Double Bedtime Dosing During Immediate-Release Morphine Administration to Cancer Patients

Condition(s) targeted: Cancer

Intervention: Morphine (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Norwegian University of Science and Technology

Official(s) and/or principal investigator(s):
Paal Klepstad, Md,PhD, Principal Investigator, Affiliation: St.Olavs University Hospital, Norway

This is a double –blind randomized crossover study to provide evidence for the expert advice based recommendation of the Expert Working Group of the European Association for Palliative Care (EAPC) that patients during treatment with IR morphine are given a double dose at bed-time that replaces the next 4-hourly dose during night. In addition to the primary, blinded clinical part of the study, an experimental part is also included. This part consists of two open study days were morphine IR is given in the same fashion as the clinical study. The aim is to study whether pharmacokinetic data supports the clinical data.

The use of a double-bedtime IR morphine dose is equal to regularly scheduled IR morphine every 4-hour during night in respect to pain relief during night for patients with pain caused by malignant disease

Official title: Double Bedtime Dosing During Immediate-Release Morphine Administration to Cancer Patients: A Randomized, Double-Blind Cross-Over Comparison of a Double Bedtime Dose Ver-Sus Two Standard Doses at Bedtime and at Night

Study design: Treatment, Randomized, Double-Blind, Placebo Control, Single Group Assignment, Efficacy Study

Primary outcome:

Primary efficacy variable

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

Secondary outcome:

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

Detailed description: 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

1. 1. 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.

1. 2. Aim of study

Working hypothesis (H0:)

The use of a double-bedtime IR morphine dose is equal to regularly scheduled IR morphine every 4-hour during night in respect to pain relief during night for patients with pain caused by malignant disease.

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

1. 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

2. Pharmacodynamic time-course efficacy of opioids measured by pupillometry will be obtained during two 4-hourly dose intervals and one 8-hour dose interval after a double dose administration

2. Ethics

2. 1. Approval from the Regional Committee for Medical Research Ethics Health Region IV must be confirmed.

2. 2. The study is performed according to the rules of the Helsinki-declaration

2. 3. All patients will during all study periods have the availability of rescue medications to give satisfactory pain relief. All patients will have access to one of the investigators during the study period. If oral morphine fails to give pain relief, a pain clinic physician will evaluate the patient.

2. 4 The patients are awakened once for taking placebo. This is necessary in order to make a valid conclusion from the study. The patients are asked to stay at the hospital for two periods of 8 hours in order to obtain blood samples. The patients are explicit informed of this feature of the study design in the information given during inclusion. The patients are not exposed to any risks other than associated with standard care. Signed confirmation of consent is obtained from the patient.

3. Methods

3. 1.1. Inclusion criteria

Patients with malignant disease

Age more than 18 year

Regular use of oral morphine or pain that indicates start of opioids for moderate or severe pain according to the WHO guidelines for treatment of cancer pain

3. 1.2. Exclusion criteria

Known morphine intolerance

History of drug abuse

Decreased gastrointestinal uptake of oral medications

Pregnancy or breast-feeding

General health condition, psychiatric disease or cognitive function failure giving that the patient is not competent to complete questionnaires.

3. 1.3. Registration of patients not included in the study

All patients considered for inclusion in the study but excluded due to one of the exclusion criteria should be recorded and the reason for exclusion notified.

3. 2. Drop-out during study period

3. 2.1. Reasons for drop-out

General health condition failure, psychiatric disease or cognitive function failure giving that the patient is not competent to take part in the study.

Acute major surgery during study period.

Patient wants to withdraw from the study.

3. 2.2. The reason for drop-out will be registered and notified

3. 3. Sample size

20 patients will be included in the study.

The number of patients needed for completion of the study was estimated from the primary efficacy variable of average pain during night. In the analysis we have applied data files obtained in the study by Todd et al 3 (personal communication). The mean pain ratings and standard deviation observed in this study (11-point numeric scale) were 2. 43 (2. 27) and 1. 33 (1. 64) during double bedtime dose and two-dose regimen, respectively. We assumed that the difference in pain intensity () between the two methods had to be more than 2,0 in order to repre-sent a clinical significant observation. The standardized difference for paired continuous data is calculated using the formula 2/Sd = 2 x 1. 5 / 2. 03 = 1. 5. A level of significance of 0. 05 and a power of 0. 90 were chosen. Applying these assumptions a total sample size of 18 patients is needed. Allowing for drop-outs a sample size of 20 is considered appropriate 4

3. 4. Study schedule

The study is divided in 4 study sessions I : Clinical test with IR morphine at bedtime and at night II : Clinical test with double bedtime IR morphine dose and placebo at night III : Pharmacokinetic test during two 4-hourly dose intervals of IR morphine IV : Pharmacokinetic test during one 8 hour dose interval after a double dose IR morphine administration.

