Dolobid

Pain control is of utmost importance in cancer patients, whether it enables patients to tolerate the rigors of diagnosis and treatment or simply allows them to live out their final days in peace and dignity. Cancer pain, particularly in advanced stages of the disease, may be especially severe. Most cancer patients are enormously fearful of uncontrolled pain in the terminal period, and this fear, as well as the pain itself, needlessly complicates the patient's care. I Pain is the most common symptom in terminally ill patients; unrelieved, it causes further anorexia, weight loss, nausea, vomiting and insomnia. Moreover, the very narcotics used to treat the pain may also cause these same symptoms. (2) Fears and complications, both real and imagined, can lead to a cycle of anxiety and despair. (3)

Most, if not all, cancer pain can be effectively treated by the family physician who understands its causes and the rational use of analgesics. Neurosurgical, anesthetic and behavioral approaches, including nerve blocks, epidural anesthesia and patient-controlled analgesia, are often used to relieve pain in cancer patients, but their use may require a certain degree of expertise, and in many cases, large-scale controlled studies that prove their efficacy are lacking. (4)

This article discusses the use of drug therapy for cancer pain control; all physicians caring for cancer patients need to be competent in prescribing these agents. Unfortunately, many patients suffer needlessly because they are given analgesics in doses that are too low or are spaced too far apart. Concerns about drug addiction and over-dosage, although generally unfounded, may result in inadequate analgesia. (5) Various studies suggest that only 10 to 50 percent of patients with severe cancer pain obtain effective relief. (1,6)

The World Health Organization (WHO) has designated cancer pain as a major world health problem. (6) The American Medical Association (7) and the American College of Physicians (8) have both outlined approaches to the control of cancer pain. These guidelines emphasize systematic diagnosis of the cause of the pain and systematic use of both nonnarcotic and narcotic analgesics. Studies indicate that use of these approaches can provide relief in 85 percent or more of patients with cancer pain.

Causes of Cancer Pain

Cancer pain is typically classified according to reasonably well-defined pain syndromes. There are many causes of cancer pain, including those related to the disease itself, to the treatment and to psychosocial factors. Careful investigation and precise delineation of the source of the pain may enable the physician to treat the underlying cause or at least choose the most appropriate analgesic.

The most common cause of pain in cancer patients is directly related to the neoplastic process; it is the cause of pain in approximately two-thirds or more of cancer patients. (2,6,9,10) Within this group, tumor invasion of bone, either locally or by distant metastases, is most frequent, followed by infiltration or compression of nerves by tumor growth. Obstruction of hollow viscera or of the ductal systems of solid organs produces characteristic colicky or diffuse visceral pain. Finally, occlusion of blood vessels and lymphatics may cause edema or ischemia; involvement of mucous membranes causes severe burning pain.

The second group of pain syndromes is due to the effects of the various anticancer therapies. Complications of chemotherapy (gastrointestinal, neurologic or hematologic effects), radiation therapy (fibrosis of connective tissue) and surgery typically account for 20 percent of the pain complaints, particularly in an outpatient population of cancer patients. (2,10)

The third group of pain syndromes includes factors unrelated to cancer and its treatment. Psychosocial factors play a major role and must not be ignored. Anxiety, fear, depression, and feelings of uncertainty and isolation can profoundly lower the patient's pain threshold and alter his or her perception of pain. Patients may perceive far more discomfort from stimuli that in other circumstances would be of little consequence. For many patients, pain was the presenting symptom of cancer, and recurrence of pain may represent to them recurrence or progression of disease. Psychologic factors may play an even greater role in patients who have had chronic pain from a preexisting, noncancerous condition. A history of chronic pain should not be viewed as a reason to be any less aggressive in the diagnosis and treatment of pain, but identification of patients in whom psychosocial factors may play a role helps the physician provide timely and insightful care.

