Am J Otolaryngol 12:154-160.1991
Pain Management in Advanced Carcinoma of the Head and Neck KERRY D. OLSEN, MD, AND EDWARD T. CREAGAN, MD
Although pain is one of the most feared consequences of cancer, pain management is rarely discussed in the literature on head and neck cancer. The pain experienced by patients with head and neck malignancies, of a biologic origin, is compounded by the emotional distress caused by alterations in function and cosmesis. Control of pain is possible, but an effective program must include more than pain medication. A current treatment program is presented, based on scientific study and clinical experience. The most helpful pain medication is immediate-release, liquid morphine sulfate (20 mg/mL) administered every 4 hours. A nonsteroidal anti-inflammatory drug may also be used and it may decrease the amount of morphine necessary. Stool softeners must be provided, and anti-nausea medication is often given. Steroid drugs are regularly used to increase appetite, decrease edema, and enhance the patient’s sense of well-being. Factors related to the selection and dosage of medications are discussed. AM J OTOLARYNGOL 12:154-160. Copyright 0 1991 by W.B. Saunders Company Key words: pain management, head and neck carcinoma
Pain, one of the most feared consequences of cancer, is subject to control, and patients with advanced head and neck cancer should be permitted to die free of its effects.’ The control of pain in the dying patient can also palliate other aspects of the disease and improve the quality of life of the patient’s remaining days.’ One patient who was dying of cancer stated, “I found that when I didn’t have pain, I could forget I had cancer.“3 In general, the treatment of patients with advanced head and neck cancer is not dissimilar to that of other cancer patients.l Successful pain management requires treatment of all aspects of pain: physical, psychological, social, and spiritual. Treatment should be matched to the patient’s specific needs. We present a clinical approach to pain management based on scientific study and daily clinical experience. Our approach attempts to assess the diverse factors producing pain and the sequelae of medical therapy. Physicians treating patients with head and neck cancer should be prepared to provide a comprehensive palliative program when conventional treatment modalities have failed.
BACKGROUND Pain management is rarely discussed in the literature on head and neck cancer. A review of the current cancer literature noted that less than 0.1% of all articles dealt with pain diagnosis and therapy.4 Less than 1% of the presentations at national oncology meetings included pain as a subject of consideration. The major oncology textbooks also devote little space to the management of cancer pain. A review of 10 important texts on the clinical management of cancer found that only 18 of 9,300 pages (0.2%) dealt with this subject. Residents in head and neck oncology receive little or no teaching about the proper management of the cancer patient with severe pain. PREVALENCE
OF CANCER
PAIN
Pain associated with direct tumor involvement has been found in 78% of patients with cancer in an inpatient population and in 62% of patients in an outpatient population.5 It has been estimated that, worldwide, 3 million people annually require treatment because of pain from cancer.6 In 72% of cancer patients were another study,’ judged to have died with pain. Physicians treating patients with head and neck tumors encounter pain frequently. If one excludes lip and larynx cancer, only 35% of head and neck malignancies are cured.’ Progressive disease and the multiple causes for pain account for the high prevalence of pain in patients with head and neck tumors. A study from the Memorial Sloan-
Received March 10, 1991, from the Department of Otorhinolaryngology and the Division of Medical Oncology, Mayo Clinic and Mayo Foundation, Rochester, MN. Accepted for publication April 6, 1991. Presented at the Annual Meeting of the American Academy of Otolaryngology-Head and Neck Surgery, San Diego, CA, September 8 through 13, 1990. Address correspondence and reprint requests to Kerry D. Olsen, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Copyright 0 1991 by W.B. Saunders Company 0196-0709/91/1203-0013$5.00/O 154
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OLSENANDCREAGAN Kettering Cancer Center found that pain was a significant factor in 80% of patients with cancer of the oral cavitye4 Pain severe enough to require opioids was experienced by more than two thirds of patients with advanced cancer of the head and neck.’ CAUSES
OF CANCER
PAIN
Pain is a complex state influenced by multiple factors. The patient’s sex, age, cultural and environmental influences, and multiple psychological factors must be considered.g The physical and emotional aspects of pain present a multifaceted problem. The physician must have a compassionate, totally encompassing approach to these patients because the pain components include emotional, social, financial, and spiritual considerations. Most patients with advanced head and neck cancers have more than one cause of pain. Cancer pain from direct tumor involvement is a common finding with head and neck squamous cell carcinoma because of its tendency for ulceration, deep infiltration, and early metastasis. Upper aerodigestive tract mucosal ulceration rapidly leads to infection, necrosis, edema, inflammation, and pain. Movement exacerbates pain and is especially severe in the oral cavity and pharynx. Vessel occlusion and lymphatic blockage can also cause edema, distension, and involvement of pain-sensitive structures in the soft tissues of the head and neck. Tumor invasion of bone is one of the most common causes of pain in the patient with head and neck cancer. The mandible, maxilla, and skull base are well-known problem areas for pain control. The early involvement of nerves, bacterial infection, and osteomyelitis are common sequelae. Bone involvement of the nasopharynx, sphenoid, jugular foramen, and clivus leads to syndromes of pain that are familiar to head and neck oncologists.* Invasion of bone is the most common cause of pain in all patients with cancer. The detection of bony involvement by bone scans or computed tomographic scans is possible 3 to 4 months earlier than by plain radiographic studies. Unfortunately, a negative bone scan does not rule out bony metastasis. The second most common source of pain is tumor compression or infiltration of nerve roots, trunks, or plexuses. Neurotropic invasion is a common finding with squamous cell carcinoma or adenoid cystic carcinoma. Involvement of mucosal and submucosal nerve endings can cause burning, uncomfortable dysesthesias, and referred pain such as otalgia. Neuralgic pain is a common source of discomfort in the patient with head and neck cancer. Pain from surgical therapy can occur from sen-
sory nerve disruption. Functional compromise from loss of portions of the jaw or tongue, for example, can exacerbate pain. The painful effects of radiation therapy-mucositis, radionecrosis of bone, tumor necrosis and infection, or subsequent fibrosis-are well known. In fact, 70% of the major problems with pain control in cancers of the head and neck occur because of neoplastic recurrence and radionecrosis.’ As pain becomes chronic, the associated symptoms of disturbed sleep, decreased appetite, impaired concentration, and irritability become more evident. This leads to physical deterioration and emotional and behavioral change. Patients become more anxious, depressed, and have less contact with friends. Some patients with severe and intractable pain become so discouraged and desperate that they may contemplate or commit suicide.4 TREATMENT
OVERVIEW
There are many ways to treat the pain of head and neck cancer. These include outpatient and inpatient drug therapy, neuroablation, nerve blocks, electrical stimulation, physical therapy, and psychological techniques. This review focuses on the most frequently used treatment modality: nonnarcotic, narcotic, and adjuvant drugs for outpatients. Effective use of these medications should produce relief of cancer pain in the majority of individuals. All physicians who care for patients with cancer should learn to administer and have confidence in an effective drug therapy program. Treatment should begin with an appropriate and specific drug applied at the lowest dose that produces analgesia. It is important to know the pharmacology of the prescribed drug, including the duration of effect and the pharmacokinetic properties of the drug’s action. The dose must be titrated to obtain a favorable result and the route of administration must be adjusted to the patient’s needs. Medication should be administered on a regular basis. The use of a combination of drugs is often efficacious for severe pain. The physician must anticipate and treat any side effects of the prescribed medication. The key to effective pain management is the constant reassessment and appropriate modification of treatment. Problems in Achieving Effective Treatment. Three common errors decrease the effectiveness of pain treatment: inadequate amounts of medication, providing the medication on an “as needed” basis, and lack of attention to the side effects of therapy. The improper application of existing knowledge on available therapeutic modalities has been cited as the most important reason for
156
inadequate pain control in the cancer patient4 Systemic analgesics should relieve the pain of cancer in most patients if the appropriate drugs are chosen and if the right dose and schedule are used. Underutilization of drugs for severe pain is, unfortunately, too frequent. This may be due to several factors, including poorly understood pharmacology and concern about possible abuse and side effects. Another problem that often occurs has been called “stacking.” A physician may not notice adequate pain relief with one narcotic drug and so will add another narcotic drug instead of increasing the dose of the first. It is much better to prescribe one drug in an adequate d0se.l’ No patient should ever suffer because of the physician’s reluctance to use an adequate level of medication.” Narcotic drugs should be administered on a regular basis, and the interval between doses should be based on the expected duration of the analgesic effect. Narcotics should not be given on a pro re nata basis. This places the burden on the patient to request the drug and does not base the decision on the known pharmacologic action of the drug.l’ The objective is to maintain a constant plasma level of the drug that is above the minimum effective concentration for pain relief. The time required to reach such a steady state depends on the half-life of the medication. Medication should be given around the clock. This includes awakening the patient from sleep, a mild inconvenience in view of the benefits of such a regimen.
