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TREATMENT OF CANCER PAIN
Many cancer pain syndromes have been identified (see TABLE 119-2). Tumors can invade bone or soft tissues, compress or infiltrate nerves or blood vessels, or obstruct a hollow viscus. Chronic pain can follow surgery, chemotherapy, or radiation therapy. Accurate diagnosis of the underlying process is essential, because specific treatment can greatly simplify pain management. However, pain should be adequately treated while the search for its cause is under way.
Nonopioid Analgesia
Managing pain is generally by a stepwise approach with analgesics. Nonopioid analgesics, specifically acetaminophen and NSAIDs (see TABLE 119-3) are often effective for mild to moderate pain (see also RHEUMATOID ARTHRITIS in Ch. 106). Many NSAIDs are available; each differs in its cost, duration of action, and side effects, and results for a given patient are often unpredictable. Unlike the opioids, NSAIDs do not produce physical dependence or tolerance. All share a ceiling effect that may be higher than the usually recommended starting doses for these drugs; if initial doses are tolerated but provide inadequate analgesia, a higher dose is warranted. If additional analgesia occurs but is still inadequate, the ceiling dose is not yet apparent and doses can be increased further. This process is empiric and must be tempered by evidence of a dose-related rise in toxicities. The dose should not be increased >1? to 2 times the usually recommended starting dose. If relatively high doses are used, patients should be monitored monthly for the presence of occult blood in the stool or changes in CBC, electrolytes, or tests of hepatic and renal function.
Opioid Analgesia
An opioid, usually propoxyphene, codeine, or oxycodone, is added if nonopioid analge-sics alone are ineffective. Each of these opioids is commercially available in combination (eg, aspirin/oxycodone or acetaminophen/codeine). The drug is given around the clock until the maximum amount of the nonopioid drug is reached (eg, 2 tablets of acetamin-ophen 325 mg/oxycodone 5 mg q 3 h). If this is inadequate, an opioid is prescribed separately and its dosage increased until either effect or intolerable side effects occur.
Available opioid analgesics are described above. Selection of an opioid for severe pain is empiric. Morphine is most widely available, but another drug may be preferred based on favorable experience, lower cost (methadone is least expensive), or limited availability. Pharmacokinetic factors should be considered; opioids with a short half-life (t)--morphine and hydromorphone--should be used as first-line agents in the elderly, who are at greater risk of toxicity due to accumulation in plasma than younger patients. Meperidine use is limited by CNS adverse effects described for synthetic opioids, above. Agonist/antagonist drugs also play a limited role because they may induce an acute abstinence syndrome in patients already physically dependent on opioids. Pentazocine (combined with naloxone) is the only one with an oral preparation, but has prominent psychotomimetic effects.
Knowledge of the equianalgesic doses of opioids is essential when switching drugs or routes of administration. Cross-tolerance between drugs is incomplete and a change from one to another should be accompanied by reducing the equianalgesic dose by 50%. The duration of analgesia of the different opioids varies little, despite variability in the plasma t, and most need to be started on a q 3 to 4 h basis. Since steady-state levels are not approached until 4 to 5 ts have passed, long t drugs (eg, levorphanol and methadone) carry the risk of delayed toxicity while plasma levels rise. Thus, it is prudent to begin using these long t drugs on an as-needed basis, changing to regular dosage only after a steady state is reached. Close monitoring is particularly important during the titration period.
Routes of administration: If possible, drugs should be given orally to prolong the effects and avoid rapid fluctuations in plasma level. One efficient technique involves the use of "rescue doses." In addition to regular doses around the clock, an extra dose of a drug with a short t (preferably the same as the one regularly given) is offered q 2 h prn. The rescue dose is empiric and based on the standing dose (eg, 15 mg morphine orally q 2 h prn for a standing order of 30 mg orally q 4 h). The standing dose can be increased daily if rescue doses continue to be needed or if pain persists.
Other techniques and routes of opioid administration have been developed in an attempt to increase analgesia and limit side effects. Slow-release morphine tablets permit a dose q 8 to 12 h, which some patients prefer. Parenteral doses are used if the oral route is un-available. IV administration often provides greater patient comfort. Continuous infusion, either IV or s.c., should be considered if repetitive parenteral doses produce a prominent bolus effect; ie, toxicity at peak levels early in the dosing interval or later breakthrough pain at trough levels. Patient-controlled analgesia (systems in which the patient can trigger additional drug delivery) can be added to an infusion to provide for supplementary doses. Epidural and intrathecal administrations of opioids are innovations requiring special expertise. By activation of opioid receptors at a spinal level, they may provide analgesia with fewer side effects. However, supraspinal redistribution of the drug with delayed tox-icity and development of tolerance and cross-tolerance with systemic opioids are major concerns. Their precise role in cancer pain management is controversial.
