Cancer Pain Management

PROLOGUE This article summarizes the discussion series relating to cancer pain management required of Doctor of Pharmacy students enrolled in the Pharmacotherapy I course at the Washington State University College of Pharmacy. A total of three hours are devoted to this subject in the course composed of 26 hours of discussion topics. The course utilizes a problem-based-learning format to obtain requisite background information. Homework and world wide web exercises, consisting of case studies, enhance facility with course content, and prepares students for classroom discussion and experiential training.


INTRODUCTION
"We must all die...but if I can save him from days of torture, that is what I feel as my great and even new privilege.Pain is a more terrible lord of mankind than even death himself." Albert Schweitzer The act of relieving pain is as old as the medical profession itself.Pain presents in 65 to 85 percent of oncology cases, and is the most common symptom experienced by patients in the terminal stages (1)(2)(3)(4)(5).Cancer pain may be acute, chronic, or intermittent, and often has a definable origin, usually related to tumor recurrence and treatment.Moreover, pain left unrelieved is a significant etiologic component of the commonly experienced symptoms of anorexia, weight loss, weakness, nausea, vomiting, and insomnia (1).Narcotic analgesic medications employed to treat cancer pain may also contribute to nausea, vomiting, and anorexia symptoms, and may be the most significant cause of constipation (3)(4)(5).Narcotics may simultaneously be the most effective means of controlling intractable coughing or intolerable dyspnea symptoms also experienced by cancer patients (3)(4)(5). 1Associate Professor of Pharmacy Practice The goal of therapy is to provide patients with enough pain relief to tolerate diagnostic and therapeutic manipulations and allow them freedom of movement and choice, while limiting medication-induced adverse effects (6).Unfortunately, 25 percent of cancer patients die without significant relief of severe pain (7 ,8).Poor pain assessment was rated by physicians as the single most important barrier to adequate pain control (7).Moreover, the health care provider's reluctance to prescribe opiates at appropriate doses, failure of patients to report pain or routinely take pain medications, and inadequate nursing staff knowledge contributed to poor pain control (7).Therefore, continual reassessment of the degree of pain and individualization of therapy is required (6,7).

PAIN ASSESSMENT
Successful pain control requires a precise and complete pain evaluation.Most patients suffering from advanced cancer have more than one pain (6).Therefore, a complete medical history must be obtained and a comprehensive physical examination must be performed to thoroughly evaluate for signs of underlying disease and possible contributing factors to each patient's pain (9,10).The history should include the pain location, duration, pattern, course, quality, severity, palliative measure, provocative factors, and other symptoms.Table I outlines some specific patient questions utilized to assess the PQRST (palliative or provocative, quality, radiation, severity, and temporal) characteristics of pain (11).Demographic data, medication history (including prescription and over-the-counter medications), adverse drug reaction profile, and medication allergies should be recorded.Moreover, a psychosocial history is important in determining the degree to which the pain has interfered with routine daily activities.Consideration should be given to mental factors that alter the pain threshold.Anxiety, depression, fatigue, fear, and anger are known to lower this threshold, whereas, mood elevation, rest, sympathy, diversion, and understanding can raise the pain threshold (10,11).
Pain is always a subjective finding.Objective symptoms such as grimacing, limping, and tachycardia may be useful, but are often absent in patients with chronic pain known to be caused by structural lesions.There are no neurophysiological or laboratory tests that can measure a patient's pain.Therefore, the clinician must rely upon the patient's assessment of their pain in the absence of strong contrary evidence.The best research instruments available for assessment of pain are the Visual Analogue Scale (VAS) and the McGill-Metzack Pain Questionnaire (10)(11)(12)(13)(14).The VAS is more amenable to clinical practice and consists of a 10 centimeter line that has no pain at all on one end and the worst pain imaginable on the other end.Even the most debilitated patient can indicate where on this line the pain is located.A 0 to 5 scale (0 = no pain; 5 = worst pain) may be used for patients who are unable to use, or do not require, a visual representation of their pain level.Alternatively, colors, with or without verbal descriptors may be used in lieu of the numbers 0 to 5. (Table II) Any of the above mentioned scales can provide sufficient data for dosage adjustments of the analgesic regimen.

