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Pharmacologic management of cancer pain.

Abstract: Chronic malignant pain is experienced by as many as 80% of patients with cancer. While these patients may experience either nociceptive or neuropathic pain, oftentimes a mixed presentation is encountered. Nociceptive pain may respond to opioid and nonopioid analgesics, while antidepressants and antiepileptics may be beneficial for neurogenic pain. New evidence points to efficacy of opioids for neuropathic, in addition to nociceptive pain syndromes, further clarifying the use of these agents for this patient population. When used properly, opioids are a safe and effective tool for the management of cancer pain.

Cancer pain has been referred to as a "thief of souls." When surveyed, patients with oncologic diseases indicated that of all possible outcomes, pain was that which they feared the most (Sutton, Porter, & Keefe, 2002). In a similar study, 60% of cancer patients surveyed claimed to have intolerable pain. This frequency rose to 90% in those with less than or equal to 1 month to live (Payne, 1997). Indeed, this sequela of malignancy may hinder quality of life to a great extent. All practitioners must understand pain management principles. This review discusses malignant pain pathophysiology and pharmacological treatment.

Pathophysiology

To effectively manage chronic malignant pain, the etiology of the pain must be ascertained. This does not refer to locating the presence of apparent tissue damage or disorders but the ability to decipher the etiology of transmission and maintenance. Painful stimuli, which are transmitted through intact afferent peripheral nerves as a result of tissue damage, are referred to, collectively, as nociception (Regan, Peng, & Chan, 1999). Nociceptive pain is generally described by the patient as constant, throbbing, crushing, aching, stabbing, and, uncommonly, burning. In addition, this type of pain typically manifests focally.

In contrast to nociceptive pain, neuropathic pain arises from direct damage, either traumatic or metabolic, to a primary afferent nerve (Woolf & Mannion, 1999). Because painful stimuli typically may not be required to elicit an action potential in these damaged neurons, neuropathic pain may be described as intermittent, stabbing, burning, "pins and needles," prickly, or a painful numbness. As compared to nociceptive pain, neuropathic pain is often described as shooting or radiating in quality. Because of the nature of neuropathic pain, it is often quite unpredictable and may prove difficult to treat with common modalities. Common causes of malignancy-related neuropathic pain may include chemotherapeutic agents, metabolic abnormalities, radiotherapy, and direct neoplastic nerve impingment. Neuropathic pain may prove difficult to manage (Besson, 1999; Fine & Ashburn, 1998).

While this provides a basic overview of the pathophysiologic mechanisms of pain, both nociceptive and neuropathic, cancer pain may present as a combination of these pain syndromes because of the enigma of processes and location of the neoplasm(s). Neoplasms may elicit painful responses from a host of factors including impingement, compression, or cytokine/peptide production. Any of these neurostimulatory processes may either lead to painful stimuli directly or decrease the threshold for which the nervous system responds to noxious stimuli (Levy, 1996).

Assessment

The assessment of pain has been well studied over the past decade. Numerous assessment tools exist, ranging from one question to comprehensive interviews. Several of the more common, easy-to-use, validated assessment tools are provided in Figure 1. Because of the subjective nature of pain and the confounding factors that often exist in patients with malignancies, physiological monitoring endpoints (i.e., blood pressure, heart rate, and so on) should be reserved for patients who are unable to provide subjective characterization of their pain, such as during conscious sedation. Pain assessment should occur regularly, usually at change of shift or when other vital signs are obtained. Note that once a pain assessment tool is selected, that specific tool should be used throughout treatment to prevent interpatient variability (Chibnall & Tait, 2001; Cleeland & Ryan, 1994; Duggleby & Alden, 1998; Payne, 2000).

[FIGURE 1 OMITTED]

Pharmacologic Treatment

The World Health Organization (WHO) has published an "analgesic ladder" to aid practitioners in treating cancer-related pain states (Levy, 1996). This approach provides a framework from which to model practice. Step 1 of the WHO analgesic ladder recommends acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs), or adjuvants as first-line therapy for mild pain. Step 2 recommends "weak" opioids in combination with acetaminophen or NSAIDs, plus or minus adjuvants for the treatment of mild to moderate pain. Step 3 recommends "strong" opioids plus or minus acetaminophen, NSAIDs, or adjuvants.

