Pharmacologic management of cancer pain should always be individualized, based on a careful consideration of the patient’s pain pattern, as well as on psychosocial and economic factors.
The treatment plan should start with the simplest dose schedules and the least invasive therapies. The three-step analgesic ladder of the World Health Organization (WHO) is based on gradations of mild, moderate, and severe pain. Patients with mild to moderate pain should be started initially on a nonopioid analgesic, such as acetaminophen, aspirin, or other NSAIDs.
When pain persists despite maximum doses of these drugs, a weak opioid, such as codeine or hydrocodone, should be added (rather than substituted). Opioids at this step-two level are most often provided in fixed combinations with NSAIDs.
Patients who have moderate to severe pain despite the use of step-two opioids should be switched to step-three medications, which consist of opioids and NSAIDs administered separately. This allows for titration of the narcotic to maximally effective levels without exceeding the maximally recommended doses of acetaminophen, aspirin, and other NSAIDs, which can limit the use of step-two medications.
Nonsteroidal anti-inflammatory drugs inhibit the cyclooxygenase pathway, thus blocking the production of prostaglandins and leukotrienes, which are important mediators of inflammation and may sensitize nerves to painful stimuli. The anti-inflammatory effect of these drugs may play a key role in alleviating pain from bone metastases. All NSAIDs have a ceiling effect on their analgesic potential, however, and severe renal and hepatic toxicity may result if patients exceed the recommended maximum doses of these agents.
Since NSAIDs do not activate opioid receptors, they can be used with opioids to provide more analgesia than can be achieved with either drug class alone. Unless contraindications exist, prostate cancer patients with metastatic bone pain should be receiving regular doses of an NSAID with or without an opioid analgesic.
A number of both over-the-counter and prescription NSAIDs are available, with wide variations in cost and dosing schedules (Table 1). No single drug in this class has been shown to be superior to any other for relieving pain due to advanced prostate cancer.
Finding an effective NSAID medication and dose may take several manipulations. Once a particular drug is chosen, the dose should be increased until the patient experiences pain relief or reaches the maximal dose. If adequate analgesia is not achieved with the maximal dose, the patient should be switched to another NSAID.
Ibuprofen is an economical, readily available medication that is often very effective in prostate cancer patients when used alone or in combination with other agents. Acetaminophen is often less effective in advanced prostate cancer patients since it has less anti-inflammatory activity than other nonsteroidal drugs. It does have an analgesic effect and does not affect platelet function, however, and therefore may be useful for select groups of patients. Doses of acetaminophen should not exceed 4 to 6 g/d to prevent liver toxicity.
Side Effects—Nonsteroidal anti-inflammatory drugs may produce a number of potentially serious side effects. Gastrointestinal (GI) irritation is the most commonly reported complication of NSAID therapy and encompasses a spectrum of symptoms, including gastritis, heartburn, nausea, vomiting, anorexia, diarrhea, constipation, bloating, flatulence, and abdominal pain or cramping. More serious side effects include the potential for GI bleeding, ulceration, and perforation.
Because of these complications, patients should be routinely asked about GI symptoms and advised to immediately reports melena or blood in their stool. Clinicians may also need to prescribe an histamine-2 antagonist, sucralfate (Carafate), or a protective agent to ameliorate or prevent GI symptoms. Misoprostol (Cytotec), 200 mg twice daily, has been shown in one study to be more effective than ranitidine, 150 mg twice daily, in preventing asymptomatic gastric ulcers in patients receiving NSAID therapy.
Nonsteroidal drugs may also cause renal and hepatic dysfunction. This may develop during acute therapy but is more often associated with long-term use. The risk of renal toxicity, in particular, increases with age, preexisting renal or hepatic dysfunction, congestive heart failure, hypovolemia, and concomitant diuretic use.
Nonsteroidal anti-inflammatory drugs also have an effect on platelet function that may, in certain cases, limit their use. Most NSAIDs cause a reversible inhibition of platelet aggregation, which is maintained as long as the drug is in the systemic circulation.
Aspirin irreversibly inhibits platelet aggregation and may prolong bleeding time for several days after administration; this makes it a poor choice for patients with advanced disease and myelosuppression due to either extensive bony metastasis or chemotherapy. Nonacelylated salicylates, such as sodium salicylate and choline magnesium trisalicylate, have minimal effects on platelet function and may be acceptable alternatives for thrombocytopenic patients.
