Oral morphine for cancer pain

  • Review
  • Intervention

Authors

  • Philip J Wiffen,

    Corresponding author
    1. University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences, Oxford, Oxfordshire, UK
    • Philip J Wiffen, Pain Research and Nuffield Department of Clinical Neurosciences, University of Oxford, Pain Research Unit, Churchill Hospital, Oxford, Oxfordshire, OX3 7LE, UK. phil.wiffen@ndcn.ox.ac.uk.

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  • Bee Wee,

    1. Churchill Hospital, Nuffield Department of Medicine and Sir Michael Sobell House, Oxford, UK
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  • R Andrew Moore

    1. University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences, Oxford, Oxfordshire, UK
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Abstract

Background

This is the second updated version of a Cochrane review first published in Issue 4, 2003 of The Cochrane Library and first updated in 2007. Morphine has been used for many years to relieve pain. Oral morphine in either immediate release or modified release form remains the analgesic of choice for moderate or severe cancer pain.

Objectives

To determine the efficacy of oral morphine in relieving cancer pain, and assess the incidence and severity of adverse effects.

Search methods

We searched the following databases: Cochrane Pain, Palliative and Supportive Care Group Trials Register (June 2013); Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 5, May); MEDLINE (1966 to June 2013); and EMBASE (1974 to June 2013).

Selection criteria

Published randomised controlled trials (RCTs) using placebo or active comparators reporting on the analgesic effect of oral morphine in adults and children with cancer pain. Trials with fewer than ten participants were excluded.

Data collection and analysis

One review author extracted data, which were checked by another review author. There were insufficient comparable data for meta-analysis to be undertaken or to produce numbers needed to treat (NNTs) for the analgesic effect. We extracted any available data on the number or proportion of participants with ‘no worse than mild pain’ or treatment success (very satisfied, or very good or excellent on patient global impression scales).

Main results

Ten new studies (638 participants) were identified for this update, bringing the total of included studies to 62, with 4241 participants. Thirty-six studies used a cross-over design ranging from one to 15 days, with the greatest number (11) for seven days for each arm of the trial.

Fifteen studies compared oral morphine modified release (Mm/r) preparations with morphine immediate release (MIR). Fourteen studies compared Mm/r in different strengths; six of these included 24-hour modified release products. Fifteen studies compared Mm/r with other opioids. Six studies compared MIR with other opioids. Two studies compared oral Mm/r with rectal Mm/r. Three studies compared MIR with MIR by a different route of administration. Two studies compared Mm/r with Mm/r at different times and two compared MIR with MIR given at a different time. One study was found comparing each of the following: Mm/r tablet with Mm/r suspension; Mm/r with non-opioids; MIR with non-opioids; and oral morphine with epidural morphine.

In this update a standard of 'no worse than mild pain' was set equivalent to a score of 30/100 mm or less on a visual analogue pain intensity scale (VAS), or the equivalent in other pain scales. Eighteen studies achieved this level of pain relief on average, and no study reported that good levels of pain relief were not attained. Where results were reported for individual participants in 17 studies, ‘no worse than mild pain’ was achieved by 96% of participants (362/377), and an outcome equivalent to treatment success in 63% (400/638).

Morphine is an effective analgesic for cancer pain. Pain relief did not differ between Mm/r and MIR. Modified release versions of morphine were effective for 12- or 24-hour dosing depending on the formulation. Daily doses in studies ranged from 25 mg to 2000 mg with an average of between 100 mg and 250 mg. Dose titration was undertaken with both instant release and modified release products. A small number of participants did not achieve adequate analgesia with morphine. Adverse effects were common and approximately 6% of participants discontinued treatment because of intolerable adverse effects.

Authors' conclusions

The effectiveness of oral morphine has stood the test of time, but the randomised trial literature for morphine is small given the importance of this medicine. Most trials recruited fewer than 100 participants and did not provide appropriate data for meta-analysis. Only a few reported how many people had good pain relief, but where it was reported, over 90% had no worse than mild pain within a reasonably short time period. The review demonstrates the wide dose range of morphine used in studies, and that a small percentage of participants are unable to tolerate oral morphine. The review also shows the wide range of study designs, and inconsistency in cross-over designs. Trial design was frequently based on titration of morphine or comparator to achieve adequate analgesia, then crossing participants over in cross-over design studies. It was not clear if these trials are sufficiently powered to detect any clinical differences between formulations or comparator drugs. New studies added to the review reinforce the view that it is possible to use modified release morphine to titrate to analgesic effect. There is qualitative evidence that oral morphine has much the same efficacy as other available opioids.

