Journal of Pain and Symptom Management
Volume 39, Issue 2 , Pages e1-e5, February 2010

Re: Update on Cancer Pain Guidelines

Palliative Medicine Department, Velindre Hospital NHS Trust, Cardiff, United Kingdom

St. Oswald's Hospice, Northumberland Tyne & Wear NHS Trust, Newcastle-upon-Tyne, United Kingdom

Cardiff University, Cardiff, United Kingdom

St. Oswald's Hospice, Newcastle University, Newcastle, United Kingdom

Article Outline

 

To the Editor:

Caraceni et al.1 draw attention to a much needed discussion about the use of opioids in the management of cancer pain, and the work that is being currently undertaken to update the World Health Organization's (WHO) and European Association for Palliative Care's guidelines is timely. Morphine, for instance, one of the most traditional and commonly used opioids, has held a fundamental role in managing cancer pain,1 yet confusion around starting doses, titration, and maintenance in its use is still widespread. Morphine prescribing has been benchmarked for many years and guidelines produced, which formed the basis of other opioid prescribing advice.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 Despite this, prescribing errors and criminal overdoses have been responsible for deaths in the UK.14, 15, 16, 17 This prompted us to review published guidance and identify discrepancies and variations in these texts.

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Methods 

A review of commonly used guidelines for opioids in the United Kingdom was conducted. Four palliative care physicians from two different U.K. centers suggested reference materials commonly used by palliative care, oncology, and primary care doctors when prescribing oral morphine. After recommendations from both centers, 15 sources were agreed upon, taking into account nationally recommended or widely used prescribing resources, such as the British National Formulary (BNF); online educational resources, including www.palliativedrugs.com; online guidelines, such as the Scottish Intercollegiate Guidelines Network (SIGN); and other Internet resources that doctors may access for advice (such as www.bmj.com). Furthermore, key textbooks, the ABC of Palliative Care and the Oxford Textbook of Palliative Medicine, were included as likely sources of guidance on morphine prescribing. Online information sources such as Wikipedia were excluded, as the authors felt it unlikely that doctors would base their prescribing decisions on public information sites and suppliers.

We subsequently set a consensus approach to reviewing the literature and what aspects we wanted to focus on. The following six questions were asked when reviewing the guidance:

•Is there an oral morphine starting dose for patients on step 1 of the WHO analgesic ladder (i.e., opioid naive)?

•Is there an oral morphine starting dose for patients on step 2 of the analgesic ladder (i.e., on “weak” opioid)?

•Is there an indicative dose range for oral morphine over 24 hours?

•Is there a recommended dose increment if pain is not controlled?

•Does the source recommend starting morphine via the oral route if possible?

•Does the guidance mention a median dose of morphine (which could suggest to prescribers an indicative norm)?

It was felt by all four authors that these were areas that should be a baseline standard for all guidance on morphine prescribing.

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Results 

A review of the 15 sources (Table 1) demonstrated marked variations.17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 Some made little or no mention of starting doses, titration advice, or advice on upper limits. Starting doses for opioid-naive patients varied from 6 to 60mg per 24 hours, whereas titration advice varied from increasing the dose by 30% every 2–3 days to 50% four hours after the previous dose. Suggested upper limits for oral morphine ranged from 300mg/24hours, through 3000mg/24hours, to statements that there is no maximum dose.

Table 1. Prescribing Advice for Oral Morphine in Adults from Palliative Care Sources
SourceOral Morphine Starting Dose for Patients on Step 1 of Analgesic Ladder (i.e., Opioid Naive)Oral Morphine Starting Dose for Patients on Step 2 of Analgesic Ladder (i.e., on “Weak” Opioid)Indicative Dose Range for Oral Morphine/24 HoursDose Increment if Pain Not ControlledRecommends Starting Morphine via Oral Route
Fallon and Hanks17General advice: no specific dosesGeneral advice: no specific doses
20–1500mg


Extra doses same as regular 4-hourly morphine.

Yes

Usually less than 200mg a day


After 24–48hours, reassess and adjust dose as necessary.

Regnard and Dean181mg 4 hourly in elderly frailConvert to equivalent oral morphine doseMedian=90mg/24hours oral morphine (or 15 mg 4 hourly)25%–50% every third day but can be faster under supervision.Yes
2.5 mg in other patients (=6–15 mg/24 hours)
Joint Formulary Committee195–10mg 4 hourly or 10–20mg 12 hourly (=20–40 mg/24 hours)
20–30mg 12 hourly (=40–60 mg/24 hours)


Up to 500 mg orally 4 hourly (i.e., up to 3000 mg/24 hours)

Fifty percent on next dose if the first dose of morphine is no more effective than the previous analgesic.Yes
Davies20No informationNo informationNo informationNo information.Advice on breakthrough pain
Ellershaw and Wilkinson21General advice: no specific doses
General advice: no specific doses


General advice: no specific doses

No information.Advice on parenteral use atend of life
Regnard and Kindlen222.5 mg 4 hourly (=15 mg/24 hours)
5mg 4 hourly (=30 mg/24 hours)


5–500mg/24 hours (90% managed on less than 500mg/24 hours)

50% every third day.Yes

Median is 100mg/24 hours

Hanks et al.235mg 4 hourly (=30 mg/24 hours)
10mg 4 hourly (=60 mg/24 hours)

No informationRescue dose (same as 4 hourly dose) can be given as often as required (up to hourly) and total dose of morphine should be reviewed daily.Yes
Sykes et al.242.5–5mg 4 hourly in elderly frail
General advice: no specific doses

No information
General advice: no specific figures.

