Pain Control in Terminal Care

Pain is a common and feared symptom in the dying.

It is not inevitable. It occurs in up to 70% of patients with advanced cancer and about 65% of patients dying of non-malignant disease.¹ Much can now be done medically to make their last few weeks or months relatively pain-free. An average GP will have 10 patients receiving terminal care each year, 5 of them dying of cancer, and good palliative care can make a huge difference to the quality of an individual's end of life.

Terminally ill patients often report that they fear intractable pain more than they do dying. Patients frequently express the desire to have open and honest dialogue with medical carers about pain and want to be involved fully in planning their pain management.^2,3 A doctor must be able to get alongside the patient and their family and to spend time presenting options, answering questions and quelling fears. Having promised to keep the patient relatively pain-free, it is paramount to meet this promise to preserve trust. Pain is easier to prevent than it is to relieve and drugs should be prescribed on a prophylactic basis with no other consideration than maintaining the patient's quality of life.

Pain is a complex subjective phenomenon and is affected by the emotional context in which it is endured. Adequate psychological support is critical as removing the fear of pain in itself will help to optimise pain control. A patient who is fearful, withdrawn and depressed often appears to have a lower pain threshold than one who is still actively engaged in enjoying what is left of their lives, even though they may have same stage disease. Non-drug measures to help psychological or spiritual distress may be as important as medication in relieving pain and suffering.

Whilst pain relief is vital, good palliative care encompasses far more. Within primary health care teams, improving the quality of palliative care can be facilitated by the Gold Standard Framework.⁴ Similarly, good practice is outlined in the Liverpool Care Pathway for the Dying,⁵ which provides an important resource for those caring for those at the end of life. Good communication within and between teams is vital, eg between primary and secondary care and between usual daytime GP and out-of-hours provision, to avoid unnecessary problems during this period.

Over 80% of cancer pain can be controlled with inexpensive oral drugs given a good assessment of pain and systematic choices of analgesics.⁶

• Always try to diagnose the cause of the pain - make a full assessment of all contributing factors.
• Explain the mechanism underlying the pain to the patient and agree on treatment goals.
• Use the WHO analgesic ladder to guide systematic pain-relief but remember other treatments (surgery, nerve blocks, radiotherapy etc) and non-drug treatments may also have a role.

  WHO analgesic ladder
  Step 1	Non-opioid+/-adjuvant
  Pain persisting or increasing?
  Step 2	Opioid for mild to moderate pain +/-non-opioid +/-adjuvant
  Pain persisting or increasing?
  Step 3	Opioid for moderate to severe pain+/-non-opioid +/-adjuvant
  Objective: Freedom from pain

• Base the choice of drug on the severity of pain and not the stage of disease. Step up to strong opioids when step 1 and 2 analgesics have failed.
• Adjuvant analgesics may be usefully added at any stage.

  Common adjuvant analgesics for cancer pain 6
  Drugs	Indications
  Non-steroidal anti-inflammatories	Bone pain Soft tissue infiltration Hepatomegaly
  Corticosteroids	Raised intracranial pressure Soft tissue infiltration Nerve compression Hepatomegaly
  Antidepressants and anticonvulsants	Nerve compression or infiltration Paraneoplastic neuropathies
  Bisphosphonates	Bone pain

• Prescribe not only to cover continuous background pain felt by the patient but also for breakthrough or incident pain that occurs with everyday activities such as walking. Explain that additional medication should be taken before undertaking a potentially pain-provoking activity. The aim is keep the patient pain-free both when sitting at home but also when undertaking normal daily activities.
• Keep the treatment as simple as possible. Aim to use the minimum number of drugs in the most acceptable form and dose intervals possible. Provide written guidance for the patient and family to reinforce the drug regimen.
• Regular review is essential to ensure that treatment goals are being met, side-effects avoided etc.
• Use anticipatory prescribing to avoid delay in response to a symptom which may predictably occur due to disease progression. Ensure adequate prn medications. Availability of equipment and drugs needs to be assured, particularly out-of-hours, so always anticipate changes with patients, district nursing teams, community pharmacists etc to avoid delays and unnecessary suffering.