The clinical part of the study (study session I and II) is performed before the pharmacokinetic part (study session III and IV) of the study. Session I and II are performed following a randomized, double-blind, cross-over design. Session III and IV is perfomed following a cross-over, open-label design.

3. 5. Inclusion

3. 5.1. Registration at time of inclusion

Patient demographics: Name, birth number, age, gender, weight, in-or out-hospital.

Concomitant diseases and medications

Cancer diagnosis, presence of metastasis, time of diagnosis and anti-tumor treatment.

Pain history: Time of pain debut, pain localization’s (pain chart), diurnal variation, pain characteristics, pain intensity and history of pain treatment modalities.

Subjective symptoms: EORTC QLQ-C30 questionnaire (version 2. 0), Karnofsky performance status and fatigue score.

Clinical chemistry values of renal and liver function obtained no less than 14 days before inclusion in the study (serum creatinine, serum ASAT and ALAT enzyme activity).

3. 5.2. Treatment of patient The treatment of the patients’ cancer disease or other intercurrent diseases is not altered due to a patient participating in this study. Such treatment is the responsibility of the physician in charge of patient treatment.

3. 6. Baseline period

3. 6.1. The baseline period starts after inclusion and last until the patients has achieved satisfactory pain relief (defined by less than or equal to 3 on a 11-point numeric pain scale) and do not use more than two daily rescue opioid medications.

3. 6.2. During baseline the following stabilization of treatment is performed

1. Patients naive to opioids for moderate or severe cancer pain: The patients are introduced to IR morphine and the dose titrated following the principle from the EPAC guidelines until the conditions in 3. 6.1 are fulfilled

2. Patients use IR morphine: The dose is if necessary adjusted until the conditions in 3. 6.1 are fulfilled.

3. Patients use SR morphine. The dose is changed to equivalent dose of IR morphine and if necessary adjusted until the conditions in 3. 6.1 are fulfilled

3. 7. Study sessions

3. 7.1. Study session I

The patient is given IR morphine at bedtime and once during night. The patient is if necessary awakened in order to take the night dose. The doses are given at 4- hour intervals. The exact times for the morphine doses is chosen after what times which will comply best with the patient normal diurnal cycle.

The patient is allowed to take rescue morphine. The dose of rescue morphine equals the 4-hourly morphine dose.

At morning the patient completes a questionnaire with the following items:

4. Pain as an average for the night applying an.

5. Pain at the time of intake of the morning IR morphine dose applying a 11-point numeric rate scale

6. Overall rating for the night of quality of sleep, nausea, xerostomia and tiredness using 11-point numeric rate scales.

7. Pain intensity applying a 11-point numeric rate scale every time the patients is awake both when the patients decide to use and do not decide on using rescue morphine.

8. Number and time for consumption of rescue medication

9. After study session I and II are completed the patients preferences between the two period is recorded.

Study session II

Study session II replicates study session I except that the patient is given a double dose IR morphine at bedtime and placebo at night.

Study session III and IV

The time-course of serum concentrations of morphine, M6G and M3G are studied at two sessions during and one 8-hour double-dose interval, respectively. Samples will be drawn from an indwelling cannula in an antecubital vein.

The time-points for samples will be: 0 min, 15 min, 30 min, 45 min , 1 h, 1h 30 min, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h and 8 h in the study session where the patients receive a double IR morphine-dose. In the study session where the patients recieve two 4-hourly standard IR morphine-doses additional samples are obtained after 4 h 30 min and 5 h 30 min. This procedure results in a total of 28 samples from each patient. The total volume of blood collected at the two study sessions from each patient will be less than 200 ml.

The patients report pain intensity at the time of each blood sample applying an 11-point numeric rate scale.

The pharmacodynamic outcome of the procedures will also be assessed in order to determine the clinical importance of pharmacokinetic observations during this part of the study. Opioid effects will be assessed by noninvasive pupillometry whenever blood samples are obtained. Pupil diameter is shown to reflect pain intensity 5. Pupil diameter, a standard and extensively validated measure of methadone and other opioid effects, will be measured under constant lighting intensity. Pupillometry has been extensively validated 6-8. Pupil diameter will be measured with Pupilscan II Model 12A (Keeler Instreument Inc, USA)

The night before and during the pharmacokinetic study session the patient are allowed to use oral oxycodone as rescue medication. Oxycodone is chosen during this period in order to not let rescue morphine interfere with the pharmacokinetic observations. The oral oxycodone rescue dose is decided to be half of the 4-hourly IR morphine dose. The number and times of rescue medications are notified.

