Pain is described by the International Association for the Study of Pain (IASP) as: “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”¹ Special consideration needs to be given to the management of pain at the end of life. 

This article will concentrate on the management of pain in the final 72 hours of life and is intended as a practical tool to aid doctors and other healthcare professionals manage pain in the dying patient. If pain is not optimally controlled it will contribute to the suffering of the dying patient and will heighten the distress of the family.

The final days

It is difficult to be accurate concerning prognostication of diseases. Generally only estimates in terms of days, weeks or months can be given to patients and their families. The clearest signs of approaching death are picked up by the day-to-day assessment of deterioration. Such signs include profound tiredness and weakness, reduced intake of food and fluids, drowsy or reduced cognition, gaunt appearance and difficulty swallowing medicine.² If such symptoms develop suddenly or unexpectedly it is important to exclude a reversible cause of the deterioration such as infection, hypercalcaemia or side-effects of medications. 

An important cause to consider is opioid toxicity. Patients can develop opioid toxicity during titration of opioids, however, toxicity can occur in patients who are stable on long-term opioids. 

Opioid toxicity is usually associated with delirium with myoclonus, vivid dreams and hallucinations.³ If these are not present other causes of delirium should be considered. It is also important to acknowledge that a patient may continue to deteriorate and die despite the treatment of infection or biochemical abnormalities. Once it is clinically considered that a patient is beginning to die the focus of the patient’s management changes to optimising comfort. Unnecessary procedures, such as phlebotomy and vital sign monitoring, should be discontinued. 

In order to decrease the burden of taking tablets, medications that are no longer essential and do not provide benefit in terms of patient comfort should be rationalised. 

Communication

It is essential for accurate information to be communicated clearly to the patient and family. Certain changes in the patient’s care will be taking place that the patient and family will be unfamiliar with, such as the discontinuation of regular medications and vital sign monitoring. It is important to anticipate patients’ and families’ fears and pre-emptively manage these concerns where possible with good communication.

Medications may need to be given parenterally, such as in a continuous subcutaneous infusion (CSI), if a patient is too weak to swallow. However, this may raise some concerns for the patient and family that it could cause or hasten death. If expressed, these fears should be explored, and the reason for using a CSI should be clearly communicated. 

It is important for the family to be aware that it is the progressive nature of the underlying condition that will lead to the patient’s death and not the use of a CSI, which is simply to deliver medication that can no longer be administered via the oral route and to prevent frequent parenteral medication usage.

Pain assessment in the dying patient 

A number of symptoms can develop during the dying phase such as pain, excessive respiratory secretions, and changes in breathing patterns. Due to a patient’s reduced consciousness they may not be able to report pain, and as such, pain is best monitored by observing a patient’s behaviours for non-verbal clues. These include facial expressions such as grimacing and frowning, vocalisations such as groaning, and body language such as a tense posture.⁴

As well as consideration being given to the assessment of pain in the dying patient, the choice of analgesic also requires special attention. 

The World Health Organisation (WHO) guide to the management of cancer pain is based on a three-step analgesic ladder. Step one analgesics include paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin. Step two analgesics include codeine and tramadol. Morphine sulphate, oxycodone, hydromorphone, buprenorphine and fentanyl are examples of ‘strong opioids’ that are commonly prescribed for use at step three of the WHO ladder. 

Some step one analgesics, such as diclofenac and paracetamol, have a role in the pain management of the dying. Paracetamol can be administered intravenously and per rectum. Diclofenac is available in Ireland as an injection. It is only licensed for intravenous and intramuscular use; however, anecdotal evidence in the palliative care setting supports its routine use subcutaneously. It is typically given as a continuous subcutaneous infusion at a dose of up to 150mg/24 hours.^5,6 Diclofenac can also be administered per rectum. 

Step two analgesics, weak opioids, have no role in pain management in the dying, as these are not administered using a continuous subcutaneous infusion. The WHO step three analgesics, strong opioids, are the mainstay of pain management in the dying because of their ease of use in CSIs.

When patients are dying they may not have any pain and may not be prescribed any regular analgesic. In this scenario it is sufficient to prescribe analgesia on a pro re nata (prn) basis that can be administered if the patient develops pain. If frequent doses are required it is less burdensome for a patient to have a continuous subcutaneous infusion to deliver the medication than regular bolus injections. A continuous subcutaneous infusion of opioids is easy to administer and can be given at home. Many opioids can be used alone or in combination with other medications in a CSI.

If a patient is currently taking regular weak opioids for pain management and the oral route is no longer available an appropriate dose of a strong opioid should be administered subcutaneously. 

Conversion tables are available of opioid equivalencies. These conversions are a guide only and doses may vary for individual patients.

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New guidelines

The National Clinical Programme for Palliative Care will publish the first clinical guidelines – Pharmacological Management of Cancer Pain in Ireland – before the end of 2013. These guidelines ‘aim to inform, aid and support healthcare professionals challenged with treating patients suffering from cancer-related pain’.⁷

All opioid drug conversions in this article are taken from a draft of this document. Some patients may already be prescribed strong opioids. A conversion ratio for oral:subcutaneous strong opioids is usually
2:1. It is important to be aware that strong opioids have different potencies. 

