Introduction^1,2

• Pain may be defined as an unpleasant sensory or emotional experience associated with actual or potential tissue damage. Chronic pain is defined as pain still present after three months despite appropriate treatment. Breakthrough pain is defined as pain of moderate or severe intensity occurring against a background of controlled chronic pain.
• Controlling pain, whether acute or chronic, is a common task for every doctor. A survey of 975 people in the UK reported that 21% experienced pain every day or on most days. 67% had visited their GP or a walk-in centre, requesting advice about pain relief.³
• The simplistic view of the pain-producing system ('hard-wiring') in which pain sensations are conducted via the nerves to the spinal cord fails to explain such phenomena as phantom limb pain and pain experienced after cordotomy. Pain specialists now talk about plasticity, in which the central nervous system (CNS) adapts to new situations and 'rewires' itself.
• Emotional, environmental and social factors are becoming increasingly recognised as issues which need to be addressed in the management of chronic pain.
• Treat underlying causes wherever possible.

Take an adequate history⁴

Pain is often mistreated or undertreated and can lead to depression, insomnia, lethargy and reduced physical and mental functioning. Successful control is more likely to be achieved if a proper assessment is made, which should include:

• The site of the pain.
• The duration, speed of onset and whether the pain is intermittent or constant.
• The character of the pain - this will indicate whether it is neuropathic or nociceptive, somatic or visceral.
• Aggravating and relieving factors.
• Impact on daily living.
• Social, emotional and psychological aspects.
• Severity - use of pain scales can make this more objective.⁵

The analgesic ladder^2,6,7,8

The successful drug management of pain relies on selecting the appropriate drug at the correct dosage and balancing efficacy against adverse effects. For this reason, the World Health Organization introduced the concept of the analgesic ladder. This has served its purpose well; however, increased survival rates in cancer and advances in the management of pain have made it less relevant in some circumstances. For example, new formulations of drugs such as nasal sprays and sublingual tablets and the increasing use of adjuvant therapy to reduce the amount of opioid have widened the options available for pain management. See separate article Pain Control in Terminal Care for more details.

Oral analgesics are usually used first-line.

The Scottish Intercollegiate Guidelines Network (SIGN) reiterates that drugs should be initiated at the step in the analgesic ladder appropriate to the level of pain as dictated by a pain scale.⁴

• Step one - non-opioid analgesics (e.g. aspirin, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs)). If anticipation of pain can be abolished, it may not be necessary to step up to opioids. Give non-opioids regularly and use adjuvants if necessary.
• Step two - mild opioids (e.g. codeine) with or without non-opioid:
  • Codeine - effective for the relief of mild-to-moderate pain but is too constipating for long-term use.
  • Dihydrocodeine - efficacy similar to codeine. Can be given 4-hourly. Doses may need to be adjusted individually according to the degree of analgesia and side-effects. If necessary, step up to morphine, or fentanyl (to initiate, consider involving a specialist in palliative care). Arrange for doses to be given at regular intervals - 'by the clock', rather than 'as required', using the oral route whenever possible.
• Step three - strong opioids with or without non-opioid:
  • Useful for moderate-to-severe pain, particularly of visceral origin. Long-term prescribing is most common for palliative care in malignant disease but also may be appropriate for chronic nonmalignant conditions, in conjunction with specialist advice.
  • One of the main reasons patients in severe pain do not receive adequate analgesia is fear of addiction. If the condition is terminal cancer, this is not an appropriate concern.
  • The main side-effects of all opioids are nausea, vomiting, constipation, drowsiness, and, in larger doses, respiratory depression and hypotension. Occasionally, hyperalgesia - hypersensitivity of the skin to touch - develops and can inhibit the analgesic effect. Such adverse effects should be anticipated, aggressively treated and regularly reassessed.
  • Long-term opioids have proved disappointing in the management of chronic non-cancer pain. Moreover, concerns have developed about the effects of opioids on the hypothalamic-pituitary-adrenal axis and on bone demineralisation. These considerations have led to a reassessment of the benefits of opioids, particularly in non-cancerous conditions.
  • Switching from one opioid to another has long been considered to be an option in reducing the side-effects whilst maximising their benefits and this is supported by a growing body of evidence.

Which strong opioid?

