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Immediate- or sustained-release morphine for dose finding during start of morphine to cancer patients: a randomized, double-blind trial

Klepstad, Pa,∗; Kaasa, Steinb; Jystad, Åsea; Hval, Bjørna; Borchgrevink, Petter Cc

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doi: 10.1016/S0304-3959(02)00328-7
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1. Introduction

The morphine dose adequate to relieve pain varies between the individual cancer patients and the correct dose in each patient is not predictable before the start of treatment. Consequently, morphine administration should be titrated in each individual patient to a dose sufficient to ensure analgesia without causing overdosage (Hanks et al., 2001). Start of morphine is recommended when opioids for mild to moderate pain (e.g. codeine), corresponding to step II of the WHO pain ladder, fail to give satisfactory analgesia (Jacox et al., 1994; Hanks et al., 2001). The European Association for Palliative Care (EAPC) guidelines and the US Agency for Health Care Policy and Research guidelines for Management of Cancer Pain recommend that titration is performed using oral immediate-release morphine given 4-hourly. The dose is increased daily until an optimal balance between analgesia and side effects is achieved. The morphine treatment is then changed to a controlled-release opioid for maintenance therapy (Jacox et al., 1994; Hanks et al., 2001). The EAPC guidelines arguments in favor of immediate-release morphine titration are to allow for steady state as quickly as possible in order to ease the assessment of analgesia during the dose finding period and to make rapid changes in dose (Expert Working Group of the European Association for Palliative Care, 1996). However, in the absence of controlled studies the guidelines for start of morphine treatment are based upon expert opinions (Jadad and Browman, 1995; Hanks et al., 2001).

Treatment of cancer pain is a common therapeutic procedure that often involves frail and elderly patients with several physical and psychological symptoms in addition to pain (Cherny et al., 1994). The use of 5–6 daily scheduled morphine doses is cumbersome and may reduce patient compliance (Ferrel, 1998). A direct start with controlled-release morphine would simplify the treatment, reduce the risk for low compliance and thereby enhance efficacy.

In order to compare the efficacy of oral immediate-release morphine titration and sustained-release morphine titration a randomized, double-blind controlled study was conducted with an expectation of sustained-release morphine having similar pain relief as immediate-release morphine.

2. Methods

2.1. Patient selection

Forty adult, hospitalized patients with documented malignant disease and pain despite ongoing treatment with opioids for weak to mild pain (codeine n=35, dextropropoxyphene n=5) were recruited. The attending physicians referred patients to the study. Referred patients with the following characteristics were not included; weak opioids not titrated to maximal recommended dose (n=3), suspected morphine intolerance (n=2), decreased gastrointestinal uptake of oral medications (n=3), lack of ability to communicate (n=2), scheduled transfer from hospital the next day (n=l) or lack of consent (n=1). The Regional ethical committee of the Health Region IV, Norway, approved the study and all patients gave informed written consent before study entry.

2.2. Treatments

A randomized, double-blind, double-dummy, parallel group design was applied. The hospital pharmacy performed a computerized randomization, and delivered coded drug containers for each patient. None of the pharmacists assigning study drugs were involved in other parts of the study. The pharmaceutical companies manufacturing the active tablets supplied placebo tablets identical in appearance and taste. During the study the assignment code was stored in a sealed, non-transparent envelope and the code was not broken until all patients had completed the study.

The patients were randomized to one of the treatment groups at study entry. Treatment with opioids for weak to moderate pain was stopped, while non-steroidal anti-inflammatory drugs (NSAIDs) (n=6) were continued. The patients received 5mg oral ketobemidone (Ketogan, Searle AS), a μ-opioid agonist with potency comparable to morphine, as rescue analgesic. If 5mg had inferior effect an increased dose of 10mg was administered. All patients received an anticonstipation regimen of lactulosis and bisakodyl. None of the patients received prophylactic antiemetic treatment.

After inclusion the patients entered a 2-day baseline period where all patients received the same pain treatments (ketobemidone per needed) in order to have identical conditions in the two study groups at the start of morphine titration. The immediate-release study group was titrated with immediate-release morphine (Morfin, NycomedPharma AS) 4-hourly plus placebo once daily. The sustained-release study group was titrated with sustained-release morphine (Kapanol, GlaxoWellcome AS) once daily plus placebo 4-hourly. In accordance to the standard practice a double bedtime dose of immediate-release morphine or placebo was given to avoid waking the patients during night (Hanks et al., 2001). The total daily dose of morphine at the start of treatment was 60mg in both study groups and was increased each study day according to a fixed titration schedule (60–90–120–180–270–360mg morphine daily) until acceptable pain relief was achieved. To exemplify, a patient titrated to a daily dose of 120mg morphine randomized to sustained-release morphine received sustained-release morphine 120mg once daily plus placebo every 4h. If randomized to immediate-release morphine the same patient would receive immediate-release morphine 20mg every 4h plus placebo once daily. Acceptable pain relief was defined as a maximum of 3 on a 7-point pain verbal rate scale (VRS) (1, no pain; 2, near unnoticeable pain; 3, little pain; 4, moderate pain; 5, severe pain; 6, very severe pain; 7, unbearable pain) and not more than two daily requests for rescue analgesics (Klepstad et al., 2000a). The study period terminated 2 days after the morphine dose was stabilized.