Tolerance (the need for increasing doses to maintain effects) occurs commonly with opioids and is first suggested by a reduced duration of analgesia. In cancer patients, the need to increase doses usually reflects neoplastic progression with progressive pain; although tolerance develops concurrently, drug tolerance alone is seldom the reason for dose escalation.
The distinction between physical dependence and psychologic dependence is fundamental. Physical dependence is a pharmacologic process marked by the occurrence of an abstinence (withdrawal) syndrome after abrupt discontinuation of an opioid drug or administration of an antagonist. Psychologic dependence (or addiction) refers to a behavioral syndrome in which there is overriding concern with the use and acquisition of the drug, resulting in drug hoarding, diversion, and unapproved escalation in dose (see also in Ch. 137). While physical dependence occurs in virtually all patients treated for chronic pain who take opioids over a long time, psychologic dependence is extremely rare and should not be considered in the decision to begin or to increase doses in patients with cancer pain.
For additional analgesia, an NSAID generally should be added to the opioid regimen. There is evidence that bone pain is particularly responsive to treatment with the NSAIDs. Many other drugs whose primary indication is not analgesia can also augment pain relief in certain settings; corticosteroids (eg, dexamethasone 4 mg q 6 h orally or more) are also useful for severe bone pain and may be very helpful in pain due to infiltration of neural structures. For neuropathic pain, a tricyclic antidepressant (eg, amitriptyline or doxepin 10 to 25 mg orally at bedtime to start, increasing to 75 to 150 mg orally at bedtime over 1 to 2 wk) may be useful. Higher doses may be needed, especially if depression is prominent. A lancinating component to neuropathic pain may respond to an anticonvulsant or baclofen (see TABLE 119-5). With these drugs (except phenytoin) dosage should be low initially and increased gradually. Phenytoin should be started at the usual maintenance dose (eg, 300 mg/day orally) or given first as a loading dose (eg, 500 mg orally q 6 h for 2 doses, then 300 mg/day). Though a relationship between analgesic effect and blood levels has not been determined, monitoring of the serum concentration may be useful to assess compliance and record an effective baseline concentration for future reference.
Adjuvant Drugs for Side Effects
Constipation is common and should be managed by increasing the fiber content of the diet to >10 gm/day and prescribing a stool softener (eg, docusate sodium 100 mg bid to tid) with or without a contact laxative (eg, senna). The dose of senna begins low but can be increased if necessary. Persisting constipation can be managed with a periodic (q 2 to 3 days) dose of an osmotic laxative (eg, magnesium citrate) or with chronic dosage of lactulose (eg, 15 mL bid).
Sedation can be treated specifically with methylphenidate 5 to 20 mg 1 to 2 times/day or dextroamphetamine 2.5 to 10 mg orally 1 to 3 times/day.
Nausea can be treated with hydroxyzine 25 to 50 mg orally q 6 h, metoclopramide 10 to 20 mg q 6 h, or with an antiemetic phenothiazine (eg, prochlorperazine 10 mg orally q 6 h).
Respiratory depression is rare in patients on chronic dosage, since tolerance to this effect develops quickly; should it occur, a contributing pathologic process should be sought. If respiratory depression requires treatment in the physically dependent patient, dilute solutions of naloxone (0.4 mg diluted in 10 mL 0.9% sodium chloride) should be given slowly IV, titrated to respiratory rate, not alertness, with caution to avoid an abstinence syndrome. Doses of naloxone must be repeated, or an infusion used, until the plasma level of the opioid has declined. This can require days with opioids of long t1/2 (eg, methadone).
Nondrug Analgesic Therapies
The nonspecialist may also use nondrug therapies in selected patients with cancer pain (see TABLE 119-6). A variety of other specialized anesthetic, neurosurgical, and invasive neuroaugmentative techniques are available (see TABLE 119-7). No controlled studies of these adjuvant techniques have been done, but large series have been reported suggesting their efficacy. The precise role each plays in easing the cancer patient's pain is undefined; special expertise that may be available only in certain centers is required for their safe application. These techniques are most useful for localized pain and should be considered only if routine noninvasive measures fail. A notable exception to this latter generalization is the anesthetic technique of celiac plexus neurolytic block for midabdominal pain, in which the benefits of early treatment appear to outweigh the potential risks.
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