摘要

口服嗎啡於癌症疼痛

背景

這是第二版更新Cochrane的回顧,第一版更新是在2007年,第一次發表是在The Cochrane Library 2003年第四期。 嗎啡已經被用來治療緩解疼痛多年。對於中度或重度癌症疼痛,不管是在立即釋放或是調整釋放,口服嗎啡仍然是首選的鎮痛治療方式。

目的

以確定的口服嗎啡對於緩解癌症疼痛和評估其副作用的發生率和嚴重的程度。

搜尋策略

我們搜尋了以下的資料庫: Cochrane 痛、緩和及支持療法族群的註冊試驗(2013年6月); Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013年,五月第五期); MEDLINE (從1966年到 2013年6月); 和 EMBASE (從1974年到2013的6月) 。

選擇標準

發表利用安慰劑的隨機對照試驗(randomised controlled trials)比較對口服嗎啡的成人和兒童癌症疼痛的鎮痛效果報告。試驗少於10個的參與者將被排除在外。

資料收集與分析

由一位回顧作者擷取數據,另一位回顧作者檢查。這裏對於鎮痛效果沒有有效的整合分析,去進行或是去產生需要治療的數目。我們攫取任何對於疼痛感到沒有變糟或是輕微疼痛或甚至治療成功的相關資料(非常滿意或非常好或極好的病人總體印象量表)。

主要結果

10個更新的研究計畫(638位病人),納入研究的總數達到了62個研究,4241位參與者。36個研究使用了交叉設計,範圍從1到15天,7天使用最大值(11)於每一個試驗的組別。

15個研究比較口服嗎啡調整釋放(morphine modified release)嗎啡立即釋放(morphine immediate release)。14個研究比較嗎啡調整釋放在不同的優勢;這些包括24小時調整釋放產品。15個研究比較嗎啡調整釋放與其他鴉片類藥物。6個研究比較嗎啡立即釋放與其他鴉片類藥物。2個研究比較口服嗎啡調整釋放與直腸嗎啡調整釋放。有3個研究比較嗎啡立即釋放在不同的給藥途徑的效果。2項研究中比較嗎啡調整釋放在不同的時間的效果和比較嗎啡立即釋放在不同時間的效果。一項研究比較以下項目:嗎啡調整釋放藥片和嗎啡調整釋放懸服液;嗎啡調整釋放與非鴉片類藥物;鴉片立即釋放與非鴉片類藥物;口服嗎啡與硬膜外嗎啡。

在此更新的“沒有超過輕微疼痛'標準是等同於30/100毫米或更小的視覺模擬疼痛強度評分(visual analogue pain intensity scale),或等值的其它疼痛量表。18個研究,平均達到緩解疼痛的標準,但並沒有研究報告指出,確實的降低其個人疼痛的程度。在17項研究中的結果,有96%(377分之362)的參與者表示“沒有超過輕微疼痛”,治療成功的63%(400/638)的結果達到了。

嗎啡是一種對於癌症疼痛有效的止痛藥物。嗎啡調整釋放和嗎啡立即釋放在緩解疼痛上沒有不同。調整釋放有效的時間12小時或24小時取決於配方。在此研究中每日劑量從25毫克至2000毫克不等,平均為100毫克和250毫克之間。劑量配置都有在立即釋放和調症釋放的產品上。少數參與者並沒有獲得足夠的鎮痛嗎啡。不良反應常見,約6%的參與者,因為難以忍受副作用而停止的治療。

作者結論

口服嗎啡的效果受限於最佳疼痛緩解時間,但在對於這一個重要藥物-嗎啡,這方面的隨機試驗文獻數量不多。大多數試驗招募了不到100人,並沒有進行攫取分析以提供相關的數據。只有少數報導有多少人有良好的疼痛緩解,但是其中90%以上的人有輕微的疼痛到沒有惡化的經驗在這短時間中。回顧顯示在研究中,使用寬劑量範圍的嗎啡,少數百分比的參與者無法忍受口服嗎啡。回顧報告還顯示了廣泛的研究設計和不一致的交叉設計。試驗設計通常基於嗎啡的劑量或比較去達到適度的鎮痛,然後交叉使用在參與者的交叉設計研究中。目前還不清楚,如果有效的製劑或對照藥物之間的臨床差異。新的研究加入,以加強回顧的視野,認為有可能使用調整釋放嗎啡去滴注以達到止痛作用。有定性的證據表明,口服嗎啡和其他鴉片類的藥物,一樣具有很多相同的功效。

譯註

翻譯者:臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

Plain language summary

Oral morphine for cancer pain

Morphine taken by mouth produced good pain relief for most people with moderate or severe cancer pain.

One person in two or three who gets cancer will suffer from pain that becomes moderate or severe in intensity. The pain tends to get worse as the cancer progresses. Morphine taken by mouth has been used since the 1950s for controlling cancer pain. In 1986 the World Health Organization recommended taking an oral solution of morphine every four hours. Morphine is now available in a number of different formats that release the morphine over various periods of time. Morphine Immediate release is rapidly absorbed, and would usually be taken every four hours. Modified release tablets are available that release morphine more slowly, so that they can be taken only twice a day or even only once a day.

In this review we set out to estimate how well morphine worked, how many people had side effects, and how severe those side effects were – for example, whether they were so severe that participants stopped taking their oral morphine. We found 62 studies with 4241 participants. The studies were often small, compared many different preparations, and used different study designs. This made it difficult to work out whether any one tablet or preparation of oral morphine was better than any other. There did not seem to be much difference between them. More than 9 in 10 participants had pain that went from moderate or severe before taking morphine to pain that was no worse than mild pain when taking morphine. More than 6 in 10 participants were very satisfied with the morphine treatment, or considered the result to be very good or excellent. Only about 1 person in 20 stopped taking morphine because of side effects. Morphine is associated with some unwanted effects, mainly constipation, and nausea and vomiting.

