{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T17:38:40Z","timestamp":1755797920585,"version":"3.41.2"},"reference-count":23,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T00:00:00Z","timestamp":1723075200000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["UG3 DA048338"],"award-info":[{"award-number":["UG3 DA048338"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Physiological Reports"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The aim of this study is to determine if extended\u2010release, bioabsorbable, subcutaneous naltrexone (NTX) implants can mitigate respiratory depression after an intravenous injection (IV) of fentanyl. Six different BIOabsorbable Polymeric Implant Naltrexone (BIOPIN) formulations, comprising combinations of Poly\u2010<jats:sc>d<\/jats:sc>,<jats:sc>l<\/jats:sc>\u2010Lactic Acid (PDLLA) and\/or Polycaprolactone (PCL\u20101 or PCL\u20102), were used to create subcutaneous implants. Both placebo and naltrexone implants were implanted subcutaneously in male dogs. The active naltrexone implants consisted of two doses, 644\u2009mg and 1288\u2009mg. A challenge with IV fentanyl was performed in 33 male dogs at 97\u2013100\u2009days after implantation. Following the administration of a 30\u2009\u03bcg\/kg intravenous fentanyl dose, the placebo cohort manifested a swift and profound respiratory depression with a ~50% reduction in their pre\u2010dose respiratory rate (RR). The BIOPIN NTX\u2010implanted dogs were exposed to escalating doses of intravenous fentanyl (30\u2009\u03bcg\/kg, 60\u2009\u03bcg\/kg, 90\u2009\u03bcg\/kg, and 120\u2009\u03bcg\/kg). In contrast, the dogs implanted with the BIOPIN naltrexone implants tolerated doses up to 60\u2009\u03bcg\/kg without significant respiratory depression (&lt;50%) but had severe respiratory depression with fentanyl doses of 90\u2009\u03bcg\/kg and especially at 120\u2009\u03bcg\/kg. Bioabsorbable, extended\u2010release BIOPIN naltrexone implants are effective in mitigating fentanyl\u2010induced respiratory depression in male canines at about 3\u2009months after implantation. This technology may also have potential for mitigating fentanyl\u2010induced respiratory depression in humans.<\/jats:p>","DOI":"10.14814\/phy2.16176","type":"journal-article","created":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T05:26:49Z","timestamp":1723181209000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Bioabsorbable, subcutaneous naltrexone implants mitigate fentanyl\u2010induced respiratory depression at 3\u2009months\u2014A pilot study in male canines"],"prefix":"10.14814","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7228-2671","authenticated-orcid":false,"given":"Robert L.","family":"Joyner","sequence":"first","affiliation":[{"name":"Richard A. Henson Research Institute, TidalHealth Peninsula Regional Salisbury  Salisbury Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0369-205X","authenticated-orcid":false,"given":"Joseph A.","family":"Hollenbaugh","sequence":"additional","affiliation":[{"name":"Labcorp  Greenfield Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donald","family":"D'Aquila","sequence":"additional","affiliation":[{"name":"Richard A. Henson Research Institute, TidalHealth Peninsula Regional Salisbury  Salisbury Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Fishman","sequence":"additional","affiliation":[{"name":"The Department of Psychiatry Johns Hopkins School of Medicine and Maryland Treatment Centers  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6633-8173","authenticated-orcid":false,"given":"Steven M.","family":"Cohen","sequence":"additional","affiliation":[{"name":"The Drug Delivery Company LLC Dba Akyso  Salisbury Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veera","family":"Holdai","sequence":"additional","affiliation":[{"name":"The Department of Mathematical Sciences Salisbury University  Salisbury Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0350-2204","authenticated-orcid":false,"given":"Jeffrey D.","family":"Benner","sequence":"additional","affiliation":[{"name":"Richard A. Henson Research Institute, TidalHealth Peninsula Regional Salisbury  Salisbury Maryland USA"},{"name":"The Drug Delivery Company LLC Dba Akyso  Salisbury Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,8,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1300274"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/adb.13350"},{"key":"e_1_2_9_4_1","unstructured":"Benner J. D. Cohen S. M. Vutukuru N. K. R. Kulkarni P. S. &Shanmugam S.(2021).Extended release bioabsorbable subcutaneous medicinal dosage delivery implant system.https:\/\/pubchem.ncbi.nlm.nih.gov\/patent\/US\u201011197819\u2010B1"},{"key":"e_1_2_9_5_1","unstructured":"ClinicalTrials.gov. (2022).The O'Neil long acting naltrexone implant (OLANI) pharmacokinetic (PK)\/safety study in healthy volunteers.https:\/\/clinicaltrials.gov\/study\/NCT03810495"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.5055\/jom.2005.0054"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.4137\/SART.S10776"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.engreg.2020.08.002"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/neurolint14010004"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0215416"},{"key":"e_1_2_9_11_1","unstructured":"Food and Drug Administration. (2006).Naltrexone \u2010 Clinical Pharmacology and Biopharmaceutics Review.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2006\/021897s000_ClinPharmR.pdfe"},{"key":"e_1_2_9_12_1","unstructured":"Food and Drug Administration. (2021).Polycaprolactone (PCL) Safety Profile (Medical Device Material Performance Study).https:\/\/www.fda.gov\/media\/158492\/download"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a039602"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2010.04.003"},{"key":"e_1_2_9_15_1","unstructured":"Lake Normal at Mooresville Animal Hospital. (2023).Why is my dog breathing so fast?https:\/\/www.mooresvilleanimalhospital.com\/site\/blog\/2020\/12\/29\/dog\u2010breathing\u2010fast"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13011\u2010019\u20100195\u20104"},{"key":"e_1_2_9_17_1","unstructured":"National Institute on Drug Abuse. (2021).Fentanyl drug facts.https:\/\/nida.nih.gov\/publications\/drugfacts\/fentanyl"},{"key":"e_1_2_9_18_1","unstructured":"National Institute on Drug Abuse. (2023).Drug overdose death rates.https:\/\/nida.nih.gov\/research\u2010topics\/trends\u2010statistics\/overdose\u2010death\u2010rates"},{"volume-title":"StatPearls","year":"2024","author":"Schiller E. Y.","key":"e_1_2_9_19_1"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13181\u2010015\u20100512\u2010x"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1467\u20102995.2005.00188.x"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt1976203315"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6911a4"},{"issue":"1","key":"e_1_2_9_24_1","first-page":"126","article-title":"Pharmacokinetics and pharmacodynamics of subcutaneous naltrexone pellets in the rat","volume":"237","author":"Yoburn B. 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