Treatment of Mild Pain. For the patient with mild pain, aspirin, acetaminophen, or nonsteroida1 anti-inflammatory drugs (NSAIDs) are generally recommended. Aspirin or acetylsalicylic acid has been available as an analgesic since 1893. The appropriate dosage is 650 mg every 4 hours. The average duration of effect is 3 to 6 hours.’ The liquid form of acetylsalicylic acid trisalicylate (500 mg/5 mL) is especially useful for patients who have head and neck cancer. The side effects of aspirin can include gastritis and an increased risk of bleeding due to the inhibition of platelet aggregation. Aspirin’s adverse effects on the mucosa of the stomach can be avoided by using a buffered form such as Ascriptin (Rorer, Fort Washington, PA) or an enteric-coated formula. Acetaminophen can be given in dosages of up to 4 g/d with no appreciable side effects. Greater dosages may be nephrotoxic or hepatotoxic. Acetaminophen has the benefit of minimal gastric irritation and no bleeding problems. The dosage is 650 mg every 4 hours. A liquid form (160 mg/5 mL) is also available. Numerous analgesic preparations are available that combine aspirin, acetaminophen, phenace-
PAIN MANAGEMENT
IN ADVANCED
CARCINOMA
tin, caffeine, or other medications. However, there is no good evidence that these combination drugs are more effective than aspirin or acetaminophen alone. One study also showed that propoxyphene hydrochloride (Darvon; Eli Lilly, Indianapolis, IN) or propoxyphene napsylate (Darvon-N; Eli Lilly] has the same analgesic activity as aspirin alone. The NSAIDs most often used to manage head and neck pain in cancer patients are available in liquid form: ibuprofen (Motrin; Upjohn, Kalamazoo, MI], naproxen (Naprosyn; Syntex, Palo Alto, CA), and indomethacin (Indocin; Merck Sharp & Dohme, West Point, PA). These NSAIDs have been shown to be effective analgesics or coanalgesics when there is evidence of bone involvement by cancer. Ibuprofen is the least expensive of the three and may cause less mucosal injury to the gastrointestinal tract than other similar drugs. It is available in a concentration of 100 mg/5 mL and is given in a dosage of 400 mg every 4 to 6 hours. Naproxen is available in a concentration of 125 mg/5 mL and has the advantage that it can be given twice daily in a dosage of 375 to 500 mg. Indomethacin (25 mg/5 mL) is given in a dosage of 25 to 50 mg every 6 to 8 hours. This medication is especially helpful if the patient has constitutional symptoms such as chills, fever, or sweating. Any NSAID must be used cautiously in elderly patients and in patients with renal insufficiency, heart failure, hypertension, or a history of bleeding or peptic ulcer disease. The maximum dose for most of the drugs in this group should not exceed 1.5 to two times the usual recommended starting dose for each of these drugs.’ The minimum period necessary to determine their efficacy is generally 2 to 3 weeks. If there is no benefit, it is reasonable to change drugs because patients may respond poorly to one medication and well to another. This is because of the different chemical classes of nonsteroidal medications.
Treatment of Moderate Pain. Codeine is commonly the first narcotic drug given to patients who do not obtain effective relief from a nonnarcotic agent. Codeine itself is a weak analgesic. Thirty milligrams of codeine is equal in effectiveness to 650 mg of aspirin. One can increase the dose of codeine; however, there will be an increase in side effects, such as nausea, vomiting, constipation, and sedation. The addition of aspirin or acetaminophen to codeine is an effective formula for increased pain relief. An elixir combination of codeine-12 mg plus acetaminophen (120 mg/5 ml)-can be given in 15mL aliquots, which is equivalent to a Tylenol No. 3 tablet (McNeil, Spring House, PA). In general, for the relief of moderate pain, codeine combined with aspirin or acetaminophen is
157
OLSEN AND CREAGAN
preferred. Its availability as a liquid is extremely helpful for patients who have head and neck cancer.
Treatment of Severe Pain. Patients with severe pain should be treated with an opiate drug. The opiates are classified as agonists, mixed agonists-antagonists, and antagonists. The most commonly used agonist is morphine. It is important to know a drug’s efficacy, which is the capacity of the drug to produce a given effect, and its potency, which is the amount of drug necessary to produce a given effect3 Potency comparisons among the opioid analgesics are important if switching from one opioid drug to another becomes necessary. In general, agonist drugs such as morphine act by binding to opioid receptors in the central nervous system, resulting in analgesia. Morphine. Morphine remains the prototypic opioid agonist analgesic. It is the standard to which all other narcotics should be compared. It is the drug of choice from the opioid class for the treatment of severe pain from head and neck cancer. The reaction of patients to the idea of morphine therapy often includes such thoughts as, “My doctor is giving up on me,” “I must be terminal,” “ I want to save it until I really need it,” “I’ll become an addict,” or “It won’t work when I really need it.” It is important for the physician to allay these concerns. Morphine has desirable properties in addition to its analgesic effect. It can relieve anxiety, create some euphoria, and provide some sedation. Its undesirable effects can include sedation, mental clouding, dizziness, nausea and vomiting, supTABLE 1.