Nonopioid Analgesics

Several barriers to successful pain management in the cancer patient exist by utilizing nonopioid analgesics. First, acetaminophen and most traditional NSAIDs are not without dose-limiting side effects and toxicities. Acetaminophen, in various conditions and doses, may contribute to hepatic failure (Schnitzer, 1998; Shimp, 1998; Tolman, 1998). Traditional NSAIDs possess dose-limiting toxicities, mainly, the risk for gastrointestinal ulceration and increased bleeding times, with other toxicities, such as prerenal azotemia, occurring at all dose ranges (Bjorkman, 1998; Cryer & Kimmey, 1998; Tolman). The newer cyclo-oxygenase II specific products (rofecoxib, celecoxib, and valdecoxib) exhibit a lower incidence of gastrointestinal ulceration, when utilized in the absence of aspirin, and platelet aggregation inhibition. However, these newer agents still pose a danger to patients with compromised renal function (Kaplan-Machlis & Klostermeyer, 1999). Dose titration to effect may be hindered by the addition of these agents in combination products. Aspirin, largely abandoned for its analgesic benefit, may still be found in opioid combination products and warrants similar cautions (hepatotoxicty, nephrotoxicity, and so on) as with those of acetaminophen and traditional NSAIDS (Bjorkman; Tolman).

Opioids

Opioids possess very minimal unmanageable toxicities when utilized appropriately (Table 1). Common adverse drug reactions to opioids are constipation, nausea, somnolence, and pruritus. Less common side effects or adverse outcomes are confusion, respiratory depression, myoclonus, hypotension, and potential substance abuse (Bruera & Neumann, 1998; Mercadante, 1999; Walsh, 2000; Walsh, 1990). Opioids have no direct effect on renal or hepatic function; they do not affect coagulation. Particular attention should be paid to constipation because it is easily treated with stimulant laxatives and opioid antagonists and serious sequelae (impaction or narcotic gut syndrome) may be prevented. Nausea typically subsides within several days of initiation and may actually depend on the opioid used (i.e., morphine versus codeine) and its route of administration (i.e., oral versus intravenous). Somnolence, like nausea, is generally not a dose-limiting side effect and usually subsides within several days to 1 week of initiation. If somnolence is experienced, low-dose methylphenidate is often effective for treatment (Walsh, 2000; Walsh, Doona, Molnar, & Lipnickey, 2000; Walsh, 1990). Respiratory depression as a direct result of opioids is extremely rare (Vielvoye-Kerkmeer, Mattern, & Uitendaal, 2000; Walsh, 1990). Substance abuse disorder is commonly at the forefront of discussion and concern for patients. Studies have largely dispelled the belief that cancer pain patients may be at significant risk for substance abuse disorder (Medina & Diamond, 1977; Perry & Heidrich, 1982; Porter & Jick, 1980). In fact, less than 1% of patients started on opioids for pain management displayed any of the behaviors associated with substance abuse disorder. With this mind, it is important to consider "pseudoaddiction" in cancer pain management, in which aberrant drug-seeking behaviors are perceived not because of true substance abuse disorder, but from inadequate provision of analgesia by the healthcare professional (Kirsh, Whitcomb, Donaghy, & Passik, 2002). Physical dependence is a concern after 2 to 3 weeks of therapy. Withdrawal symptoms include agitation, diaphoresis, anxiety, confusion, and, in extreme cases, seizures. Discontinuation of an opioid should be done by titrating the dose down slowly, monitoring for these aforementioned symptoms frequently.

Instituting opioid therapy for cancer pain patients is relatively straightforward. Although several methods exist, the most commonly utilized strategy is presented (Coluzzi, 1998; McQuay, 1999; Mercadante, 1999). The opioid to be used should be determined first. The opioids of choice in cancer pain management are the pure [mu]-agonists. These include morphine, oxycodone, fentanyl, hydromorphone, methadone, morphine, and hydrocodone. Typically, all partial agonists/agonist-antagonists (buprenorphine, nalbuphine, pentazocine, butorphanol), as well as codeine, meperidine, and prophoxyphene, are avoided because of toxic metabolites or inability to titrate to increasing doses.

These medications, within their respective classes, are relatively homogenous with minor differences allowing the "finetuning" of analgesic therapy. The opioid of choice should be initiated first in its short-acting form. Beginning with the lowest available dose, the medication may be offered on an "as-needed" basis, with directions to take one or two doses every 2 hours. Although the duration of action for most opioids is 4 hours, peak analgesic effect is seen at approximately 1 and 1 1/2 to 2 hours. At this time the patient will know whether one dose is sufficient or whether a second dose is required. Under no circumstances should the interval between doses be limited to greater than 4 hours. To allow for steady-state accumulation of a drug, assessment of opioid utilization should be determined approximately 48 to 72 hours after initiation. By averaging the consumption of "as needed" doses in milligrams over a 24-hour period, total daily opioid need may be ascertained. Then the patient should be placed on scheduled, around-the-clock dosing, with the long-acting products providing more convenience for the patient and improved pain control. Conversion to a long-acting preparation of the same opioid as used in initial dosing is preferred to minimize the potential for uncontrolled pain or dose-related toxicities, which may be encountered when equianalgesic tables are used. Allowance for breakthrough pain episodes must be considered and a continued supply of the short-acting opioid made available (Levy, 1996; Portenoy, 1997; Walsh, 2000).

