Oxycodone/naloxone PR versus oxycodone PR in advanced cancer: A multi-centre randomised trial (ENhANCE trial)

Abstract

Background:

Opioid-induced constipation is a common side effect of Oxycodone. Oxycodone/Naloxone Prolonged Release (OXN PR) mitigates opioid-induced constipation in non-cancer pain, however its evidence is limited in people with pain from advanced cancer.

Aims:

To demonstrate analgesic non-inferiority, and superiority in reducing constipation for Oxycodone/Naloxone Prolonged Release (OXN PR) compared to Oxycodone Prolonged Release (Oxy PR).

Design:

Multi-centre open-label randomised controlled trial comparing OXN PR to Oxy PR over 5 weeks. The primary aim was to demonstrate analgesic non-inferiority of OXN PR compared to Oxy PR. The secondary aim was to demonstrate superiority of constipation reduction in the OXN PR arm.

Setting/participants:

Participants with moderate-severe pain (⩾4/10) from advanced cancer were eligible.

Results:

Thirty seven of planned 96 patients were recruited with the study stopping early due to enrolment challenges during the COVID-19 pandemic. Average pain was −1.5 points (95% CI −3.3; 0.4) favouring the OXN PR arm compared to Oxy PR at 5 weeks, meeting analgesic non-inferiority, defined as falling within a one point non-inferiority margin. The OXN PR arm demonstrated less constipation with a significantly lower Bowel Function Index score (−24.87 (95% CI 47.54; 2.21), p = 0.03) compared to Oxy PR. Adverse effect safety profile favoured OXN PR.

Conclusions:

OXN PR is non-inferior to Oxy PR in analgesic effectiveness and superior in reducing constipation. These results indicate OXN PR as the choice of opioid preparation in advanced cancer. Future studies may explore adding naloxone to other slow and immediate release opioid preparations.

Trial registry:

Australian New Zealand Clinical Trials Registry

Trial registration number:

ACTRN12619001282178

URL of trial registry record:

https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377673&isReview=true

Keywords

opioid analgesics palliative care cancer pain opioid-induced constipation

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References

Broemer

Hinz

Koch

, et al Prevalence and severity of pain in cancer patients in Germany. Front Pain Res (Lausanne) 2021; 2: 703165.

Wiffen

Wee

Derry

, et al Opioids for cancer pain - an overview of cochrane reviews. Cochrane Database Syst Rev 2017; 7(7): Cd012592.

van den Beuken-van Everdingen

Hochstenbach

Joosten

, et al Update on prevalence of pain in patients with cancer: systematic review and meta-analysis. J Pain Symptom Manag 2016; 51(6): 1070–1090.e9.

World Health Organisation. WHO guidelines for the pharmacological and radiotherapeutic management of cancer pain in adults and adolescents. Geneva: World Health Organisation, 2019.

International Narcotics Control Board. Report of the International Narcotics Control Board for 2022. Vienna: United Nations, 2023.

Lalovic

Kharasch

Hoffer

, et al Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther 2006; 79(5): 461–479.

Holzer

. Treatment of opioid-induced gut dysfunction. Expert Opin Investig Drugs 2007; 16(2): 181–194.

King

Reid

Forbes

, et al A systematic review of oxycodone in the management of cancer pain. Palliat Med 2011; 25(5): 454–470.

Panchal

Müller-Schwefe

Wurzelmann

. Opioid-induced bowel dysfunction: prevalence, pathophysiology and burden. Int J Clin Pract 2007; 61(7): 1181–1187.

10.

Morlion

Mueller-Lissner

Vellucci

, et al Oral prolonged-release oxycodone/naloxone for managing pain and opioid-induced constipation: a review of the evidence. Pain Pract 2018; 18(5): 647–665.

11.

Ahmedzai

Nauck

Bar-Sela

, et al A randomized, double-blind, active-controlled, double-dummy, parallel-group study to determine the safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate/severe, chronic cancer pain. Palliat Med 2012; 26(1): 50–60.

12.

Dupoiron

Stachowiak

Loewenstein

, et al Long-term efficacy and safety of oxycodone-naloxone prolonged-release formulation (up to 180/90 mg daily) - results of the open-label extension phase of a phase III multicenter, multiple-dose, randomized, controlled study. Eur J Pain 2017; 21(9): 1485–1494.

13.

Clemens

Mikus

. Combined oral prolonged-release oxycodone and naloxone in opioid-induced bowel dysfunction: review of efficacy and safety data in the treatment of patients experiencing chronic pain. Expert Opin Pharmacother 2010; 11(2): 297–310.

14.

Choi

Billings

. Opioid antagonists: a review of their role in palliative care, focusing on use in opioid-related constipation. J Pain Symptom Manag 2002; 24(1): 71–90.

15.

Smith

Hopp

Mundin

, et al Low absolute bioavailability of oral naloxone in healthy subjects. Int J Clin Pharmacol Ther 2012; 50(5): 360–367.

16.

Comelon

Wisloeff-Aase

Raeder

, et al A comparison of oxycodone prolonged-release vs. oxycodone + naloxone prolonged-release after laparoscopic hysterectomy. Acta Anaesthesiol Scand 2013; 57(4): 509–517.

