*Prevention of opioid-induced constipation in patients with advanced cancer*

More than 70% of patients with metastatic cancer have pain that often requires
treatment with opioids (morphine-like agents) (Teunissen 2007). Constipation
occurs in 59% of patients treated with opioids (Davies 2021). Opioid-induced
constipation (OIC) has a significant negative effect on the quality of life of
patients, due to physical problems, psychological problems and social
consequences (Bell 2009, Christensen 2017, Davies 2021, Dhingra 2013,
Penning-van Beest 2010). It has consequences that range from daily discomfort
with social insecurity and disability to intestinal obstruction. It leads to
limitations in self-management, a reduced quality of life and a risk of need
for more care, including hospital admission. Standard laxatives are recommended
to prevent OIC, although there is little evidence to support this (Farmer
2019). There have been only two randomised studies with laxatives in
symptomatic OIC (Freedman 1999, Hawley 2020). Freedman (1999) performed a
double-blinded randomised study in 57 drug-dependent men and women with OIC
receiving methadone, comparing macrogol/electrolytes with lactulose and
placebo. Macrogol/electrolytes and lactulose produced more *nonhard* stools
than the placebo (P<0.01) and baseline(P <0.003). There was no statistically
significant difference between macrogol/elektrolytes and lactulose.
Macrogol/electrolytes produced the loosest stool (P<0.0001) compared with
baseline, whereas lactulose had the most adverse effects. Hawley (2020)
compared macrogol/electrolytes with sennosides in a randomised, double-blind,
double-dummy cross-over study in 70 cancer patients (of whom 42 completed the
first treatment) at risk or already experiencing OIC. She found weak evidence
that macrogol/electrolytes was superior to sennosides in terms of more days
with a satisfactory bowel movement during three weeks of treatment. A recent
review found moderate benefit for osmotic or stimulant laxatives for patients
with cancer and symptomatic OIC (Ginex 2020). Magnesium hydroxide is registered
as an antipeptic drug, but also used as a laxative (but not registered for this
indication). In the past and in previous studies magnesium oxide was used. As
magnesium oxide is transformed in the stomach tot magnesium hydroxide, these
drugs are considered to be the same. Presently, only magnesium hydroxide is
prescribed in The Netherlands. There have been no studies on magnesium
(hydr)oxide in symptomatic OIC. There have been no randomised studies about
prevention of OIC by magnesium (hydr)oxide. Two prospective non-randomised
studies compared the prevalence of OIC after 14 days with or without
prophylactic laxatives (mostly magnesium oxide): 48% versus 65% (Tokoro 2019,
prospective study) and 34% versus 55% (Ishihara 2012). Thus, approximately 60%
of patients starting with opioids and not using laxatives will develop
constipation and 40% will not. Dutch guidelines on pain in cancer patients
(2019, www.pallialine.nl) and constipation in palliative care patients (2010,
www.pallialine.nl) recommend either macrogol/electrolytes or magnesium
hydroxide as first-line laxative treatment to prevent OIC. The guideline on
constipation in palliative care patients is currently being revised. The
preliminary advice of the concept guideline is unchanged. Thus,
macrogol/electrolytes has been proven to be effective for symptomatic OIC based
on two randomised studies (Freeman 1999, Hawley 2020 ) and is registered for
this indication. However, it has not been proven to be effective for prevention
of OIC and is not explicitly registered for this indication. It is sometimes
perceived by patients as unpleasant due to its taste. For magnesium oxide
retrospective data are available (Ishihara 2012, Tokoro 2019), suggesting that
it may prevent OIC and it has a neutral taste. Although it is also recommended
by the guideline, it has not been registered for the treatment or prevention of
constipation. To support the advice of the guideline and to prove that a choice
is possible, it is important to demonstrate that magnesium hydroxide is not
inferior to macrogol / electrolytes and to compare side-effects and
tolerability.

This study has been transitioned to CTIS with ID 2023-509462-38-00 check the CTIS register for the current data.

Primary Objective: In patients with advanced cancer, starting with opioids for
pain: • To prove non-inferiority of magnesium hydroxide to
macrogol/electrolytes in the prevention of OIC, based on the percentage of
patients without obstipation (BFI-score <30) after 14 days of treatment.
Secondary Objectives: In patients with advanced cancer, starting with opioids
for pain: • To compare magnesium hydroxide with macrogol/electrolytes with
regard to the Rome IV criteria after 14 days of treatment; • To compare
magnesium hydroxide with macrogol/electrolytes with regard to quality of life
(as measured with the EQ5D) after 14 days of treatment; • To compare magnesium
hydroxide with macrogol/electrolytes with regard to side effects and patient
satisfaction with laxative after 14 days of treatment; • To compare magnesium
hydroxide with macrogol/electrolytes with regard to difference in pain score
between laxative treatment after 14 days of treatment; • To compare magnesium
hydroxide with macrogol/electrolytes with regard to comparative
cost-effectiveness; • To predict non-resp[onders by gender, age, BMI, site of
cancer, site of metastases and use of medication.

A randomized, open-label study during 14 days (days 1-14). After informed
consent (maximally a day after the start of the opioid), randomization
(locally), stratified per centre, will be performed between
macrogol/electrolytes and magnesium hydroxide.
Patients with advanced cancer starting with opioids for pain will be included
from the departments of medical oncology, pulmonology and radiotherapy of both
academic and non-academic hospitals in The Netherlands.
This study is considered to be a low-intervention trial according to European
Union regulation no. 536/2014 of the European parliament and of the Council of
the European Union
(https://ec.europa.eu/health/sites/default/files/files/eudralex/vol-1/reg_2014_5
36/reg_2014_536_en.pdf). .

Randomization between macrogol/electrolytes or magnesium hydroxide to prevent
OIC at the start of treatment with opioids for a treatment period of 14 days.
Macrogol/electrolytes is started at a dose of 1 sachet once daily and magnesium
hydroxide at a dose of 724 mg t.i.d., both orally. Macrogol/electrolytes is
regarded as the standard treatment (usual care) to which magnesium hydroxide
will be compared. The dose of macrogol/electrolytes and magnesium hydroxide may
be increased to 2 sachets daily and 1448 mg t.i.d., respectively, or may be
decreased during the study period. Macrogol/elektrolytes and magnesium
hydroxide may also be discontinued during the study period.

The burden and risks of the study are expected to be minimal. The patients
receive the same treatment as in regular practice. They have to complete two
questionnaires, taking about 15 minutes per questionnaire.
OIC has a significant negative effect on the quality of life of patients, due
to physical problems, psychological problems and social consequences. The
results of this study will lead to better prevention of OIC in patients with
advanced cancer using opioids for pain, leading to better quality of life.
Possibly, it may also lead to better pain control, as opioid treatment will be
less hampered by dose reductions or changes of pain treatment due to
constipation. Finally, it may lead to registration of magnesium hydroxide for
this indication.
The study can only be performed using these patient groups.