Choice of Analgesics

Choice of analgesic

Paracetamol and NSAIDs are the first choice analgesics for treating mild to moderate pain and are also used in moderate to severe pain to potentiate the effects of opioids. They are suitable for use in acute or chronic pain. Aspirin and paracetamol are of similar potency in most types of pain but paracetamol only has a weak anti-inflammatory effect. NSAIDs are particularly effective in bone pain of malignant origin and pain due to inflammation. The selective inhibitors of cyclo-oxygenase-2 (COX-2) are said to be as effective as the non-selective NSAIDS. Dependence and tolerance are not a problem with non-opioid analgesics but as the dose is increased, their efficacy reaches a ceiling. Aspirin and other non-selective NSAIDs inhibit blood platelet function, adversely affect the gastrointestinal tract, and can precipitate hypersensitivity reactions including asthma. The risk of serious upper gastrointestinal adverse effects is lower with the COX-2 inhibitors than the non-selective NSAIDs; however, in other respects, the COX-2 inhibitors share similar side-effect profiles to those of the non-selective NSAIDs. Paracetamol does not have the haematological or gastrointestinal adverse effects of aspirin but large doses can produce severe or sometimes fatal hepatotoxicity.

For the treatment of moderate or moderate to severe opioid-sensitive pain codeine is the traditional choice; alternatives include dextropropoxyphene and dihydrocodeine. They are often given together with non-opioid analgesics. Combinations of codeine with paracetamol produce a small but significant increase in analgesia compared with paracetamol alone and might be appropriate for occasional pain relief, but the incidence of adverse effects increases with repeated use. Combinations of dextropropoxyphene with paracetamol or aspirin are no more effective in acute pain than the non-opioid alone; efficacy in chronic pain is unclear and adverse effects may become troublesome.

More potent opioids such as morphine are mainly used in the treatment of severe acute non-malignant pain and cancer pain. Their use in chronic non-malignant pain is somewhat controversial because of fears of psychological dependence and respiratory depression. However, in practice such problems rarely occur and those fears should not prevent patients being given effective analgesic therapy. Opioids may also be of value in neuropathic pain in some patients.

Morphine is the opioid of choice in severe pain. It is well absorbed when given orally and has a short half-life so that the use of immediate-release oral preparations offers a flexible means of dosage titration. Once initial pain relief has been achieved, administration of a modified-release preparation every 12 or 24 hours is more convenient for maintenance of analgesia in severe chronic pain. It may also be given parenterally, or rectally or transdermally, where there would be problems with the oral route.

Occasionally other opioids may be useful as an alternative to morphine. Methadone or oxycodone have a longer duration of action than morphine, but it should be noted that methadone, which has a long half-life, should not be given more than twice daily when used long term because of the risk of progressive CNS depression and overdosage. A rapid onset of action is provided by pethidine, alfentanil, and fentanyl. Diamorphine or hydromorphone may be preferred to morphine when the parenteral route has to be used because they are more soluble and can be given in a smaller volume.

Adverse effects of opioids include sedation, nausea, vomiting, constipation, and, most seriously, respiratory depression. Tolerance generally develops to all of these effects except constipation, which may be prevented by regular use of laxatives.

A number of other groups of drugs have significant roles in pain management either alone or as analgesic adjuvants.

Subantidepressant doses of tricyclic antidepressants (usually amitriptyline) are considered to be useful in refractory chronic pain, including neuropathic pain of the burning, dysaesthetic type such as postherpetic neuralgia and diabetic neuropathy; shooting pain has also been reported to respond. They may be used in addition to conventional analgesics, notably in the treatment of cancer pain of mixed aetiology. There is little evidence for benefit in acute pain although musculoskeletal pain has sometimes responded. Amitriptyline has also been found to be useful for tension-type headache and for the prophylaxis of migraine. The role of other antidepressants in the treatment of neuropathic pain is less clear although venlafaxine may be useful.

Antiepileptics (often carbamazepine and, more recently, gabapentin) have been found useful in the relief of neuropathic pain especially when there is a stabbing (lancinating) element, as in trigeminal neuralgia; there have also been reports of efficacy in the treatment of diabetic neuropathy and for migraine prophylaxis.

Benzodiazepines and other muscle relaxants such as baclofen or dantrolene are useful for relieving painful muscle spasm in acute or chronic conditions.

Bone modulating drugs such as calcitonin and bisphosphonates may be useful in cancer pain arising from bone metastases but have a slow onset of action and are second choice to NSAIDs. Bisphosphonates may cause an initial transient increase in bone pain.

Caffeine has been used with the aim of enhancing the effects of non-opioid and opioid analgesics but is of debatable benefit. There are similar doubts about whether caffeine enhances the effect of ergotamine in the treatment of migraine; it may also add to gastrointestinal adverse effects and in large doses can itself cause headache.

Corticosteroids have produced improvement, often substantial, in neuropathic pain. They can also relieve headache caused by raised intracranial pressure and refractory pain caused by bone metastases, and have the added benefits of increasing well-being and appetite.

Some inhalational anaesthetics are used in subanaesthetic doses as inhalation analgesics for acute pain. In particular, nitrous oxide is given with oxygen for pain relief in obstetrics and during dental and other procedures, and in emergency management. Isoflurane, enflurane, and in some countries methoxyflurane or trichloroethylene have been used similarly.

Miscellaneous drugs. Following the discovery that epidural or intrathecal injection of opioids can produce effective analgesia many other drugs have been tried by these routes, either alone or with opioids or local anaesthetics, but their role, if any, in the management of pain remains to be determined. Some of these drugs, such as clonidine and ketamine, also appear to have analgesic properties when given by other routes. Some antiarrhythmics may be effective in chronic neuropathic pain, but must be used with extreme caution. The use of antipsychotics, such as the phenothiazines, as adjuvant analgesics is controversial; levomepromazine is sometimes used as an adjunct in palliative care.