The first of two articles considers options for pain control in palliative care

This article, which can be used for CPD, reviews pharmacological approaches to managing persistent and breakthrough pain. It should help you improve the experiences of patients, their caregivers and other professionals who come to you for help.

Which are the main analgesics used in palliative care?
Morphine is the standard against which other analgesics are compared. Oxycodone is about twice as potent and slightly less sedating. Fentanyl is about 100 times more potent than morphine and can be administered as transdermal patches.

What about breakthrough pain?
Oral morphine is used in about one sixth of the daily dose being given for background analgesia. Transmucosal, buccal, and nasal fentanyl preparations act more quickly and may be useful for patients who experience side effects with other immediate release opioids.

In 2008 the Department of Health published an End of Life Care Strategy to bring about a "change in access to care for all people approaching end of life". It was envisaged that improvements would be achieved using a systems and care pathway approach for commissioning and providing integrated services, improving co-ordination. It would involve workforce development to effect relief of suffering, enhance quality of life and support for patients and their families and encourage initiation of palliative care early in a patient's illness, even when he or she is still receiving life-prolonging treatment.

It supported the use of the Gold Standards Framework, the Liverpool Care Pathway and Preferred Place of Care tools. However, the needs of carers and professionals involved in providing palliation and end of life care for patients with non-malignant disease, including neurological diseases and dementia, cardiovascular, renal and respiratory diseases, and for children and people with learning disabilities remain poorly supported.

The End of Life Care in Primary Care 2009 audit identified improvements needed to help more people die in their own homes. These include better access to medicines, proactive planning to improve clinical management of complex problems, carer information and support, and hospital discharge planning and liaison.

Pain management
Pain is the most common symptom of cancer. It occurs in up to 90 per cent of patients with advanced disease and about 67 per cent of patients with non-malignant illness. Moderate to severe background (persistent) pain and breakthrough cancer pain (BCP) can, in most cases, be treated successfully with opioid analgesics and adjuvant drugs. Treatment or avoidance of the underlying cause of pain may be important. Psychological distress also impacts on pain tolerance.

Care is needed with prescriptions for children or elderly patients and for those with impaired renal or hepatic excretion. Appropriate assessment and re-assessment of pain is important both at initiation of opioid treatment and when converting from one opioid to another Ð see the table below for equivalent doses. Dose titration according to pain control or adverse effects may be required.

Opioid treatment is not thought to carry a high risk of addiction in patients suffering chronic pain, a point that may be worth mentioning to some patients who are reluctant to take such medication.

Table 1. Approximate equivalent potencies of oral opioids to oral morphine

Equivalent potencies are only approximate and can be unpredictable. When converting from one opioid to another, it is often appropriate to use a lower dose than the suggested equivalence above. Close monitoring for side effects and efficacy is mandatory, especially at higher doses.

Converting from another oral opioid to oral morphine: Multiply the total daily dose of oral opioid by its potency equivalence to determine the equivalent total daily dose of oral morphine.

Converting from oral morphine to another oral opioid: Divide the total daily dose of oral morphine by the potency equivalence for the oral opioid which you are converting to.

Opioids in common use
Morphine This potent analgesic is used in the treatment of moderate to severe cancer pain and is the standard against which other analgesics are compared. It can be administered by the oral (immediate and modified-release formulations), rectal and parenteral (sc, im, iv), spinal and epidural routes for pain management. Oral (Oramorph, Sevredol, Morphgesic, MST Continus, MXL, Zomorph) or rectal administration leads to 70 per cent first pass metabolism in the liver and metabolites are largely excreted by the kidney. Reduced excretion rates may lead to sedation or respiratory depression.  A 25 per cent dose reduction is recommended if the patientÕs creatinine concentration is in the range 150-300mmol per litre. With more severe renal impairment, dose reduction and frequency change is required. The side effects of euphoria or dysphoria and itching are also common.

The RPSGB Practice Committee does not recommend routine brand-name prescribing of modified-release morphine but states that pharmacists should take steps to prevent the unintentional change of the brand supplied to patients.

Diamorphine Diamorphine is about twice as potent as morphine. It is available in powder form for reconstitution and is essentially a pro-drug Ð it is activated by deacetylation to morphine. It has a faster onset of action than morphine and
a shorter duration of action, especially when administered intravenously.