Oxycodone is more potent than oral morphine sulphate; hydromorphone is more potent than oxycodone. For example, morphine sulphate 10mg is equivalent to oxycodone 5mg, which is equivalent to hydromorphone 2mg (see Table 2). Transdermal opioid medication should only be used in patients with stable pain. As frequent changes to analgesic dosing may be required during the dying phase, the use of transdermal patch medications such as those that contain buprenorphine and fentanyl should not be initiated. 

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For patients who have a patch in place, who are close to death, the patch should be left in situ and additional analgesia used as required.⁸

There are tables available, as manufacturer guidelines, of transdermal buprenorphine/fentanyl and morphine sulphate equivalencies that advise the breakthrough opioid dose that should be prescribed. The choice of strong opioid to use depends on opioid availability, patient comorbidities and drug volumes. For 25 years, oral morphine sulphate has been considered to be the drug of choice for the treatment of moderate to severe cancer pain.⁹

Special considerations

Special consideration is needed when prescribing the correct analgesia for patients with renal and hepatic impairment.

Renal impairment

In mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-89ml/min) all opioids that are appropriate for cancer pain can be used, with consideration of dose reduction or frequency at lower eGFR levels.¹⁰

In severe and end-stage renal impairment (eGFR < 30ml/min) fentanyl is the first-line analgesic. It is metabolised in the liver to inactive and non-toxic compounds, with less than 10% excreted unchanged in urine.

Alfentanil is a synthetic derivative of fentanyl. It is less potent than fentanyl and is metabolised in the liver, with urinary excretion of the metabolites (which are thought to be inactive).^5,10

Hepatic impairment

Liver function can be altered as a result of malignancy due to either primary liver cancer or secondary metastatic disease. There is a lack of reliable information on the behaviour of commonly used palliative care medicines in patients with liver disease.¹¹

In patients with cirrhotic liver disease, opioids should be initiated at lower doses and titrated slowly using extended dosing intervals.¹²

Co-analgesics

Co-analgesics, such as antidepressants and anti-epileptic medications, including amitriptyline and gabapentin, respectively, are commonly used for the management of neuropathic pain. These agents are only available via the oral route and cannot be replaced parenterally. When the oral route is no longer available another analgesic, usually an opioid, needs to be substituted .

In addition to managing pain in the dying patient, other symptoms that are commonly encountered include delirium, breathlessness, nausea, agitation, anxiety and excessive respiratory secretions. It is important to manage these symptoms adequately as they may contribute to the patient’s distress.

Conclusion

When the patient is dying and unable to tolerate oral medications for symptom relief they should be administered subcutaneously, which is more practical than intravenously. If medications are required regularly they should be administered in a CSI. Problems with other symptoms that could potentially occur should be anticipated and appropriate medications for the relief of these symptoms prescribed routinely on a pro re nata basis.

References

1. Classification of chronic pain: Descriptions of chronic pain syndromes and definitions of pain terms. Prepared by the International Association for the Study of Pain, Subcommittee on Taxonomy. Pain Suppl 1986; 3: S1-S226
2. National Council for Hospice and Specialist Palliative Care Services. Changing Gear – Guidelines for Managing the Last Days of Life in Adults (Revised ed). NCPC, London, 2006
3. Lawlor P, Gagnon B, Mancini I, et al. Occurrence, causes, and outcome of delirium in patients with advanced cancer: a prospective study. Arch Intern Med 2000; 160: 786-794
4. The management of persistent pain in older persons: AGS Panel on persistent pain in older persons. J Am Geriatr Soc 2002; 50: S205-S224
5. Twycross R, Wilcock A, Eds. PCF 4; Palliative Care Formulary (4th ed), Nottingham: palliativedrugs.com, 2011
6. Hall E. Subcutaneous diclofenac: An effective alternative? Palliat Med 1993; 7: 339-340
7. HSE. Pharmacological management of cancer pain in adults: Draft National Clinical Guidelines, May 2013 www.healthireland.ie/eng/about/Who/clinical/natclinprog/palliativecareprogramme/painguide.pdf 
8. Scottish Intercollegiate Guidelines Network (SIGN). Control of pain in adults with cancer. A national clinical guideline (106). NHS. No 106. Edinburgh, 2008
9. Caraceni A, Pigni A, Brunelli C. Is oral morphine still the first choice opioid for moderate to severe cancer pain? A systematic review within the European Palliative Care Research Collaborative guidelines project. Palliat Med 2011; 25: 402-409
10. King S, Forbes K, Hanks G et al. A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment: A European Palliative Care Research Collaborative opioid guidelines project. Palliat Med 2011; 25: 525-552
11. Watson M, Lucas C, Hoy A et al. Palliative Adult Network Guidelines (3rd ed). Belfast, 2011: 332
12. Davis M, Glare P, Hardy J (Eds). Opioids in Cancer Pain (2nd Ed). Oxford: Oxford University Press, 2005.