Which drug is used as a palliative treatment for a client with tumor-induced spinal cord compression

Pharmacologic Approaches

Pharmacologic approaches are the most commonly used method for managing cancer pain. The World Health Organization recognizes that analgesic drug therapy is the mainstay of pain treatment for cancer patients as part of the Cancer Pain and Palliative Care Program, and advocates the three-step approach shown in Figure 78-1.9,45 Validation studies of the WHO guidelines reveal successful treatment of cancer pain in 69 to 100% of patients.46–48 Such an approach advocates the use of nonopioid, opioid, and adjuvant analgesics alone and in combination, titrated to the needs of the individual patient. The Agency for Health Care Policy and Research and The American Pain Society have developed similar guidelines which have been widely disseminated.6,49 The effective use of these analgesic drugs should be a major part of every physician's armamentarium in managing patients with pain.

Figure 78-1

The WHO three-step approach to pharmacologic management of pain.

Table 78-4 details the specific guidelines for the use of pharmacologic approaches. The fundamental concept that underlies this approach is individualization of pharmacotherapy. The selection of the right analgesic administered in the right dose on a regular schedule to maximize pain relief and to minimize adverse effects begins with the use of nonopioids for mild pain. In patients with moderate pain that is not controlled with nonopioids such as acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs) and adjuvant medications (WHO step 1) alone, the so-called “weak” opioids (codeine, hydrocodone, and tramadol) alone or in combination are prescribed (step 2). In patients with severe pain, a strong opioid (morphine, hydromorphone, fentanyl, methadone, oxycodone, oxymorphone, and levorphanol) is the drug of choice (step 3). At all levels, certain NSAIDs and adjuvant drugs may be used for specific indications. It is critical that patients presenting in severe pain should generally be treated with a strong opioid immediately.

Table 78-4

Guidelines for the Use of Analgesic Drugs in Cancer Pain Management.

Nonopioid Analgesics

The nonopioid analgesics include acetaminophen and the NSAIDs of which aspirin is the prototypic agent. These compounds are most commonly used orally, but their analgesia is limited by a ceiling effect so that increasing the dose beyond a certain level (eg, 3 to 4 g of acetaminophen in 24 h) will produce no increase in peak effect. Tolerance and physical dependence do not occur with repeated administration. NSAIDs have analgesic, antipyretic, antiinflammatory, and antiplatelet actions. Acetaminophen, which is equally potent to aspirin, is an analgesic and antipyretic, but is much less effective as an antiinflammatory agent and does not interfere with platelet function. As a group these compounds have an analgesic effectiveness that is equal to or greater than that of aspirin. These drugs are thought to produce analgesia by inhibiting activation of peripheral nociceptors through their prevention of the formation of prostaglandin E2 to nociceptive stimulation from tissue injury.

Nonsteroidal Antiinflammatory Drugs

The drugs in this group have a higher analgesic potential than aspirin and serve as an important first step in the management of patients with pain and cancer (Table 78-5). They differ from each other in duration of analgesic action and in their pharmacokinetic profile. These drugs may have a special role to play in the management of bone pain because numerous studies show that aspirin inhibits tumor growth in an animal model of metastatic bone tumors. However, a meta-analysis of NSAIDs in bone pain did not demonstrate them to be more effective than weak opioids.50

Table 78-5

Nonopioid Analgesics Commonly Used for Mild to Moderate Pain.