Prothrombin time or partial thromboplastin time should be monitored carefully in patients who are taking both NSAIDs and warfarin or other anticoagulants.
Cyclooxygenase-2 (COX-2) inhibitors, such as the recently approved agent celecoxib (Celebrex), have no effect on bleeding time and can be used safely in patients receiving warfarin. Since these agents are less likely to cause GI irritation, they may be useful as step-one medications for patients with advanced prostate cancer.
Potential Effects on Disease Progression—Recent data also have suggested that the regular use of NSAIDs may actually slow down the progression of prostate cancer. One study of 317 newly diagnosed prostate cancer patients and 480 age-matched controls showed a trend toward a reduced risk of advanced prostate cancer associated with regular use of NSAIDs and aspirin. Studies have reported increased levels of prostaglandin E2 in human prostate cancer tissue, and in vitro data suggest that NSAIDs may inhibit cell proliferation of human prostate cancer cell lines.[18,19]
When a prostate cancer patient continues to experience mild to moderate pain despite maximal doses of an NSAID given around-the-clock, he should also be given opioids, which are the mainstay of pain therapy for cancer patients. Both endorphins (endogenous morphine-like substances) and opioid drugs provide analgesia and other effects by binding to specific opioid receptors in the brain and spinal cord.
Pure opioid agonists, such as morphine, are particularly useful in treating cancer pain because they have relatively straight-line dose curves; ie, they fully occupy the opioid receptor, and increased doses provide increased analgesic effects. Full opioid agonists, such as morphine, hydromorphone, codeine, oxycodone, hydrocodone, methadone, levorphanol (Levo-Dromoran), and fentanyl, are most commonly used in the treatment of cancer pain. These drugs have no ceiling effects, and, therefore, dosage can be safely and predictably titrated upward as needed to achieve satisfactory analgesia (Table 2).
Partial agonists (buprenorphine) and mixed agonist/antagonists (pentazocine, butorphanol tartrate) do not have such straightforward effects, however, and for that reason are not commonly used in cancer pain management. Partial agonists bind to opioid receptors but do not fully activate them; thus, they have lower and flatter dose-response curves than the pure agonists and also have limited analgesic efficacy. Combination opioid agonist/antagonists have ceiling effects similar to partial agonists and can also reduce analgesia and even precipitate physical withdrawal symptoms in patients taking weak opioids. Finally, meperidine is a very poor choice for treating chronic cancer pain since it has a short half-life and its metabolite, normeperidine, is toxic and can lead to central nervous system (CNS) stimulation and seizures.
Step-two drugs, including codeine, dihydrocodeine, hydrocodone, oxycodone, and propoxyphene, are short-acting opioids generally used in patients with moderate pain that has been inadequately controlled with around-the-clock NSAIDs. Many of these opioids, such as hydrocodone and oxycodone, are available in fixed combinations with aspirin or acetaminophen and the maximum daily dose is limited by the potential toxicity of the nonopioid. Others have dose-limiting side effects that make adequate titration impossible; codeine, for example, is associated with a high side effect profile at doses over 1.5 mg/kg of body weight. Still, these so-called “weak” opioids provide adequate analgesia in a significant percentage of patients with advanced prostate cancer, either on around-the-clock schedules or with as-needed dosing.
Step-Three Drugs—Patients with moderate to severe pain that is not well controlled with step-two opioids require step-three opioids, which include morphine, hydromorphone, oxycodone, and fentanyl. These medications are pure opioid agonists; they have no ceiling effects, and, therefore, dosage can be titrated upward until adequate analgesia is achieved or the patient experiences unacceptable side effects. When pain is continuous, these analgesic medications should be administered around-the-clock.
There is tremendous variation in the dose needed to achieve adequate pain control, even in patients with similar pain profiles. Hence, the dose and frequency of administration need to be titrated to individual response. Although most cancer pain can be controlled with doses of £ 240 mg/d of oral morphine, patients with severe pain may require much higher doses. Some prostate cancer patients have very severe pain, particularly in the terminal stage of their disease, and the physician should not hesitate to increase opioid doses until adequate pain relief is achieved.
Morphine and Oxycodone—Morphine is the most common, most economical of the pure opioid antagonists; it is widely available in a variety of preparations and has a well-characterized pharmacologic profile. In addition to immediate release preparations, several controlled-release morphine preparations are available that can be dosed every 8 or 12 hours and can be easily titrated. Oxycodone also is available in both short-acting and 12-hour, extended release formulations and may have fewer side effects than morphine.