Breakthrough pain (BTP) is typically classified into three categories: incident, idiopathic, and end-of-dose failure (Portenoy & Hagen, 1990). Having the patient or caregiver administer a short-acting opioid dose to the patient 30 min. prior to the inciting stimulus (i.e., turning, ambulating, and the like) may usually prevent incident BTP. End-of-dose failure may be seen in as many as 30% of patients receiving long-acting opioids and is commonly experienced at consistent times of the day corresponding with the end of the analgesic window for the chosen opioid dosage form. Idiopathic BTP is by far the most common (Reddy & Nguyen, 2000). Immediaterelease opioid products should be used to manage this, reserving dose increases of long-acting opioids for instances in which four or more immediate-release opioid doses are being consumed per 24 hours. By attempting to treat baseline and breakthrough pain with long-acting products, the patient frequently experiences intolerable somnolence. When four or more immediate-release doses are needed per 24 hours, the long-acting product should be increased by the daily consumption of the immediate release product (i.e., four doses of 10 mg immediate release results in an increase in long-acting product by 40 mg). After the patient's pain scores are improving and no immediate release doses are needed, it is prudent to decrease the long-acting daily dose by 25% on weekly intervals as tolerated.

Opioids may be changed or rotated based upon equianalgesic potencies (Table 2). When changing opioids, it is prudent to decrease the total daily dose of the new medication by approximately 25% to avoid dose-dependent toxicities. This phenomenon is likely due to lack of cross-sensitivity among the various opioid subreceptors (Bruera et al., 1996; de Stoutz, Bruera, & Suarez-Almazor, 1995; Mercadante, 1999). Caution should be exercised when changing opioids based upon equianalgesic data widely published. Unfortunately, much of this data was acquired from single dose studies and has proven to be inaccurate in several instances (Bruera et al., 1996; Daeninck & Bruera, 1999; de Stoutz et al., 1995; Lawlor, Turner, Hanson, & Bruera, 1997; Mercadante, 1999). Most notable is methadone, which was originally thought to be equipotent to morphine. Recent reports suggest that this unique opioid may be as much as 10 times as potent as morphine, depending on previous patient opioid exposure (Bruera & Neumann, 1999; Mercadante et al., 1998; Mercadante, Casuccio, & Calderone, 1999). An outline of equianalgesic potencies between opioids and dosage forms is provided in Table 2.

Adjuvants/Radiotherapy/Interventional Analgesia

While opioids are considered the mainstay of therapy for cancer pain management, some types of pain frequently experienced by oncology patients may not respond to opioids or other treatment modalities. Neuropathic pain has traditionally responded best to antidepressants and antiepileptic drugs. Oftentimes therapeutic doses for depression or seizures are unwarranted when neuropathic pain is being treated with these agents. These drugs should be initiated at low doses and titrated up to effect slowly, usually at weekly intervals. Amitriptyline, nortriptyline, desipramine, and gabapentin are currently considered first-line therapy for neuropathic pain with selection between these three agents based upon patient specific variables. Other promising agents for the treatment of neuropathic pain are clonidine, venlafaxine, fluvoxamine, mirtazipine, and tiagabine. In addition, mexiletine and transdermal lidocaine have shown benefit for neuropathic pain states as well (Lipman, 1998). Recent data suggest that opioids may be just as effective as antidepressants and antiepileptic drugs in certain types of neurogenically mediated pain syndromes (Raja et al., 2002).

Pain due to metastatic bone disease may respond to opioids, but generally the best effects are seen with NSAIDs, corticosteroids, and/or pamidronate. A radiopharmaceutical, strontium 89, may also be considered; however, the expense and delayed response typically preclude its use (McEwan, 1997). Calcitonin may also be of benefit for pain due to bone metastases; however, this effect is typically short lived (Payne, 1997).

Pain refractory to oral or parenteral analgesia may be responsive to alternative therapy. These methods should be considered on a patient-specific basis only. Cancer pain may be manageable with palliative doses of site-specific radiotherapy. Sources about radiation for pain management are available (Arcangeli et al., 1998; Gaze et al., 1997; Gressen, Werner-Wasik, Cohn, Topham, & Curran, 2000; Janjan, 1997). In addition, Interventional analgesia may be of use in the patient uncontrolled on standard therapy or unable to tolerate the less invasive alternatives. Interventional analgesia includes epidural, spinal, and intrathecal opioids, sometimes in combination with parenteral anesthetics (de Leon-Casasola, 2000; Miguel, 2000). Peripheral nerve blocks may be especially efficacious for short-term management of plexopathies involving the celiac, mesenteric, and subclavian plexus. Patients should be referred to trained pain specialists for these procedures. Trigger-point injections of corticosteroids, usually triamcinolone, may also be of benefit, but usually to a lesser degree.