Because family physicians provide continuous, comprehensive care, they are in the best position to continually reassess the patient's response to therapy. If the patient is not doing as well as expected, the treatment approach should be reconsidered or the possibility of a new cause of symptoms should be investigated. (2)

Commonly used analgesics for cancer patients are generally classified as nonnarcotic, narcotic (or opioid) and adjuvant analgesics. The WHO advocates the use of an "analgesic ladder". a stepwise approach to the use of analgesics in patients with cancer pain. (11,12)

Nonnarcotic Analgesics

Nonnarcotic analgesics are typically the first-line treatment for mild to moderate cancer pain (13) (Table 1). These include aspirin, acetaminophen and the nonsteroidal anti-inflammatory drugs (NSAIDs). Aspirin or acetaminophen, usually given in a dose of 650 to 1,000 mg every three to four hours, provides significant pain relief as compared to that produced with placebo. Whether aspirin has any increased analgesic effect above a dose of 650 mg is uncertain. In contrast, acetaminophen is probably more effective in a dose of 1,000 Mg. (14) A 650-mg dose of aspirin or acetaminophen is at least equal to standard doses of weak oral narcotics, such as 60 mg of codeine phosphate, 65 mg of propoxyphene hydrochloride (Darvon, Dolene, Doxaphene, etc.) or 100 mg of propoxyphene napsylate (Darvon-N). (14,15)

The side effects of aspirin are well known, particularly gastrointestinal ulceration, inhibition of platelet aggregation and aspirin hypersensitivity. Elderly patients are especially predisposed to these complications. Conversely, acetaminophen is usually safe and free of side effects when given in dosages under 4 g per day. (15) Hepatotoxicity may occur at a higher dosage, but this is a rare complication. In general, aspirin appears to be more effective than acetaminophen for the pain caused by bony metastases. (1,2)

NSAIDs provide yet another choice in the management of specific pain syndromes. These agents include ibuprofen (Motrin, Rufen), diflunisal (Dolobid), indomethacin (Indameth, Indocin) and naproxen (Anaprox, Naprosyn), among others. NSAIDs are inhibitors of prostaglandin synthesis and are similar to aspirin in their degree of analgesia and side effects. They may be somewhat better tolerated than aspirin, particularly with chronic administration of higher doses, but they too are associated with a relatively small risk of renal toxicity.

Ibuprofen is generally well tolerated and is a reasonably effective agent; it is usually administered in doses of 400 to 600 mg every four to six hours. Naproxen has the advantage of a relatively long half-life and can be administered on a twice-daily schedule in doses of 250 to 500 mg.

NSAIDs offer considerable flexibility, particularly in the treatment of metastatic bone disease. Failure of analgesia with one NSAID does not necessarily preclude benefit from another compound. Acetaminophen may enhance the analgesic effect of NSAIDs, and combination therapy with these two analgesics is most useful for pain with an inflammatory component. (14.15)

Combination Analgesics

The use of nonnarcotic analgesics in the treatment of somewhat more severe cancer pain is limited by a ceiling for analgesia. The analgesic effects are not increased at higher doses, even as the risks of side effects and cumulative toxicity increase. While nonnarcotic analgesics exert their effects peripherally, the narcotic (or opioid) analgesics work by combining with specific opiate receptors in the central nervous system. As is the case with nonnarcotic agents, maximal oral doses of narcotic agents are limited by gastrointestinal and central nervous system effects.

Given by themselves, the weak oral narcotics are no more effective than nonnarcotic analgesics. However, combination therapy with an optimal dose of acetaminophen, aspirin or an NSAID and an oral opioid, such as codeine, oxycodone or methadone, produces an enhanced analgesic effect. The increased pain relief is due to more than the additive effects, and combination therapy has fewer side effects than equianalgesic dosages of either component alone. (15,16)

A variety of nonnarcotic-narcotic combinations are available (Table 2). Even greater flexibility may be obtained by continued administration of the maximal dose of the nonnarcotic analgesic while the dose of the opioid is titrated according to the patient's needs.