GOALS OF THERAPY
The goal of therapy is to reduce or remove the sensation and thought of pain.This is achieved by scheduled around-theclock (ATC) medication scheduling, limiting adverse effects, and permitting a level of daily function that will allow each patient freedom of movement and choice (6,10).Unfortunately, this goal may not be achieved because of poor pain assessment, inadequate dose titration, fear of analgesic side effects and addiction, interpatient variability in analgesic doses needed, and improper scheduling of analgesic doses (7,10).ATC scheduling with a sustained-release (SR) analgesic as opposed to an as needed (PRN) schedule is the best approach in minimizing fluctuations in pain control.ATC administration will reduce the number of pain episodes experienced by patients when analgesic concentrations fall below the therapeutic range (9).PRN schedules with immediate release (IR) preparations can be employed as an adjunct to ATC regimens for relief of breakthrough pain during ATC medication titration (6,(8)(9)(10).

NONPHARMACOLOGIC INTERVENTIONS
Psychologic techniques such as relaxation training, controlled mental imagery, reinforcement of appropriate actions, controlled attention or distraction, and biofeedback are very helpful in relieving pain experienced in malignant disease (15,16).Physical modalities such as cutaneous stimulation, exercise, repositioning, immobilization, and counterstimulation may prove useful in patients with generalized weakness, deconditioning, and cancer pain (15).Treatment modalities such as these have proven especially useful in conjunction with pharmacologic therapy (16).Supportive care, in and outside of the hospital, utilizing programs such as hospice, is one of the most important factors in assisting cancer patients to accept their illness and cope with their pain (15,17).The use of such programs should be part of routine care for all cancer patients.

DRUG THERAPY Aspirin and Acetaminophen
Aspirin and acetaminophen are useful first line agents for mild pain (16,(18)(19)(20).The recommended doses for aspirin and acetaminophen in chronic cancer pain patients are 650mg four to five times a day and 650mg every four to six hours (not to exceed four to six grams of acetaminophen per day), respectively (10,(21)(22)(23).The risk of acetaminophen toxicity is higher in patients with compromised liver function (21,22).Therefore, acetaminophen should be used with caution or avoided in patient with hepatic insufficiency (21,22).Aspirin is contraindicated in patients with documented salicylate hypersensitivity or bleeding disorders, and should be used with caution in those with a history of gastritis, nasal polyps, chronic rhinitis, coagulation abnormalities, low platelet count, or peptic ulcer disease.Aspirin should be avoided in patients with asthma or chronic urticaria (17,24).Major adverse effects of aspirin therapy include gastrointestinal irritation and/or bleeding, gastric ulcers, tinnitus, and hypersensitivity reactions (10,23,24).Adverse effects to acetaminophen are extremely rare, making acetaminophen an excellent analgesic for mild pain in patients with asthma, peptic ulcer disease, gastrointestinal bleeding, and aspirin hypersensitivity patients (23,24).

Nonsteroidal Anti-Inflammatories
Mild to moderate or discomforting pain can be effective treated with a nonsteroidal antiinflammatory agent (NSAIA) (18,19).NSAIAs have also proven efficacious as adjuvant therapy in patients suffering from bone metastasis pain (10,(18)(19)(20)25).Moreover, NSAIAs, in addition to narcotic analgesics, should be routinely administered to patients experiencing distressing to excruciating pain (pain score of 4 to 5 on a 0 to 5 scale), unless or until NSAIA therapy becomes contraindicated.The selection of a NSAIA is largely empirical, and there is no way to predict which agent will be the most effective in a given patient (9,10,20,23).Therefore, if one NSAIA does not prove useful, then another agent (usually from a different chemical class) should be tried.Several agents may need to be investigated to identify the most efficacious agent for each individual patient.It is recommended to begin with a low dose and increase cautiously at two-week intervals.Ketorolac is the only injectable NSAIA available in the United States.Be- cause of the ketorolac's potential to cause gastrointestinal (GI) bleeding and renal failure, a major retrospective analysis was undertaken in 1994 (26).The authors recommended a maximum ketorolac dose, for patients 65 or older and those with body weights less than 50kg, of 15mg by injection every 6 hours be used (26).The duration of ketorolac therapy (oral or injectable) should not exceed five days (26).
Adverse effects associate with NSAIAs include, GI bleeding and/or ulceration, tinnitus, skin rash, dizziness, blurred vision, renal damage, and cross allergenicity (especially with the propionic acid derivatives) (21,24,27).NSAIAs are contraindicated in patients with active peptic ulcer disease, and should be used cautiously in patients with previous history of NSAIA-induced gastritis.NSAIA-induced side effects including GI ulceration, impaired renal function, hypersensitivity, and prolonged bleeding time are of increased concern in the elderly.GI side effects can be minimized by avoiding long-term therapy or the addition of misoprostil in patients requiring extended therapy or are at increased risk of toxicity (i.e., elderly, history of GI ulceration, or cigarette smoking) (10,20).