The patient is admitted in hospital for study session III and IV.

The patients are allowed free intake of fluids and light meals.

Serum samples and whole blood will be obtained for storage for confirmatory analysis and / or further pharmacological or pharmacogenetic analyses.

3. 7. Placebo medications and blinding

The placebo tablet is identical looking and tasting in order to achieve proper blinding. The hospital pharmaceutical department prepares the drug dispensers and performs the randomization procedure. The dispensers are marked with study number. The code for the blinded medication will be available at the pharmaceutical department and to the responsible investigator in a sealed envelope. This will ensure a double-blind randomized study design. The personnel responsible for the randomization procedure are not involved in any other part of the study.

3. 8 Study period duration

The study period last until all four study session are completed. The minimum period between study session is 2.

3. 9. Analytical methods

Blood samples are obtained for determination of serum concentrations of morphine, M6G and M3G. The blood samples are placed in EDTA tubes until separated by centrifugation

(3000 r. p.m, ten minutes) and stored at - 850 C until analyzed. All samples are analyzed

for serum concentrations of morphine, M6G and M3G applying. The limits of detection were for morphine 0,35 nmol/l and for M6G and M3G 2,2 nmol/l. The analytical coefficients of variation were for morphine 3,0%, for M6G 5,5% and for M3G 7,0%.

Serum values of creatinine concentrations, aspartat aminotransferase activities (ASAT) and albumine concentrations are determined using standard analytical methods.

4. Publication

The results from the study will be submitted to an international journal within the pain field. Authorship will be defined according to the Vancouver Rules.

5. Statistics

Comparison of data will be performed with the paired student t-test for continuous data and the Wilcoxin test for categorical and non-parametric data.

The estimation of sample size is reported in section 3. 3

10. Plan for study time frame

The study will start primo 2002 and will be finished after 20 patients are included.

Finacial support

The study is supported by grants from The Norwegian Research Council

9. References

1. Zech DFJ, Grond S, Lynch J, Hertel D, Lehmann KA: Validation of World Health Organization Guidelines for cancer pain relief: a 10-year prospective study. Pain 1995; 63: 65-76

2. Hanks, G. W., De Conno, F., Cherny, N., Hanna, M., Kalso, E., McQuay, H. J., Mercadante, S., Meynadier, J., Poulain, P., Ripamonti, C., Radbruch, L., Roca I Casas, J., Sawe, J., Twycross, R., and Ventafridda, V. Morphine and alternative opioids in cancer pain: the EAPC recommendations. British Journal of Cancer 84, 587-593. 2001.

3. Todd, J., Rees, E., Gwilliam, B., and Davies, A. N. An assessment of the efficacy and tolerability of a "double-dose" of immediate-release morphine at bedtime. Eur. J.Palliat. Care Abstract of the 7th Congress of teh European Association for Palliative Care, 14. 2001.

11. Altman DG: Practical statistics for medical research, 1 Edition. London, Chapman & Hall, 1991 12. Ellermeyer E, Westphal W. Gender differences in pain ratings and pupil reactions to painful pressure stimuli. Pain 1995; 61: 435-9 13. Radzius A, Welch P, Cone EJ, Henningfeld JE. A portable pupilometer system for measuring pupillaray size and light reflex. Behaviour Res. Methods, Instruments, Computers 1989;21(6):611-8 14. Weinhold LL, Bigelow GE. Opioid miosis: effects of lighting intensity and mo-nocular and binocular exposure. Drug Alcohol Depend. 1993;31(2):177-81, 15. Phimmasone S, Kharasch ED. A pilot evaluation of alfentnil-induced miosis as a non-invasive probe for hepatic cytochome P450 3A4 (CYP3A4) activity in humans. Anesthesiology, 2001, In press.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Patients with malignant disease

Age more than 18 year

Regular use of oral morphine or pain that indicates start of opioids for moderate or severe pain according to the WHO guidelines for treatment of cancer pain

Exclusion criteria

Known morphine intolerance

History of drug abuse

Decreased gastrointestinal uptake of oral medications

Pregnancy or breast-feeding

General health condition, psychiatric disease or cognitive function failure giving that the patient is not competent to complete questionnaires.

St Olavs University Hospital, TRondheim 7006, Norway

The Norwegian Univeristy of tecknology and science, Trondheim 7006, Norway

Starting date: April 2002
Ending date: May 2006
Last updated: January 24, 2007