Diamorphine injection is usually included in "Just in Case" boxes for anticipatory end of life care.

Oxycodone Oxycodone is about twice as potent as morphine. When taken orally it undergoes first-pass metabolism in the liver (50 per cent). It is slightly less sedating than morphine and is available as normal release (OxyNorm capsules and liquid), sustained release (Oxycontin) and a parenteral formulation (OxyNorm). It is also available in the compound preparation Targinact (see below). The manufacturers of oxycodone advise against its use in patients with severe renal failure.

Fentanyl Fentanyl is about 100 times more potent than morphine. It is usually administered from a transdermal patch delivery system (Durogesic DTrans, Fentalis, Matrifen, Mezolar, Osmanil, Victanyl). The transdermal preparation is available in a reservoir (Durogesic) or matrix formulation and provides 72 hours of potent analgesia. Reservoir patches of fentanyl should never be cut to deliver a smaller dose because this disrupts the drug-release mechanism. A patch releasing 12mcg per hour of fentanyl allows for greater ease of titration, especially for patients for whom side effects may be problematic.

The RPSGB Practice Committee has advised there is no evidence of a difference in the rate of delivery of fentanyl patches of different brands when used in accordance with the product licence. However, manufacturers advise against brand changes and recommend counselling to ensure the patient and carers understand the reasons if such changes become necessary. Parenteral administration of fentanyl is generally only used when close continual clinical monitoring is available. 

Side effects

It is important to counsel patients and caregivers about side effects associated with use of opioids. Nausea and vomiting occur in about two thirds of patients starting opioids and last for up to seven days; these side effects are uncommon when the opioid dose is stable. An anti-emetic may be prescribed at initiation of opioid prescribing. Sedation is a common side effect occurring usually in the first five to seven days of treatment and may affect some patients" ability to drive.
Constipation is a very common and persistent effect of oral opioids, occurring in up to 90 per cent of patients. Treatment for opioid-induced bowel dysfunction will be reviewed next week in the second Update article in this series. Prophylactic laxatives should be prescribed on an individual basis for patients starting long-term opioids.

Two new medicines containing opioid antagonists have been introduced. These are subcutaneous methylnaltrexone (Relistor) and a combination product containing oxycodone and nalaxone (Targinact), in a ratio of 2:1 opioid to naloxone, for oral administration.

Methylnaltrexone has been approved by the Scottish Medicines Consortium for restricted use by palliative care specialists "when response to usual laxative therapy has not been sufficient". 

It will not be reviewed by Nice as its impact on population health and NHS budgets does not warrant the resources required to conduct this type of appraisal.

Breakthrough cancer pain

Breakthrough cancer pain (BCP) has been defined as "a transient exacerbation of pain that occurs either spontaneously or in relation to a specific predictable or unpredictable trigger despite relatively stable and adequately controlled background pain". The typical episode reaches peak intensity within three minutes and is of short duration (median 30 minutes). 

Assessment is important to allow identification of any underlying cause and re-assessment of the treatment of background pain. For many years, the only pharmacological treatment option for BCP or incident pain (eg caused by a procedure or movement) was immediate release morphine or oxycodone equivalent to about a sixth of the daily dose of oral opioid.

Oral transmucosal fentanyl is now marketed specifically for the management of breakthrough pain. Three products are licensed: Actiq lozenges (lollipop), Abstral sublingual tablets and Effentora buccal tablets. They have a faster onset of action than immediate-release oral formulations of morphine or oxycodone (10-15 minutes compared with 20-30 minutes) and a shorter duration of action (one hour compared with four to six hours). The transmucosal formulations are licensed for use in patients taking at least 60mg of oral morphine per day, or an equivalent dose of another opioid (eg 25 microgram transdermal fentanyl per hour, 30mg oral oxycodone daily), for at least a week. With all these products the rescue dose cannot be predicted from the background opioid dose, so titration is necessary.

Intranasal fentanyl (Instanyl) has recently been introduced for the management of breakthrough pain in adults who are already receiving opioid therapy for background pain. The initial dose is 50 microgram (one spray) repeated after 10 minutes if necessary. Another intranasal formulation (Nasalfent) may soon be marketed.