pression of the cough reflex, physical dependence, spasmogenic constipation, and possible tolerance.13 Morphine can be given intramuscularly, orally, or rectally. It is important to withdraw the drug slowly because rapid termination of morphine therapy can lead to agitation, tremors, insomnia, fever, or marked autonomic system hyperexcitability 6 to 12 hours after its cessation.’ In 1976, Mount’ reported the successful use of liquid morphine in controlling pain when it was given in a 10% alcohol solution. The oral route avoids the discomfort and complications of repeated injections. It is more convenient and is essential for patients with head and neck cancer. The intramuscular to oral relative potency ratio with morphine is stated to be 1:6 after a single dose. However, with chronic use, the intramuscular to oral ratio becomes 1:2 to 1:3. Therefore, 10 mg of morphine given intramuscularly is equivalent to 20 to 30 mg given orally. The traditional concentration of liquid morphine (10 mg/5 mL) has now been replaced by the highly concentrated 20 mg/mL of morphine sulfate (Roxanol; Roxane, Columbus, OH) (Table 1). This is now readily obtainable, easily titrated, and comes in a convenient calibrated eyedropper dispenser. It has a bland but acceptable taste. It is available in 8- or 16-ounce bottles at this concentration. A reasonable starting dose of liquid morphine is 5 to 10 mg every 4 hours around the clock, not as needed. Because morphine has a short half-life (2 to 3 hours], it must be administered every 4 hours. If, instead, morphine is given every 6 hours, between the fourth and sixth hours there will be a low therapeutic level. Morphine applied every 4 hours maintains a steady plasma concentration
Analgesics for Head and Neck Cancer Pain ORAL FORM
ADULT DOSAGE
DRUG ASA
650 mg every
4 hr
Acetaminophen
650 mg every
4 hr
Ibuprofen Naproxen
400 mg every 4-6 hr 375-500 mg every 12 hr
Indomethacin
25-50
Codeine
30-60 mg every
mg every
Codeine plus acetaminophen
Codeine
plus
Morphine ASA. acetylsalicylic
4 hr
325 500 325 500 200 250 375 500 25 50 30 50 No. 3: 30 mg codeine, 300 mg acetaminophen No. 4: 300 No. 3: 325 No. 4: 325
ASA
Abbreviation:
6-8 hr
Pill (mg)
acid.
60 mg 30 mg 60 mg
mg codeine, acetaminophen mg codeine, ASA mg codeine, ASA 15
Liquid
(mg/5 mL) 500 160 100 125
25
12 mg codeine plus 120 mg acetaminophen/5 -
20 mg/mL
mL
158
and precludes pain. Most patients achieve control of their pain at dosages of up to 30 mg on this schedule. However, there is no upper dose limit. Morphine remains the single most effective orally administered analgesic for patients with severe pain when given at adequate levels and on a regular around-the-clock basis. For individuals unable to take liquid morphine, suppositories are an appropriate alternative. Morphine is available in 5-, lo-, ZO-, and 30-mg rectal suppositories. It should be given at the same dosage and on the same fixed schedule as oral preparations of morphine. Sustained-relief morphine products such as MS Contin or Roxanol SR can be given every 8 to 12 hours. Less frequent applications may result in greater patient acceptance. It is first necessary to titrate the dose of one of the usual short-acting morphine agents. Once a stable state is reached, one can switch to sustained-release products divided into two equal doses every 12 hours. Longacting morphine therapy works if the patient is receiving a consistently stable dose of regular morphine. However, head and neck cancer patients usually have increasing analgesic requirements because of tumor progression, and breakthrough pain is common when long-acting morphine drugs are used. MS Contin is only available in certain strengths: 15, 30, 60, and 100 mg.
Concerns When Opiate Drugs Are Used. Tolerance and addiction do not present real clinical problems in patients with advanced cancers of the head and neck. For a terminally ill patient, consideration of a drug’s addictive potential is irrelevant and remains an impediment to the delivery of optimal pain relief. There is no evidence that the chronic use of narcotic drugs for analgesia is associated with a high risk of addiction.14 The rate of addiction among patients who receive narcotic therapy for pain is no more than 0.1%.12 Patients may become dependent on a drug without becoming addicted to it. The question of tolerance is another source of misunderstanding that may prevent physicians from prescribing adequate amounts of narcotic medication. Tolerance is a state in which increasing dosages of a drug are needed to maintain an equal analgesic effect.* However, in patients with head and neck cancer, increased opioid requirements probably do not indicate the development of pharmacologic tolerance; most likely they have progressive disease and therefore an increased need for pain relief. The dosages of morphine necessary for pain relief in terminal cancer patients can be enormous; levels as high as 500 mg of morphine per hour may be given by continuous infusion to some patients with severe discomfort. Phy-
PAIN MANAGEMENT
IN ADVANCED CARCINOMA
sicians’ concerns that patients receiving narcotic drugs will become addicted and that the dose required will increase because of tolerance are unsupported.
Addition of an Anti-inflammatory Drug to Opioid Therapy. Because NSAIDs work in the peripheral and narcotics work in the central nervous system, their combined use can be efficacious. Aspirin or acetaminophen (650 mg every 4 hours) combined with a narcotic drug increases the analgesic effect and effectively decreases the total dose of narcotic drug required. This additive effect has been described for codeine and is also well known with morphine. The dosage of morphine often can be decreased by half. A randomized, double-blind, cross-over study in which ibuprofen and morphine were used demonstrated a significant increase in analgesia without a concomitant increase in side effects.15 Aspirin, acetaminophen, ibuprofen, naproxen, or indomethatin can improve pain relief in combination with morphine. One of these drugs should be used routinely for all patients who receive morphine if there are no medical contraindications due to side effects of the non-opioid drug.
Constipation. Constipation is a common and distressing symptom in patients with cancer. It is important to encourage patients who are receiving narcotic drugs to be active, maintain a high fluid intake, and add fiber to their diet.*‘j In the absence of a diet high in fiber, a bulk laxative containing bran or methylcellulose can be provided. Contact cathartics are also helpful. These increase mucosal secretion and provide an increase in the motility of the intestinal tract. Numerous medications are available including bisacodyl (Dulcolax; Boehringer Ingelheim, Ridgefield, CA) and milk of magnesia. We prescribe dioctyl sulfosuccinate (Peri-Colace; Mead Johnson, Levansville, IN), taken two or three times per day. Other cathartics that can be added include senna compounds that affect mucosal electrolyte transport and motility. Senna concentrate (Senokot, two to three tablets at bedtime; Purdue Frederick, Norwalk, CT) is also helpful. The constipation caused by opioid drugs is much easier to prevent than it is to treat. Nausea and Antiemetics. The incidence of nausea with narcotic therapy is greatest during the first week of therapy. Morphine is a more common cause of nausea in ambulatory patients. Nausea occurs from the interaction of the narcotic analgesic with brain stem centers mediating the sensation of nausea and the function of emesis. Nausea will develop in 40% of patients receiving narcotic therapy. ‘*17 Fortunately, this resolves af-
OLSEN
159
ANDCREAGAN
ter several days and is not a problem after prolonged use. In the first few days, drugs such as prochlorperazine (Compazine, 5 to 10 mg every 4 to 6 hours: Smith Kline & French, Philadelphia, PA] or haloperidol (Haldol, 0.5 mg every 8 hours; McNeil) are helpful. If nausea is not a problem, the drug dose can be tapered quickly or, if nausea continues, the drugs can be continued for several weeks. If early satiety or epigastric fullness is a problem, metoclopramide (Reglan; Robins, Richmond, VA) can enhance gastric emptying. hproved We//-Being. Adrenal corticosteroid treatment can be extremely helpful in the treatment of terminal cancer patients. Steroid agents can cause euphoria, stimulate appetite, and create a sense of well-being. A short course of steroid therapy should be given to patients with advanced cancer when there are no major contraindications to its use. In one double-blind study,*’ 32 mg of methylprednisolone was administered to patients with advanced cancer. Patients receiving steroid therapy reported less pain, less depression, and improved appetite. There was general improvement in their overall well-being.18 Moertel et all9 reported the use of dexamethasone in 116 patients with gastrointestinal cancer. Steroid therapy caused improved strength and appetite after 2 weeks, but not after 4 weeks.l’ The exact dose of steroids remains an empiric question, as is the duration of the effect. Therefore, after several weeks, one attempts to taper the
steroid dose to zero or to a low maintenance level. The use of steroids on a twice daily basis gives patients a “lift” in the PM, when they most often seem to need it. Prednisone can be given at a starting dose of 20 to 30 mg twice daily; the dose then can be reduced slowly. Another treatment approach is to give dexamethasone (8 mg three times a day) for several days and, if benefit is noted, reduce the dose to 4 mg twice daily.17 The long-term use of steroid drugs is associated with weakness, delirium, osteoporosis, immunosuppression, diabetic potential, peptic ulcers, and sodium retention. Most studies, however, report no toxicity when these drugs are used as we have described. Patients with cancer who received prednisone for 2 to 16 weeks had an increased (3%) but low risk of peptic u1cer.l The use of adrenal corticosteroids remains a helpful adjunct in the management of patients dying of cancer. Their use may permit a decrease in narcotic requirements, and the associated euphoria, improved appetite, and weight gain can enhance the quality of life. The benefits of steroid therapy in patients with advanced cancer most certainly outweigh the slight risk of complications. Drowsiness and Sedation. Drowsiness has been reported in 26% of patients treated with narcotic drugs6 Sedation is a more common effect of drugs with a long plasma half-life, such as levorphanol or methadone. Amphetamines can be used with narcotics, if necessary, to counteract the sedative effects.