Narcotic Analgesics
Narcotic analgesics are recommended for patients suffering from moderate to excruciating pain (pain score of 3 to 5 on a scale of 0 to 5).Table III outlines the most commonly used narcotic analgesics and their relative equianalgesic doses (6,10,18,28,29).

Codeine and Hydrocodeinone
The addition of codeine to either aspirin or acetaminophen may effectively control mild to discomforting pain (pain score of 1 or 2 on a scale of 0 to 5) (6,30).Distressing pain (pain score of 3 on a scale of 0 to 5) often requires a more potent narcotic such as hydrocodone in combination with aspirin or acetaminophen.Care must be taken not to exceed four to six grams of acetaminophen per day.How- ever, the potential for aspirin or acetaminophen toxicity and the dose-related side effects of these agents limit their use to patients with pain scores of 1 to 3 only( 6).New products containing hydrocodone 10mg plus acetaminophen 650mg, and hydrocodone 7.5mg plus ibuprofen 200mg are now available for pain management.

Morphine
The majority of patients with advanced cancer have pain described as intense or excruciating (rated as 4 or 5 on a scale of 0 to 5), and will require more potent narcotics, best administered in pure form.This avoids limitations in narcotic dosing because of dose-related toxicity from a combination component (i.e., aspirin, acetaminophen, ibuprofen).Morphine, oxycodone, hydromorphone, methadone, and transdermal fentanyl are commonly prescribed for patients with moderate to severe cancer pain (6).
Morphine is both safe and effective when administered by the oral, subcutaneous, rectal, continual intravenous infusion, patient-controlled intermittent intravenous or subcutaneous, epidural, or intrathecal route (28,(31)(32)(33)(34)(35)(36).The oral route of administration is preferred, provides relatively predictable serum levels, and has a longer duration of action than intravenous therapy (33).Oral morphine SR products are especially useful for their convenient ATC dosing (usually given every 8 to 12 hours), consistent analgesia, and often times fewer adverse reactions (e.g., nausea, vomiting) relative to oral morphine IR and other analgesic products (37).It is recommended that patients taking morphine SR orally for cancer pain also have a supply of morphine IR available in the event of breakthrough pain (6,33).Morphine SR doses can be further titrated based on the amount of morphine IR utilized for periods of breakthrough pain (Table IV).
As stated previously, there is a high degree of interpatient variability in each patient's response to narcotics (7,10).Some patients will require small doses to effectively control their pain, while others may need significantly larger doses to produce the desired effect.Low doses (ie.10mg tablets or solution) of morphine IR for narcotic naive patients should be used initially, followed by upward titra-tion until adequate analgesia is experienced.There is no maximum dose of morphine for patients with severe pain.
Patients unresponsive to oral morphine (e.g., malabsorption syndromes) can often be effectively managed with continuous subcutaneous morphine administration via portable ambulatory infusion devices, thereby obviating the need for frequent painful intramuscular injections or a long term intravenous access site (32,34).Morphine can also be administered rectally using the suppository formulation (available in 5, 10, 20, and 30mg doses) (35,38).Systemic absorption via the rectal route is similar to the oral route of morphine administration (39).No more than two suppositories should be administered rectally at one time.Therefore, the usefulness of commercially available suppositories are limited to those patients requiring doses of 60mg or less administered every three to four hours.Finally, morphine can be administered via the epidural or intrathecal route (36).However, more controlled clinical studies are required to document the optimal dose and the advantages in selecting these routes of administration for chronic cancer pain management over the other routes already discussed.