2.3. Assessments

Patients reported daily average pain for the previous 24h using a visual analogue scale (VAS) (anchored 0mm, no pain; 100mm, unbearable pain) and a 7-point VRS (Klepstad et al., 2000a). The daily use of rescue medication was recorded.

Nausea, loss of sleep, tiredness, loss of appetite, constipation and vertigo were reported on a VRS (1, not at all; 2, some; 3, severe; 4, very severe). Additional variables obtained at inclusion were Kamofsky performance status and health related quality of life (HRQOL) assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire (version 2.0) (Schag et al., 1984; Aaronson et al., 1993). The HRQOL scores were calculated according to standardized guidelines (Fayers et al., 1995). At the end of the study, HRQOL assessments were repeated and the patients reported global satisfaction with the pain treatment on a 5-point VRS.

2.4. Statistical analysis

The sample size calculation was based on the primary outcome measure specified as time needed to achieve pain relief. The clinical relevant difference was defined as 1.5 days, and a standard deviation of 1.47 days observed in a previous descriptive study on the start of morphine treatment was applied (Klepstad et al., 2000a). A one-tail test with power of 0.90 and a level of significance 0.05, required 34 patients (Campbell et al., 1995).

All data are given as absolute numbers or as means and 95% CIs. In the comparisons between the two study groups student t-test was applied for continuous variables while Mann–Whitney-U test was applied for the non-continuous variables. Significance was defined as P value 0.05 or less.

3. Results

3.1. Patients

The two study groups had similar patients' characteristics at inclusion (Tables 1 and 2). Six patients did not complete the study because of impairment due to progressive disease (n=l), sepsis (n=1), unstable angina pectoris (n=1), spontaneous remission of pain (n=1), acute spinal cord compression (n=1) or refusal to participate further in the study (n=1) (Fig. 1). None of the patients dropped out of the study because of failure to achieve pain relief or because of morphine related adverse effects. Of the patients assessed for efficacy, 15 received immediate-release morphine and 19 received sustained-release morphine (Fig. 1).

Table 1:
Patient characteristics in the treatment groupsa
Fig. 1.:
Flow of patients through trial

3.2. Treatment effects on pain relief

Patients receiving titration with sustained-release morphine did not need more time to achieve stable pain control than patients titrated with immediate-release morphine. Acceptable pain relief was achieved after 2.1 (1.4–2.7) days in the immediate-release morphine group and after 1.7 (1.1–2.3) days in the sustained-release morphine group. The titrated daily morphine doses in the two study groups were 94mg (71–117mg) for immediate-release morphine and 82mg (68–96mg) for sustained-release morphine. The VRS pain scores, use of rescue medication and fraction of patients stabilized on morphine dose during the titration procedure were similar for both groups (Fig. 2). VRS pain intensity scores at completion of titration were 2.9 (2.2–3.5) for patients treated with immediate-release morphine and 2.7 (2.3–3.1) for patients treated with sustained-release morphine. The corresponding VAS pain scores were 26 (17–36) and 22 (14–29), respectively.

Fig. 2.:
Pain VRS score (panel A), consumption of rescue pain medication (ketobemidone mg/24 h) (panel B) and percentage of patients completed morphine titration (panel C) during baseline and morphine titration for immediate-release morphine (squares) and sustained-release morphine (circles). VRS pan scores and rescue medications consumption are given as mean and 95% CIs (CIs are shown in one direction for the purpose of clarity).

3.3. Side effects and health-related quality of life

Patients receiving sustained-release morphine reported statistically significant lesser tiredness than patients receiving immediate-release morphine. No other differences in intensity of symptoms were associated with the use of sustained-release morphine titration compared to immediate-release morphine (Table 2). None of the HRQOL scores were influenced by the choice of immediate versus sustained-release morphine for titration (Table 3).

Table 2:
Intensity of symptoms before and after titration with immediate-release and sustained-release morphinea
Table 3:
Health related quality of life function scores (EORTC QLQ-C30) before and after titration with immediate- and sustained- release morphinea

3.4. Global satisfaction with pain treatment

Most patients in both treatment groups rated their global satisfaction with the pain treatment as ‘satisfied’ or ‘very satisfied’ (immediate-release morphine 13/16, sustained-release morphine 10/13; Table 4).