TABLE 2. Adjunct Medications for Head and Neck Cancer
Pain ORALFORM
DRUG
ADULT DOSAGE
Dexamethasone
Prednisone
Peri-Colace Senokot Prochlorperazine (Compazine) Haloperidol (Haldol) Metoclopramide (Reglan) Chlorpromazine (Thorazine) Imipramine (Tofranil) Amitriptyline (Elavil)
2-3 times a day 1-2 at bedtime 5-10 mg every 4-6 hr 0.5 mg every
8 hr
IO-15 mg 4 times
a day
25-50 mg 4 times
a day
75-100
mg at bedtime
75-150
mg at bedtime
Pill (mg) 0.25 0.5 0.75 1.5 4 1 2.5 5 10 20 Capsule Tablet 5 10 0.5 1.0 2.0 5 10 10 25 50 25 50 25 50
Liquid
(mgi5 mL)
0.5
5
Syrup, Syrup,
15-30 mL lo-15 mL 5
2 mg/mL
5 30 mg/mL
PAIN MANAGEMENT
Respiratory depression in a patient with severe pain is unlikely as long as the pain is unrelieved. Pain remains a natural antagonist to the action of opiates; the stronger the pain, the more opiate is required. Patients who develop tolerance to the analgesic effect of a narcotic will also acquire tolerance to its respiratory depressive effect. Respiratory depression is a rare phenomenon in patients tolerant to narcotics. The physician should give whatever dose is required to relieve pain without fear of the patient suffering respiratory depression.”
Antipsychotics and Antidepressants. Antipsychotic drugs (neuroleptics) can also act as analgesics, either alone or in combination with narcotic drugs. Haloperidol (Haldol; McNeil), 1 to 2 mg at bedtime, or chlorpromazine hydrochloride (Thorazine; Smith Kline & French), 25 to 50 mg four times a day, also calms the agitated patient and provides some antiemetic action. Narcotic drugs have also been used with the tricyclic antidepressants. Imipramine (Tofranil; Geigy, Ardsley, NJ), 75 to 150 mg at bedtime, or amitriptyline (Elavil; Merck Sharp & Dohme), 75 to 150 mg at bedtime, is also helpful if insomnia is a problem or if the patient is depressed. The analgesic effect of tricyclic antidepressants can be helpful; however, their sedative and anticholinergic side effects are additive. It is useful first to titrate the dose of the opioid drug and then to add other medications as an adjunct if necessary. Start the patient on a low dose of 10 to 25 mg of amitriptyline at bedtime and gradually titrate this to a single dose of 50 to 15~1 mg at bedtime. All physicians should be well aware of the indications, contraindications, action, dosage, and side effects of any medication they prescribe. Patients who appear unresponsive to narcotics may have significant psychosocial problems, including personal, financial, professional, sexual, or other matters. The sensitive investigation and
IN ADVANCED
CARCINOMA
recognition of these problems can lead to compassionate treatment with medication and/or counseling (Table 2). References 1. Foley KM: The treatment of cancer pain. N Engl J Med 1985; 313:84-95 2. Moertel CG: Treatment of cancer pain with orally administered medications. JAMA 1980; 244:2448-2450 3. McGivney WT, Crooks GM: The care of patients with severe chronic pain in terminal illness. JAMA 1984: 251:11821188 4. Bonica JJ: Management of cancer pain. Recent Results Cancer Res 1984; 89:13-27 5. Foley KM: Current issues in the management of cancer pain: Memorial Sloan-Kettering Cancer Center. NIDA Res Monogr 1980; 36:169-181 6. Ventafridda V, Tamburini M, Caraceni A, et al: A validation study of the WHO method for cancer pain relief. Cancer 1987; 59:850-856 7. Daut RL, Cleeland CS: The prevalence and severity of pain in cancer. Cancer 1982; 50:1913-1918 8. Raj PP, Phero JC: Pain control in cancer of the head and neck, in Thawley SE, Panje WR (eds): Comprehensive Management of Head and Neck Tumors, vol 1. Philadelphia, PA, Saunders, 1987, pp 42-68 9. Foley KM: Clinical assessment of cancer pain. Acta Anesthesiol Stand Suppl 1982; 74:91-96 10. Hill CS. Ir: Narcotics and cancer nain control. CA 1988; 38:322-326 ' 11. Marks RM, Sachar EJ: Undertreatment of medical inpatients with narcotic analgesics. Ann Intern Med 1973; 78:173181 12. Angel1 M: The quality of mercy. N Engl J Med 1982; 306:98-99 13. Inturrisi CE: Narcotic drugs. Med Clin North Am 1982; 66:1061-1071 14. Kanner RM, Foley KM: Patterns of narcotic drug use in a cancer pain clinic. Ann N Y Acad Sci 1981; 362:161-172 15. Ferrer-Brechner T, Ganz P: Combination therapy with ibuprofen and methadone for chronic cancer pain. Am J Med 1984; 77:78-83 (Special Issue 1A) 16. Portenoy RK: Constipation in the cancer patient: Causes and management. Med Clin North Am 1987; 71:303-311 17. Levy MH: Pain management in advanced cancer. Semin Oncol 1985; 12:394-410 18. Bruera E, Rota E, Cedar0 L. et al: Action of oral methylprednisolone in terminal cancer patients: A prospective randomized double-blind study. Cancer Treat Rep 1985; 69:751754 19. Moertel CG, Schutt AJ, Reitemeier RJ, et al: Corticosteroid therapy of preterminal gastrointestinal cancer. Cancer 1974; 33:1607-1609
Pain Management in Advanced Carcinoma of the Head and Neck KERRY D. OLSEN, MD, AND EDWARD T. CREAGAN, MD
Although pain is one of the most feared consequences of cancer, pain management is rarely discussed in the literature on head and neck cancer. The pain experienced by patients with head and neck malignancies, of a biologic origin, is compounded by the emotional distress caused by alterations in function and cosmesis. Control of pain is possible, but an effective program must include more than pain medication. A current treatment program is presented, based on scientific study and clinical experience. The most helpful pain medication is immediate-release, liquid morphine sulfate (20 mg/mL) administered every 4 hours. A nonsteroidal anti-inflammatory drug may also be used and it may decrease the amount of morphine necessary. Stool softeners must be provided, and anti-nausea medication is often given. Steroid drugs are regularly used to increase appetite, decrease edema, and enhance the patient’s sense of well-being. Factors related to the selection and dosage of medications are discussed. AM J OTOLARYNGOL 12:154-160. Copyright 0 1991 by W.B. Saunders Company Key words: pain management, head and neck carcinoma
Pain, one of the most feared consequences of cancer, is subject to control, and patients with advanced head and neck cancer should be permitted to die free of its effects.’ The control of pain in the dying patient can also palliate other aspects of the disease and improve the quality of life of the patient’s remaining days.’ One patient who was dying of cancer stated, “I found that when I didn’t have pain, I could forget I had cancer.“3 In general, the treatment of patients with advanced head and neck cancer is not dissimilar to that of other cancer patients.l Successful pain management requires treatment of all aspects of pain: physical, psychological, social, and spiritual. Treatment should be matched to the patient’s specific needs. We present a clinical approach to pain management based on scientific study and daily clinical experience. Our approach attempts to assess the diverse factors producing pain and the sequelae of medical therapy. Physicians treating patients with head and neck cancer should be prepared to provide a comprehensive palliative program when conventional treatment modalities have failed.