Yes
5–10mg in others (=15–60 mg/24 hours)
Gowans25No information
30mg 12 hourly (=60 mg/24 hours)


No maximum dose

No information.No information

Reconsider cause of pain when dose>300mg/24 hours

Doyle et al.26General advice: no specific doses
10mg 4 hourly (=60 mg/24 hours)

Absolute dose is immaterial30%–50%.Yes
Stannard and Booth27General advice: no specific doses
General advice: no specific doses


General advice: no specific doses

No information.Yes
Twycross and Wilcock28General advice: no specific doses10mg 4 hourly or 20–30mg 12 hourlyTwo-thirds never need >30mg 4 hourly33%–50% every 2–3 days.Yes
5mg 4 hourly in the frail and elderly (=30–60 mg/24 hours)
Back292.5 mg 4 hourly in elderly frail
10mg 4 hourly or 30mg 12 hourly (=60 mg/24 hours)

No preset maximum30%–50% every 1–2 days but can be twice a day in severe pain.Yes
5mg 4 hourly in other patients or 20mg 12 hourly (=15–40 mg/24 hours)Very few patients require more than 600mg daily
SIGN (Scottish Intercollegiate Guidelines Network)305–10mg 4 hourly in young and middle aged
General advice: no specific doses

General advice: no specific dosesNo information.Yes
2.5–5mg in the elderly
Twycross et al.31General advice: no specific doses10mg 4 hourly or 20–30mg 12 hourlyTwo-thirds never need >30mg 4 hourly33%–50% every 2–3 days.Yes
5mg 4 hourly in the frail and elderly (=30–60 mg/24 hours)

Titration advice also varied. For example, the section of BNF (March 2009) on “Prescribing in Palliative Care” recommended the following after commencing immediate-release morphine solution or tablets every four hours: “If the first dose of morphine is no more effective than the previous analgesic, the next dose (four hours later) should be increased by 50%, the aim being to choose the lowest dose that prevents pain.” Given that the recommended starting dose in the BNF can be as high as 20mg of normal-release morphine every four hours, this could in theory mean that a patient is started on morphine 20mg at 8 am, then receives 30mg at noon, then a further 45mg at 4 pm increasing to 65mg at 8 pm, and so on. Additionally, the patient may receive rescue doses of immediate-release morphine. The most recent edition of the BNF32 (September 2009) has changed the upward titration advice from 50% to 30–50% every four hours if required. Despite this recent revision in titration guidance, such a rapid upward titration of morphine does not appear to accurately reflect current palliative care practice in both centers involved in reviewing guidance for this article. Similar titration advice to the BNF appears to also be advocated elsewhere. One such source was accessed on the British Medical Journal's Web site (www.bmj.com) and, therefore, constitutes an easily accessible reference guide for any doctor wanting information on prescribing morphine.33

Finally, although the median expected dose—derived from routine practice—could provide a reference point for an inexperienced prescriber, it was only mentioned in one source of information reviewed. We believe that indicating the usual median dose of morphine is important to make clear that most of the patients do not require high doses. Two articles have provided valuable data regarding median doses and found a median dose of 60mg of morphine over 24hours.34, 35 Furthermore, an upper indicative dose limit could help provide guidance for clinicians on when to seek help or revise analgesic management. Walsh and Cheater35 demonstrated that only 1% of patients require more than 600mg over 24hours, thereby suggesting an upper limit of morphine for generalist prescribing at 600mg over 24hours.

The review of morphine prescribing guidance showed limitations in the following areas:

•Of the 15 sources reviewed, some made little or no mention of starting doses, titration advice, or advice on upper limits.

•Starting doses for opioid-naive patients varied from 6 to 60mg orally per 24 hours.

•Titration advice varied from increments of 30% every 2–3 days to a 30%–50% increase four hours after the previous dose if pain was not controlled.

•Suggested upper limits for oral morphine varied from 300mg/24hours, through 3000mg/24hours, to statements that there was no maximum dose.

•Median doses of morphine were not mentioned in most of the available prescribing guidance reviewed.

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Discussion 

Poorly written or incomplete guidance risks delivering an ambiguous message, potentially open to misinterpretation. Those with little experience in prescribing morphine to cancer patients may wrongly conclude that any dose is acceptable and titrate upward regardless of efficacy and side effects. Indeed, some may infer that the only adverse effect of high-dose opioids is sedation and that this is acceptable in cancer patients nearing the ends of their lives. Furthermore, there are a variety of situations where titration must carefully consider factors such as renal, hepatic, and brain impairment. Inconsistent guidelines across the literature are likely to confuse clinicians.

Our review has limitations in that it only reviewed a small section of available guidelines that are commonly used in our localities. Although it may not be widely generalizable, it raises difficult questions about the consistency of available guidance on morphine and other opioids. Therefore, the forthcoming EPCRC-EAPC (European Palliative Care Research Collaborative- European Association for Palliative Care) guidelines next year are to be welcomed. Although their program and aims are ambitious and cover many areas, they should also endeavor to get the fundamentals of our practice, such as morphine prescribing, precise, consistent, and reproducible, so that other guidelines can follow suit.

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PII: S0885-3924(09)01135-X

doi:10.1016/j.jpainsymman.2009.11.240

Journal of Pain and Symptom Management
Volume 39, Issue 2 , Pages e1-e5, February 2010

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