- 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.
- 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. Animal models suggest that developmental plasticity of nociceptive pathways occurring during early experience of pain (ie in the neonatal period) may lay the foundations for an individual's sensitivity to pain in later life.
- 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 history
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.
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 Palliative 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.
- Step one - non-opioid analgesics (eg, 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 (eg, 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 four-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 non-malignant 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?
- 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 four 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 (eg, 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 (eg, 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 four 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 subcutaneously, 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 (eg, by 100 times or more) may be required, particularly among patients with spinal or CNS metastatic tumours.
- When reducing or stopping opioids, doses should be tapered gradually to avoid causing severe pain flare or withdrawal symptoms.
- Enables prompt analgesia but has a 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 - eg, eye surgery.
- 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.
- 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.
- In June 2014 the prescribing regulations concerning tramadol were changed. It is now listed as a Schedule 3 drug which means it cannot be issued as an electronic prescription or prescribed in a quantity exceeding 30 days' supply.
- An increasing number of reports have appeared in the literature in recent years concerning tramadol dependency and withdrawal problems.
- Tramadol can react with a number of antidepressants. Its interaction with selective serotonin reuptake inhibitors (SSRIs) can increase the risk of serotonin toxicity.
- This acts as an opioid-receptor agonist and also inhibits noradrenaline reuptake.
- It causes less nausea, vomiting and constipation than other strong opioids.
- It is available as immediate-release tablets, modified release tablets and oral solution.
- 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 six to eight 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 seven days. Transtec® and Hapoctasin® are 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.
- There is no need for dosage adjustments in the elderly or those with compromised renal function and this, combined with its once-weekly dose, makes it particularly useful in these groups of patients.
- Vomiting may be a problem.
Alfentanil, fentanyl and remifentanil - used for intra-operative analgesia. Alfentanil or fentanyl are given by initial intravenous injection followed either by successive intravenous injections or an intravenous infusion. Remifentanil can be given as an initial injection or by continuous infusion but successive intravenous injections should not be given intra-operatively.
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 previously available appears to be as effective and safe as other standard oral and transdermal opioid treatments.A Cochrane review confirmed that patients using transdermal fentanyl for cancer pain had fewer problems with constipation than those taking oral morphine.Fentanyl is also available in the form of buccal lozenges and nasal sprays, which may be useful in breakthrough pain.It appears to be effective in both older and younger age groups.
See monographs of individual drugs for further details.
- Antidepressants - low-dose antidepressants (eg, amitriptyline 75-150 mg nocte) are useful for controlling neuropathic pain. Older tricyclics were thought to be more effective than SSRIs. However, recent positive trials of SSRIs have called for their re-evaluation, particularly escitalopram, which seems to be considerably beneficial for some patients. See separate article Neuropathic Pain and its Management for more details.
- Anticonvulsants, most commonly carbamazepine, are also useful for neuropathic pain although they have performed inconsistently in random controlled trials. 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 - eg, 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 neuron have a role in the conduction of pain and NMDA receptor agonists, such as ketamine and methadone, may be useful adjuncts in pain control.
- There is increasing interest in the efficacy of two-drug combinations such as gabapentin and nortriptyline for the control of neuropathic pain.
- 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. There is supportive evidence for this combination in the control of pain from disc herniation and spinal stenosis.
- 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. The effectiveness of TENS has been challenged but a systematic review found that efficacy was more likely to be demonstrated if appropriate technique and dosage were used. The authors concluded that TENS should continue to be considered a valid pain control option.
- 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'. The evidence base supporting their use in cancer pain is limited. However, there are a large number of positive anecdotal reports and they still have a place in cancer pain, principally 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.The effectiveness of dorsal column stimulation has improved with advances in technology.There is renewed interest in destructive procedures such as rhizotomy, cordotomy and dorsal root entry zone (DREZ) lesions in the management of cancer pain but further research is needed.
Systemic radioisotope therapy may be useful in controlling pain from bone metastases.
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.
Anti-oestrogen therapy for breast cancer can have a major effect on the control of pain from metastatic disease.Anti-androgen therapy is effective in controlling the pain from metastatic prostate disease but its effectiveness in localised prostate cancer require further research.
These are increasingly used to control metastatic bone pain in a variety of cancers. They do not, however, inhibit the development of new metastases. Drugs such as denosumab and the use of radionuclides are currently being explores in this respect.
- Acupuncture - systematic reviews suggest benefit for certain types of pain such as osteoarthritis.However, there are few trials comparing it to other more conventional options.
- Chiropractic - randomised controlled trials support the use of this discipline in the management of acute and chronic neck pain and acute and chronic low back pain.[30, 31]
- 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.
Further reading and references
Wiffen PJ, Derry S, Moore RA; Impact of morphine, fentanyl, oxycodone or codeine on patient consciousness, appetite and thirst when used to treat cancer pain. Cochrane Database Syst Rev. 2014 May 295:CD011056. doi: 10.1002/14651858.CD011056.pub2.
Guidance on the management of pain in older people; British Geriatrics Society (2013)
The Oxford Pain Internet Site; Bandolier
Schwaller F, Fitzgerald M; The consequences of pain in early life: injury-induced plasticity in developing pain pathways. Eur J Neurosci. 2014 Feb39(3):344-52. doi: 10.1111/ejn.12414.