Narcotic Analgesics

For persistently severe pain, the narcotic agents remain the gold standard for analgesia. These agents produce a much greater analgesic effect than the nonnarcotic analgesics. Guidelines for the use of narcotic agents are summarized in Table 3. This class of drugs may cause withdrawal symptoms in patients who have developed physical dependence on the opioids. (1)

Morphine sulfate is the prototype drug of this class. It is the opioid most of ten used for the control of severe pain in patients with far-advanced cancer. The opioids are further classified as agonists and antagonists; the narcotic agonists, such as morphine, methadone and codeine, bind to specific opiate receptors to produce analgesia, while the narcotic antagonists, such as naloxone (Narcan), block the effects of opioids at opiate receptors.

There is also a group of drugs termed "mixed" agonist-antagonists, but these agents are of limited utility. Although the degree of physical dependence may be less with the mixed agents than with the opioid agonists, high doses of the mixed agents produce psychotomimetic effects, particularly visual and auditory hallucinations. Of the agonist-antagonist narcotics, only pentazocine (Talwin) is available in an oral form, and that preparation is combined with a nonnarcotic analgesic (i. e., aspirin).

In proper dosages, morphine sulfate is a highly effective and safe analgesic for patients with severe pain. Although potency following oral administration is only one-sixth to one-third of that following parenteral administration, oral morphine is effective if the dose is appropriately adjusted. (2)

Unfortunately, significant misconceptions and lack of understanding about morphine may needlessly prolong the suffering of cancer patients for whom morphine is indeed the drug of choice. Confusion over the proper definitions of the terms tolerance, physical dependence and psychologic dependence (addiction) has contributed to the underutilization of morphine. Tolerance develops when increasing doses of an analgesic are required to achieve the same effect; physical dependence is marked by withdrawal symptoms if the necessary doses are not achieved or are discontinued. Neither tolerance nor physical dependence is the same as psychologic dependence or addiction. Addiction is characterized by an abnormal behavior pattern that centers on obtaining and using the drug. While long-term use of narcotic analgesics in patients with severe cancer pain will produce tolerance and physical dependence, addiction is rare. (1,17,18) The misplaced fear of drug addiction in terminally ill patients deprives these patients of adequate pain control and a peaceful death.

MORPHINE

In general, no other narcotic analgesics are superior to morphine. (2,17) While sometimes useful in certain specific situations, most other narcotic analgesics are limited in their usefulness by side effects, by the accumulation of toxic metabolites or by overly complex pharmacology. Hydromorphone (Dilaudid) and levorphanol (LevoDromoran) are more similar to morphine than other agents but still offer no consistent advantages. Comprehensive discussions of the use of these other narcotics are found in articles written by Levy (2) and by Foley and Inturrisi. (19)

Morphine should be given at fixed intervals, by the most effective and convenient route. Several issues are of paramount importance: continuous pain requires continuous pain management; "as-needed" dosing may result in dramatic fluctuations in plasma levels, so that patients typically have inconsistent analgesia alternating with periods of toxicity from excessively high plasma levels. Around-the-clock schedules, with relatively equal intervals between doses, are superior to sporadic dosing and facilitate the most consistent analgesia. (17) Occasionally, additional doses of morphine may be required for breakthrough pain, but the fixed schedule should be maintained. (2) The plasma half-life of morphine sulfate is approximately two to three and one-half hours. It is generally more appropriate to administer the drug closer to every four hours than every six hours. (2) To achieve the most effective palliation, patients should initially be awakened at night for a dose of morphine. After approximately two to three days of therapy, most patients can be given a bedtime dose that is one and one-half to two times greater than the usual every-four-hour dose. This technique may then allow for elimination of the dose that would normally be given in the middle of the night. (2) A nighttime sedative or hypnotic may be a useful adjunct.