Short-acting oral opioids start to exert an analgesic effect within a half hour of administration, and analgesia lasts approximately 4 hours. If pain returns sooner, the opioid dose should be increased until pain relief is achieved for 4 hours.
The controlled-release preparations have the benefit of less frequent administration, which is often important to cancer patients. These medications usually begin to exert an analgesic effect 1 hour after administration, peak in 2 to 3 hours, and last for 12 hours. Controlled-release morphine may be given at lower doses every 8 hours, but long-acting oxycodone should be administered only every 12 hours, and doses should be increased if the analgesic effect wears off sooner. Patients need to be advised that controlled-release opioids should not be crushed or broken, as doing so makes the entire dose of the drug immediately available and may lead to toxicity.
Transdermal fentanyl (Duragesic) patches control pain for up to 72 hours. Because transdermal fentanyl bypasses GI absorption, it may be associated with less nausea than other long-acting opioids. These patches are available in 25-, 50-, 75-, and 100-µg/h sizes, and the maximum recommended dose is 300 µg/h. Plasma levels rise slowly over the first 12 to 18 hours after patch administration and peak between 24 and 48 hours. When a patient first starts therapy with transdermal fentanyl or increases the dose by adding an additional patch, he should be advised that he will need to continue with oral breakthrough medication for the first 12 to 18 hours until plasma levels of the new dose peak.
Since titration is not as simple as with oral medications, transdermal fentanyl is a good analgesic choice for patients with stable pain and infrequent episodes of breakthough pain. When compared with oral morphine, studies suggest that transdermal fentanyl is preferred by cancer patients, improves sleep quality and morning vigilance, and is associated with decreased levels of nausea, vomiting, and constipation. The cost of transdermal fentanyl is significantly higher than that of morphine and other oral opioids, however, and this may clearly play a role in the choice of treatment.
Methadone is an inexpensive synthetic opiate receptor agonist that is infrequently used in the treatment of cancer pain but may be very useful for selected patients whose pain is poorly controlled with standard opioids. Methadone is rapidly absorbed from the GI tract, and plasma drug levels are measurable 30 minutes after administration.
There are tremendous interindividual variations in the pharmacokinetics of methadone, and its long elimination half-life requires up to 1 week to achieve steady-state plasma drug levels.[26,27] These considerations make methadone a potentially difficult drug to titrate to acceptable analgesia, but it may prove to be a good alternative for patients whose pain is refractory to other oral step-three opioids.
Patients with moderate pain that is unrelieved with their current oral opioid dose may increase the dose by 25% to 50% every 24 hours until adequate analgesia is achieved. Patients with severe, unrelieved pain should increase the dose by 50% to 100% every day until they achieve a desired level of pain control.[10,21]
Medications for Breakthrough Pain—Patients receiving long-acting step-three opioids often experience breakthrough pain or transient flares of otherwise well-controlled, persistent pain. These episodes may or may not be predictable (eg, occur with increased activity or stress), but all patients taking controlled-release medications should also be provided with immediate-release medications to treat breakthrough pain.
The effective dose of this as-needed medication may vary with each individual; however, in general, 10% to 20% of the total daily dose of a long-acting medication should provide pain relief in this setting. Immediate-release forms of morphine, hydromorphone, and oxycodone are all available in tablet form.
A transmucosal lozenge form of fentanyl citrate (Actiq) that is absorbed through the highly permeable, well-vascularized oral mucosa recently became available in the United States. This fentanyl lozenge produces more rapid pain relief than other immediate-release opioid tablets, with peak effect seen 15 to 20 minutes after oral administration.
Nonoral Administration Routes—Although the vast majority of patients with advanced prostate cancer can take oral medications and experience satisfactory analgesia with these formulations, a small subset of patients have pain that is much more difficult to control and may require different routes of administration. Transdermal fentanyl may be a good choice for these patients. Rectal morphine suppositories also are available, although these are not generally a popular choice with patients or caregivers.
Morphine and hydromorphone can be administered by continuous infusion, either subcutaneously or intravenously, in patients who cannot tolerate oral medications and in patients with acutely increasing pain that requires rapid dose escalation. Portable, easily programmable infusion pumps also are available, which allow patients to control analgesia in an outpatient setting.
