学会誌 VOL.14 No.3 September 2021

原著論文

Pharmacological Analysis of Hydromorphone Acting as a β-Arrestin-Nonpreferred Strong μ-Opioid Receptor Ligand
Yoshinori TAKEMURA, Yoshiyuki IWASE, Yusuke HAMADA, Michiko NARITA Kensuke YAMASHITA, Moe NAKAHAMA, Yukari SUDA, Kanako MIYANO Mitsuaki YAMAZAKI, Naoko KUZUMAKI, Tomohisa MORI, and Minoru NARITA

Abstract:　It has been considered that dichotomous signal transduction pathways (G protein-coupled signaling pathway and β-arrestin recruitment pathway) can explain distinct pharmacological effects after the activation of µ-opioid receptors. Although µ-opioids have different pharmacological profiles including a prominent analgesic action, the characteristics of each opioid-oriented effect have not yet been fully described. In this study, we focused on the µ-opioid receptor agonist hydromorphone and further analyzed its pharmaco-logical profile. By using an in vitro assay, we confirmed that fentanyl could predominantly activate the β-arrestin-dependent pathway, whereas hydromorphone as well as morphine and oxycodone could act as a β-arrestin-nonpreferred µ-opioid receptor ligand. In an in vivo analysis using mice, hydromorphone produced potent antinociceptive and locomotor-enhancing effects, and inhibited gastrointestinal transit through a pattern different from that seen with morphine and oxycodone. Under these conditions, we found for the ﬁrst time that the discriminative stimulus effect of hydromorphone was distinct from that of a β-arrestin-preferred µ-opioid receptor agonist, fentanyl. These ﬁndings indicate that hydromorphone may produce a discriminative stimulus effect, which could be distinguished from that after activation of a β-arrestin-dependent signaling pathway by µ-opioids. Our present findings provide useful insight to further understand the distinct pharmacological proﬁles of hydromorphone in comparison to those of other standard µ-opioids.

Key words：µ-opioid, hydromorphone, G protein-coupled signaling pathway, β-arrestin

がん患者の角層水分量がフェンタニル貼付剤のフェンタニル皮膚移行率に及ぼす影響
島本一志、松井美月、田島正教、杉山恵理花、佐藤均、渡邊徹、市川度、佐々木忠徳

［要旨］　皮膚の乾燥がフェンタニル貼付剤（FP）の吸収低下をもたらすことがラットにおいて報告されているが，ヒトでは明らかとなっていない．そこで，ヒトの角層水分量が FP のフェンタニル皮膚移行率に影響するかどうかを調査した．昭和大学藤が丘病院入院中の患者を対象に，FP 貼付前の角層水分量を測定した．貼付 24 時間後の FP 中のフェンタニル残存量を測定し，皮膚移行率を求め，角層水分量との関係性を調査した．9 名の患者から36 枚の FP が回収できた．角層水分量および血清 Alb 値と皮膚移行率の間に正の相関性が認められ，以下の回帰式が得られた．皮膚移行率（％）＝ 0.46 ×角層水分量（a.u.）＋ 32.83 ×血清 Alb 値（mg/dL）− 10.17（R2 ＝ 0.958， p ＜ 0.001，n ＝ 9）．血清 Alb 値および角層水分量の低下は FP のフェンタニル皮膚移行率低下につながることが示唆された．FP 使用時は，血清 Alb 値，および角層水分量を考慮した用量設計が必要と考える．

キーワード：角層水分量，フェンタニル貼付剤（FP），フェンタニル皮膚移行率

The Effect of Oral Methadone on the QTc Interval and Pain in Japanese Patients with Cancer Pain
Hideya KOKUBUN, Chizuko TAKIGAWA, Satomi CHIHARA Satoshi HARA, and Yasuhito UEZONO

Abstract:　Methadone tablets were approved for use in Japan in March 2013, and have used as a strong opioid for the WHO 3-step ladder to treat cancer pain. However, methadone may have severe adverse effects such as respiratory depression and QT prolongation, and it must be used with caution. In this study, we investigated whether methadone blood concentration and dosage affect severe adverse effects and analgesic effects in Japanese cancer pain patients using methadone. Twenty-four patients were enrolled into this study. It was observed that VAS decreased signiﬁcantly with increasing blood concentration (p ＜ 0.0001). The mean QTc after methadone administration was not significantly changed. In addition, there was no significant increase in QTc with the increase in blood methadone concentration (r ＝ 0.166, p ＝ 0.380). Also, there was no signiﬁcant increase in QTc and QTc change rate with increasing cumulative methadone dose (r ＝ 0.153, p ＝0.363, and r ＝ 0.259, p ＝ 0.244). No patients had increased nausea or vomiting after the start of methadone, but one patient had a respiratory rate of 10 or less per minute. Oral methadone provided a rapid analgesic effect, and severe adverse effects such as respiratory depression and QT prolongation were rare. In addition, QTc did not correlate with blood concentration and dose of methadone.

Key words：methadone, QT prolongation, cancer pain, respiratory rate, adverse effects

短報

頭頸部悪性腫瘍に対する改良モーズペースト（モーズ親水クリーム）の使用経験
佐藤淳也、橋本竜、竹内秀之、黒﨑隆、守田侑真、梅田鈴香、塚越真由美、山田祐

［要旨］　利便性を改良するため親水クリームを基剤としたモーズペースト（モーズ親水クリーム）を調製し，患者に適用した．頸部に直径 5 cm 大の腫瘍をもつ中咽頭がん患者に 1 回 50 g のモーズ親水クリームを 60 分間塗布した．初適用から 4，8，13，21 日目に計 5 回塗布を繰り返し，腫瘍は平坦となった．モーズ親水クリームにおける本使用経験は，症例報告ながら製剤の有効性と医療者の利便性を確認できるものであった．

キーワード：モーズペースト，親水クリーム，頭頸部，悪性腫瘍

難渋する神経障害性疼痛・しびれに対してデュロキセチンが著効した子宮体がん椎骨転移症例
祝千佳子、今井哲司、高折彩、馬場長、万代昌紀、中川貴之

［要旨］　神経障害性疼痛・しびれを有する子宮体がん椎骨転移患者に，オキシコドンおよびプレガバリンを投与したが，再燃を繰り返した．デュロキセチンを追加したところ，最大 Numeric Rating Scale（NRS）10 の痛みとしびれがいずれも 0 となり，1 カ月以上維持できた．この間にオキシコドンの減量を試みたところ，痛みは NRS 10に再燃したが，しびれは 0 で維持できた．デュロキセチンはがん患者における難治性のしびれに有効であることが示唆された．

キーワード：デュロキセチン，がん性疼痛，しびれ

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