17.

Simpson

Leyendecker

Hopp

, et al Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe noncancer pain. Curr Med Res Opin 2008; 24(12): 3503–3512.

18.

Meissner

Leyendecker

Mueller-Lissner

, et al A randomised controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. Eur J Pain 2009; 13(1): 56–64.

19.

Löwenstein

Leyendecker

Hopp

, et al Combined prolonged-release oxycodone and naloxone improves bowel function in patients receiving opioids for moderate-to-severe non-malignant chronic pain: a randomised controlled trial. Expert Opin Pharmacother 2009; 10(4): 531–543.

20.

Löwenstein

Leyendecker

Lux

, et al Efficacy and safety of combined prolonged-release oxycodone and naloxone in the management of moderate/severe chronic non-malignant pain: results of a prospectively designed pooled analysis of two randomised, double-blind clinical trials. BMC Clin Pharmacol 2010; 10: 12.

21.

Vondrackova

Leyendecker

Meissner

, et al Analgesic efficacy and safety of oxycodone in combination with naloxone as prolonged release tablets in patients with moderate to severe chronic pain. J Pain 2008; 9: 1144–1154.

22.

Mercadante

. Cancer pain treatment strategies in patients with cancer. Drugs 2022; 82(13): 1357–1366.

23.

Genova

Dix

Thakur

, et al Chronic non-cancer pain management and addiction: a review. Cureus 2020; 12(2): e6963.

24.

Fine

Chen

Wittbrodt

, et al Impact of opioid-induced constipation on healthcare resource utilization and costs for cancer pain patients receiving continuous opioid therapy. Support Care Cancer 2019; 27(2): 687–696.

25.

Rahmadi

Madina

Sulianto

, et al Study on dosage range evaluation opioid analgesic for breakthrough pain in cancer patients: a retrospective study. Ann Palliat Med 2021; 10(2): 1237–1243.

26.

Mercadante

Maltoni

Russo

, et al The prevalence and characteristics of breakthrough cancer pain in patients receiving low doses of opioids for background pain. Cancers 2021; 13(5): 1058.

27.

Corsetti

Landes

Lange

. Bisacodyl: a review of pharmacology and clinical evidence to guide use in clinical practice in patients with constipation. Neurogastroenterol Motil 2021; 33(10): e14123.

28.

Therapeutic Goods Administration. Australian Public Assessment Report for Oxycodone hydrochloride/Naloxone hydrochloride. Canberra: Australian Government Department of Health and Ageing, 2010.

29.

Aggarwal

Douglas

, et al Oxycodone/naloxone prolonged-release tablets in patients with moderate-to-severe, chronic cancer pain: challenges in the context of hepatic impairment. Asia Pac J Clin Oncol 2022; 18(1): 13–18.

30.

Wong

Grobler

. ENhANCE trial protocol: a multi-centre, randomised, phase IV trial comparing the efficacy of oxycodone/naloxone prolonged release (OXN PR) versus oxycodone prolonged release (Oxy PR) tablets in patients with advanced cancer. Contemp Clin Trials Commun 2022; 30: 101036.

31.

Abernethy

Shelby-James

Fazekas

, et al The Australia-modified Karnofsky Performance Status (AKPS) scale: a revised scale for contemporary palliative care clinical practice [ISRCTN81117481]. BMC Palliat Care 2005; 4(1): 7.

32.

Mendoza

Mayne

Rublee

, et al Reliability and validity of a modified brief pain inventory short form in patients with osteoarthritis. Eur J Pain 2006; 10(4): 353–361.

33.

Ducrotté

Caussé

. The Bowel Function Index: a new validated scale for assessing opioid-induced constipation. Curr Med Res Opin 2012; 28(3): 457–466.

34.

Rentz

Müller-Lissner

, et al Validation of the bowel function index to detect clinically meaningful changes in opioid-induced constipation. J Med Econ 2009; 12(4): 371–383.

35.

Fayers

Bjordal

Groenvold

, et al (eds). EORTC QLQ-C30 scoring manual. 3rd ed. Brussels: EORTC Quality of Life Group, 2001.

36.

Australian and New Zealand College of Anaesthetists. Opioid Dose Equivalence Calculation Table 2021, https://www.betterpainmanagement.com/catalog?pagename=Useful-Links (Accessed 5 February 2025)

37.

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Editor E9 (R1). Addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials. In: Proceedings of the international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use, 2019.

38.

Grobler

Lee

Wong

, et al Handling missing data and drop out in hospice/palliative care trials through the estimand framework. J Pain Symptom Manag 2022; 63(4): e431–e9.

39.

Raman

Ding

Chow

, et al Minimal clinically important differences in the EORTC QLQ-C30 and brief pain inventory in patients undergoing re-irradiation for painful bone metastases. Qual Life Res 2018; 27(4): 1089–1098.

40.

Wong

Macleod

Robinson

, et al Oxycodone/naloxone preparation can cause acute withdrawal symptoms when misused parenterally or taken orally. Clin Toxicol 2015; 53(8): 815–818.

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