Adjuvant Analgesics

When "traditional" analgesics (i.e., acetaminophen, NSAIDs, and opioids) do not completely alleviate pain, adjuvant drug therapy may be useful. These agents may enhance the effect or allow dosage reduction of commonly used analgesics, treat concurrent symptoms that exacerbate pain, or be more effective therapeutic agents in the treatment of specific pain syndromes. It is important for the practitioner to understand the role of adjuvant analgesics, including preferred drug selection in older adults.

NSAID agents have long been used to treat a wide spectrum of mild-to-moderate pain syndromes. NSAIDs may also serve as adjunctive therapy to treat specific pain complaints, such as from bone metastasis, soft-tissue infiltration, arthritis, serositis, and surgery (16). NSAIDs have also been shown to allow opioid dosage reduction when administered concurrently. Refer to Chapter 6 for a further discussion of the use of NSAID agents in older adults.

Use of bisphosphonates (i.e., pamidronate disodium, zoledronic acid, and alendronate sodium) has been studied in patients with painful bone metastases (36). Bisphosphonate therapy is associated with multiple adverse reactions, such as GI adverse effects (i.e., nausea, vomiting, diarrhea, constipation); hypocalcaemia, hyperphosphatemia, and renal impairment; musculoskeletal pain; and miscellaneous adverse effects such as transitory febrile reactions and hypersensitivity secondary to intravenous infusion.

Pharmacological properties of corticosteroids include the ability to reduce inflammation, edema, and neuronal excitability; to increase appetite; and to reduce nausea (37). Corticosteroids may be used to treat pain resulting from acute nerve compression and headache, visceral distension, increased intracranial pressure, soft-tissue infiltration, bone pain, and neuropathic pain (16,37). Dexamethasone is frequently used as an adjunctive agent; however, betamethasone and methylprednisolone have also been used with success. As useful as corticosteroids are, their adverse effect profile is considerable and may worsen concomitant diseases experienced by the elderly. Toxicities seen early in therapy include hypertension, hyperglycemia, immunosuppression, GI ulceration, and psychiatric disorders (37). With long-term administration, adverse effects include Cushing's disease, osteoporosis, proximal myopathy, and aseptic necrosis of the bone (37). If the patient has a life-limiting illness, it is important to frequently reevaluate the risk/benefit ratio of continuing corticosteroid therapy.

Neuropathic pain is frequently not completely controlled by opioids alone; the addition of an adjunctive agent may be very useful. Antide-pressants (particularly tricyclic antidepressants [TCAs] such as amitrip-tyline, nortriptyline, and desipramine), anticonvulsants (i.e., carbamazepine, phenytoin, valproic acid, gabapentin, and lamotrigine), anesthetics, antiarrhythmic agents (i.e., lidocaine and mexiletine), and other agents (i.e., baclofen, corticosteroids, calcitonin, bisphosphonates, capsaicin) have reported benefits for relief of neuropathic pain (38).

TCAs have long been considered a primary intervention for the treatment of many neuropathic pain syndromes. Clinical trials have demonstrated the efficacy of TCAs in treating painful diabetic neuropathy, postherpetic neuralgia, central poststroke pain, and cancer-related neuropathic pain syndromes (38). These agents probably act by inhibiting nociceptive pain pathways by blocking the reuptake of serotonin and norepinephrine. It is important to note that the selective serotonin reuptake inhibitor antidepressants (i.e., fluoxetine, paroxetine, sertraline) have not demonstrated significant efficacy in treating neuropathic pain (39).

The adverse effects caused by TCAs are well recognized and include those related to their anticholinergic activity (constipation, dry mouth, blurred vision, urinary retention, cognitive changes, and tachycardia).