Non-opioids

• Paracetamol is a weak analgesic with very few side effects.
• NSAIDs are particularly useful for bone pain that is often poorly controlled by opioids. Their main side effect is GI bleeding - often a PPI is co-prescribed to counter this risk.

Weak opioids

These are used when non-opioids are ineffective. These include codeine phosphate and dihydrocodeine tartrate and are often used in combination with paracetamol.

Strong opioids

Oral morphine

This forms the backbone of first-line therapy. Patients and family are commonly concerned at the outset and it needs to be explained that morphine is an effective analgesic, conferring overall benefit and does not imply imminent death. Other common myths and misunderstandings include:

• It is not normally addictive. Patients commonly reduce their dose if other measures counter the cause of the pain.
• Respiratory depression is not usually a problem. Pain tends to counteract this effect even in those with respiratory disease and it is useful for symptomatic relief of dyspnoea.
• Significant tolerance to morphine does not usually develop. Patients are normally maintained for several weeks on a constant dose and this is only increased because of advancing disease.
• Morphine is not stupefying. At the correct dose patients can continue with normal activities. Always warn patients that initial sedation may occur but that it usually settles within 48 hours.

Dose titration

• Initially give 4 hourly as normal release tablets or elixir.
• Allow extra doses of the same size for 'breakthrough pain' as required.
• After 24 hours total the previous day's intake and divide by 6 to provide 4 hourly doses, thus adjusting the regular dose upwards if needed.
• A regular four hourly starting dose for opioid naive patients is usually 5-10 mg.
• Patients who have already been using weak opioids should not be considered opioid naive - codeine and dihydrocodeine are 1/10 morphine's potency and tramadol 1/5 morphine's potency and starting dose should be calculated on the basis of previous requirements.

Maintenance dose

• Once pain relief is at a satisfactory and stable level, sustained release preparations can be substituted to allow od or bd dosing.
• Any breakthrough pain not associated with unusual activity should be treated with morphine elixir or ordinary tablets at 1/6 total daily dose. Review the daily dose of sustained release morphine and increase by anything from 30% to 100%. Remember that the aim is prevent pain occurring rather than relieving it.

Common side-effects

Use the lowest necessary dose for full analgesic effect to minimise side-effects.

• Sedation - usually subsides within a few days.
• Nausea and vomiting - common in opioid-naive patients. Usually settles within a few days but can be prevented using anti-emetics (eg metoclopramide 10 mg tds or haloperidol 1.5 mg or nocte).
• Constipation - very common and laxatives should be prescribed prophylactically.
• Dry mouth - advise good mouth care: frequent sips of iced drinks, dental floss, saliva replacements or stimulants.
• Pruritis - related to histamine release. Try oral antihistamine to control itch.
• Bronchoconstriction - again related to histamine release. Use i.v./i.m. antihistamine and bronchodilators and switch to a pharmacologically distinct opioid such as methadone.
• Toxicity - appears as agitation, hallucinations, confusion, vivid dreams and myoclonic jerks. Worsening renal or hepatic function will alter the metabolism of morphine and may cause accumulation and toxicity. Consider adjusting dose downwards or increasing dose interval.

Parenteral routes

Syringe drivers

• If vomiting, dysphagia or increasing weakness prevent patients from taking oral morphine, then usual practice is to convert to a subcutaneous infusion of opioid via a device such as a syringe driver. Injection site should be changed every 2-3 days.
• Diamorphine is approximately 3 times as powerful as oral morphine as an analgesic. Subcutaneous morphine can be used in its place when diamorphine is not available and is twice the potency of oral morphine. Daily doses for the syringe driver, when moving from tablets to subcutaneous infusion, are simple to calculate.⁷

Examples of equivalent doses:

Many other drugs can be mixed with diamorphine in the syringe driver to help with nausea and vomiting, restlessness etc but check compatibility first.