At one level these are good results. On another level, we could wish for more consistency in study design, and especially in study reporting, which should include the outcome of pain reduced to tolerable levels – no worse than mild pain – so that people with cancer are not bothered by pain.

淺顯易懂的口語結論

口服嗎啡於癌症疼痛

對於多數有中度或重度癌症疼痛,口服嗎啡有良好緩解疼痛效果。

罹患癌症中二到三個人其中的一位,將遭受密集性的中度或重度的疼痛。因為癌症疾病的進展,疼痛往往會更糟。口服嗎啡自從1950年代以來,被用於控制癌症疼痛。在1986年世界衛生組織建議,每四個小時使用一次口服嗎啡液體。 目前有許多不同形式的嗎啡,有多種釋放嗎啡時間。嗎啡立即釋放是迅速被吸收,每四個小時會使用一次。調整釋放錠劑是緩慢地釋放嗎啡劑量,以便一天使用二次或是甚至一天一次。

在這次回顧當中,我們開始評估如何使嗎啡作用效果好、有多少人有副作用,以及多嚴重的副作用,例如:是否有參與者的副作用嚴重到不再繼續使用口服嗎啡。我們發現62個研究有4241位參與者。這些研究往往很小,相比許多不同的製劑和不同的研究設計。這使得它很難找出,是否有任何一種錠劑或口服嗎啡的製劑比任何其他更好的。在藥品之間似乎沒有很大的差異。在十個參與者中有超過9個人以上,在服用口服嗎啡前有經歷中度或重度的疼痛,服用嗎啡止痛後沒有超過輕微疼痛的疼痛。十位當中有超過六位的參與者都非常滿意嗎啡的治療效果,或認為其結果是良好或非常好。二十位當中的一位會因其副作用而停止服用。和嗎啡相關聯的副作用,主要是便秘、噁心和嘔吐。

就某一層面而言,這些都是很好的效果。在另一層面,我們希望研究設計能有更多的一致性,特別是在研究報告,其中應包括疼痛的結果降低到可接受的範圍-沒有超過輕微疼痛- 使癌症病友免於疼痛的困惱。

譯註

翻譯者:臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

Laički sažetak

Uzimanje morfina na usta za karcinomsku bol

Cochrane sustavni pregled pokazuje da davanje morfina na usta djelotvorno ublažava bol u većine bolesnika koji pate od umjerene ili intenzivne karcinomske boli.

Jedna od dvije ili tri osobe koje obole od karcinoma trpi bolove koji mogu biti umjereni ili vrlo intenzivni. Bol se često pogoršava kako karcinom napreduje. Morfin uzet na usta koristi se za kontrolu karcinomske boli od 1950-tih godina. Svjetska zdravstvena organizacija je 1986. preporučila uzimanje otopine morfina svakih nekoliko sati. Morfin je danas dostupan u nizu različitih oblika koji otpuštaju lijek kroz različito vrijeme. Postoje oblici morfina koji brzo otpuštaju lijek i lako se upijaju i koji se obično uzimaju svako par sati. Dostupne su i tablete koje morfin otpuštaju polako tako da se mogu uzimati svega dvaput dnevno ili čak i jednom dnevno.

U ovom Cochrane sustavnom pregledu cilj je bio istražiti koliko je djelotvoran morfin za karcinomsku bol, koliko ljudi razvije nuspojave i koliko su teške nuspojave - primjerice, jesu li nuspojave toliko ozbiljne da će ispitanici prestati uzimati morfin na usta. Pronađene su 62 studije s 4241 ispitanika. Studije su uglavnom bile malene, uspoređivale su brojne različite vrste morfina, i koristile su drugačije ustroje istraživanja. Zbog toga je teško procijeniti je li jedna tableta ili oblik morfina koji se uzima na usta bolji od nekog drugog. Čini se da među njima nema velike razlike. Bol koja je bila umjerena ili intenzivna se nakon uzimanja morfina u više od 90% bolesnika smanjila na blagu ili nikakvu bol. Više od 60% bolesnika bili su vrlo zadovoljni terapijom morfinom i smatrali su rezultate vrlo dobrima ili izvrsnima. Otprilike 1 osoba od 20 ispitanika prestala je uzimati morfin zbog nuspojava. Morfin je povezan s određenim štetnim učincima, uglavnom zatvorom stolice (konstipacija), mučninom i povraćanjem.

U jednu ruku to su dobri rezultati. Međutim, s druge strane, bilo bi dobro da su kliničke studije sličnije po ustroju istraživanja i načinu prikazivanja studija; primjerice, u tim studijama trebalo bi ispitati smanjenje boli do prihvatljive razine - smanjenje do razine boli koja nije veća od blage boli, koja onda više ne uzrokuje velik problem bolesnicima.

Bilješke prijevoda

Hrvatski Cochrane
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