BACKGROUND Pain management is rarely discussed in the literature on head and neck cancer. A review of the current cancer literature noted that less than 0.1% of all articles dealt with pain diagnosis and therapy.4 Less than 1% of the presentations at national oncology meetings included pain as a subject of consideration. The major oncology textbooks also devote little space to the management of cancer pain. A review of 10 important texts on the clinical management of cancer found that only 18 of 9,300 pages (0.2%) dealt with this subject. Residents in head and neck oncology receive little or no teaching about the proper management of the cancer patient with severe pain. PREVALENCE
OF CANCER
PAIN
Pain associated with direct tumor involvement has been found in 78% of patients with cancer in an inpatient population and in 62% of patients in an outpatient population.5 It has been estimated that, worldwide, 3 million people annually require treatment because of pain from cancer.6 In 72% of cancer patients were another study,’ judged to have died with pain. Physicians treating patients with head and neck tumors encounter pain frequently. If one excludes lip and larynx cancer, only 35% of head and neck malignancies are cured.’ Progressive disease and the multiple causes for pain account for the high prevalence of pain in patients with head and neck tumors. A study from the Memorial Sloan-
Received March 10, 1991, from the Department of Otorhinolaryngology and the Division of Medical Oncology, Mayo Clinic and Mayo Foundation, Rochester, MN. Accepted for publication April 6, 1991. Presented at the Annual Meeting of the American Academy of Otolaryngology-Head and Neck Surgery, San Diego, CA, September 8 through 13, 1990. Address correspondence and reprint requests to Kerry D. Olsen, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Copyright 0 1991 by W.B. Saunders Company 0196-0709/91/1203-0013$5.00/O 154
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OLSENANDCREAGAN Kettering Cancer Center found that pain was a significant factor in 80% of patients with cancer of the oral cavitye4 Pain severe enough to require opioids was experienced by more than two thirds of patients with advanced cancer of the head and neck.’ CAUSES
OF CANCER
PAIN
Pain is a complex state influenced by multiple factors. The patient’s sex, age, cultural and environmental influences, and multiple psychological factors must be considered.g The physical and emotional aspects of pain present a multifaceted problem. The physician must have a compassionate, totally encompassing approach to these patients because the pain components include emotional, social, financial, and spiritual considerations. Most patients with advanced head and neck cancers have more than one cause of pain. Cancer pain from direct tumor involvement is a common finding with head and neck squamous cell carcinoma because of its tendency for ulceration, deep infiltration, and early metastasis. Upper aerodigestive tract mucosal ulceration rapidly leads to infection, necrosis, edema, inflammation, and pain. Movement exacerbates pain and is especially severe in the oral cavity and pharynx. Vessel occlusion and lymphatic blockage can also cause edema, distension, and involvement of pain-sensitive structures in the soft tissues of the head and neck. Tumor invasion of bone is one of the most common causes of pain in the patient with head and neck cancer. The mandible, maxilla, and skull base are well-known problem areas for pain control. The early involvement of nerves, bacterial infection, and osteomyelitis are common sequelae. Bone involvement of the nasopharynx, sphenoid, jugular foramen, and clivus leads to syndromes of pain that are familiar to head and neck oncologists.* Invasion of bone is the most common cause of pain in all patients with cancer. The detection of bony involvement by bone scans or computed tomographic scans is possible 3 to 4 months earlier than by plain radiographic studies. Unfortunately, a negative bone scan does not rule out bony metastasis. The second most common source of pain is tumor compression or infiltration of nerve roots, trunks, or plexuses. Neurotropic invasion is a common finding with squamous cell carcinoma or adenoid cystic carcinoma. Involvement of mucosal and submucosal nerve endings can cause burning, uncomfortable dysesthesias, and referred pain such as otalgia. Neuralgic pain is a common source of discomfort in the patient with head and neck cancer. Pain from surgical therapy can occur from sen-
sory nerve disruption. Functional compromise from loss of portions of the jaw or tongue, for example, can exacerbate pain. The painful effects of radiation therapy-mucositis, radionecrosis of bone, tumor necrosis and infection, or subsequent fibrosis-are well known. In fact, 70% of the major problems with pain control in cancers of the head and neck occur because of neoplastic recurrence and radionecrosis.’ As pain becomes chronic, the associated symptoms of disturbed sleep, decreased appetite, impaired concentration, and irritability become more evident. This leads to physical deterioration and emotional and behavioral change. Patients become more anxious, depressed, and have less contact with friends. Some patients with severe and intractable pain become so discouraged and desperate that they may contemplate or commit suicide.4 TREATMENT
OVERVIEW
There are many ways to treat the pain of head and neck cancer. These include outpatient and inpatient drug therapy, neuroablation, nerve blocks, electrical stimulation, physical therapy, and psychological techniques. This review focuses on the most frequently used treatment modality: nonnarcotic, narcotic, and adjuvant drugs for outpatients. Effective use of these medications should produce relief of cancer pain in the majority of individuals. All physicians who care for patients with cancer should learn to administer and have confidence in an effective drug therapy program. Treatment should begin with an appropriate and specific drug applied at the lowest dose that produces analgesia. It is important to know the pharmacology of the prescribed drug, including the duration of effect and the pharmacokinetic properties of the drug’s action. The dose must be titrated to obtain a favorable result and the route of administration must be adjusted to the patient’s needs. Medication should be administered on a regular basis. The use of a combination of drugs is often efficacious for severe pain. The physician must anticipate and treat any side effects of the prescribed medication. The key to effective pain management is the constant reassessment and appropriate modification of treatment. Problems in Achieving Effective Treatment. Three common errors decrease the effectiveness of pain treatment: inadequate amounts of medication, providing the medication on an “as needed” basis, and lack of attention to the side effects of therapy. The improper application of existing knowledge on available therapeutic modalities has been cited as the most important reason for
156
inadequate pain control in the cancer patient4 Systemic analgesics should relieve the pain of cancer in most patients if the appropriate drugs are chosen and if the right dose and schedule are used. Underutilization of drugs for severe pain is, unfortunately, too frequent. This may be due to several factors, including poorly understood pharmacology and concern about possible abuse and side effects. Another problem that often occurs has been called “stacking.” A physician may not notice adequate pain relief with one narcotic drug and so will add another narcotic drug instead of increasing the dose of the first. It is much better to prescribe one drug in an adequate d0se.l’ No patient should ever suffer because of the physician’s reluctance to use an adequate level of medication.” Narcotic drugs should be administered on a regular basis, and the interval between doses should be based on the expected duration of the analgesic effect. Narcotics should not be given on a pro re nata basis. This places the burden on the patient to request the drug and does not base the decision on the known pharmacologic action of the drug.l’ The objective is to maintain a constant plasma level of the drug that is above the minimum effective concentration for pain relief. The time required to reach such a steady state depends on the half-life of the medication. Medication should be given around the clock. This includes awakening the patient from sleep, a mild inconvenience in view of the benefits of such a regimen.
