Received: 11 November 2020 | Revised: 15 November 2020 | Accepted: 16 November 2020 DOI: 10.1111/jcpt.13320 COMMENTARY Are opioid receptor antagonists adequate for “Opioid” overdose in a changing reality? John F. Peppin DO, FACP1,2 | Joseph V. Pergolizzi Jr. MD3,4,5 | Albert Dahan MD, PhD6 | Robert B. Raffa PhD3,4,7,8 1Marian University College of Osteopathic Medicine (Clinical Adjunct Professor), Abstract Indianapolis, IN, USA What is known and Objective: Deaths due to opioid- induced respiratory depression 2Clinical Professor Internal Medicine, Pikeville University, College of (OIRD) continue to rise despite intense regulatory and professional actions. COVID- 19 Osteopathic Medicine, Pikeville, USA has only worsened this situation.1 An opioid receptor antagonist (ORA) such as nalox- 3 Enalare Therapeutics Inc, Naples, FL, one is the most common intervention for OIRD. However, with increasing overdose USA from highly potent illicit opioids and polysubstance abuse, appraisal of the adequacy 4Neumentum Inc., Summit, NJ, USA 5NEMA Research Inc., Naples, FL, USA of ORA seems warranted and timely. 6Leiden University Medical Center, Leiden, Comment: OIRD results from the binding of an excess number of agonist molecules The Netherlands to opioid receptors. Mechanistically, it makes sense to reverse this by displacing ago- 7University of Arizona College of Pharmacy (Adjunct Professor), Tucson, nist molecules by administering an ORA. But realistically, the trend to higher-potency AZ, USA agonists and polysubstance abuse diminishes the effectiveness of this approach. We 8 Temple University School of Pharmacy are left facing a crisis without a solution. (Professor emeritus), Philadelphia, PA, USA What is new and Conclusion: For the increasingly common OIRD from highly potent illicit agonists and polysubstance overdose, ORAs are correspondingly less effective. Correspondence John F. Peppin, DO, FACP, Marian Clinical Alternatives are needed— soon. Professor Internal Medicine, Pikeville University, College of Osteopathic KEYWORDS Medicine, Pikeville, USA adverse effect, naloxone, opioid antagonist, opioid overdose, polysubstance use Email: [email protected] 1 | WHAT IS KNOWN AND OBJECTIVE developed to make it easier to administer, even by members of the lay public. And it is now relatively common that a naloxone prescrip- The “opioid crisis” has had a profound impact internationally. Death tion is added to a prescription for an opioid to have readily available rates continue to climb, with an alarming spike during, and possibly at home. The US Federal Government has even fast- tracked nalox- attributable to, stresses of the COVID- 19 pandemic.1,2 Despite nu- one nasal delivery products to address the crisis. merous attempts to reduce these deaths through federal and state Unfortunately, a focus on prescription opioid overdose, perhaps regulations, federal and professional recommendations (eg CDC initially appropriate, is a bit dated. Illicitly manufactured fentanyl Guidelines), and the issuance of stricter medical board oversight, (IMF) and analogs (alfentanil, carfentanil, sufentanil, etc) have been deaths have not abated. introduced and are responsible for an increase in opioid deaths; The treatment of choice (both mechanistically and practically) for deaths from prescription opioids have fallen to low levels. It also an opioid overdose is an opioid receptor antagonist (ORA). Naloxone misses the more common misuse of multiple substances together is the most commonly used opioid receptor antagonist, and it has (polysubstance abuse). Most drug overdoses involve multiple sub- become a focused treatment option at multiple points during the stances, which greatly complicates treatment and makes antagonists interaction with healthcare providers. Delivery systems have been such as naloxone less effective. J Clin Pharm Ther. 2021;00:1–6. wileyonlinelibrary.com/journal/jcpt © 2020 John Wiley & Sons Ltd | 1 2 | COMMENTARY 2 | COMMENT be required. In addition, fentanoids may affect how naloxone acts at MOP,13 reducing naloxone's ability to displace fentanyl.13 2.1 | Traditional opioids and opioid receptors Masquerading as other drugs further complicates matters.15 The abuse of fentanoids can set up a potential “double whammy”: The binding of an endogenous or exogenous opioid to a seven- chest- wall rigidity along with respiratory depression.13 The inci- transmembrane G coupled– protein opioid receptor (7- TM GPCR) dence has been estimated anywhere between 8% and 100%.16 A elicits the characteristic opioid actions (analgesia, constipation, fairly recent review suggests that it may be an even more significant euphoria, etc). The mu (MOP), delta (DOP) and kappa (KOP) opioid contributor to death than previously thought,16 and a clear