Summary

Pain presents in various forms based upon site of stimulus, etiology, and mode of transmission. Choice of analgesic should be patient specific and tailored to provide the most convenience. Common side effects of these analgesics are easily treated and should be anticipated. Although this review is meant to provide a brief, working overview of malignancy-related pain, readers interested are urged to explore these areas discussed as well as numerous specific pain syndromes, human immunodeficiency virus related pain, as well as complex regional pain syndromes.
Table 1. Common Adverse Effects of Opioids and Their Management

Adverse Effect Duration

Constipation Indefinitely with ongoing opioid therapy

Somnolence Usually subsiding within several days

Myoclonus Rare in the absence of inappropriately high
 initiation
 or titration doses. Renal impairment may
 predispose
 those receiving morphine sulfate.

Nausea Usually subsiding within several days
 postopioid
 initiation

Pruritus May be seen with first several doses; result
 of mast
 cell destabilization.

Respiratory Depression Extremely rare at recommended titration
 schedules

Confusion May be seen at higher doses; usually subsides
 within
 days of initiation or dosage increase

Adverse Effect Management

Constipation Stimulant laxatives (senna, lactulose,
 sorbitol,
 bisacodyl) plus/minus softeners (docusate);
 naloxone
 may be of benefit orally in doses less than 18
 milligrams per day.

Somnolence Ongoing somnolence responds well to low doses
 of
 methylphenidate (5 mg am and noon).

Myoclonus Benzodiazepines are the mainstay of treatment.
 Lorazepam and midazolam are by far the most
 studied.
 Phenobarbital is also of benefit.

Nausea Primarily dopaminergic in etiology.
 Metoclopramide,
 prochlorperazine, promethazine, and
 haloperidol
 considered mainstays of therapy. May initiate
 prophylactically for 2-3 days when starting
 opioid.

Pruritus Responds well to common antihistamines.
 Hydroxyzine or chlorpheniramine recommended as
 diphenhydramine may exacerbate somnolence.

Respiratory Depression Naloxone should be administered.

Confusion May respond to methylphenidate.

Note: From "Cancer pain management, "by C.M. Herndon, 2001, Panhandle
Health, 3. p. 30. Copyright 2001 by Panhandle Health. Reprinted with
permission.

Table 2. Classes and Conversion of Opioids

Class Generic Name Conversion Ratio

Agonists Morphine 1 *

 Hydromorphone 0.125-0.25 ([dagger])
 Oxycodone 0.5
 Methadone 0.1 ([double-dagger])
 Hydrocodone 1-2.5
 Meperidine 10 ([section])
 Levorphanol 0.033 ([section])
 Codeine 30 ([section])
 Propoxyphene 50 ([section])
 Fentanyl 0.01 (//)
 Sufentanyl 0.001
 Alfentanyl 0.04
 Remifentanyl N/A
 Oxymorphone 0.1

Agonist-Antagonists Nalbuphine 1 ([section])
 Butorphanol 0.2 ([section])

Partial Agonists Dezocine 1 ([section])
 Buprenorphine 0.04 ([section])

Antagonists Naloxone N/A (#)
 Naltrexone N/A

Note: From "Cancer pain management. by C.M. Herndon, 2001. Panhandle
Health, 3, p. 30. Copyright 2001 by Panhandle Health. Reprinted with
permission.

* Morphine considered standard for equianalgesic dosing. Conversion
between oral and parenteral 3 to 1 (90 mg PO = 30 mg IV).

([dagger]) hydromorphone oral to parenteral conversion is 4 to 1 (40 mg
PO = 10
mg IV).

([double-dagger]) Methadone conversion may range from 10% to 25% of
morphine dose.
Use should be limited to persons experienced with initiation and
titration.

([section]) Use of these agents should generally be avoided in
cancer-related pain.

(//) Conversion based on parenteral dose of morphine. New data
suggest this
conversion should be utilized based on oral dose of morphine.
Transmucosal fentanyl should not be dosed based upon total daily opioid
consumption. Initiation should begin at lowest available dose and
titrated up
as needed.

(#) Use caution when reversing meperidine with naloxone because of
increased
risk of seizure activity from unopposed normeperidine metabolite.

Note: These equianalgesic ratios are approximate and critical clinical
evaluation should follow the change of any medication. (Many of these
figures
are based upon poor or single-dose studies.)


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Author:Herndon, Christopher M.
Publication:Journal of Neuroscience Nursing
Date:Dec 1, 2003
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