Treatment of Mild Pain. For the patient with mild pain, aspirin, acetaminophen, or nonsteroida1 anti-inflammatory drugs (NSAIDs) are generally recommended. Aspirin or acetylsalicylic acid has been available as an analgesic since 1893. The appropriate dosage is 650 mg every 4 hours. The average duration of effect is 3 to 6 hours.’ The liquid form of acetylsalicylic acid trisalicylate (500 mg/5 mL) is especially useful for patients who have head and neck cancer. The side effects of aspirin can include gastritis and an increased risk of bleeding due to the inhibition of platelet aggregation. Aspirin’s adverse effects on the mucosa of the stomach can be avoided by using a buffered form such as Ascriptin (Rorer, Fort Washington, PA) or an enteric-coated formula. Acetaminophen can be given in dosages of up to 4 g/d with no appreciable side effects. Greater dosages may be nephrotoxic or hepatotoxic. Acetaminophen has the benefit of minimal gastric irritation and no bleeding problems. The dosage is 650 mg every 4 hours. A liquid form (160 mg/5 mL) is also available. Numerous analgesic preparations are available that combine aspirin, acetaminophen, phenace-
PAIN MANAGEMENT
IN ADVANCED
CARCINOMA
tin, caffeine, or other medications. However, there is no good evidence that these combination drugs are more effective than aspirin or acetaminophen alone. One study also showed that propoxyphene hydrochloride (Darvon; Eli Lilly, Indianapolis, IN) or propoxyphene napsylate (Darvon-N; Eli Lilly] has the same analgesic activity as aspirin alone. The NSAIDs most often used to manage head and neck pain in cancer patients are available in liquid form: ibuprofen (Motrin; Upjohn, Kalamazoo, MI], naproxen (Naprosyn; Syntex, Palo Alto, CA), and indomethacin (Indocin; Merck Sharp & Dohme, West Point, PA). These NSAIDs have been shown to be effective analgesics or coanalgesics when there is evidence of bone involvement by cancer. Ibuprofen is the least expensive of the three and may cause less mucosal injury to the gastrointestinal tract than other similar drugs. It is available in a concentration of 100 mg/5 mL and is given in a dosage of 400 mg every 4 to 6 hours. Naproxen is available in a concentration of 125 mg/5 mL and has the advantage that it can be given twice daily in a dosage of 375 to 500 mg. Indomethacin (25 mg/5 mL) is given in a dosage of 25 to 50 mg every 6 to 8 hours. This medication is especially helpful if the patient has constitutional symptoms such as chills, fever, or sweating. Any NSAID must be used cautiously in elderly patients and in patients with renal insufficiency, heart failure, hypertension, or a history of bleeding or peptic ulcer disease. The maximum dose for most of the drugs in this group should not exceed 1.5 to two times the usual recommended starting dose for each of these drugs.’ The minimum period necessary to determine their efficacy is generally 2 to 3 weeks. If there is no benefit, it is reasonable to change drugs because patients may respond poorly to one medication and well to another. This is because of the different chemical classes of nonsteroidal medications.
Treatment of Moderate Pain. Codeine is commonly the first narcotic drug given to patients who do not obtain effective relief from a nonnarcotic agent. Codeine itself is a weak analgesic. Thirty milligrams of codeine is equal in effectiveness to 650 mg of aspirin. One can increase the dose of codeine; however, there will be an increase in side effects, such as nausea, vomiting, constipation, and sedation. The addition of aspirin or acetaminophen to codeine is an effective formula for increased pain relief. An elixir combination of codeine-12 mg plus acetaminophen (120 mg/5 ml)-can be given in 15mL aliquots, which is equivalent to a Tylenol No. 3 tablet (McNeil, Spring House, PA). In general, for the relief of moderate pain, codeine combined with aspirin or acetaminophen is
157
OLSEN AND CREAGAN
preferred. Its availability as a liquid is extremely helpful for patients who have head and neck cancer.
Treatment of Severe Pain. Patients with severe pain should be treated with an opiate drug. The opiates are classified as agonists, mixed agonists-antagonists, and antagonists. The most commonly used agonist is morphine. It is important to know a drug’s efficacy, which is the capacity of the drug to produce a given effect, and its potency, which is the amount of drug necessary to produce a given effect3 Potency comparisons among the opioid analgesics are important if switching from one opioid drug to another becomes necessary. In general, agonist drugs such as morphine act by binding to opioid receptors in the central nervous system, resulting in analgesia. Morphine. Morphine remains the prototypic opioid agonist analgesic. It is the standard to which all other narcotics should be compared. It is the drug of choice from the opioid class for the treatment of severe pain from head and neck cancer. The reaction of patients to the idea of morphine therapy often includes such thoughts as, “My doctor is giving up on me,” “I must be terminal,” “ I want to save it until I really need it,” “I’ll become an addict,” or “It won’t work when I really need it.” It is important for the physician to allay these concerns. Morphine has desirable properties in addition to its analgesic effect. It can relieve anxiety, create some euphoria, and provide some sedation. Its undesirable effects can include sedation, mental clouding, dizziness, nausea and vomiting, supTABLE 1.
