Pain and Pain Relief (Analgesics)

• 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.
• 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 adapts to new situations and 're-wires' 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.

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 Organisation introduced the concept of the analgesic ladder. Oral analgesics are usually the first line.

Drugs should be introduced in the following order:

• Step one - Non-opioid analgesics (e.g. aspirin, paracetamol, 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 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 commonest 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.
  • Main side effects of all opioids are nausea, vomiting, constipation, drowsiness. Respiratory depression and hypotension in larger doses. Such adverse effects should be anticipated, aggressively treated, and regularly reassessed.
  • Which Strong Opioid?
    • Morphine:
      • Most valuable for severe pain, though nausea and vomiting 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 next dose by 50% if the previous dose no more effective than preceding analgesic
      • Choose the lowest dose which prevents pain and consider adjuvant analgesics (e.g. NSAIDs)
      • In the case of the modified-release tablets give half the total 24-hour dose (which is then divided into 6 portions to be given every 4 hours)
      • Titrate stepwise depending on response
      • Omit overnight dose if double the usual dose given at bedtime
      • Consider rescue doses for breakthrough pain and prophylactic doses 30 minutes before potentially painful procedure (e.g. dressing changes)
      • Once daily requirement established, give total dose od or bd (use appropriate modified-release preparation)
      • If required, increase strength of dose, not frequency of administration
      • Give the first dose of modified-release preparation 4 hours after last oral dose
      • 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
      • 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 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 spine 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 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 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) 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 50-2999 mg. This means that withdrawal symptoms are possible at low/normal doses, and after treatment periods of <6 months.⁵
    • Buprenorphine:
      • Opioid agonist and antagonist properties and may precipitate withdrawal symptoms, including pain, in patients dependent on other opioids
      • However, longer duration of action than morphine and sublingually is an effective analgesic for 6 to 8 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 new 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.⁶ Fentanyl appears to be effective in both older and younger age groups.⁷

See monographs of individual drugs for further details.

• Antidepressants - low-dose antidepressants (e.g. amitriptyline 75-150 mg nocte) useful for controlling neuropathic pain. Older tricyclics better than newer SSRIs. If benefit is going to occur, it is usually seen within one week.
• Anticonvulsants, most commonly carbamazepine, also useful for neuropathic pain.¹⁰ Gabapentin and pregabalin are also licensed for this use. Main indication diabetic neuropathy, 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.

• 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
    • Not known whether addition of steroid to local anaesthetic is essential
    • Better results obtained the earlier the patient is treated and in patients who have not had spinal surgery
    • May take up to a week for benefit to be felt
    • Worth repeating if 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 spine extension
  • TENS - rationale is the gate theory. Limited efficacy in acute pain. Patient education in use of technique is important. 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 ability of CNS to 're-wire' but have a place in cancer pain when there is short prognosis, or where alternatives not helping or possible.
  • Surgery - neurosurgical interventions often used for orthopaedic pain - e.g include dorsal column stimulation, rhizotomy, cordotomy and dorsal root entry zone (DREZ) lesions. Some controversy about long-term efficacy.

• Acupuncture - systematic reviews suggest benefit but short-lived. 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 behaviour 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.