Commissioned by Ethypharm UK Ltd

This Guidelines supplement has been developed in partnership with Ethypharm UK Ltd. Ethypharm UK Ltd suggested the topic, commented on the author brief, and funded the production of the supplement. The views and opinions in this supplement are not necessarily those of Ethypharm UK Ltd. or of Guidelines, its publisher, advisers, or advertisers. The copyright of Guidelines (including the Guidelines brand, logo, and the design and format of the book) rests with MGP Ltd unless otherwise stated. No part of this publication may be reproduced in any form without the permission of the publisher.

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The role of morphine in the management of cancer pain

Dr Andrew Dickman, Consultant Pharmacist—Palliative Care, Royal Liverpool and Broadgreen University Hospitals NHS Trust

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Traditionally, the management of cancer patients has been viewed as the responsibility of secondary care. However, as approaches to treatment continue to develop, primary care must adapt and evolve. Strong opioids, particularly morphine, are the principal treatments for pain related to cancer, and their use has increased significantly in the primary care setting. The number of opioid analgesics prescribed in primary care in England increased by 11.9 million between 2006 and 2016,1 although it is likely the majority of prescriptions were for chronic non-cancer pain.2 It is important to stress that cancer pain is managed differently to chronic non-cancer pain, especially when considering the risks and benefits of opioids.3

Pain has been shown to be the most frequent symptom to prompt out-of-hours primary care contact for people with a diagnosis of cancer.4 Cancer pain can be caused directly by tumour growth, which can induce tissue damage and the release of inflammatory mediators as well as nerve damage through compression or infiltration, and indirectly by treatment (e.g. chemotherapy, radiotherapy, or surgery). Patients may experience continuous pain (i.e. background pain) or intermittent pain (which may be spontaneous or related to movement).

It is now recognised that pain is not a simple, linear response to injury, inflammation, and other tissue damage. Rather, pain is a subjective experience that can be influenced by many factors, including emotional state, past experiences, attention, and distraction, which serve to augment or attenuate the pain experience. Dame Cicely Saunders introduced the concept of ‘total pain’ to describe the interaction between the physical, emotional, psychological, and social distress experienced by patients with cancer.5 Pain is experienced as a result of a complex interplay between cognition, emotion, and mediated by several diverse brain regions rather than a sensory input caused by injury or inflammation.6 Hence, analgesics may only constitute one part of the management strategy for cancer pain.

Prevalence of cancer pain

A systematic search of the literature reported that pain is experienced by 66.4% of patients with advanced, metastatic, or terminal disease.7 The frequency and intensity of pain tends to increase with disease progression, reportedly affecting up to 90% of patients at the end of life.8 The impact of pain on the quality of life of patients with cancer can be overwhelming: patients with cancer pain exhibit a significantly lower performance status and higher incidence of total mood disturbance than those who are pain-free.9 These symptoms can further complicate pain management. Nonetheless, acceptable pain relief is considered possible in up to 76% of patients with cancer using the World Health Organization three-step analgesic ladder, which culminates in the use of a single strong opioid for moderate to severe pain.10

Role of morphine sulphate

Opioids are the mainstay of cancer pain management and the only analgesics with a proven benefit when the pain is moderate to severe. Evidence has shown no important differences in terms of efficacy or tolerability between morphine, oxycodone, and hydromorphone for moderate to severe cancer pain when given orally.11 Consequently, oral sustained-release morphine remains the first-line strong opioid for the management of moderate to severe cancer pain because of factors such as availability, cost, and familiarity.11,12

Prescribing morphine sulphate

Patients with advanced and progressive cancer should have the opportunity to make informed decisions about their treatment and discuss concerns such as adverse effects. Patients should be provided with verbal and written information about the treatment plan, which should include: 

  • rationale
  • management of background pain and treatment of pain flares
  • expected benefits and adverse effects
  • implications for driving
  • signs of excessive dose
  • out-of-hours contacts.


The dose of morphine should be carefully titrated against the patient’s pain. It is recommended the dose of oral morphine should not exceed 120 mg daily (or equivalent for alternative opioids) without specialist advice.3 Dose escalation can be limited by adverse effects, such as constipation, drowsiness, and nausea. These issues can be addressed in several ways, including proactive management with co-prescription of laxatives and antiemetics.

Generic or branded prescribing of morphine?

There are several branded modified-release oral morphine preparations available. Generic prescribing of drugs in the UK has been advocated as a method of reducing healthcare costs, but generic prescribing of modified-release oral morphine preparations may increase the risk of medication errors and burden the NHS in terms of both acquisition and hidden costs.

Firstly, there is a risk that preparations are not therapeutically equivalent. This is highlighted by the British National Formulary (BNF), which states that, for modified-release oral morphine preparations, dosage requirements should be reviewed if the brand is changed.13 The Medicines and Healthcare products Regulatory Agency (MHRA) also alludes to this by permitting the statement, ‘It is not possible to ensure bio-equivalence between different brands of prolonged release morphine products,’ in the summary of product characteristics (SPCs) of several of the modified-release oral morphine products.14,15 If a prescription is written generically, there is no guarantee that patients will receive the same product each time it is dispensed, which could lead to loss of pain control and associated consequences such as the need for additional input from healthcare professionals.

