Analgesics and Antipyretics

Pain Assessment

Assessment of pain is essential for correct treatment and is best based on the patient's report and clinical signs. In addition to taking a full history, physical examination and psychosocial assessment, the patient should be questioned on the severity, quality and site of pain, its frequency and duration, and effect on lifestyle. In chronic pain, a body chart can be used to indicate the site of pain, while a pain diary and visual analogue scale can be used to record the severity. Using this approach and continuing it during follow-up, will allow assessment of efficacy, adverse effects and determination of whether continuing pain is related to disease progression or not.

Who Analgesic Ladder

The WHO's analgesic ladder ascending from non-opioids through weak opioids to strong opioids according to the severity of the pain is widely regarded as the best approach to pain management. The objective of treatment in all types of pain, irrespective of origin, is to achieve symptom control and improve quality of life.

Mild Pain

Analgesics such as aspirin, paracetamol or NSAIDs are indicated for mild pain. They are even effective in patients already receiving strong opioids who develop mild pains such as tension headaches.

Aspirin has analgesic and antipyretic activity and, in higher doses, anti-inflammatory activity. It is particularly effective for tension headache and musculoskeletal pain. It may cause gastric irritation and, because of the risk of Reye's syndrome, should not be used in children except for Still's disease, and then only under close supervision. Dispersible tablets are useful for a rapid effect. Enteric-coated tablets reduce gastric irritation but delay onset of action.

Paracetamol has analgesic and antipyretic activity, but no anti-inflammatory action. It causes less gastric irritation and may be preferable for elderly patients. Solid dose, liquid and suppository formulations are available. It should not be used in liver impairment or in overdose, as it is dangerously hepatotoxic. Fixed dose formulations of paracetamol with methionine (Paradote) offer some protection against liver damage should overdose occur.

NSAIDs (non-aspirin) have analgesic, anti-inflammatory and anti-pyretic activity. They can relieve acute pain such as headache, dysmenorrhoea, post-operative pain and musculoskeletal pain, or chronic pain such as rheumatoid arthritis or osteoarthritis, with additional analgesics taken when required for breakthrough pain. In cancer pain they have an opioid sparing effect, and are particularly suitable for pain associated with bone metastases. NSAIDS have ceilings to their efficacy, and patient tolerance and response to NSAIDs is variable. If the desired response is not obtained at the upper limit of the recommended dose, or if side effects are unacceptable, an NSAID from a different chemical class should be tried, they should not be combined.

Moderate Pain

Weak opioids alone or in conjunction with mild analgesics are the treatment of choice for moderate pain.

Dextropropoxyphene with paracetamol, dihydrocodeine with paracetamol, codeine with paracetamol and codeine with aspirin are usually used first-line. If I greater analgesia is required, proprietary fixed-dose combinations that have a greater dose of weak opioid than the standard formulations, should ' be employed. Towards the top end of the moderate pain scale, fixed dose combinations may be less suitable because of the risk of exceeding the maximum dose of the non-opioid. In such circumstances, it is better to use codeine, dihydrocodeine ortramadol as single ingredient formulations, adding in paracetamol, aspirin or an NSAID separately if required. Weak opioids, particularly codeine, can cause severe 'constipation. Laxatives may be used pro phylactically rather than being witheld until constipation develops. Clinical experience with tramadol suggests it is less constipating.

Severe Pain

Strong opioids such as morphine, oxycodone, fentanyl, buprenorphine, hydromorphone andmethadone may be required for most forms of severe continuous pain such as cancer pain but may not be very effective in neuropathic pain. Intermittent pain does not respond well to opioids. Strong opioids may also be used in severe musculoskeletal pain, but long term use should be avoided. Morphine is the most commonly used of the strong opioids and is particularly suitable for severe continuous pain of visceral or soft tissue origin. When initiating therapy, titrate the dose by 50% to 100% every four hours until pain is controlled. Once control is established switch to a sustained-release formulation with a dose interval of 12 hours (MST Continus, Zomorph) or of 24 hours (Morcap SR, MXL capsules). It is imperative that doses are given "around the clock"; do not wait until the patient experiences pain. If there is breakthrough pain, immediate release formulations should be given at 1/6th of the total daily dose. Review regularly the total daily dose and adjust the sustained-release formulation if necessary. Contrary to popular misconception, there is no maximum dose for morphine in such circumstances. When used to control true continuous pain, there is no danger of addiction, tolerance or respiratory depression. As long as with each incremental dose an incremental degree of analgesia is obtained, it is safe to continue to titrate upwards to optimum pain control. There is no ceiling effect. Constipation with morphine is severe, so laxatives such as co-danthramer or co-danthrusate must be used prophylactically from the start of therapy in malignant pain.

