[Pharmacotherapy of cancer pain. 3. Adjuvant drugs.].
Adjuvant analgesics are drugs that are not primarily used as analgesics but can produce analgesia in certain types of pain. Adjuvant analgesics can be administered together with non-opioid and opioid analgesics on each step of the WHO analgesic ladder. They should be given when an additional or specific indication exists, but should not be used as a substitute for a thorough treatment with opioids and nonopioids. Adjuvant analgesics can be classified into groups according to the type of pain to be treated: continuous neuropathic pain or lancinating neuropathic pain, sympathetically maintained pain, bone pain and those for multipurpose use. Adjuvant drugs used for continuous neuropathic pain include local anaesthetics, clonidine, capsaicin, and antidepressants. Tricyclic antidepressants are the group that have been best investigated, and are therefore the drugs of choice. An analgesic effect is probably produced via enhancement of transmitter concentrations in pain-modulating pathways. This occurs at lower doses than those necessary to treat depression. Anticholinergic actions, acute glaucoma, constipation, orthostatic hypotension and cardiac arrhythmias are adverse effects that are seen predominantly with teritiary amine drugs and less often with secondary amine compounds. Initial doses should be small to avoid these adverse effects. Local anaesthetics are used less often, because of the high incidence of side effects (especially with tocainide, flecainide). An analgesic effect has been described in neuropathic pain, however, probably due to membrane stabilization and reduction of aberrant signal conduction. Mexiletine is considered to be the safest local anaesthetic, and should be used initially in small doses (100-150 mg/d). If side effects do not occur, doses can be increased step-wise up to 900 mg/d. Local anaesthetics are indicated for the treatment of severe neuropathic pain; this treatment is contraindicated in patients with cardiac arrhythmias. Systemic or intrathecal clonidine can be tried in neuropathic pain refractory to opioid therapy. The same stands for the topical application of capsaicin in certain types of pain. Lancinating neuropathic pain is an indication for anticonvulsant drugs. Carbamazepine, clonazepam, valproate and phenytoin seem to reduce aberrant signal conduction in damaged nerves in a manner similar to the supression of epileptiform activities in the brain. Common side effects include sedation, dizziness and nausea. Of greater concern are the more severe side effects, such as bone marrow depression (carbamazepine) and hepatotoxicity (phenytoin, valproate). Low initial doses and stepwise increases in dosage, repeated blood counts, and monitoring of plasma levels are helpful in recognizing and avoiding these adverse effects. Baclofen, a GABA agonist primarily used for spasticity, is effective in the treatment of trigeminal neuralgia and is often used in the management of lancinating pain of unspecific origin. The initial dosage is 10-15 mg/d, increasing to 30-90 mg/d, or higher. If neural blockade fails to reduce sympathetically maintained pain sufficiently specific adjuvants can be used. Sympatholytic drugs, e.g. phenoxybenzamine (60-120 mg/d) or prazosin, can be administered to patients without major cardiovascular dysfunction. There is experimental evidence of the involvement of calcium channels in nociception, and a beneficial clinical effect of nifidepine in reflex sympathetic dystrophy (RDS) has been demonstrated. Bone pain is common in tumor patients and can often be treated effectively with non-steroidal anti-inflammatory drugs. Biphosphonates (etidronate, clodronate, pamidronate derivates) also produce analgesic effects in patients with bone metastases. However, differences among the various compounds have not been clearly evaluated yet. Potent and specific radioisotopes are still under development and the use of calcitonin in bone pain is considered controversial.
Cherny
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NI
Department of Internal Medicine and Medical Oncology, Shaare-Zedek Medical Center, 91031, Jerusalem, Israel.
Portenoy
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RK
Raber
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M
Zenz
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M