Most patients can be provided with durable palliation from oral morphine preparations, thereby avoiding the discomfort and inconvenience of intravenous or intramuscular injections. Parenteral administration usually results in high plasma concentrations initially, followed by a rapid decline, which produces less consistent analgesia than that provided by oral administration. Morphine sulfate elixirs are available in a variety of concentrations; the oral morphine solution in a concentration of 20 mg per mL provides a considerable morphine concentration with relatively low volume. This formulation is ideal for patients with head and neck cancers or upper gastrointestinal neoplasms.

An underutilized method of administration is the suppository form of morphine. The pharmacokinetics following rectal administration are remarkably similar to those following oral administration. For selected circumstances, patients can of ten remain at home and comfortably medicated even if their condition precludes oral administration of analgesics. The availability of morphine suppositories in a variety of strengths, ranging from 5 to 30 mg, allows considerable flexibility with this route of administration.

Although immediate-release morphine sulfate remains the analgesic standard for severe cancer pain, the every-four-hour dosing schedule can be cumbersome for patients and caregivers alike. Multiple-dose schedules at frequent intervals increase the possibility of medication errors and untoward side effects, and may be associated with poor patient compliance. Each of these factors may contribute to an inadequate pain management program. The development of sustained- and controlled-release morphine sulfate preparations (MS Contin, Roxanol SR) has been welcomed. MS Contin is available in 30-mg and 60-mg tablets.

In a typical clinical setting, a patient's total daily requirement of immediate-release morphine is established by the patient's own perception of the adequacy of analgesia. Patients can be switched to MS Contin by administering one-half of a total 24-hour dosage at 12-hour intervals. For most patients, the analgesia from MS Contin appears to be more durable and more consistent than that provided by immediate-release morphine, at a slightly lower dose. (20)

Orally or rectally administered narcotics provide effective analgesia for most patients until the very final stage of cancer. Even if patients are unable to communicate, it is likely that pain persists, and appropriate doses of a parenteral narcotic should be administered. Decreasing levels of consciousness generally indicate disease progression and, under most circumstances, should be allowed to continue. Only when objective signs of narcotic overdosage are present should subsequent doses be decreased or withheld. Inadequate amounts of narcotic in the terminal stages only increase patient discomfort and agitation, causing unnecessary distress for patients and their families, their nurses and their doctors. (2)

SIDE EFFECTS OF MORPHINE

A number of well-recognized clinical complications are associated with morphine use. Anticipation and management of the side effects can dramatically enhance the well-being of patients with terminal illness.

Constipation is a notorious side effect, the result of decreased peristalsis and diminished gastrointestinal secretions. Inadequate fluid intake and confinement to bed profoundly aggravate gastrointestinal complications. A preventive program should be carefully reviewed with patients and their caregivers; patients should regularly ingest adequate amounts of fluids, fruit and bran, if possible. Stool softeners such as docusate sodium (Colace, etc.), peristaltic stimulants such as senna concentrate (Senokot, etc.), and glycerin suppositories must be part of the pain management program.

Morphine-induced nausea and vomiting are also well-recognized side effects, particularly in ambulatory patients, (17) but can be effectively treated with antinausea medications 21 (Table 5).

Drowsiness and confusion are less frequent complications but may be more pronounced at the initiation of narcotic therapy or following a significant increase in the dosage. These effects usually abate within three days and can be managed by dose modification, the use of alternate agents and frank discussions with patients, forewarning them about these problems.