Secondly, a branded product may have been chosen for a specific reason. For example, one brand of modified-release morphine capsules (12-hourly) may be prescribed for a patient with swallowing difficulties who has been instructed to sprinkle the contents onto food. The pharmacist would be unaware of the prescriber’s intentions on receiving a generic prescription. The consequences may include poor patient compliance, loss of pain control, and the need for additional healthcare professional input.

Finally, to avoid patient confusion, it is important that brand substitution does not occur without adequate explanation (although the problems described above may still occur). If a patient receives two different brands (perhaps from two different healthcare settings) and they look completely dissimilar, it is possible that both may be taken together. It is unfortunate that there is no national formal guidance on branded prescribing of modified-release opioid products, despite the warnings and precautionary statements mentioned by the BNF and, indirectly, the MHRA.

Treatment review

Pain relief and the use of morphine should be regularly reviewed. There are no set rules for this approach; the prescriber will need to be guided by the patient and agree a plan at the outset. During the initial dose-titration period, some patients may require weekly review, whereas others may need to be reviewed more frequently. Once the dose has been stabilised, the patient can be reviewed less frequently, such as monthly (especially as the usual maximum supply on prescription is for 30 days’ treatment), but should be seen at least every 6 months.

Conflicts of interest

Dr Dickman has received consulting and/or speaker fees from Grunenthal Ltd, Napp Pharmaceuticals Ltd and Kyowa Kirin Ltd. He has also received unrestricted educational grants from Ethypharm UK Ltd and Kyowa Kirin Ltd.

Summary

  • Pain is a subjective experience, involving both sensation and cognition
  • A significant number of patients with advanced disease can experience cancer pain; if left untreated, this pain can impact their quality of life
  • Morphine sulphate is the first-line strong opioid for the management of moderate to severe cancer pain
  • Patients must be involved in the decision to start taking an opioid
  • Modified-release oral morphine preparations should be prescribed by brand
  • Pain relief and the use of morphine should be regularly reviewed. 

References

  1. NHS Direct. Prescriptions Dispensed in the Community - Statistics for England, 2006-2016. Leeds: NHS Direct, 2017.  Available at: https://digital.nhs.uk/data-and-information/publications/statistical/prescriptions-dispensed-in-the-community/prescriptions-dispensed-in-the-community-statistics-for-england-2006-2016-pas (accessed 13 July 2018).
  2. Zin C et al. Eur J Pain 2014; 18 (9): 1343–1351.
  3. Royal College of Anaesthetists. Opioids Aware: a resource for patients and healthcare professionals to support prescribing of opioid medicines for pain. RCA, 2017. Available at: www.rcoa.ac.uk/faculty-of-pain-medicine/opioids-aware
  4. Adam R et al. Br J Gen Pract 2014; 64 (619): e99–104.
  5. Clark D. ‘Total pain’, disciplinary power and the body in the work of Cicely Saunders, 1958–1967. Soc Sci Med 1999; 49 (6): 727–736.
  6. Melzack R. Pain and the neuromatrix in the brain. J Dent Educ 2001; 65 (12): 1378–1382.
  7. van den Beuken-van Everdingen M et al. J Pain Symptom Manage 2016; 51 (6):1070–1090.
  8. Costantini M et al. Ann Oncol 2009; 20 (4): 729–735.
  9. Lin C et al. J Pain Symptom Manage 2003; 25 (1): 29–37.
  10. Zech D et al. Pain 1995; 63 (1): 65–76.
  11. Caraceni A et al. Lancet Oncol 2012; 13 (2):e58–e68.
  12. NICE. Palliative care for adults: strong opioids for pain relief. NICE Clinical Guideline 140. NICE, 2012. Available at: www.nice.org.uk/cg140
  13. British National Formulary website. Morphine. Available at: bnf.nice.org.uk/drug/morphine.html (accessed 3 July 2018).
  14. Concordia International - formerly AMCo. Morphgesic SR 100mg Tablets—summary of product characteristics. May 2015. www.medicines.org.uk/emc/product/4689/smpc#
  15. Napp Pharmaceuticals Limited. MST Continus tablets 100 mg—summary of product characteristics. March 2018. www.medicines.org.uk/emc/product/7662/smpc

ZOM/UK/0010/18

Date of preparation: September 2018

This Guidelines supplement has been developed in partnership with Ethypharm UK Ltd. Ethypharm UK Ltd suggested the topic, commented on the author brief, and funded the production of the supplement. The views and opinions in this supplement are not necessarily those of Ethypharm UK Ltd. or of Guidelines, its publisher, advisers, or advertisers. The copyright of Guidelines (including the Guidelines brand, logo, and the design and format of the book) rests with MGP Ltd unless otherwise stated. No part of this publication may be reproduced in any form without the permission of the publisher.