Immediate-release fentanyl products are useful for relieving BCP for patients who experience sedation or other side effects after other immediate-release opioids.

Anticipatory dying

Around 65 per cent of people on a care register dying at home or in a care home receive anticipatory prescribing. The Just in Case Box is dispensed for use in the treatment of an individual patient and is held in the patient's room. It is stocked with medicines that may be used when the healthcare team agrees the patient is in the dying phase. Examples of good practice in the supply, storage and safe use of these medicines are available at the Gold Standards Framework website.

Future developments

The Good Practice Guide in the Management of Controlled Drugs, updated in 2009, provides recommendations on the safe possession, storage, supply, and administration of controlled drugs. At present nurse and independent pharmacist prescribers may not prescribe, possess, supply, offer to supply, administer and give directions to administer controlled drugs specified in schedules 2 to 5 of the Misuse of Drugs Regulations 2001. The regulations may be amended to allow this to happen in the future.

Every year about half a million people die in England. The number of deaths is set to rise due to an ageing population and greater prevalence of long-term conditions. Community pharmacists actively contribute to multi-professional teams involved in palliative and end of life care for patients through dispensing for patients receiving care in the community, care homes, hospices and from out-of-hours services.

By completing training programmes relevant to local and national services, members of the pharmacy team can ensure appropriate access of medicines, contribute to symptom management and allow patients to feel supported in their preferred place of care.

Doreen Cochrane MRPharmS is an independent pharmacist and trainer

Reflect

How does renal impairment affect morphine dosing? How much more potent than morphine is oxycodone? Which opioid analgesic is most effective for breakthrough cancer pain?

Plan

This article discusses end of life care, focusing on pain management. It includes information about morphine, diamorphine, oxycodone and fentanyl. It also discusses breakthrough cancer pain and future developments.

Act

• Read more about pain control in terminal care on the Patient UK website at http://tinyurl.com/painrelief10. A diagram of the WHO analgesics ladder can be found on the Pain Talk website at http://tinyurl.com/painrelief20. 
  
• Revise your knowledge of the doses and formulations of the opioid analgesics available by reading section 4.7.2 of the BNF.
  
• Find out more about breakthrough pain by reading the information for professionals from breakthroughcancer pain.org at http://tinyurl.com/painrelief30 and about Just in Case boxes from the Gold Standards Framework at http://tinyurl.com/painrelief40. 
  
• Consider the aspects of pain management in the end of life care of patients you have known. How could you improve your services?

Evaluate

Are you now confident in your knowledge of pain management in end of life care? Could you give advice about this to a patient or carer?

Further reading

-  Allen M. Update: issues in palliative care. Chemist+Druggist, March 22, 2008.  
-  Davies AN, Dickman A, Reid C et al. The management of cancer-related breakthrough pain. European Journal of Pain, 2009, 13: 331Ð338. 
-  National GSF Central Team. ABC of Palliative Care, 2nd edn. Fallon M, Hanks G (eds). Walsall: GSF, 2010. http://tinyurl.com/palliativeabc
-  National Prescribing Centre. A guide to good practice in the management of controlled drugs in primary care (England), 3rd end. Liverpool: NPC, 2009. http://tinyurl.com/cdsgoodpractice
-  Scottish Intercollegiate Guidelines Network. SIGN 106: Control of pain in adults with cancer. Edinburgh: SIGN, 2008. www.sign.ac.uk/ guidelines/fulltext/106/index.html.
-  Omega. The end of life care in primary pare: 2009 national snapshot. Shrewsbury: Omega, 2009. 
-  Palliative Care. Palliative care formulary, 3rd edn. Twycross R, Wilcock A (eds). Nottingham: Palliative Care, 2010. www.palliativedrugs.com.
-  National GSF Central Team. Good practice resource guide for just in case boxes. Walsall, GSF, 2006. www.goldstandardsframework.nhs.uk.
-  Macmillan Cancer Support. www.macmillan.org.uk.
-  Marie Curie Cancer Care. Delivering choice programme. London: Marie Curie Cancer Care, 2010. http://tinyurl.com/deliveringchoice.