The NSAIDs inhibit cyclooxygenase, which results in decreased prostaglandin synthesis. In addition to this peripheral action, they may also interfere with the action of glutamate and substance P in the central nervous system when cyclooxygenase is inhibited.51 Two isoforms of the cyclooxygenase enzyme have been identified. Cyclooxygenase (COX)-1 is a normal constituent of blood vessels, stomach and kidney. COX-2 is induced in the setting of peripheral inflammation and acts as an attractant of inflammatory mediators. The COX-2 inhibitors reduce inflammation without the gastrointestinal and hematologic toxicity typically associated with other NSAIDs.52

In clinical experience, some patients respond better to one NSAID than to another, and each patient therefore should be given an adequate trial of one drug on a regular basis before switching to another. Survey data from WHO demonstration projects suggest that between 20 and 40% of patients obtain pain relief with the use of nonopioid analgesics alone.9,53 Intravenous ketorolac is the only NSAID available in the United States for IV use. Although very useful as an opioid-sparing or opioid-reducing agent in cancer patients who are difficult to manage with morphine alone, its use is limited to a 5-day course due to gastrointestinal toxicity.54

Numerous studies have elucidated the major risk factors for gastrointestinal (GI) toxicity associated with NSAID use.55,56 While all of the NSAIDs may be associated with GI toxicity, a recent meta-analysis demonstrated that ibuprofen in doses lower than 1,600 mg/d was associated with the least risk of hemorrhage; aspirin, indomethacin, naproxen, and sulindac had intermediate risk; ketoprofen and piroxicam were associated with the highest risk.57 Although nausea and upper abdominal pain may be produced by NSAIDs and raise concern about more serious toxicity when they occur, dyspepsia is a poor predictor of ulceration, and two-thirds of NSAID users have absolutely no symptoms before bleeding or perforation. Various factors contribute to the high risk of ulcer complications, including advanced age, use of higher doses, concomitant administration of corticosteroids, and a history of either ulcer disease or previous GI complications from NSAIDs.58,59 Although the use of prophylactic therapies remains controversial, misoprostol is highly effective in the management of GI side effects. In patients who fail to receive adequate relief with nonopioids or who are unable to tolerate them, the use of opioid analgesics is considered as the next step.

Opioid Analgesics

The opioid analgesics as a class consist of heterogeneous compounds whose pharmacologic effects are derived from their interaction with multiple central nervous system opiate receptors.60 The morphine agonist drugs bind to discrete opiate receptors and produce analgesia. The opioid antagonists also bind to opioid receptors but block the effects of morphine-like agonists and do not have analgesic properties of their own. The agonist drugs with morphine as the prototype are most commonly used in the management of cancer patients with pain. Table 78-6 lists the available opioid analgesics.

Table 78-6

Opioid Analgesics Commonly Used for Moderate to Severe Pain.

Drugs such as codeine and tramadol (Ultram) have a limited analgesic efficacy. These drugs are used for the management of mild to moderate pain and have been included in step 2 of the analgesic ladder because of the wide availability of these compounds in most countries and because of their acceptability to patients for mild to moderate pain. Approximately 15% of the population cannot convert codeine to morphine because of the lack of a specific enzyme.61 This factor should be taken into consideration in patients who do not obtain effective analgesia from codeine. Tramadol was recently approved in the United States for the treatment of mild to moderate pain. Although not scheduled as an opioid, tramadol binds weakly to the mu receptor and inhibits reuptake of serotonin and norepinephrine. It is 10-fold less potent in mu receptor binding than codeine and 6,000-fold less potent than morphine.62 Given its low affinity for opioid receptors it does not cause significant dependence or respiratory depression. It has been compared favorably to morphine in European trials and was shown to be safe and effective in a double-blind randomized placebo-controlled trial for the treatment of diabetic neuropathic pain.63,64

Oxycodone is included in both step 2 and step 3 of the analgesic ladder. Oxycodone is available in combination with acetaminophen (Percocet, Tylox) or alone in tablet form and liquid form. When used in a 5 mg dose combined with acetaminophen, it has a higher analgesic efficacy than codeine. Equally potent to morphine, oxycodone can be used alone to treat moderate to severe pain. Oxycodone is now available in a controlled-release oral preparation, which, in a randomized, double-blind, crossover trial, was found to be as safe and effective as controlled-release morphine.65 Given its lack of active metabolites, oxycodone may be useful as an alternative to morphine particularly in the elderly or when the development of side-effects precludes the use of morphine. The controlled-release form of oxycodone, OxyContin, is also as effective as the immediate-release preparation.66