Table 4:
Global satisfaction with titration of morphine treatment

4. Discussion

The EAPC guidelines and the US guidelines for management of cancer pain published by the U.S. Agency for of Health and Human Service recommend that titration of morphine is performed with immediate-release morphine (Jacox et al., 1994; Hanks et al., 2001). The argument stated in favor of immediate-release morphine is that a short action of duration allows steady state to be achieved as quickly as possible (Expert Working Group of the European Association for Palliative Care, 1996). These recommendations based upon expert opinion were not supported by this randomized, double-blinded study comparing the use of immediate-release and sustained-release morphine for dose finding during the start of morphine treatment. The use of sustained-release morphine increased neither the time needed to find the correct dose, nor the intensity of opioid induced adverse effects.

Several studies have observed equal efficacy and risk of adverse effects from immediate-release and controlled-release morphine during chronic morphine therapy (Thirlwell et al., 1989, Deschamps et al., 1992, Broomhead et al., 1997; Gourlay et al., 1997). However, to our knowledge, no studies have compared the efficacy of different morphine formulations during the start of morphine treatment. Observational studies on the start of morphine treatment using oral morphine solution, immediate-release morphine and intravenous morphine patient controlled analgesia report the time needed for dose finding similar to or longer than the titration time observed in this study (Vijayaram et al., 1990, Radbruch et al., 1999, Klepstad et al., 2000a). These findings support that the titration procedure applied in this study is not inferior to other titration protocols. Comparisons of start with immediate-release and controlled-release formulations of other opioids are also sparse. Salzman et al. (1999) reported that dose titration was accomplished as readily with controlled-release as with immediate-release oxycodone. However, because the majority of patients were treated with other opioids for moderate to strong pain at inclusion, this study did not assess the start of opioid therapy.

The use of controlled-release morphine from day one of morphine treatment has several potential advantages. First, the patients are spared from a multiple dose schedule. Besides increased convenience, this reduces the potential for decreased patient compliance and confusion concerning medications (Ferrel, 1998). This consideration should be especially important in old or frail patients, namely the typical cancer patient in need of an opioid for achieving pain control (Ferrel 1995; Klepstad et al., 2000b). Second, direct start of controlled-release morphine omits the need for conversion of morphine therapy to a controlled-release preparation after dose finding with immediate-release morphine. Consequently, the physician does not need to educate the patients to a new opioid regimen, which reduces both patient and doctor burden, and gives less chance of confusion and errors during pain therapy. Furthermore, it is reasonable to assume that the use of controlled-release morphine for scheduled morphine therapy and immediate-release morphine used only as rescue analgesic, will make the distinction between scheduled and rescue morphine therapy more clear-cut.

Our result is based on a strict design following recommendations for randomized controlled trials. In order to secure blinding all patients had to receive medications 4-hourly. As a consequence, this study could not reflect the possible improved patient satisfaction associated with replacing multiple daily doses with morphine given once daily. Another possible limitation of the study is that anticancer treatment was allowed during the study period. It could be argued that studies on cancer pain therapy should exclude patients receiving anticancer treatment since such treatment can influence on symptoms. However, the aim of our study was to observe clinically relevant changes associated with the start of morphine therapy. Palliative and anticancer therapies are often administered concomitantly and to exclude patients who receive anticancer treatment limits a study generalizability into daily clinical practice.

The titration used in this study was not adhering to the EAPC guidelines in all details. First, in order to secure identical conditions during titration the patients entered a 2-day baseline period before the start of titration. Second, to keep the blinding of the study intact, the upward titration was performed in predefined steps while the EAPC guidelines titration procedure increases the dose each day according to the consumption of rescue opioids the foregoing day. For methodological reasons we chose to have a baseline period securing identical conditions at the start of titration and predefined titration steps to keep the blinding of the study intact at the cost of having an exact EAPC guidelines replica. We believe that the comparisons between the study groups are valid because the same approach for dose increments and rescue medications were used in both study groups.

In conclusion, sustained-release morphine given once daily is equally effective and has no more side effects than titration with immediate-release morphine given 4-hourly. Given that the clinical efficacy is equal we suggest that the more convenient method using sustained-release morphine is to be recommended.


We appreciate the advice concerning determination of sample size from statistician Peter Fayers. We are grateful for the assistance in randomizing and drug assignment from the pharmacists Janne Koroutcha and Astrid Gilje. We also appreciate the support from Lene Mathisen who participated in the planning of the study. The study was supported by research grants from the Norwegian Cancer Society and The Norwegian Research Council. Placebo sustained-release tablets were supplied free of cost from GlaxoWellcome, AS.


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Pain; Cancer; Morphine; Start; Sustained-release morphine; Immediate-release morphine

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