• Primary efficacy variable
  
• Patient rating of average pain intensity during night measured on a 11-point nu-meric rate scale
  

• Secondary efficacy variables
  
• Pain rating of "pain now" before scheduled morning dose measured on a 11-point numeric rate scale
  
• Number of rescue opioid medications during night
  
• Patient overall rating of sleep quality during night measured on a 11-point nu-meric rate scale
  
• Number of episodes being awake during night
  
• Rating of pain intensity measured on a 11-point numeric rate scale when being awake at night
  
• Overall rating of side effects (nausea, xerostomia, tiredeness) during night meas-ured on 11-point numeric rate scales
  
• Pain preference of treatments:
  
• Time-course of serum concentrations of morphine, morphine-6-glucurnide (M6G) and morphine-3-glucuronide (M3G) will be obtained during two 4-hourly dose intervals and one 8-hour dose interval after a double dose administration
  
• Pharmacodynamic time-course efficacy of opioids measured by pupillometri will be obtained during two 4-hourly dose intervals and one 8-hour dose interval after a double dose administration
  

PROTOCOL

Double bedtime dosing during immediate-release morphine administration to cancer patients:

A randomized, double-blind cross-over comparison of a double bedtime dose versus two standard doses at bedtime and at night

Introduction

Oral morphine is recommended by the World Health Organization for pain control in moderate or strong cancer pain 1. At our hospital we use the practice recommended by the Expert Working Group of the European Association for Palliative Care for introduction of strong opioids with titration with immediate-release (IR) morphine dosed every 4 hour until an optimal balance between analgesia and side effects is achieved. After the optimal daily dose is defined slow-release (SR) morphine in the same total daily morphine dose is started 2. One of the features of the EPAC guidelines is that patients during treatment with IR morphine are given a double bed-time that replaces the next 4-hourly dose during night 2. The rationale behind this recommendation is that giving a double dose will prolong duration of morphine analgesia and eliminate the need for awaking the patient during night. However, this recommendation is based on expert opinion and not evidence from clinical studies 2. Todd et al. has recently presented results that challenge this approach from a cross-over study in which the patients received either a double bedtime dose or regular doses every 4-hour 3. This study showed that patients receiving a double bedtime dose reported more pain, more use of rescue medications and reported inferior sleep quality compared to patients receiving regularly scheduled doses. A limitation of this study was that they did not perform the study blinded and thus consequently the results are subject to bias. It is a need for a placebo-controlled study before the evidence carries enough weight to change current recommendations.

Besides a clinical study it is also relevant to obtain pharmacokinetic observations during double bedtime and regularly IR morphine dosing. Repeated blood sampling will disturb the patients during night and hence confound the clinical observations (e.g. sleep quality). Consequently, the blood samples will not be obtained in the same dosing interval where the clinical data are obtained.