• Morphine:
  • Most valuable for severe pain, although nausea and vomiting are frequent.
  • Additional beneficial effects - detachment and euphoria.
  • First-line oral medication for severe pain in palliative care.
  • Give by mouth as an oral solution or as standard ('immediate-release') tablets regularly every 4 hours, the initial dose depending largely on the patient's previous treatment
  • Increase the next dose by 50% if the previous dose is no more effective than the preceding analgesic.
  • Choose the lowest dose which prevents pain and consider adjuvant analgesics (e.g. NSAIDs).
  • If double the usual dose is given at bedtime, the patient may not need to be disturbed four hours later to administer another dose.
  • Once the total dose of immediate-release morphine needed in 24 hours has been calculated, the same dose can be given in the form of a modified-release preparation (divided into two portions for 12-hourly administration).
  • Titrate stepwise depending on response.
  • Consider rescue doses for breakthrough pain and prophylactic doses 30 minutes before a potentially painful procedure (e.g. dressing changes).
  • Once the daily requirement is established, give total dose od or bd (use an appropriate modified-release preparation).
  • If required, increase strength of dose, not frequency of administration.
  • Give the first dose of modified-release preparation with, or within 4 hours of, the last oral dose of the immediate-release preparation.
  • Opioid doses should be calculated and checked with care.
  • If oral administration is not tolerated, alternatives include intravenous, continuous subcutaneous, transdermal patches, or rectal route (morphine suppositories).
  • Give an adequate dose which effectively relieves pain.
  • Intramuscular (IM) morphine should be given at half the oral solution dose.
  • Diamorphine (heroin) - may cause less nausea and hypotension than morphine.
  • Greater solubility allows effective doses to be injected in smaller volumes and this is important in the emaciated patient.
  • Diamorphine can be given in a smaller volume, IM or subcutaneous, approximately a third of the oral dose of morphine.
  • Subcutaneous infusion of diamorphine via syringe driver is another option.
  • Substitute oral morphine if the patient can resume taking medicines by mouth.
  • Steep escalation of opioid doses (e.g. by 100 times or more) may be required, particularly among patients with spinal or central nervous system metastatic tumours.
  • When reducing or stopping opioids, doses should be tapered gradually to avoid causing severe pain flare or withdrawal symptoms.
• Pethidine:
  • Enables prompt analgesia but has short duration of action.
  • Less constipating than morphine but less potent.
  • Not suitable for severe continuing pain (build-up of metabolite norpethidine can cause tremor, confusion and convulsions).
  • Used rarely in children but sometimes given IV for short surgical procedures, e.g. eye surgery.
• Methadone:
  • Less sedating than morphine and acts for longer periods.
  • Risk of accumulation and overdose if administered more than twice a day long-term.
  • May be used instead of morphine when excitation (or exacerbation of pain) occurs with morphine.
• Tramadol:
  • This has an opioid effect and causes an enhancement of serotonergic and adrenergic pathways.
  • There are fewer of the typical opioid side-effects (notably, less respiratory depression, less constipation and less addiction potential).
  • Psychiatric reactions have been reported.
  • A recent report from the Swedish Medical Products Agency states that withdrawal reactions may be a bigger problem than previously thought. The Swedish adverse reactions database (SWEDIS (= SWEdish Drug Information System)) contains 71 reports of abstinence/withdrawal symptoms with tramadol, 25 of which were also classed as dependence, habituation or increased tolerance. Treatment duration ranged from 1 week to more than 3 years at dosages of 50-2,999 mg. This means that withdrawal symptoms are possible at low/normal doses and after treatment periods of <6 months.⁹
• Buprenorphine:
  • Opioid agonist and antagonist properties and may precipitate withdrawal symptoms, including pain, in patients dependent on other opioids.
  • However, it has longer duration of action than morphine and sublingually is an effective analgesic for 6 to 8 hours.
  • It is also available as a patch. BuTrans® is available in three strengths releasing 5 micrograms, 10 micrograms and 20 micrograms per hour respectively. The patch needs to be changed every 7 days. Transtec® is also available in three strengths releasing 35 micrograms, 52.5 micrograms and 70 micrograms per hour. The patch needs to be changed after 96 hours.
  • Vomiting may be a problem.
• Alfentanil, fentanyl and remifentanil - used by injection for intra-operative analgesia. Fentanyl is available at a transdermal patch and has a 72-hour duration of action. This makes it useful in palliative care but it is significantly more expensive than morphine. A matrix patch which has 35-50% less fentanyl than those currently available appears to be as effective and safe as other standard oral and transdermal opioid treatments.¹⁰ Fentanyl is also available in the form of buccal lozenges and nasal sprays, which may be useful in breakthrough pain.¹¹ It appears to be effective in both older and younger age groups.¹²

See monographs of individual drugs for further details.

Adjuvant therapy^8,13,14

• Antidepressants - low-dose antidepressants (e.g. amitriptyline 75-150 mg nocte) are useful for controlling neuropathic pain. Older tricyclics are better than newer selective serotonin reuptake inhibitors (SSRIs). If benefit is going to occur, it is usually seen within one week. See separate article Neuropathic Pain and its Management for more details.
• Anticonvulsants, most commonly carbamazepine, are also useful for neuropathic pain.¹⁵ Gabapentin and pregabalin are also licensed for this use. Their main indication is in diabetic neuropathy, and trigeminal neuralgia but, also, in shooting pain which does not respond to antidepressants, e.g. phantom limb pain.
• Muscle spasm - consider a muscle relaxant such as diazepam or baclofen.
• Nerve compression may be reduced by a corticosteroid such as dexamethasone, which reduces oedema around the tumour, thus reducing compression.
• N-methyl-D-aspartate (NMDA) receptors in the postsynaptic area of the neurone have a role in the conduction of pain and NMDA receptor agonists, such as ketamine and methadone, may be useful adjuncts in pain control (SIGN recommends initiation by a pain control expert).