Given its place on the essential drug list of the WHO, familiarity to physicians, and wide oral use in the management of cancer pain, a WHO expert consensus panel named morphine as the drug of choice for the management of patients with pain and cancer.9 Morphine, the prototypic drug, has an oral bioavailability that varies from 35 to 75% and a plasma half-life of 2 to 3 h, which is somewhat shorter than its duration of analgesia of 4 to 6 h. With repeated administration, the pharmacokinetics of morphine and its metabolites remain linear, and there does not appear to be autoinduction or biotransformation, even following large chronic doses.67 These properties contribute to the safe use of morphine. As judged by single-dose studies in both acute and chronic pain, the relative potency of intramuscular (IM) morphine to oral morphine is 1:6, that is, 10 mg IM produce equianalgesia to 60 mg of oral morphine. On the basis of a series of survey studies in clinical practice, several authors have suggested that the relative potency of morphine with repeated administration is 1:2 or 1:3.68 Several explanations have been offered to explain the differences, including metabolic and/or pharmacokinetic factors, the use of adjuvant analgesics in the hospice setting, and the fact that pain relief is maintained with repetitive doses.69 In clinical practice, the 1:2 or 1:3 ratio is most commonly used in titrating a patient with morphine.

Morphine is predominantly metabolized at the three and six positions by hepatic glucuronidation to morphine-3-glucuronide (M-3-G 55%) and morphine-6-glucuronide (M-6-G 15%).69 M-6-G binds to the opiate receptor and, in animal studies, when injected either by the ventricular or intrathecal route, is approximately 90- to 650-fold more potent as an analgesic than is morphine.70 M-3-G does not bind to opiate receptors and makes little if any contribution to the analgesic potency of morphine. Conflicting data have been reported on the role of M-3-G and the development of tolerance.71 Some studies suggest that the accumulation of M-3-G may be associated with the side-effects of central nervous system excitation (eg, myoclonus and delirium), whereas M-6-G accumulation may result in the depressive side-effects (eg, drowsiness and respiratory depression).69 Children younger than age 10 years have significantly lower concentrations of these metabolites, whereas patients older than age 70 years have higher plasma metabolite concentrations, which may partly explain the increased sensitivity to morphine side-effects commonly observed in elderly patients.69 In humans, M-6-G occurs in higher levels following oral administration and accumulates in renal failure.72,73 Recent surveys suggest that there is a large interindividual variability in the relationship between renal impairment and the degree of M-6-G accumulation; consequently, the impact on patient side effects of a relatively increased morphine-6-G/morphine ratio remains unclear. Tiseo and colleagues noted an overall positive correlation between serum creatinine level and M-6-G/morphine ratio but no association between this ratio and either the occurrence of encephalopathy or myoclonus.74 In short, morphine doses should be adjusted in patients with renal insufficiency and carefully titrated to the needs of the individual. Morphine is now available in a wide variety of preparations including immediate release tablets, oral solutions, controlled-release tablets (for 8, 12, or 24 h), buccal tablets, rectal suppositories, as well as parenteral forms (intravenous, subcutaneous, epidural, and intrathecal).75

Hydromorphone (Dilaudid) is a strong opioid (1.5 mg of IV hydromorphone is equipotent to 10 mg of morphine) and a useful alternative to morphine in the treatment of moderate to severe cancer pain. Although myoclonus has been described in the setting of continuous high-dose infusion possibly due to accumulation of other metabolites (eg, 3-0 methyl or a glucuronide),76 hydromorphone may be a suitable alternative to morphine in the setting of toxicity. Given its water solubility, availability in a high-potency formulation (10 mg/mL), and 87% bioavailability, hydromorphone is the drug of choice for chronic subcutaneous administration. In a double-blind trial that compared morphine and hydromorphone patient-controlled analgesia, no differences were found with respect to analgesia or side effects.77 Although cognitive performance was somewhat poorer in the hydromorphone patients, they did report better mood as compared to the patients who received morphine.