Oxycodone
Oxycodone in combination with acetaminophen is often prescribed for distressing to intense pain (pain score of 3 on a scale of 0 to 5)(6).Oxycodone's short half-life requiring doses every three to four hours in most patients, and potential for acetaminophen toxicity has limited the use of the combination product to patients with pain scores of up to 3 only(6).However, a sustained release formulation of oxycodone dosed every 12 hours is now available.Oxycodone SR is a useful alternative to morphine SR (6).

Hydromorphone
Hydromorphone is a potent, safe, and effective narcotic agent that is essentially interchangeable with morphine in its efficacy for patients with advanced cancer (6,20).Hydromorphone is four times as potent as morphine, allowing for smaller injection or infusion volumes for patients requiring parenteral administration (6,20).Hydromorphone is also available as a 3 mg suppository.Again, as with the morphine suppositories, only two of these 3 mg dosage units can be administered rectally at one time, thereby limiting pain control via this route to a maximum dose of 6 mg or less given every four to six hours.Currently, there are no advantages of selecting oral hydromorphone over oral morphine.Morphine SR preparations scheduled every 8 to 12 hours are preferable to hydromorphone IR administered every three to four hours.However, a hydromorphone SR formulation has been developed and should be available in the United States in the near future (40).

Levorphanol and Methadone
Levorphanol and methadone have longer half-lives and can be administered every six to eight hours (8)(9)(10).Levorphanol is available in a 2mg oral tablet or 2mg/ml injectable.However, individualization of levorphanol therapy may be difficult due to its potency and limited available dosage formulations.Levorphanol's extended halflife and high lipid solubility can result in medication accumulation and excessive sedation, which is especially evident in elderly patients (8)(9)(10).Because of its long half-life, methadone carries risks of accumulation and excessive sedation similar to those of levorphanol.Methadone should be sched- uled every six to eight hours for effective analgesia (41)(42)(43).However, due to the propensity for patients or clinicians to administer methadone more frequently than its half-life would safely allow (i.e., every four hours), it is not uncommon to see methadone patients over-sedated with their pain unrelieved (10,41,42).Methadone's greatest advantages are that it is noncross-reactive with morphine for patients with a true morphine allergy, and that if administered properly, it can be a safe and effective narcotic analgesic (41).However, given the risk of accumulation (especially in the elderly) levorphanol and methadone are usually not recommended for initial therapy (6,41).Methadone and levorphanol are best administered by health care providers with extensive practical experience with these agents.

Meperidine
Meperidine is usually not recommended for long-term use because of its relatively short half-life and central nervous system hyperirritability as a result of the accumulation of its pharmacologically active major metabolite, normeperidine (10,18,19,44).Moreover, meperidine has very low potency when administered via the oral route, and its short, one to two hour duration of effect does not provide convenient ATC dosing.

Fentanyl
Fentanyl is available in a sustained-release transdermal therapeutic system (TTS) formulation (in 25, 75, and 100 mcg/hr) which is administered every three days.When applied to an area of intact skin, the TTS delivers the fentanyl at a controlled rate over the 72 hours (45,46).Therefore, the fentanyl TTS may provide a convenient dosing alternative for patients unable to take oral analgesic medications because of intolerance or poor compliance.
Most of the clinical trials with fentanyl TTS in the management of chronic pain involve patients who have previously received other narcotics and in whom some degree of tolerance was likely.A conversion method utilized to switch patients to from oral morphine to transdermal fentanyl is outlined in Table V (45).
There is significant interpatient variation in skin penetration or bioavailability with fentanyl TTS (28,45).Nearly 50 percent of these patients will require an increased dose after initiation of fentanyl TTS (45,46).Moreover, patients initially started on fentanyl TTS will not attain full analgesic effects for several days (28,45,46).Therefore, these patients should also have short-acting narcotic medications available to cover periods of breakthrough pain.Dosage titration to optimize fentanyl TTS therapy should not occur more frequently than every four to six days (45,46).Patients with poor adhesion to the skin (especially those who are cachectic or emaciated) should not be prescribed fentanyl TTS (28).
Health care providers must also consider the financial status of the patient because of the cost associated with fentanyl TTS (28).Adverse effects of fentanyl TTS include those commonly associated with narcotic analgesics (e.g., nausea, vomiting, sedation), as well as, transient and mild dermatological reactions (e.g., local irritation, erythema) (45,46).Rotation of the patch to alternate application sites can reduce the incidence of local dermatological reactions.

