Adjuvant Analgesics

The term 'adjuvant analgesic' describes a drug that has a primary indication other than pain but is analgesic in some conditions. A large group of such drugs, which are derived from diverse pharmacological classes, is now used to manage non-malignant pain. In the post-operative patients, these drugs may be combined with primary analgesics in any of the three steps of the 'analgesic ladder' to improve the outcome for patients who cannot otherwise attain an acceptable balance between relief and side effects. The potential utility of an adjuvant analgesic is usually suggested by the characteristics of the pain or by the existence of another symptom that may be amenable to a non-analgesic effect of the drug. Whenever an adjuvant analgesic is selected, differences between the use of the drug for its primary indication and its use as an analgesic must be appreciated. Because the nature of dose-dependent analgesic effects has not been characterized for most of these drugs, dose titration is reasonable with virtually all. Low initial doses are appropriate given the desire to avoid early side effects. The use of low initial doses and dose titration may delay the onset of analgesia, however, and patients must be forewarned of this possibility to improve compliance with the therapy. There is great interindividual variability in the response to all adjuvant analgesics. Although patient characteristics, such as advanced age or coexistent major organ failure, may increase the likelihood of some (usually adverse) responses, neither favourable effects nor specific side effects can be reliably predicted in the individual patient. Furthermore, there is remarkable intraindividual variability in the response to different drugs, including those within the same class. These observations suggest the potential utility of sequential trials of adjuvant analgesics. The process of sequential drug trials, like the use of low initial doses and dose titration, should be explained to the patient at the start of therapy to enhance compliance and reduce the distress that may occur if treatments fail. In the management of postoperative pain, adjuvant analgesics can be broadly classified based on conventional use. The adjuvant drugs more frequently used in post-operative pain are corticosteroids, topical and local anaesthetics, neuroleptics and benzodiazepines.

Corticosteroids

Corticosteroids are among the most widely used adjuvant analgesics. They have been demonstrated to have analgesic effects in different conditions to significantly improve quality of life and to have beneficial effects on appetite, nausea, mood and malaise. The mechanism of analgesia produced by these drugs may involve anti-oedema effects, anti-inflammatory effects and a direct influence on the electrical activity in damaged nerves. The relative risks and benefits of the various corticosteroids are unknown and dosing is largely empirical. In the United States, the most commonly used drug is dexamethasone, a choice that gains theoretical support from the relatively low mineralocorticoid effect of this agent. Dexamethasone has also been conventionally used for raised intracranial pressure and spinal cord compression. Prednisone, methylprednisolone and prednisolone have also been widely used for other indications. Patients who experience pain and other symptoms may respond favourably to a relatively small dose of cortico-steroid (e.g. dexamethasone 1-2 mg twice daily). In some settings, however, a high-dose regimen may be appropriate. Although high steroid doses are more likely to lead to adverse effects, clinical experience with this approach has been favourable. Although the effects produced by cortico-steroids in patients with postoperative pain are often very gratifying, side effects are potentially serious and increase with prolonged usage. The varying constellations of adverse effects associated with brief or prolonged administration or with the withdrawal of these drugs following long-term use are widely appreciated. The risk of peptic ulcer is approximately doubled in patients chronically treated with corticosteroids. Several risk factors for peptic ulceration have been identified: relatively high dose, previous history of peptic ulceration, and concurrent administration of an NSAID. In general, the combined administration of a corticosteroid and an NSAID should be avoided. Patients who are predisposed to peptic ulcer disease can be considered for ulcer prophylaxis. Active peptic ulcer disease and systemic infection are relative contraindications to the use of corticosteroids as adjuvant analgesics.