Oxymorphone (Numorphan) is only available in parenteral and suppository forms and is used for severe pain in patients who are unable to tolerate oral analgesics. It has less histamine-release effects when compared to the other morphine congeners, and can be used in patients who develop histamine-induced headache or itch.

The choice of any one of these drugs is empiric. In patients who are unable to tolerate morphine or who have excessive side effects of nausea or sedation, switching to one of the congeners is often helpful. In patients over the age of 65, hydromorphone, oxycodone, and fentanyl may be better tolerated with fewer side effects than morphine. Levorphanol should be considered a second-line drug and used cautiously because drug accumulation associated with its long half-life may produce adverse effects.

Advantages to using methadone in cancer pain include 85% bioavailability, lack of active metabolites, low cost, long half-life resulting in larger intervals between doses, and improved patient compliance.78 Its plasma half-life averages 24 h but may range from 13 to 50 h, whereas the duration of analgesia is only 4 to 8 h. Methadone is a useful alternative to morphine, but requires greater sophistication in its clinical use, and for that reason it is a second-line drug. Sedation, confusion, and even death can occur when patients are not carefully monitored and dosages are adjusted during the accumulation period, which can last from 5 to 10 days. In the opioid-naïve patient, doses should be titrated carefully. Several groups have reported a broad experience in the use of methadone and have further confirmed the need for careful dose titration.78 Given its relatively short analgesic half-life methadone may be prescribed on a two, three, or four times per day schedule, depending upon the individual patient.

Most equianalgesic opioid tables suggest a dose ratio of 1:1 between oral morphine and oral methadone. However, recent studies of interindividual differences in responses to opioid analgesics demonstrate the dramatically reduced doses of methadone that provide analgesia in patients who are switched from morphine or hydromorphone.78,79 In rotating patients from morphine to methadone, Ripamonti and colleagues used a dose ratio of 4:1 for patients who received 30 to 90 mg of morphine daily, 6:1 for patients who received 90 to 300 mg daily, and 8:1 for patients who received 300 mg or more daily.80,81 As little as one-tenth the equianalgesic dose of methadone can provide effective analgesia in patients tolerant to other opioid analgesics.82 Bruera and colleagues demonstrated that the hydromorphone/methadone ratio is correlated with total opioid dose and that in switching from hydromorphone to methadone much lower doses than expected may provide satisfactory analgesia. In patients receiving more than 330 mg of hydromorphone prior to the switch, the dose ratio was 1.6:1, whereas in patients receiving less than 330 mg of hydromorphone daily, the dose ratio was 0.95:1.82 In general, caution should be taken when switching patients to methadone. Mercandante recently reported that in comparing the use of methadone versus morphine in advanced-cancer pain management at home, those who received methadone required fewer dose escalations, supporting a definite role for methadone in the hands of an experienced clinician.83

Fentanyl is now available for intravenous use in a transdermal patch (Duragesic) and in an oral transmucosal preparation (Actiq). Fentanyl is 80 to 100 times more potent than morphine. Advantages of the transdermal patch include excellent patient compliance as it only needs to be replaced every 72 h, continuous controlled-release analgesia, and lack of an oral first-pass effect. Four milligrams of intravenous morphine is approximately equivalent to 100 μg of intravenous fentanyl.

There is a delay in the onset of analgesia, taking up to 12 to 15 h for peak plasma levels to occur after a patch is applied, and, therefore, patients need to have their pain controlled during this titration phase. When rotating from intravenous to transdermal fentanyl, we recommend using a 1:1 conversion ratio. For example, when rotating from a 100 μg/h fentanyl infusion to a 100 μg strength transdermal patch, apply the 100 μg patch and in 6 h decrease the infusion rate by 50%. Twelve hours after the application of the patch the infusion should be discontinued. Steady-state is generally achieved within 12 to 24 h following application of the patch.