Narcotic Side Effect Management
The most common adverse effects from narcotic administration include nausea, vomiting, sedation, constipation, and urinary retention (8)(9)(10)20,28).Hemodynamically compromised patients, are also at greatest risk of respiratory depression.The incidence of nausea and vomiting varies from one narcotic to another, and is interpatient dependent.Moreover, vomiting usually occurs more frequently in am-bulatory patients.Table VI outlines treatment strategies for nausea and vomiting control (20,28).It may prove beneficial to switch a patient experiencing nausea and vomiting to another analgesic if antiemetic therapy is ineffective.
All narcotics produce sedation, but tolerance usually occurs with regular administration (8,28).Care should be taken to avoid administering concomitant medications with sedative effects in patients requiring narcotic therapy.If sedation persists, dosage reduction of the narcotic may be necessary (20,28).
Constipation resulting from a decrease in intestinal secretion, a reduction in peristalsis, and an increase in anal sphincter tone is the most common adverse effect of opiate analgesics (20).All patients regularly dosed with narcotic agents should be maintained on some form of bowel regimen from the outset of their narcotic therapy.Dietary modifications and bulk laxatives alone are seldom tolerable or adequate.Stool softeners can prevent this problem; however, stimulant cathartics, enemas, or manual disimpaction are often required (20,47).Table VII outlines the constipation treatment ladder for patients on narcotic analgesics (6,20,47).
Tolerance, physical dependence, and addiction are significant concerns for patients, families and health care providers, and are often significant obstacles in the achieve-ment of adequate pain control (20,28).However, neither of these three aspects of narcotic usage present a documented clinical problem in patients with advanced cancer and the incidence of addiction (psychologic dependence) in these patients is extremely rare (8,20,28).Therefore, health care providers need not consider psychologic dependence or addiction when selecting appropriate therapy for patients with terminal cancer.
Families and patients should be counseled about the adverse effects, tolerance, physical dependence, and the incidence of addiction, as well as, the importance of avoiding abrupt discontinuance of narcotic therapy.Family members and caregivers should be able to recognize the signs and symptoms associated with physical withdrawal, and who to contact in case of an emergency.

Antidepressants
Tricyclic antidepressants (TCADs) are first-line adjuvant therapy for neuropathic pain (6,48,49).Patients with underlying depression and insomnia may also benefit from TCAD therapy.Amitriptyline has been the most widely used, but is also the least tolerated because of its potent anticholinergic adverse effects (dry mouth, urinary retention, delirium) (50).Sedation and orthostatic hypotension are frequently encountered and may limit the concomitant use of TCADS with opiate analgesics.Nortriptyline and desipramine have fewer side effects compared to other TCADs (6,48,50).Low doses (10 to 25mg) of desipramine or nortriptyline can be used at bedtime and titrated every few days to a maximally tolerated dose.The doses needed to treat neuropathic pain may, in fact, be lower than those required for treatment of depression.However, nightly doses of 100 to 150mg of nortriptyline and 150mg to 300mg of desipramine may be required to maximize their adjuvant effects (6,50).

Benzodiazepines
Benzodiazepines are beneficial in some cancer patients suffering from recurrent anxiety, where antidepressant therapy is not indicated (20,51).They are best considered only after adequate doses of analgesics and reassurance have not relieved anxiety (51).Benzodiazepines have no analgesic properties, can enhance sedation, and increase the risk of respiratory depression in patients receiving narcotic analgesics (51).Therefore, careful dosage titration of these medications is required with best results achieved utilizing agents without active metabolites (e.g.lorazepam) reducing the potential for toxic accumulation.

