Pharmacokinetic Interaction between Naloxone and Naltrexone Following Intranasal Administration to Healthy Subjects

Abstract

Naloxone (17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one HCl), a m-opioid receptor antagonist, is administered intranasally to reverse an opioid overdose but its short half-life may necessitate subsequent doses. The addition of naltrexone [17-(cyclopropylmethyl)-4,5a-epoxy-3,14-dihydroxymorphinan-6-one], another m-receptor antagonist, which has a reported half-life of 3 1/2 hours, may extend the available time to receive medical treatment. In a phase 1 pharmacokinetic study, healthy adults were administered naloxone and naltrexone intranasally, separately and in combination. When administered with naloxone, the C max value of naltrexone decreased 62% and the area under the concentration-time curve from time zero to infinity (AUC 0-inf) decreased 38% compared with when it was given separately; lower concentrations of naltrexone were observed as early as 5 minutes postdose. In contrast, the C max and AUC 0-inf values of naloxone decreased only 18% and 16%, respectively, when given with naltrexone. This apparent interaction was investigated further to determine if naloxone and naltrexone shared a transporter. Neither compound was a substrate for organic cation transporter (OCT) 1, OCT2, OCT3, OCTN1, or OCTN2. There was no evidence of the involvement of a transmembrane transporter when they were tested separately or in combination at concentrations of 10 and 500 mM using Madin-Darby canine kidney II cell monolayers at pH 7.4. The efflux ratios of naloxone and naltrexone increased to six or greater when the apical solution was pH 5.5, the approximate pH of the nasal cavity; there was no apparent interaction when the two were coincubated. The importance of understanding how opioid antagonists are absorbed by the nasal epithelium is magnified by the rise in overdose deaths attributed to long-lived synthetic opioids and the realization that better strategies are needed to treat opioid overdoses.

Are opioid receptor antagonists adequate for “Opioid” overdose in a changing reality?

“…However, sublingual absorption of naloxone might be greater than originally thought 30 . There is no apparent evidence that either naltrexone or naloxone is transported by p‐glycoprotein, 31 but it has been suggested that naloxone and fentanyl may share a cellular membrane transporter 28 . This transporter may become saturated at high doses and plasma concentrations of fentanyl, reducing the blood‐brain barrier transport of naloxone 28 …”

“…The plasma half‐life of naloxone is about 8.3 hours, that of nalmefene 1.3 h, but the brain residency time of nalmefene might be significantly longer than that of naloxone 32 . Naltrexone has a plasma half‐life of approximately 3.5 h, 31 but brain residency 72 to 108 h 32 . This suggests that naltrexone might be a better option for opioid overdose, although to date little data have been generated to prove this point.…”

“…As an alternative to naloxone, nalmefene, currently off‐market in the United States, has been suggested as a better option in IMF overdose cases, but more research is needed 23 . It has also been suggested that a combination of naltrexone and naloxone might give better results 31 …”

Clinical Pharmacology, Toxicity, and Abuse Potential of Opioids

“…Naloxone has a comparably short half‐life and duration of action of around 60‐90 minutes. whereas many opioids have a longer half‐life or are formulated as sustained‐release preparations, which may require additional naloxone doses and close monitoring of the patient 174 . In addition, naloxone and other competitive opioid‐receptor antagonists may require a higher dose to overcome highly potent opioid agonists, such as fentanyl analogues and buprenorphine 91,175 .…”

Neuroendocrine effects of naltrexone versus nalmefene in humans

“…Naltrexone is also approved for the treatment of opioid use disorders, most recently as an intramuscular depot formulation (Lee et al, ; Woody & Metzger, ). Very recent studies have also examined whether novel formulations of naltrexone or nalmefene could be useful as potent and long‐lasting medications against overdose caused by μ‐agonists such as fentanyl (Krieter, Chiang, Gyaw, Skolnick, & Snyder, ; Krieter, Gyaw, Crystal, & Skolnick, ).…”