Transdermal fentanyl was reported to be effective and safe in the long-term management of patients with advanced cancer of the gastrointestinal tract and head and neck84 and with other malignancies.85 Several studies now suggest that patients who receive transdermal fentanyl may be more satisfied and less troubled by side effects when compared with those who receive sustained-release morphine.86–88

Oral transmucosal fentanyl citrate (OTFC) is a new and valuable option for the treatment of cancer-related breakthrough pain.89 Breakthrough pain has been defined as a transient increase in pain, increasing to moderate or severe intensity, in conjunction with a baseline pain that is well controlled. The prevalence of breakthrough pain among inpatients with cancer has been reported as 64%.90 Two formulations of OTFC are approved for use in the United States (Table 78-7). Fentanyl Oralet is approved as an anesthetic premedication in children and for procedure-related pain in adults and children. It is available in 100, 200, 300, and 400 μg and is indicated for opioid-naïve patients who generally require lower doses than do opioid-tolerant patients who require relief for breakthrough pain. Fentanyl Actiq is available in a wider range of dosages (200 to 1,600 μg) and is indicated for the management of breakthrough pain in opioid-tolerant adults. Twenty-five percent of both preparations are absorbed transmucosally over a 15-min period and an additional 25% is absorbed via the gastrointestinal tract over the following 90 min. Onset of relief may occur within 5 min.89 OTFC in dose-titration trials is safe and effective in comparison with other agents used for breakthrough pain.91,92 In multicenter dose-titration trials, the effective OTFC dose did not correlate with the prior opioid requirements. The optimal dose needs to be determined by titration in approximately 75% of patients.91

Meperidine (Demerol) is a drug that should not be administered for chronic cancer pain. Studies demonstrate that repetitive dosing can lead to accumulation of normeperidine, a toxic metabolite, which results in central nervous system hyperexcitability. This adverse effect is characterized by subtle mood changes, followed by tremors, multifocal myoclonus, and occasionally seizures. This complication occurs more commonly in patients with renal disease, but can occur following repeated administration in patients with normal renal function.93

The role of opioids in the management of neuropathic pain has been reviewed in recent years. Several placebo-controlled trials have demonstrated the use of opioids in the management of neuropathic pain.94–98 Patients with neuropathic pain should be given a trial of an opioid to assess the degree of opioid responsiveness, particularly in the setting of ongoing pain despite a trial of adjuvant agents. A recent study suggests that neuropathic cancer pain may be successfully managed with gabapentin in addition to opioid agents.99 We commonly employ both adjuvant agents and opioids when managing severe neuropathic malignant pain.

Start with a Specific Drug for a Specific Type of Pain

Choosing an analgesic regimen requires knowledge of the pharmacokinetic and pharmacodynamic properties of these drugs as well as the type of pain (nociceptive versus neuropathic). Each physician should become familiar with several drugs in each of these groups and adapt them to the needs of his or her clinical practice. Cherny and colleagues have documented the strategies used by pain physicians for the selection of analgesic drugs and routes of administration. In a prospective study, 80 of 100 patients referred to the Memorial Sloan-Kettering Cancer Center Pain Service required changes in either opioid or route of administration to obtain adequate analgesia with tolerable side effects. Many patients experienced significantly better analgesia and a reduction in side effects with the substitution of one opioid for another.100 This study found that opioid substitution or rotation is a common clinical practice and suggested that competent care of the cancer patient with pain requires comfort with use of the equianalgesic table and available guidelines. Cherney reported that the most common reasons for requesting a pain consultation were either because of uncontrolled pain despite analgesic therapy or excessive side effects without adequate analgesia. Ashby demonstrated that substituting fentanyl or oxycodone for morphine in patients in his series produced improved cognitive function, less sedation, and better pain relief.101 Bruera and Ripamonti have used opioid rotation to maximize analgesia and have demonstrated the use of significantly lower doses of methadone in switching patients from morphine and hydromorphone (see above).

