Today. Corrected Copy by USA Today ed2020.
- 65Davis GG. National Association of Medical E, American College of Medical Toxicology Expert Panel on E, Reporting Opioid D. Complete republication: National Association of Medical Examiners position paper: Recommendations for the investigation, diagnosis, and certification of deaths related to opioid drugs. J Med Toxicol. 2014; 10(1): 100-106.
- 66Sastre C, Bartoli C, Baillif-Couniou V, Leonetti G, Pelissier-Alicot AL. Post Mortem Redistribution of Drugs: Current State of Knowledge. Curr Pharm Des. 2017; 23(36): 5530-5541.
- 67Miron J. Are, "fatal" opioid concentrations really fatal? Cato Institute. https://www.cato.org/blog/are-fatal-opioid-concentrations-really-fatal. Accessed October 25, 2020.
- 68Millichamp T, Johnston ANB. Interventions to support safe medication administration by emergency department nurses: An integrative review. Int Emerg Nurs. 2020; 49: 100811.
- 69Raleigh MD, Baruffaldi F, Peterson SJ, et al. A Fentanyl Vaccine Alters Fentanyl Distribution and Protects against Fentanyl-Induced Effects in Mice and Rats. J Pharmacol Exp Ther. 2019; 368(2): 282-291.