Transdermal fentanyl

An alternative to both oral morphine and s.c. diamorphine is transdermal fentanyl patches. They can be useful in ambulatory patients where:

• Problems with the oral route
• Intractable constipation
• Morphine intolerance

Fentanyl is a very powerful synthetic opioid (150x potency of oral morphine). It diffuses across the skin to provide a continuous level of analgesia without tablets or needles.They are, however, comparatively expensive.⁸

• Patches are worn for 72 hours.
• Time for the drug to take effect or to clear from the body needs to be allowed. Steady-state of fentanyl is achieved after 36-48 hours and minimal effective plasma concentration from 3-23 hours (note large individual differences), therefore rescue medication will be necessary particularly in the first 24 hours.
• Only use with patients whose pain is stable because of the long time needed to titrate the dose upwards.
• If effective analgesia lasts less than 3 days, increase the patch strength rather than the frequency of patch changes.
• After removing a patch, elimination plasma half-life is almost 24 hours so care should be taken not to overdose.⁹

About 10% terminal patients have 'difficult pain'.¹ Pain that is difficult to control is often:

• Poorly responsive to opioids
• Episodic and breaks through despite background opioid analgesia
• Caused or aggravated by non-physical factors

Morphine intolerance

Factors affecting the ability to tolerate opioids include:

• Responsiveness of the pain to opioids
• Previous exposure to opioids
• Rate of dose titration
• Additional medication
• Concomitant disease
• Genetic factors
• Renal & hepatic function

Strategies for improving tolerance include:

• Start with a low initial dose of opioid and titrate slowly upwards. Avoid inducing tolerance or toxicity unnecessarily.
• Use short-acting preparations until dose is stabilised.
• Pain may appear to be morphine-resistant if underdosing (insufficient dose, not taken by the clock, taken prn).
• Consider if agitated confusion is due to opioid toxicity rather than uncontrolled pain before giving further opioids
• Consider switching to an alternative opioid such as methadone. Methadone's receptor binding profile differs from that of pure μ-agonists and often gives better analgesia and reduced side-effects. Other possibilities include hydromorphine and oxycodone.
• Manage side-effects with additional medication.
• Consider changing the route of administration eg where GI absorption is poor, consider switching to skin patches.
• Consider other causes of pain.

Neuropathic pain

• Described as aching, burning, shooting or stabbing in quality. May be associated with abnormal sensation and allodynia (normal touch felt as painful).
• Caused by nerve damage due to tumour invasion or compression as well as surgery, chemo and radiotherapy.
• Often poorly responsive to opioids.
• Try an adjuvant analgesic: tricyclic antidepressants (eg amitriptyline 10-75 mg nocte) and anticonvulsants (eg carbamazepine 100-200 mg nocte, gabapentin 100 mg nocte titrating up to 600 mg tds) are commonly used.
• Little evidence for combining adjuvants. Often a second is added if the first has been titrated to an upper limit and pain has only partially responded. Adding a second usually means reducing the dose of the first.
• Other options include:
  • Psychological techniques eg cognitive behavioural therapy, simple relaxation, hypnosis
  • Capsaicin cream
  • Local nerve blocks and epidurals
  • Acupuncture
  • Transcutaneous electrical nerve stimulation (TENS)

Episodic pain

Bony pain due to metastases in the spine, pelvis or femora, exacerbated by walking or weight-bearing can be particularly problematic.

• Opioids plus NSAIDs are the mainstay, but doses sufficient to control pain on movement cause sedation when the patient is at rest.
• Advise prn doses of normal release opioid in anticipation of movement.
• Other options:
  • Radiotherapy
  • Surgical stabilization of pathological fractures
  • Bisphosphonates
  • Epidurals
  • Appropriate appliances and aids

'Total pain'

Pain can be a physical expression of compound psychological/spiritual and social distress and requires a holistic approach.³Consider:

• Counselling
• Access to spiritual advisors
• Antidepressants or anxiolytics
• Complementary therapies

Doctors find the care of terminal patients with resistant pain particularly stressful. Where pain control proves difficult, seek help. Possible sources of advice³ include:

• Specialist palliative care teams (hospital or hospice based)
• Macmillan teams
• GPs with special interest in palliative care