A small subset of patients who require extremely large doses of oral, transdermal, or parenteral opioids, or who experience intolerable side effects from systemic administration of these drugs, may benefit from epidural or intrathecal infusion. Epidurally administered opioids are 5 to 10 times more potent than those administered parenterally; drug diffuses into the epidural space, through the dura into the CNS and then into the spinal cord. Intrathecal opioids are 10 times more potent than those administered epidurally, but these catheters for intrathecal drug administration must be placed by a neurosurgeon and are very costly.
Because the epidural and intrathecal routes deliver drug in close proximity to the dorsal horn of the spinal cord, patients require relatively small doses of opioids. This may decrease side effects associated with the drugs.
Side effects associated with opiates are frequent but may be limited or treatable. Constipation is almost universal with long-term opioid use due to decreased peristalsis (which may be compounded by decreased food and fluid intake from anorexia and progressive disease). Unless contraindications exist, all patients who are receiving around-the-clock opioid therapy should be started concomitantly on a bowel regimen.
Prevention may be adequately maintained with a stool softener plus a stimulant taken at bedtime (eg, Peri-colace, Ducolax, Senocot-S). Doses may be increased to two or three times per day as needed, up to eight tablets per day, and supplemented with lactulose or magnesium hydroxide. Patients should also be encouraged to stay as active as possible and consume adequate amounts of fluid and fiber.
Nausea and vomiting are experienced by about 30% of patients taking opioids, but these symptoms generally resolve within a week of initiating therapy. Unresolved nausea may be treated with neuroleptics, such as prochlorperazine, chlorpromazine, and haloperidol. Metoclopramide, at doses of 10 mg up to four times per day, may also successfully treat nausea.
Transient sedation often occurs during opioid dose titration or when doses are rapidly increased. Older adults are more likely to experience sedation with opioid use; initial doses in these patients should be lower and should be increased more slowly to avoid oversedation.
If sedation persists, it may be eased by decreasing the amount of opioid in each dose and increasing the dosing frequency. Persistent sedation also may be treated with CNS stimulants, such as dietary caffeine, methylphenidate (at doses of 5 to 10 mg in the morning and mid-afternoon and titrated upward as needed), dextroamphetamine (2.5 to 7.5 mg twice daily), or pemoline (Cylert; 18.5 to 37 mg orally every day). Opioid-induced myoclonus may be treated with clonazepam (Klonopin; 0.25 to 0.5 mg orally three times daily).
Respiratory depression is relatively rare in patients receiving long-term opioid therapy. Acute respiratory depression may be treated with careful use of naloxone, which should be titrated to improve respiratory function without reversing analgesia and stimulating opioid withdrawal symptoms.
Tolerance, Addiction, and Physical Dependence—When a patient develops tolerance to large doses of an opioid or experiences intolerable side effects, the clinician should consider switching to another opioid. Because cross-tolerance among these drugs is incomplete, the new drug should be dosed initially at 50% of the calculated equianalgesic dose and then rapidly titrated upward to an acceptable level of analgesia.
Patients often have reservations about the use of narcotics based on fears of addiction and tolerance, and may need to be educated about the safety and efficacy of these drugs in treating cancer pain. Addiction, a psychological dependence on pain medications particularly for their euphoric effect, is extremely rare in cancer patients, with an estimated incidence of approximately 0.1%. Tolerance, which refers to the need to use increasing doses of an opioid to maintain adequate pain relief, is not a common problem in cancer patients. Usually, the need for increased analgesic doses in patients with advanced prostate cancer is due to disease progression.
Physical dependence, which is not the same as addiction, causes a physical reaction when an opioid is abruptly withdrawn or naloxone is administered. This is a common but not a worrisome phenomenon that occurs in virtually all patients who receive long-term opioids.
Anxiety, irritability, chills, sweats, joint pain, rhinorrhea, diaphoresis, nausea, vomiting, diarrhea, abdominal cramping, and mild flu-like symptoms are all possible symptoms of this withdrawal syndrome, which can develop after as few as 2 weeks of opioid therapy. This possibility is an important consideration when effective therapies or pain changes warrant decreases in or discontinuation of opioids. Abrupt discontinuation of these drugs will often precipitate withdrawal symptoms; this may be avoided by carefully titrating the opioid dose downward over several days. The drugs may be gradually withdrawn by giving half the prior daily dose each day for 2 days and then decreasing the daily dose by 25% every 2 days until the total dose is the equivalent of 30 mg/d of morphine. After 2 days of this dose, the opioid may be safely discontinued.
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