Steroids
Steroids can be useful in some clinical situations associated with acute and chronic cancer pain (18,20).One to two weeks of steroid treatment (dexamethasone 24mg per day or its equivalent) may be useful in management of pain caused by acute nerve compression, increase intracranial pressure, visceral distension, and soft-tissue infiltration when large doses of opiates have proven ineffective (52).Patients with acute spinal cord compression or severely increased intracranial pressure may benefit from a short course of corticosteroid therapy (dexamethasone 10 to 20mg IV Q6H or methylprednisolone 40 to 80mg IV Q6H) (6,52).Doses should be gradually tapered to the lowest possible effective dose or discontinued, impossible, to avoid long-term adverse effects (52).In moribund patients where chronic adverse effects of steroids are not a concern, steroids may produce euphoria, enhance appetite, and relieve tumor-related pain; chronic adverse effects of steroids should not be a concern in this situation.Long-term corticosteroid therapy can produce weight gain, Cushing's syndrome, proximal myopathy and increased risk of gastrointestinal bleeding (when used in combination with NSAIAs) (52,53).The risks versus benefits of chronic steroidal therapy should always be considered before using these medications.

Anticonvulsants
Anticonvulsant medications may be added to a TCAD for neuropathic pain that are incompletely relieved by a therapeutic dose of the TCAD (10,18).An anticonvulsant may be used as alternatives in patients who cannot tolerate antidepressant drug therapy.Carbamazepine (200mg BID to QID) and clonazepam (0.5 to 1mg TID) are preferred for neuropathic pain (6,51).Carbamazepine can potentially cause bone marrow suppression.Therefore, white blood cell counts should be periodically monitored in patients receiving carbamazepine (6,51).

Miscellaneous Adjuvants
Levodopa, antihistamines, and amphetamines are often utilized as adjuvant pain medications (6,53,54).However, relatively few patients benefit from the use of these agents, with anecdotal data or retrospective surveys providing the majority of rationale for their use.Therefore, larger, well controlled, clinical trials need to be conducted to fully evaluate their role in the treatment in cancer pain.

SUMMARY
Pain is the most common symptom experienced in patients with advanced cancer.The goal of therapy is to provide sufficient pain relief to improve quality of life and permit patients to function at a level that will allow freedom of movement and choice.Unfortunately, 25 percent of patients with cancer die without significant relief of severe pain as a result of poor pain assessment, health care provider's reluctance to prescribe the required medications at appropriate doses, failure of patients to report pain or routinely take pain medications, inadequate nursing staff knowledge and reluctance to administer pain medications (7).Successful pain management requires a precise and complete pain evaluation that includes a comprehensive history and physical examination.Assessment tools, such as the Visual Analog Scale, can assist patients in quantifying their level of pain and provide clinicians with sufficient data to individualize therapy.
The majority of patients with advanced cancer have pain described as intense or excruciating.Morphine SR with convenient Q12H ATC administration is the medication of choice.Morphine can be administered subcutaneously, intravenously, and rectally which provides enhanced flexibility for dosing patients unable to take oral medications.Fentanyl TTS is a convenient dosing alternative when oral morphine preparations are not tolerated.Finally, some patients with advanced cancer may require other adjunctive medications such as NSAIAs, TCADs, steroids, benzodiazepines, and/or anticonvulsants, as well as, psychologic techniques, to assist in pain management.The decision to utilize these adjunctive therapies will depend on each patient's clinical progress.

Table IV . Titration of sustained-release (SR) and immediate-release MR) morphine
1.The oral morphine SR dose should be reduced by 25 percent when converting from other narcotic regimens for patients who are elderly or well controlled (pain free).2. Initially, titrate the patient's morphine SR dose by 25 to 50 percent every 24 hours as needed based on the pain assessment and daily morphine use.3. Increase the 12 hour morphine SR dose not it's frequency.