Novel Opioid Analgesics for the Development of Transdermal Opioid Patches That Possess Morphine-Like Pharmacological Profiles Rather Than Fentanyl: Possible Opioid Switching Alternatives Among Patch Formula

  • Akane Komatsu
    Department of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
  • Kanako Miyano
    Department of Pain Control Research, The Jikei University School of Medicine, Tokyo, Japan
  • Daisuke Nakayama
    Daiichi Sankyo Company, Limited, Nihonbashihonmachi, Tokyo, Japan
  • Yusuke Mizobuchi
    Department of Pain Control Research, The Jikei University School of Medicine, Tokyo, Japan
  • Eiko Uezono
    Department of Pain Control Research, The Jikei University School of Medicine, Tokyo, Japan
  • Kaori Ohshima
    Department of Pain Control Research, The Jikei University School of Medicine, Tokyo, Japan
  • Yusuke Karasawa
    Department of Pain Control Research, The Jikei University School of Medicine, Tokyo, Japan
  • Yui Kuroda
    Department of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
  • Miki Nonaka
    Department of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
  • Keisuke Yamaguchi
    Department of Pain Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Japan
  • Masako Iseki
    Department of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
  • Yasuhito Uezono
    Department of Pain Control Research, The Jikei University School of Medicine, Tokyo, Japan
  • Masakazu Hayashida
    Department of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

抄録

<jats:sec> <jats:title>BACKGROUND:</jats:title> <jats:p>Transdermal fentanyl is widely used in the treatment of severe pain because of convenience, safety, and stable blood concentrations. Nevertheless, patients often develop tolerance to fentanyl, necessitating the use of other opioids; transdermal buprenorphine patch is widely used as an analgesic agent, though available formulation does not provide comparable analgesic effect as transdermal fentanyl patch. Opioids bind to the opioid receptor (OR) to activate both G protein–mediated and β-arrestin–mediated pathways. We synthesized morphine-related compounds with high transdermal absorbability (N1 and N2) and evaluated their OR activities pharmacologically in comparison with fentanyl and morphine.</jats:p> </jats:sec> <jats:sec> <jats:title>METHODS:</jats:title> <jats:p>In cells stably expressing μ-opioid receptor (MOR), δ-opioid receptor (DOR), and κ-opioid receptor (KOR), G protein–mediated pathways were assessed using the CellKey and an intracellular cyclic adenosine monophosphate (cAMP) assay, while β-arrestin–mediated pathways were analyzed with β-arrestin recruitment and receptor internalization assays. Furthermore, analgesic effects were evaluated using a tail-flick test in mice, and the analgesic effect on fentanyl-tolerant mice was evaluated.</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS:</jats:title> <jats:p>In the CellKey and cAMP assays, both N1 and N2 showed the highest affinity for MOR and acted as full agonists as well as partial agonists for DOR and KOR. In the β-arrestin and internalization assays, only fentanyl acted as a full agonist; N1 and N2 acted as partial agonists of MOR. In the mouse tail-flick test, N1 and N2 showed analgesic effects equivalent to those of fentanyl and morphine. In fentanyl-tolerant mice, fentanyl showed a diminished analgesic effect, whereas N1 and N2 as well as morphine retained their analgesic effects.</jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSIONS:</jats:title> <jats:p>While N1 and N2 have higher transdermal absorbability than fentanyl, they also have analgesic effects comparable to those of morphine, suggesting that they may be attractive compounds for the development of novel opioid patches for transitioning from fentanyl patches.</jats:p> </jats:sec>

収録刊行物

  • Anesthesia & Analgesia

    Anesthesia & Analgesia 134 (5), 1082-1093, 2022-04-05

    Ovid Technologies (Wolters Kluwer Health)

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