pression of the cough reflex, physical dependence, spasmogenic constipation, and possible tolerance.13 Morphine can be given intramuscularly, orally, or rectally. It is important to withdraw the drug slowly because rapid termination of morphine therapy can lead to agitation, tremors, insomnia, fever, or marked autonomic system hyperexcitability 6 to 12 hours after its cessation.’ In 1976, Mount’ reported the successful use of liquid morphine in controlling pain when it was given in a 10% alcohol solution. The oral route avoids the discomfort and complications of repeated injections. It is more convenient and is essential for patients with head and neck cancer. The intramuscular to oral relative potency ratio with morphine is stated to be 1:6 after a single dose. However, with chronic use, the intramuscular to oral ratio becomes 1:2 to 1:3. Therefore, 10 mg of morphine given intramuscularly is equivalent to 20 to 30 mg given orally. The traditional concentration of liquid morphine (10 mg/5 mL) has now been replaced by the highly concentrated 20 mg/mL of morphine sulfate (Roxanol; Roxane, Columbus, OH) (Table 1). This is now readily obtainable, easily titrated, and comes in a convenient calibrated eyedropper dispenser. It has a bland but acceptable taste. It is available in 8- or 16-ounce bottles at this concentration. A reasonable starting dose of liquid morphine is 5 to 10 mg every 4 hours around the clock, not as needed. Because morphine has a short half-life (2 to 3 hours], it must be administered every 4 hours. If, instead, morphine is given every 6 hours, between the fourth and sixth hours there will be a low therapeutic level. Morphine applied every 4 hours maintains a steady plasma concentration
Analgesics for Head and Neck Cancer Pain ORAL FORM
ADULT DOSAGE
DRUG ASA
650 mg every
4 hr
Acetaminophen
650 mg every
4 hr
Ibuprofen Naproxen
400 mg every 4-6 hr 375-500 mg every 12 hr
Indomethacin
25-50
Codeine
30-60 mg every
mg every
Codeine plus acetaminophen
Codeine
plus
Morphine ASA. acetylsalicylic
4 hr
325 500 325 500 200 250 375 500 25 50 30 50 No. 3: 30 mg codeine, 300 mg acetaminophen No. 4: 300 No. 3: 325 No. 4: 325
ASA
Abbreviation:
6-8 hr
Pill (mg)
acid.
60 mg 30 mg 60 mg
mg codeine, acetaminophen mg codeine, ASA mg codeine, ASA 15
Liquid
(mg/5 mL) 500 160 100 125
25
12 mg codeine plus 120 mg acetaminophen/5 -
20 mg/mL
mL
158
and precludes pain. Most patients achieve control of their pain at dosages of up to 30 mg on this schedule. However, there is no upper dose limit. Morphine remains the single most effective orally administered analgesic for patients with severe pain when given at adequate levels and on a regular around-the-clock basis. For individuals unable to take liquid morphine, suppositories are an appropriate alternative. Morphine is available in 5-, lo-, ZO-, and 30-mg rectal suppositories. It should be given at the same dosage and on the same fixed schedule as oral preparations of morphine. Sustained-relief morphine products such as MS Contin or Roxanol SR can be given every 8 to 12 hours. Less frequent applications may result in greater patient acceptance. It is first necessary to titrate the dose of one of the usual short-acting morphine agents. Once a stable state is reached, one can switch to sustained-release products divided into two equal doses every 12 hours. Longacting morphine therapy works if the patient is receiving a consistently stable dose of regular morphine. However, head and neck cancer patients usually have increasing analgesic requirements because of tumor progression, and breakthrough pain is common when long-acting morphine drugs are used. MS Contin is only available in certain strengths: 15, 30, 60, and 100 mg.
Concerns When Opiate Drugs Are Used. Tolerance and addiction do not present real clinical problems in patients with advanced cancers of the head and neck. For a terminally ill patient, consideration of a drug’s addictive potential is irrelevant and remains an impediment to the delivery of optimal pain relief. There is no evidence that the chronic use of narcotic drugs for analgesia is associated with a high risk of addiction.14 The rate of addiction among patients who receive narcotic therapy for pain is no more than 0.1%.12 Patients may become dependent on a drug without becoming addicted to it. The question of tolerance is another source of misunderstanding that may prevent physicians from prescribing adequate amounts of narcotic medication. Tolerance is a state in which increasing dosages of a drug are needed to maintain an equal analgesic effect.* However, in patients with head and neck cancer, increased opioid requirements probably do not indicate the development of pharmacologic tolerance; most likely they have progressive disease and therefore an increased need for pain relief. The dosages of morphine necessary for pain relief in terminal cancer patients can be enormous; levels as high as 500 mg of morphine per hour may be given by continuous infusion to some patients with severe discomfort. Phy-
PAIN MANAGEMENT
IN ADVANCED CARCINOMA
sicians’ concerns that patients receiving narcotic drugs will become addicted and that the dose required will increase because of tolerance are unsupported.
Addition of an Anti-inflammatory Drug to Opioid Therapy. Because NSAIDs work in the peripheral and narcotics work in the central nervous system, their combined use can be efficacious. Aspirin or acetaminophen (650 mg every 4 hours) combined with a narcotic drug increases the analgesic effect and effectively decreases the total dose of narcotic drug required. This additive effect has been described for codeine and is also well known with morphine. The dosage of morphine often can be decreased by half. A randomized, double-blind, cross-over study in which ibuprofen and morphine were used demonstrated a significant increase in analgesia without a concomitant increase in side effects.15 Aspirin, acetaminophen, ibuprofen, naproxen, or indomethatin can improve pain relief in combination with morphine. One of these drugs should be used routinely for all patients who receive morphine if there are no medical contraindications due to side effects of the non-opioid drug.
Constipation. Constipation is a common and distressing symptom in patients with cancer. It is important to encourage patients who are receiving narcotic drugs to be active, maintain a high fluid intake, and add fiber to their diet.*‘j In the absence of a diet high in fiber, a bulk laxative containing bran or methylcellulose can be provided. Contact cathartics are also helpful. These increase mucosal secretion and provide an increase in the motility of the intestinal tract. Numerous medications are available including bisacodyl (Dulcolax; Boehringer Ingelheim, Ridgefield, CA) and milk of magnesia. We prescribe dioctyl sulfosuccinate (Peri-Colace; Mead Johnson, Levansville, IN), taken two or three times per day. Other cathartics that can be added include senna compounds that affect mucosal electrolyte transport and motility. Senna concentrate (Senokot, two to three tablets at bedtime; Purdue Frederick, Norwalk, CT) is also helpful. The constipation caused by opioid drugs is much easier to prevent than it is to treat. Nausea and Antiemetics. The incidence of nausea with narcotic therapy is greatest during the first week of therapy. Morphine is a more common cause of nausea in ambulatory patients. Nausea occurs from the interaction of the narcotic analgesic with brain stem centers mediating the sensation of nausea and the function of emesis. Nausea will develop in 40% of patients receiving narcotic therapy. ‘*17 Fortunately, this resolves af-
OLSEN
159
ANDCREAGAN
ter several days and is not a problem after prolonged use. In the first few days, drugs such as prochlorperazine (Compazine, 5 to 10 mg every 4 to 6 hours: Smith Kline & French, Philadelphia, PA] or haloperidol (Haldol, 0.5 mg every 8 hours; McNeil) are helpful. If nausea is not a problem, the drug dose can be tapered quickly or, if nausea continues, the drugs can be continued for several weeks. If early satiety or epigastric fullness is a problem, metoclopramide (Reglan; Robins, Richmond, VA) can enhance gastric emptying. hproved We//-Being. Adrenal corticosteroid treatment can be extremely helpful in the treatment of terminal cancer patients. Steroid agents can cause euphoria, stimulate appetite, and create a sense of well-being. A short course of steroid therapy should be given to patients with advanced cancer when there are no major contraindications to its use. In one double-blind study,*’ 32 mg of methylprednisolone was administered to patients with advanced cancer. Patients receiving steroid therapy reported less pain, less depression, and improved appetite. There was general improvement in their overall well-being.18 Moertel et all9 reported the use of dexamethasone in 116 patients with gastrointestinal cancer. Steroid therapy caused improved strength and appetite after 2 weeks, but not after 4 weeks.l’ The exact dose of steroids remains an empiric question, as is the duration of the effect. Therefore, after several weeks, one attempts to taper the
steroid dose to zero or to a low maintenance level. The use of steroids on a twice daily basis gives patients a “lift” in the PM, when they most often seem to need it. Prednisone can be given at a starting dose of 20 to 30 mg twice daily; the dose then can be reduced slowly. Another treatment approach is to give dexamethasone (8 mg three times a day) for several days and, if benefit is noted, reduce the dose to 4 mg twice daily.17 The long-term use of steroid drugs is associated with weakness, delirium, osteoporosis, immunosuppression, diabetic potential, peptic ulcers, and sodium retention. Most studies, however, report no toxicity when these drugs are used as we have described. Patients with cancer who received prednisone for 2 to 16 weeks had an increased (3%) but low risk of peptic u1cer.l The use of adrenal corticosteroids remains a helpful adjunct in the management of patients dying of cancer. Their use may permit a decrease in narcotic requirements, and the associated euphoria, improved appetite, and weight gain can enhance the quality of life. The benefits of steroid therapy in patients with advanced cancer most certainly outweigh the slight risk of complications. Drowsiness and Sedation. Drowsiness has been reported in 26% of patients treated with narcotic drugs6 Sedation is a more common effect of drugs with a long plasma half-life, such as levorphanol or methadone. Amphetamines can be used with narcotics, if necessary, to counteract the sedative effects.