Topical and Local Anaesthetics

Local anaesthetics are amazing drugs now commonly used in prevention and management of post-operative pain. Injected into tissue, around a nerve or for a regional block, they produce reversible block. For some operations, as inguinal hernia repair, there is proven advantage of regional over general anaesthesia. The use of local anaesthetics can produce reduced blood loss, faster surgery, reduced morbidity and faster rehabilitation. Local infiltration, blockade of peripheral nerves and plexuses, epidural blockade and regional analgesia represent the most frequent techniques adopted. Lidocaine and Bupivacaine are the most common local anaesthetics used in clinical practice. Particular attention to maximum drug dosing is required; excessive doses can cause seizures, cardiac depres sion and rhythm anomalies [5, 92]. Often local anaesthetic are combinated with epidural opioids to provide reliable analgesia in several pain contexts and extradural infusions of these drugs are used widely now for postoperative analgesia. Epidural local anaesthetics and opioids have been used for many years in the management of acute post-operative pain, and trauma. Several studies have confirmed synergism between local anaesthetics and opioids and support what has been observed clinically; that low doses of local anaesthetic and opioid can produce good analgesia. The mechanism of the synergy is not know. It may be that the local anaesthetic, by reducing the afferent input, is moving the opioid dose-respone to the right. Clinical observations suggest that chronic infusion of these two drugs can produce selective blockade, blocking pain fibers while leaving other sensory input intact. The adverse effects of these two drug classes are different. Epidural local anaesthetics can produce hypotension because of sympathetic blockade. Epidural opioids can produce delayed respiratory depression, urinary retention, priritus, nausea and vomiting. The epidural combination of these two drugs can produce pain relief, and the synergism between the drug classes offers the potential of effective analgesia at low doses of the components, minimizing the adverse effects of both. A clear demonstration of the advantage of the combination of local anaesthetic and opioid was seen in a comparison of 0.125% bupivacaine in saline, diamorphine 0.5 mg in 15 ml and diamorphine mixed with 0.125% bupivacaine infused for pain after major gynaecological surgery. The combination produced significantly superior analgesia to either of its component alone, without major side effects. Giving the diamorphine intravenously with epidural bupivacaine was significantly less effective than giving the same dose epidurally in combination with epidural bupivacaine. Three strategies in dosage of combination of these drugs are discernible: the low, the intermediate, and the high. High doses (bupivacaine 0.5% 25 mg/h and morphine 0.5 mg/h) were used to produce analgesia immediately after upper abdominal surgery but a some risk. Lower doses (bupivacaine 0.1% 4 mg/h and morphine 0.4 mg/h) did not provide total pian relief after major surgery, as thoracotomy. The issue of the minimum effective dose is of great importance, and unfortunately may have to be defined for particular circumstances. Topical formulations are useful for needle procedures, including EMLA, a cream containing an eutecthic mixture of 2 local anaesthetics (lidocaine 2.5% and prilocaine 2.5%). It is very effective in numbing the skin and the tissues just underneath the skin. Topical local anaesthetics can be used in the management of painful cutaneous and mucosal lesions and as a premedication prior to skin puncture. However, the depth of the skin which becomes numb is dependent upon how long the cream is left on. The maximum depth is about six to seven millimeters, after the cream has been left on the skin for two hours. This medication has been successfully used for a number of painful procedures, as bone marrow aspiration and lumbar puncture; the cream should be applied from 30 min to 1 hour before the shot or needle procedure [93]. Satisfactory numbing of the skin occurs 1 hour after application, reaches a maximum at 2 to 3 hours (1 hour for children less than 3 months), and lasts 1 hours after removal. EMLA has beeen proven to be safe, with low plasma local anaesthetic concentration. Mild side effects generally disappear spontaneously within 1 or 2 hours (skin paleness, redness, a changed ability to feel hot or cold, swelling, itching, and rash). It should not be used in children affected by a rare condition of congenital or idiopathic methaemoglobinemia, or in infants under the age of 12 months who are receiving treatment with methaemoglobin-inducing agents [93].

Neuroleptics

The role of neuroleptic drugs in the management of postoperative pain is limited. Methotrimeprazine is a proven analgesic and has been useful in bedridden patients with postoperative pain who experience pain associated with anxiety, restlessness or nausea. In this setting, the sedative, anxiolytic and antiemetic effects of this drug can be highly favourable and side effects, such as orthostatic hypotension, are less of an issue. Metho-trimeprazine may be given by continuous SC administration, SC bolus injection or brief IV infusion (administration over 20-30 minutes). A prudent dosing schedule begins with 5-10 mg every 6 hours or a comparable dose delivered by infusion, which is gradually increased as needed. Most patients will not require more than 20-50 mg every 6 hours to gain the desired effects. Given their potential for serious toxicity and the limited evidence in support of analgesic efficacy, other neuroleptics should be used only for the treatment of delirium and nausea.

Benzodiazepines

There is little evidence that benzodiazepines have meaningful analgesic properties in most clinical circumstances and, indeed, there is some evidence that they may, in some circumstances, antagonize opioid analgesia. These drugs may play a role in the management of anxiety and muscle spasm.

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