User definitions and glossary; The British Pain Society
Analgesia - mild-to-moderate pain; NICE CKS, August 2010 (UK access only)
NOP Pain Survey; British Pain Society, 2005
Schwaller F, Fitzgerald M; The consequences of pain in early life: injury-induced plasticity in developing pain pathways. Eur J Neurosci. 2014 Feb39(3):344-52. doi: 10.1111/ejn.12414.
Control of pain in adults with cancer; Scottish Intercollegiate Guidelines Network - SIGN (November 2008)
Pain scales in multiple languages; The British Pain Society
WHO's cancer pain ladder for adults; World Health Organization
Cancer pain management; British Pain Society, January 2010
Hadley G, Derry S, Moore RA, et al; Transdermal fentanyl for cancer pain. Cochrane Database Syst Rev. 2013 Oct 510:CD010270. doi: 10.1002/14651858.CD010270.pub2.
Nebhinani N, Singh SM, Gupta G; A patient with Tramadol dependence and predictable provoked epileptic seizures. Indian J Psychiatry. 2013 Jul55(3):293-4. doi: 10.4103/0019-5545.117153.
Tashakori A, Afshari R; Tramadol overdose as a cause of serotonin syndrome: a case series. Clin Toxicol (Phila). 2010 May48(4):337-41. doi: 10.3109/15563651003709427.
Afilalo M, Morlion B; Efficacy of tapentadol ER for managing moderate to severe chronic pain. Pain Physician. 2013 Jan16(1):27-40.
Plosker GL; Buprenorphine 5, 10 and 20 mug/h transdermal patch: a review of its use in the management of chronic non-malignant pain. Drugs. 2011 Dec 2471(18):2491-509. doi: 10.2165/11208250-000000000-00000.
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.
British National Formulary (BNF); NICE Evidence Services (UK access only)
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-Aug24(6):536-43.
McQuay H; Pain and its control, Bandolier
Chaparro LE, Wiffen PJ, Moore RA, et al; Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev. 2012 Jul 117:CD008943. doi: 10.1002/14651858.CD008943.pub2.
Manchikanti L, Abdi S, Atluri S, et al; An update of comprehensive evidence-based guidelines for interventional techniques in chronic spinal pain. Part II: guidance and recommendations. Pain Physician. 2013 Apr16(2 Suppl):S49-283.
Manchikanti L, Buenaventura RM, Manchikanti KN, et al; Effectiveness of therapeutic lumbar transforaminal epidural steroid injections in managing lumbar spinal pain. Pain Physician. 2012 May-Jun15(3):E199-245.
Johnson M; Transcutaneous electrical nerve stimulation: review of effectiveness. Nurs Stand. 2014 Jun 1028(40):44-53. doi: 10.7748/ns.28.40.44.e8565.
Klepstad P, Kurita GP, Mercadante S, et al; The evidence of peripheral nerve blocks for cancer-related pain: a systematic review. Minerva Anestesiol. 2014 Nov 11.
Jeon YH; Spinal cord stimulation in pain management: a review. Korean J Pain. 2012 Jul25(3):143-50. doi: 10.3344/kjp.2012.25.3.143. Epub 2012 Jun 28.
Raslan AM, Cetas JS, McCartney S, et al; Destructive procedures for control of cancer pain: the case for cordotomy. J Neurosurg. 2011 Jan114(1):155-70. doi: 10.3171/2010.6.JNS10119. Epub 2010 Aug 6.
Burstein HJ, Temin S, Anderson H, et al; Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. J Clin Oncol. 2014 Jul 2032(21):2255-69. doi: 10.1200/JCO.2013.54.2258. Epub 2014 May 27.
Potosky AL, Haque R, Cassidy-Bushrow AE, et al; Effectiveness of primary androgen-deprivation therapy for clinically localized prostate cancer. J Clin Oncol. 2014 May 132(13):1324-30. doi: 10.1200/JCO.2013.52.5782. Epub 2014 Mar 17.
Erdogan B, Cicin I; Medical treatment of breast cancer bone metastasis: from bisphosphonates to targeted drugs. Asian Pac J Cancer Prev. 201415(4):1503-10.
Manyanga T, Froese M, Zarychanski R, et al; Pain management with acupuncture in osteoarthritis: a systematic review and meta-analysis. BMC Complement Altern Med. 2014 Aug 2314:312. doi: 10.1186/1472-6882-14-312.
Schroder S, Lee S, Efferth T, et al; Acupuncture and herbal medicine for cancer patients. Evid Based Complement Alternat Med. 20132013:313751. doi: 10.1155/2013/313751. Epub 2013 Nov 25.
Bryans R, Decina P, Descarreaux M, et al; Evidence-based guidelines for the chiropractic treatment of adults with neck pain. J Manipulative Physiol Ther. 2014 Jan37(1):42-63. doi: 10.1016/j.jmpt.2013.08.010. Epub 2013 Nov 19.
Lawrence DJ, Meeker W, Branson R, et al; Chiropractic management of low back pain and low back-related leg complaints: a literature synthesis. J Manipulative Physiol Ther. 2008 Nov-Dec31(9):659-74. doi: 10.1016/j.jmpt.2008.10.007.
Bao Y, Kong X, Yang L, et al; Complementary and alternative medicine for cancer pain: an overview of systematic reviews. Evid Based Complement Alternat Med. 20142014:170396. doi: 10.1155/2014/170396. Epub 2014 Apr 13.
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