TABLE 2. Adjunct Medications for Head and Neck Cancer
Pain ORALFORM
DRUG
ADULT DOSAGE
Dexamethasone
Prednisone
Peri-Colace Senokot Prochlorperazine (Compazine) Haloperidol (Haldol) Metoclopramide (Reglan) Chlorpromazine (Thorazine) Imipramine (Tofranil) Amitriptyline (Elavil)
2-3 times a day 1-2 at bedtime 5-10 mg every 4-6 hr 0.5 mg every
8 hr
IO-15 mg 4 times
a day
25-50 mg 4 times
a day
75-100
mg at bedtime
75-150
mg at bedtime
Pill (mg) 0.25 0.5 0.75 1.5 4 1 2.5 5 10 20 Capsule Tablet 5 10 0.5 1.0 2.0 5 10 10 25 50 25 50 25 50
Liquid
(mgi5 mL)
0.5
5
Syrup, Syrup,
15-30 mL lo-15 mL 5
2 mg/mL
5 30 mg/mL
PAIN MANAGEMENT
Respiratory depression in a patient with severe pain is unlikely as long as the pain is unrelieved. Pain remains a natural antagonist to the action of opiates; the stronger the pain, the more opiate is required. Patients who develop tolerance to the analgesic effect of a narcotic will also acquire tolerance to its respiratory depressive effect. Respiratory depression is a rare phenomenon in patients tolerant to narcotics. The physician should give whatever dose is required to relieve pain without fear of the patient suffering respiratory depression.”
Antipsychotics and Antidepressants. Antipsychotic drugs (neuroleptics) can also act as analgesics, either alone or in combination with narcotic drugs. Haloperidol (Haldol; McNeil), 1 to 2 mg at bedtime, or chlorpromazine hydrochloride (Thorazine; Smith Kline & French), 25 to 50 mg four times a day, also calms the agitated patient and provides some antiemetic action. Narcotic drugs have also been used with the tricyclic antidepressants. Imipramine (Tofranil; Geigy, Ardsley, NJ), 75 to 150 mg at bedtime, or amitriptyline (Elavil; Merck Sharp & Dohme), 75 to 150 mg at bedtime, is also helpful if insomnia is a problem or if the patient is depressed. The analgesic effect of tricyclic antidepressants can be helpful; however, their sedative and anticholinergic side effects are additive. It is useful first to titrate the dose of the opioid drug and then to add other medications as an adjunct if necessary. Start the patient on a low dose of 10 to 25 mg of amitriptyline at bedtime and gradually titrate this to a single dose of 50 to 15~1 mg at bedtime. All physicians should be well aware of the indications, contraindications, action, dosage, and side effects of any medication they prescribe. Patients who appear unresponsive to narcotics may have significant psychosocial problems, including personal, financial, professional, sexual, or other matters. The sensitive investigation and
IN ADVANCED
CARCINOMA
recognition of these problems can lead to compassionate treatment with medication and/or counseling (Table 2). References 1. Foley KM: The treatment of cancer pain. N Engl J Med 1985; 313:84-95 2. Moertel CG: Treatment of cancer pain with orally administered medications. JAMA 1980; 244:2448-2450 3. McGivney WT, Crooks GM: The care of patients with severe chronic pain in terminal illness. JAMA 1984: 251:11821188 4. Bonica JJ: Management of cancer pain. Recent Results Cancer Res 1984; 89:13-27 5. Foley KM: Current issues in the management of cancer pain: Memorial Sloan-Kettering Cancer Center. NIDA Res Monogr 1980; 36:169-181 6. Ventafridda V, Tamburini M, Caraceni A, et al: A validation study of the WHO method for cancer pain relief. Cancer 1987; 59:850-856 7. Daut RL, Cleeland CS: The prevalence and severity of pain in cancer. Cancer 1982; 50:1913-1918 8. Raj PP, Phero JC: Pain control in cancer of the head and neck, in Thawley SE, Panje WR (eds): Comprehensive Management of Head and Neck Tumors, vol 1. Philadelphia, PA, Saunders, 1987, pp 42-68 9. Foley KM: Clinical assessment of cancer pain. Acta Anesthesiol Stand Suppl 1982; 74:91-96 10. Hill CS. Ir: Narcotics and cancer nain control. CA 1988; 38:322-326 ' 11. Marks RM, Sachar EJ: Undertreatment of medical inpatients with narcotic analgesics. Ann Intern Med 1973; 78:173181 12. Angel1 M: The quality of mercy. N Engl J Med 1982; 306:98-99 13. Inturrisi CE: Narcotic drugs. Med Clin North Am 1982; 66:1061-1071 14. Kanner RM, Foley KM: Patterns of narcotic drug use in a cancer pain clinic. Ann N Y Acad Sci 1981; 362:161-172 15. Ferrer-Brechner T, Ganz P: Combination therapy with ibuprofen and methadone for chronic cancer pain. Am J Med 1984; 77:78-83 (Special Issue 1A) 16. Portenoy RK: Constipation in the cancer patient: Causes and management. Med Clin North Am 1987; 71:303-311 17. Levy MH: Pain management in advanced cancer. Semin Oncol 1985; 12:394-410 18. Bruera E, Rota E, Cedar0 L. et al: Action of oral methylprednisolone in terminal cancer patients: A prospective randomized double-blind study. Cancer Treat Rep 1985; 69:751754 19. Moertel CG, Schutt AJ, Reitemeier RJ, et al: Corticosteroid therapy of preterminal gastrointestinal cancer. Cancer 1974; 33:1607-1609