treat- receptor (OR) subtypes are naloxone- sensitive. The non- classic ment paradigm has not yet been developed.17 Carfentanil has an nociceptin/orphan- FQ receptor is naloxone- insensitive.3 Opioid even higher potency than fentanyl12 and is relatively easy to make. receptor densities vary in different areas of the body and under It also has a potential for “re- narcotization” that requires larger and 4 12 different conditions. ORs couple to Gi/Go proteins and enhance repeat dosing of an ORA. the efflux of potassium, hyperpolarizing postsynaptic neurons. Binding to opioid receptors also closes voltage- gated Ca2+ chan- nels, which reduces release of presynaptic neurotransmitters that 2.3 | Opioid receptor antagonists transmit pain signalling.3 Newer research has elucidated a role for ß- arrestin3 and interaction among receptors both in a physi- The development of opioid receptor antagonist (ORA) agents was cal sense (as heterodimers) and at a systems level.3 Heterodimers founded on the concept that minor changes in chemical structure can be combinations of OR subtypes or form with non- opioid re- could convert an opioid agonist into an opioid antagonist. The first ceptors,5 and have different response profiles than the individual published report of an ORA, nalodeine (N- allylnorcodeine), ap- receptors of which they are composed. The endogenous opioid peared in 1915,18,19 but it was not marketed. In the 1940s, nalor- families6,7 play important roles in physiologic processes8 and have phine (N- allylnormorphine) was synthesized.20 Both compounds had targeted actions and short half- lives. In contrast, exogenously ad- significant negative effects on mood. To overcome this problem, ministered opioids are (too) widely distributed and have long half- naloxone, N- allylnoroxymorphone, was developed in the 1960s.21 lives. Their effects (good and bad) are thus exaggerated. Tolerance Naloxone has a short- lasing action compared with the opioids that (diminished response to the same dose of drug) develops when are commonly encountered in overdose, so there was a need to receptors have a reduced ability to propagate a signal after over- develop a longer- acting agent; naltrexone came onto the market in exposure.4 This physiologic compensatory mechanism can be the 1980s.18,22 Naloxone and naltrexone were designed using oxy- blunted by excess drug use,4 as can mechanisms to remove a drug morphone, a thebaine derivative, as a base.18 Nalmefene (originally from the body.4 Once this occurs, even small increases in drug in- nalmetrene) is a derivative of naltrexone and is equipotent to na- take can result in disproportionate increases in adverse effects.4 loxone, but longer- acting,22 and reported higher affinity for MOP.23 Much drug- discovery effort has been directed at attempts to try Nalmefene was withdrawn from the US market due to low sales in to mitigate these problems.9 2008,23 but is available internationally. Naloxone, naltrexone and nalmefene bind to MOP, DOP and KOP24; however, the binding af- finity for MOP is much higher than for DOP or KOP. They are com- 2.2 | The complications introduced by the petitive reversible antagonists.25 “Fentanoids” Naloxone can be administered by multiple routes: IV, IM, SC, intranasal, inhalational 26 and endotracheal tube in intubated pa- Fentanyl is used for legitimate medical purposes in both IV and tients.27 Highly lipophilic, it undergoes rapid hepatic metabolism transdermal formulations. It is metabolized by the cytochrome and most is excreted through the kidneys as conjugated metabo- P450- 3A4 isozyme10; thus, CYP- 3A4 inhibitors (as might be en- lites.28 It is usually not administered orally since it undergoes ex- countered in polysubstance use) can increase toxicity.11 The re- tensive 1st- pass metabolism.29 However, sublingual absorption of cent influx of illicitly manufactured fentanyl (IMF) has greatly naloxone might be greater than originally thought.30 There is no ap- complicated treatment of “opioid” overdoses.12,13 Fentanyl and parent evidence that either naltrexone or naloxone is transported by analogs (“fentanoids”) enter into the brain rapidly,12 due to high p- glycoprotein,31 but it has been suggested that naloxone and fen- lipid- solubility and other factors.14 As a consequence, there has tanyl may share a cellular membrane transporter.28 This transporter been: “increasing awareness that respiratory depression by fenta- may become saturated at high doses and plasma concentrations of noids is harder to reverse with naloxone than that by other opioids fentanyl, reducing the blood- brain barrier transport of naloxone.28 such as heroin, and may require multiple and/or higher doses of The plasma half- life of naloxone is about 8.3 hours, that of naloxone.”13 nalmefene 1.3