COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia

Abstract

Morphine and its congener opioids are the main therapy for severe pain in cancer. However, chronic morphine treatment stimulates angiogenesis and tumour growth in mice. We examined if celecoxib (a cyclooxygenase-2 (COX-2) inhibitor) prevents morphineinduced tumour growth without compromising analgesia. The effect of chronic treatment with celecoxib (by gavage) and/or morphine (subcutaneously), or PBS on tumour prostaglandin E 2 (PGE 2 ), COX-2, angiogenesis, tumour growth, metastasis, pain behaviour and survival was determined in a highly invasive SCK breast cancer model in A/J mice. Two weeks of chronic morphine treatment at clinically relevant doses stimulates COX-2 and PGE 2 (4.5-fold compared to vehicle alone) and angiogenesis in breast tumours in mice. This is accompanied by increased tumour weight (B35%) and increased metastasis and reduced survival. Coadministration of celecoxib prevents these morphine-induced effects. In addition, morphine and celecoxib together provided better analgesia than either agent alone. Celecoxib prevents morphine-induced stimulation of COX-2, PGE 2 , angiogenesis, tumour growth, metastasis and mortality without compromising analgesia in a murine breast cancer model. In fact, the combination provided significantly better analgesia than with morphine or celecoxib alone. Clinical trials of this combination for analgesia in chronic and severe pain in cancer are warranted.

Safety and Therapeutic Effect of Metronomic Chemotherapy with Cyclophosphamide and Celecoxib in Advanced Breast Cancer Patients

“…Recently, elevated COX-2 expression in breast cancer has been also associated with the presence of distant metastases [14]. Celecoxib (Cel) is a selective inhibitor of COX-2 that has shown antiangiogenic [15] and antiproliferative [16] properties in breast cancer cell lines.…”

Does regional anaesthesia and analgesia or opioid analgesia influence recurrence after primary cancer surgery? An update of available evidence

“…[128] Proposed mechanisms for effects of tumour growth rate include enhanced angiogenesis, including enhancing cyclooxygenase-2 (COX-2) and increased PGE 2 production, [129] and activation of VEGF and epidermal growth factor. [130] When studied in a breast cancer cell line, while demonstrating no direct proliferative effect, morphine has also been linked to augmented production of urokinase plasminogen activator (UPA).…”

Impact of anesthesia for cancer surgery: Continuing Professional Development

“…Ces effets ont été évités par l'administration concomitante de célécoxib. 27 Dans les études chez l'homme, l'administration intrathécale de morphine (0,5 mg) a supprimé l'activité des cellules NK au premier jour postopératoire, avec une récupération dès le deuxième jour. La suppression n'a pas été observée avec une dose de 0,1 mg de morphine, suggérant un effet dose-dépendant.…”

“…These effects were prevented by co-administration of celecoxib. 27 In human studies, intrathecal morphine 0.5 mg suppressed NK cell activity on day one post-surgery, with recovery by day two. Suppression was not seen with 0.1 mg morphine, also suggesting a dose-dependent effect.…”