When appropriately prescribed, narcotic analgesics rarely cause significant respiratory depression. Agents that have a significantly short duration of action relative to the plasma half-life (for example, methadone) may cause respiratory depression because of the accumulation of metabolites. If necessary, respiratory depression can be treated with naloxone, 0.4 to 0.8 mg intravenously, intramuscularly or subcutaneously. The half-life of one dose of naloxone is approximately 20 minutes; thus, careful observation and multiple doses may be required in certain circumstances. Adjuvant Analgesic Drugs

Adjuvant analgesic agents constitute a third group of drugs used to treat patients with cancer pain. This group encompasses a number of chemically and pharmacologically diverse agents, including corticosteroids, tricyclic antidepressants, anticonvulsive agents, antihistamines and others. These agents are most useful for treating specific symptoms or complications of advancing cancer. They may also be given when the use of narcotic analgesics is limited because of tolerance or side effects.

Corticosteroids are an important adjunct for symptomatic management of selected syndromes in patients with advanced cancer. Table 6 outlines the appropriate doses of dexamethasone for various types of cancer pain. Corticosteroids can consistently increase appetite in most patients and provide a sense of well-being and euphoria, even in the face of terminal illness. By reducing inflammation and local edema, corticosteroids are an important alternative in the treatment of neurologic syndromes caused by increased intracranial pressure or by infiltrative and entrapment neuropathy, which is often associated with metastatic bronchogenic carcinoma or breast cancer. Corticosteroids are also important in the management of radiation-induced brachial plexus injuries. Deep, intractable visceral pain associated with pelvic and retroperitoneal tumors can often be ameliorated by coadministration of corticosteroids and conventional analgesics.

Neuropathic syndromes associated with cranial neuropathies from head and neck cancer can sometimes be modified by a judicious steroid program. Simultaneous use of a corticosteroid and a tricyclic antidepressant, such as amitriptyline (Amitril, Elavil, Endep, etc.), at a relatively small dose (10 to 25 mg at bedtime) can sometimes provide dramatic palliation from profoundly disabling dysesthetic syndromes.

Like the narcotic analgesics, corticosteroids pose little threat of long-term sequelae in patients with advanced cancer. However, fluid retention, hyperglycemia and proximal myopathy can occur relatively quickly in the debilitated patient, and the clinician must be alert to these potential complications. Additionally, a relatively low dose of a corticosteroid can sometimes provoke profound hyperglycemia in the cachectic cancer patient with underlying mild glucose intolerance. The debilitated patient receiving corticosteroid therapy is also prone to the development of oral candidiasis; this can usually be managed with antifungal agents administered as lozenges or troches.

Final Comment

Providing effective analgesia for the patient with severe chronic pain due to terminal illness requires a systematic approach to diagnosis and rational use of various medications. Pain is neither inevitable nor unavoidable, and a pain-free state should be a management goal in every patient with cancer. By working closely with the patient, family and other caregivers, the physician will help the cancer patient make this last transition with peace and dignity.

REFERENCES

1. Foley KM. The treatment of cancer pain. N Eng] J Med 1985;313:84-95.

2. Levy MH. Pain management in advanced cancer. Semin Oncol 1985;12:394-410.

3. Posner RB. Physician-patient communication. Am J Med 1984; 77(3A); 59-64.

4. Payne R, Foley KM. Advances in the management of cancer pain. Cancer Treat Rep 1984; 68: 173-83.

5. Schuster CR. Does treatment of cancer pain with narcotics produce junkies? In: Hill CS, Fields WS, eds. Advances in pain research and therapy. Vol 11. New York: Raven, 1989:1-3.

6. Stjernsward J. Cancer pain relief: an important global public health issue. In: Fields HL, Dubner R, Cervero F, eds. Advances in pain research and therapy. Vol 9. New York: Raven, 1985:555-8.

7. McGivney WT, Crooks GM. The care of patients with severe chronic pain in terminal illness. JAMA 1984;251:1182-8.

8. Drug therapy for severe, chronic pain in terminal illness. Ann Intern Med 1983;99:870-3.

9. Bonica JJ. Treatment of cancer pain: current status and future needs. In: Fields HL, Dubner R, Cervero F, eds. Advances in pain research and therapy Vol 9. New York: Raven, 1985:589-616.