Physical methods^8,13,16

• Reversible:
  • Local anaesthetics:
    • Block nerve conduction reversibly.
    • Frequent blocks sometimes effect a permanent cure.
    • Regional blocks have been used to good effect in shoulder pain, intercostal neuralgia, postoperative scar pains and other peripheral neuralgias.
  • Epidural steroids and facet joint blocks:
    • Commonly used for chronic back pain.
    • Trials show statistically significant improvement for up to one year.
    • it is not known whether addition of steroid to local anaesthetic is essential.
    • Better results are obtained the earlier the patient is treated and in patients who have not had spinal surgery.
    • It may take up to a week for benefit to be felt.
    • They are worth repeating if there is short-lived relief, and a course of three injections is often recommended.
    • Facet joint injection with local anaesthetic and steroid is indicated when pain is worse when sitting and pain is provoked by lateral rotation and spinal extension.
  • Transcutaneous electrical nerve stimulation (TENS) - rationale is the gate theory. There is limited efficacy in acute pain. Patient education in use of technique is important. There have been many trials but no systematic reviews.
• Irreversible:
  • Neurolytic blocks - aimed at destroying nerves conducting pain by cutting, burning or damaging. Plasticity theory counsels against this approach due to the ability of the CNS to 'rewire' but they have a place in cancer pain when there is short prognosis, or where alternatives are not helping or possible.
  • Surgery - specific examples where surgery may be appropriate include the internal fixation of pathologically fractured long bones, the stabilisation of vertebral fractures and the construction of a shunt to drain progressive ascites into the superior jugular vein.
  • Neurosurgical interventions often used for orthopaedic pain - for example, including dorsal column stimulation, rhizotomy, cordotomy and dorsal root entry zone (DREZ) lesions. There is some controversy about long-term efficacy.

Radiotherapy⁸

Systemic radioisotope therapy may be useful in controlling pain from bone metastases.

Chemotherapy⁸

Whilst many cancers become chemotherapy-resistant in the latter stages, multiple myeloma and small cell lung cancer retain their sensitivity and this can be exploited in the control of pain from bone metastases.

Hormone therapy⁸

Anti-androgenic treatment for prostate cancer and anti-oestrogen therapy for breast cancer can have a major effect on the control of pain from metastatic disease in these conditions.

Bisphosphonates⁸

These are increasingly used to control metastatic bone pain in a variety of cancers.

Alternative methods⁸

• Acupuncture - systematic reviews suggest benefit but short-lived. There is paucity of trials comparing with conventional procedures.
• Physiotherapy - popular and economically viable but limited long-term success demonstrated in systematic reviews.
• Behavioural management - back schools, cognitive behavioural therapy, fitness training, activity scheduling and pain management methods do seem to promote improvement using outcome measures of medication reduction, consultation rates and depression.
• Complementary medicine - homeopathy, hypnosis and herbal treatments - lack of controlled clinical trials but found helpful by some patients.

Document references

1. User definitions and glossay; The British Pain Society, 2008
2. Analgesia - mild-to-moderate pain, Clinical Knowledge Summaries (August 2010)
3. NOP Pain Survey, British Pain Society, 2005
4. Control of pain in adults with cancer - guidelines, Scottish Intercollegiate Guidelines Network (SIGN), 2008
5. Pain scales in multiple languages, The British Pain Society, 2008
6. WHO Pain Relief Ladder, World Health Organization
7. Finkel JC, Finley A, Greco C, et al; Transdermal fentanyl in the management of children with chronic severe pain: results from an international study.; Cancer. 2005 Dec 15;104(12):2847-57. [abstract]
8. Cancer pain management, British Pain Society (January 2010)
9. National Electronic Library for Medicines; News 2007
10. Kress HG, Von der Laage D, Hoerauf KH, et al; A Randomized, Open, Parallel Group, Multicenter Trial to Investigate Analgesic Efficacy and Safety of a New Transdermal Fentanyl Patch Compared to Standard Opioid Treatment in Cancer Pain. J Pain Symptom Manage. 2008 Jun 5;. [abstract]
11. British National Formulary
12. Likar R, Vadlau EM, Breschan C, et al; Comparable analgesic efficacy of transdermal buprenorphine in patients over and under 65 years of age. Clin J Pain. 2008 Jul-Aug;24(6):536-43. [abstract]
13. McQuay H; Bandolier - Pain and its control.
14. McQuay HJ; Pharmacological treatment of neuralgic and neuropathic pain.; Cancer Surv. 1988;7(1):141-59. [abstract]
15. Eisenberg E, River Y, Shifrin A, et al; Antiepileptic drugs in the treatment of neuropathic pain. Drugs. 2007;67(9):1265-89. [abstract]
16. Arner S, Lindblom U, Meyerson BA, et al; Prolonged relief of neuralgia after regional anesthetic blocks. A call for further experimental and systematic clinical studies.; Pain. 1990 Dec;43(3):287-97. [abstract]

Internet and further reading

• The Physiotherapy Pain Association
• Bandolier, The Oxford Pain Internet Site
• Palliative care - pain; Palliative cancer care - pain, Clinical Knowledge Summaries (March 2009)

Acknowledgements