Liquid formulations of morphine are available if swallowing is difficult. Transdermalbuprenorphine or fentanyl are alternatives to morphine in the relief of chronic intractable malignant or non-malignant pain. Each patch provides 72 hours continuous pain relief equivalent to that of morphine, but possibly with a lower incidence and severity of constipation. The strength of patch chosen depends on the patient's opioid history. As it can take 24 hours to reach optimal plasma levels, previous analgesic therapy should be continued during this period. Assessment of analgesic efficacy should be made after 72 hours, Immediate release oral morphine or sublingual buprenorphine must be available prn for breakthrough pain or symptoms of withdrawal. Conversely, oral mucosal delivery of fentanyl may be used to treat breakthrough pain in patients receiving opioid therapy for chronic pain. Methadone can be a useful analgesic in patients who have severe chronic pain that is non-responsive to morphine or in those who cannot tolerate the side effects. Transfer using a dose of methadone of 10% of the daily morphine dose but, because methadone has a long half-life, dosages should be prescribed 8- 12 hourly.

Regular users/abusers of opioids may require larger doses than normal for acute painful episodes.

Adjunctive Therapy

Some types of pain eg bone pain, incident-related pain, nerve and cerebral compression pain, and neuropathic pain are only partially responsive to opioids and may require adjunctive therapy. Adjuvant drugs can be used at all stages of the analgesic ladder to enhance the analgesic effect. Corticosteroids can be considered for patients with neuropathic pain from nerve compression or infiltration, bone pain, hepatomegaly, and raised intracranial pressure. Dexamethasone and betamethasone are the drugs of choice due to their high glucocorticoid activity relative to mineralocorticoid activity. They have an anti-inflammatory effect and reduce compression pain by reducing oedema.

The GABA analogue and anticonvulsant, gabapentin, is licensed for neuropathic pain of all aetiologies including diabetic peripheral neuropathy and postherpetic neuralgia. Antidepressants, anticonvulsants, antiarrhythmics-Although not all are licensed, low doses of antidepressants (amitriptyline, imipramine), anticonvulsants (clonazepam, carbamazepine, valpreate) and antiarrhythmics (lignocaine, flecainide. mexiletine) have been shown to be of value in neuropathic pain.

Diazepam can be used to relieve associated muscle spasm in musculo skeletal pain but should only be used to the acute episode.

Physical measures such as rest/ice/ compression/elevation (RICE) or aspiration of effusions may also be used to relieve musculo-skeletal pain associated with sprains and strains.

If pain control cannot be achieved by drugs, non-pharmacological procedures such as acupuncture, transcutaneous electrical nerve stimulation (TENS) and neuronal blockade may be performed specialist centres.

Emollients and anti-pruritics

Dry Skin

Emollients are used to smooth the surface of the skin and to increase its degree of hydration. They act either by occluding water loss from the outer layer of skin, eg white soft paraffin, greasy emollients, emulsions and sprays - or by improving the binding of water to the skin, eg urea creams. Some patients experience a stinging sensation after application of a urea containing cream and also find their odour unpleasant. Stinging is reduced if preparations are applied to moist skin. Lanolin containing creams can cause allergic sensitisation unless rendered hypoallergenic by purification. Emollients can be added to the bath or used in the shower and are especially useful in atopic eczema and ichthyoses. Some may also be used as substitutes for soap. Sodium pyrrolidone carboxylate is a key constituent of the natural moisturising factor (NMF), which occurs in high concentrations in skin. It is a potent hygroscopic agent which is thought to repair, rehydrate and maintain the skin.

Eczema

A deficiency in cutaneous fatty acids is suspected as being implicated in the pathogenesis of atopic eczema, resulting in a defective immune system and impaired suppression of inflammatory responses. Topical application of the evening primrose extract, gamolenic acid, may help to correct the deficiency of this essential fatty acid, thereby reducing the symptoms of atopic dermatitis such as ; irritation and dryness.

When applied topically, immunomodulators such as tacrolimus ointment inhibit calcium dependent signal transduction in T-cells, thereby preventing the transcription and synthesis of interleukins and other cytokines involved in the inflammatory process. They have also been shown to inhibit the release of inflammatory mediators from mast cells, basophils and eosinophils. Pimecrolimus cream, a skin selective anti-inflammatory, has a similar mode of action with a low potential to impair local and systemic immunosurveillance. These agents have the advantage that they can be applied to delicate areas such as the face and neck, and do not cause the side effects commonly associated with topical steroids. In infected eczema, emollients containing antibacterial agents such as benzalkonium chloride are effective against the causative bacterium Staphylococcus aureus.

Pruritus

Antipruritics act by counter-irritation, and are applied topically. Crotamiton relieves itching, partly by production of erythema and a feeling of warmth. Antihistamines block H1-receptors and reduce the swelling and irritation caused by the histamine that is released in response to injuries such as sunburn, insect stings and bites. Topical application however may cause sensitisation and so anthistamines are best given orally, preferably as elixirs or syrups to increase their rate of absorption. n

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