10. Foley KM. Pain syndromes in patients with cancer. Med Clin North Am 1987; 71:169-84.

11. Cousins MJ, Gourlay GK, Cherry DA, Plummer JL. Treatment of cancer pain with orally and spinally administered opioids. Aust NZ J Surg 1989;59:307-15.

12. Ventafridda V, Tamburini M, De Conno F. Comprehensive treatment in cancer pain. In: Fields HL, Dubner R, Cervero F, eds. Advances in pain research and therapy. Vol 9. New York: Raven, 1985:617-28.

13. Moertel CG. Treatment of cancer pain with orally administered medications. JAMA 1980; 244:2448-50.

14. Amadio P Jr. Peripherally acting analgesics. Am J Med 1984;77(3A):17-26.

15. Beaver WT. Combination analgesics. Am J Med 1984;77(3A):38-53.

16. Ferrer-Brechner T, Ganz P. Combination therapy with ibuprofen and methadone for chronic cancer pain. Am J Med 1984; 77(lA): 78-83.

17. Inturrisi CE. Role of opioid analgesics. Am J Med 1984;77(3A):27-37.

18. Porter J, Jick H. Addiction rare in patients treated with narcotics [Letter]. N Engl J Med 1980;302: 123.

19. Foley KM, Inturrisi CE. Analgesic drug therapy in cancer pain: principles and practice. Med Clin North Am 1987; 71:207-32.

20. Brooks I, De Jager R, Blumenreich M, George E, Savarese JJ. Principles of cancer pain management. Use of long-acting oral morphine. J Fam Pract 1989;28:275-80.

21. Gralla RJ, Tyson LB, Kris MG, Clark RA. The management of chemotherapy-induced nausea and vomiting. Med Clin North Am 1987;71: 289-301.

TABLE 3

Guidelines for the Use of Narcotic Analgesics in Pain Management

1 Start with a specific drug for a specific type of, pain

2. Know the pharmacology of the drug prescribed

a. Duration of the analgesic effect

b. Pharmacokinetic properties of the drug

c. Equianalgesic doses for the drug and its route of administration

3 .Adjust the route of administration to the patient's needs

4. Administer the analgesic on a regular basis after initial titration of the dose

5. Use drug combinations to provide additive analgesia and reduce side effects (e.g., nonsteroidal anti-inflammatory drugs, antihistamine [Hydroxyzine] and amphetamine [Dexedrine])

6. Avoid drug combinations that increase sedation without enhancing analgesia, such as a benzodiazepine (e.g., diazepam [Valium]) and a phenothiazine (e. g., chlorpromazine [Thorazine])

7. Anticipate and treat side effects

a. Sedation

b. Respiratory depression

c. Nausea and vomiting

d. Constipation

8. Watch for the development of tolerance

a. Switch to an alternative analgesic

b. Start with one-half the equianalgesic dose and titrate the dose for pain relief

9. Prevent acute withdrawal

a. Taper drugs slowly

b. Use diluted doses of naloxone (0.4 mg in 10 mL of saline) to reverse respiratory depression in the physically dependent patient, and administer cautiously

10. Do not use placebo to assess the nature of pain

11. Anticipate and manage complications

a. Overdose

b. Multifocal myoclonus

c. Seizures

Adapted from Foley KM. The treatment of cancer pain. N Engl J Med 1987;313:84-95.

EDWARD T. CREAGAN, M.D. is professor of medical oncology at Mayo Medical School and Mayo Clinic, Rochester, Minn. Dr. Creagan is a graduate of New York College, New York City, and completed an internal medicine residency at the University of Michigan, Ann Arbor, and oncology fellowships at the National Cancer Institute, Bethesda, Md., and at Mayo Clinic.

JOHN M. WILKINSON, M.D. is an instructor in family medicine at Mayo Medical School. A graduate of Mayo Medical School, Dr. Wilkinson completed a residency in family medicine at Mayo Clinic.

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