Antagonists of the Mu-Opioid Receptor in the Cancer Patient: Fact or Fiction?

Abstract

Purpose of Review Antagonists of mu-opioid receptor role in cancer progression remains to be elucidated. The objective of this review was to summarize the available evidence on antagonists of mu-opioid receptor effect on tumor progression and prognosis in different types of cancers and an evaluation of the available findings on their mechanism of action. Recent Findings We have found studies related to methylnaltrexone (MNTX) and naltrexone (NTX) usage in cancer outcomes-related setting. We found consistent preclinical evidence of a potential action of MNTX and NTX on cancer growth and spread mediated mainly by effect on the opioid growth factor receptor (OGFr) axis, which results in depressed cell replication. However, clinical results are scarce and limited to poor-quality evidence. Summary Further high-quality studies are warranted to study antagonists of mu-opioid receptor role as a therapeutic option in different types of cancer, especially in patients where the classical treatment causes unacceptable side effects.

Fentanyl activates opposing opioid and non-opioid receptor systems that control breathing

“…The lack of effect of the 1.0 and 2.5 mg/kg doses of NLXmi on resting ventilatory parameters and the behaviors of vehicle-treated rats (no visible signs of arousal, for example) are consistent with previous findings and suggest that central opioidergic systems potentially accessed by NLXmi are not tonically active ( Lewanowitsch and Irvine, 2002 ; 2003 ; Lewanowitsch et al, 2006 ; Leppert, 2010 ; Yamamoto and Sugimoto, 2010 ; Mori et al, 2013 ; Henderson et al, 2014 ; Belltall et al, 2022 ). The finding that the 1.0 mg/kg dose of NLXmi did not cause arousal in the fentanyl-injected rats is most likely because insufficient amounts of the opioid receptor antagonist reached key areas in the brain.…”

“…The administration of NLXmi elicits minor observable changes in behavior and cardiorespiratory parameters in naïve rats and mice, whereas it exerts important effects on the analgesic, behavioral, and cardiorespiratory effects of opioids, including fentanyl ( Lewanowitsch and Irvine, 2002 ; 2003 ; Lewanowitsch et al, 2006 ; Leppert, 2010 ; Yamamoto and Sugimoto, 2010 ; Mori et al, 2013 ; Henderson et al, 2014 ; Belltall et al, 2022 ). Although the available evidence suggests that NLXmi is peripherally restricted, this evidence stems from behavioral/pharmacological studies, and it should be noted that there is no direct evidence as to the blood–brain penetrability of NLXmi and, therefore, the amounts of the drug that enter the brain ( Leppert, 2010 ; Henderson et al, 2014 ).…”

“…The roles of μ-, δ-, and κ-opioid receptors ( Trescott et al, 2008 ; Valentino and Volkow, 2018 ), cell-signaling/molecular mechanisms ( Al-Hasani and Bruchas, 2011 ; Shang and Filizola, 2015 ), and multiple sites of action of opioids ( May et al, 1989 ; Lalley, 2003 ; Vadivelu et al, 2011 ; Henderson et al, 2013 ; 2014 ; Baby et al, 2018 ; Birdsong and Williams, 2020 ; Rossi and Bodnar, 2021 ) have been extensively studied. With regard to in vivo pharmacological approaches, the acute systemic administration of centrally acting opioid receptor antagonists such as naloxone and peripherally restricted antagonists such as methyl-naloxone (naloxone methiodide, NLXmi) has provided important evidence pertaining to the central and peripheral sites involved in mediating the actions of opioids ( Lewanowitsch and Irvine, 2002 ; 2003 ; Lewanowitsch et al, 2006 ; Leppert, 2010 ; Yamamoto and Sugimoto, 2010 ; Mori et al, 2013 ; Henderson et al, 2014 ; Belltall et al, 2022 ).…”

T Cell-Mediated Tumor Killing Sensitivity Gene Signature-Based Prognostic Score For Acute Myeloid Leukemia

“…Capmatinib is an inhibitor of cellular-mesenchymal-epithelial transition factor (c-Met), which belongs to the MET family. Early preclinical and clinical evidence shows that MET inhibition may be a valuable target for refractory and relapsed AML(51, 52) GSK-1521398 is a mu-opioid receptor antagonist primarily trialled in addiction and obesity (53), however mu-opioid receptors are understood to play signi cant roles in cancer immunoregulation, and positive effects of other mu-opioid antagonist drugs have been noted (54). Li rafenib is a dual inhibitor of BRAF-kinase and EGFR that has shown positive effects in several solid tumors in preliminary investigations (55).…”

Intraoperative opioids and disease-free survival in glioblastoma multiforme

“…Moreover, in a study published in 2015, the authors listed several studies showing a direct relationship between increased expression of the µ receptor in tumor cells and tumor dissemination and studies showing the action of an opioid antagonist (methylnaltrexone) as an inhibitor of tumor growth [29]. Speci cally, regarding opioid antagonists as possible therapeutic targets in the control of various types of malignancies, Belltall et al published a review and found that most studies were preclinical; therefore, there is insu cient evidence for this conclusion [30].…”