Additional adverse effects include orthostatic hypotension, sedation, falls, and weight gain. Generally, the secondary amines (desipramine and nortriptyline) are preferred for older adults because they cause fewer anticholinergic and sedative effects than the tertiary amines (i.e., amitrip-tyline) (38). TCAs should be administered cautiously to patients with preexisting conditions (i.e., angle-closure glaucoma, benign prostatic hypertrophy, constipation, cardiovascular disease or impaired liver function) that could be worsened by the effects of these agents (38). The dosage should be started low in older adults, such as 10 mg at bedtime (to minimize impact of sedation), and increased by titration every 3 to 5 days as tolerated. A therapeutic effect should be seen in 3-10 days (more quickly than the antidepressant effect), generally at doses less than 100 mg per day. If one TCA does not adequately treat the neuropathic pain, it is worth a trial with a different agent (taper off the first agent).

Anticonvulsant agents are also considered agents of choice in the treatment of a wide variety of neuropathic pain complaints, particularly with lancinating or tic-like pain. The older anticonvulsants (e.g., carbamazepine, phenytoin, and valproic acid) probably act by increasing membrane stability (as seen with seizures). Clonazepam has also been used to treat neuropathic pain, and it acts by enhancing y-aminobutyric acid (GABA)A-receptor-mediated inhibition. Gabapentin, an analog of GABA, has been very popular in the treatment of neuropathic pain, but its action mechanism is not known (38).

Carbamazepine has been used to treat painful diabetic neuropathy and trigeminal neuralgia (40). Carbamazepine autoinduces its hepatic metabolism, so the practitioner must start at low doses (i.e., 100 mg po twice daily) and increase the dosage weekly to the therapeutic dose (approx 1200 mg po qd, although dosages up to 1600 mg per day have been necessary for pain relief) (38). Carbamazepine is responsible for many drug interactions because of its ability to induce hepatic enzyme activity. Adverse effects include CNS effects (drowsiness, vertigo, ataxia, diplopia, and blurred vision); GI effects (nausea, vomiting); serious hematologic toxicity (aplastic anemia, agranulocytosis); transient increase in hepatic enzymes; and hypersensitivity reactions (dermatitis, eosinophilia, lymphadenopathy, splenomegaly) (41).

Phenytoin has also been used to treat a variety of neuropathic pain complaints. Careful attention to detail is required with phenytoin dosing because the drug exhibits capacity-limited or storability metabolism. At therapeutic concentrations, the rate of metabolism is close to the limit, and small dosage increases may result in significantly higher serum concentrations. Phenytoin is also highly bound to serum albumin, and a higher "free" or unbound fraction would be expected in patients who are hypoalbuminemic, potentially causing toxicity despite a therapeutic "total" phenytoin serum concentration. Phenytoin is involved in many drug interactions with other highly protein bound medications. Chronic phenytoin dosing and toxicity include adverse effects such as dose-related cerebellar-vestibular effects, CNS effects, behavioral changes, increased seizure frequency, GI symptoms, gingival hyperplasia, osteomalacia, and megaloblastic anemia. Older adults are at greater risk for phenytoin-related toxicity (41). It is also worth mentioning that phenytoin can adversely diminish vitamin D status, a problem commonly seen in older patients (42).

Gabapentin (Neurontin) has become quite popular in recent years in the treatment of neuropathic pain because of its tolerability and efficacy in treating a variety of pain, including reflex sympathetic dystrophy, diabetic neuropathy, trigeminal neuropathy, postherpetic neuralgia, radiation myelopathy, central poststroke pain, and neuropathic cancer pain (38). In addition to its efficaciousness, gabapentin has fewer adverse effects and drug interactions than carbamazepine or phenytoin. The major adverse effects associated with gabapentin therapy are sedation, dizziness, ataxia, and fatigue (43). Tolerance generally develops to these adverse effects; however, it is prudent to begin therapy at a low dose and titrate the dose to effect. Dosing generally begins at 100 mg three times daily, although some older adults may require once or twice daily to start. Titration to effect should balance against side effects. Most patients who respond will do so at total daily doses of 900 to 1800 mg. Some practitioners have pushed the daily dosage higher if a partial response is seen by 1800 mg per day.

Other medications used to treat neuropathic pain adjunctively include mexiletine, clonidine, lamotrigine, lidocaine, baclofen, corticosteroids, calcitonin, capsaicin, bisphosphonates (pamidronate), and strontium chloride (16,37,38,44,45).

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