A common approach is to start a patient on a nonopioid followed by the use of codeine or oxycodone alone or in combination with the nonopioid. If with repeated doses the patient does not obtain effective pain relief, switch the patient to morphine, hydromorphone, fentanyl, levorphanol, or methadone. We commonly choose morphine, but in patients intolerant to morphine, we use hydromorphone as our first-line drug. For patients over the age of 65, we often choose oxycodone, hydromorphone or fentanyl before morphine because our clinical empiric data suggest that these drugs may produce fewer central nervous system side effects than morphine.102 Levorphanol and methadone tend to be second-line drugs, particularly in the elderly patient where their long half-lives present a potential risk of producing adverse effects. However, growing clinical experience suggests that with proper dosing, using the ratios suggested above, and careful titration, methadone may be an efficacious alternative, especially when other analgesics are not well tolerated. Regardless of the drug chosen, the dose must be titrated to the individual patient.

In choosing a dose, it is most useful to start with one that is equivalent to one-half the equianalgesic dose of the previous drug used and dose the patient to analgesia. Recent studies in opioid rotation suggest that the published equianalgesic guidelines may require modification on an individual patient basis according to prior opioid exposure and the specific opioid selected for the substitution.103 We first order the medication on a regular basis, usually every 3 to 4 h, and instruct the patient to take the medication on this fixed schedule. If the patient has had no prior opioid exposure and presents with severe pain, start the medication on an as-needed basis requesting that the patient ask for medication when the patient feels the pain beginning to return. Within one or two doses, it is possible to assess the needs of the individual patient and to adjust the timing of the doses accordingly.

Rescue medications equivalent to 15 to 20% of the standing dose should be made available to patients and ordered on a regular dosing schedule in case their pain is not adequately relieved or if they have breakthrough pain.6 The next scheduled dose should be given on time without regard to the intervening rescue doses.

Recent work in drug interactions commonly seen in the pain and palliative care setting suggests extensive genetic polymorphism in the cytochrome P450 family of enzymes.104 Pharmacokinetic interactions, which involve the CYP 2D6 isozyme and result in poor or rapid opioid metabolism, may result in undertreatment or overtreatment if not recognized. For example, if haloperidol (Haldol) is added to a patient's drug regimen, which already includes codeine, the patient's metabolism of codeine is slowed, which could result in toxicity and further problems if switched to another opioid.104

Choose the Route of Administration to Fit the Needs of the Individual Patient

The majority of cancer patients require at least two routes of administration of analgesic drugs, and 30% of patients require three routes of administration during the course of their pain management.105

Oral Route

The oral route is convenient and preferable. Numerous studies have led to the use of oral opioid analgesics in chronic cancer pain and have demonstrated that these drugs work effectively when used in the appropriate equianalgesic doses for the intended route of administration.67 When given orally, the opioids differ substantially with respect to their presystemic elimination, that is, the degree to which they are inactivated as they are absorbed from the gastrointestinal tract and passed through the liver into the systemic circulation. As indicated in Table 78-6, morphine and hydromorphone have parenteral-to-oral-potency ratios of 1:3 and 1:5, respectively, and methadone and levorphanol are subject to less presystemic elimination, resulting in an intravenous-to-oral-potency ratio of at least 1:2. The failure to recognize these differences often results in a substantial reduction in analgesia when changing from the parenteral to the oral route. In general, orally administered drugs have a slower onset of action and a longer duration of effect; drugs administered parenterally have a more rapid onset of action but a shorter duration of effect.

Intranasal, Sublingual, Buccal, Rectal, and Transdermal Routes

The intranasal, sublingual, buccal, rectal, and transdermal routes of administration provide alternative approaches for patients who cannot take oral drugs. These routes obviate the need for parenteral administration and offer the advantage of eliminating the first-pass effect through the liver because they are rapidly taken up into the systemic circulation.

Intranasal butorphanol, a mixed agonist antagonist, provides adequate analgesia for patients with acute postoperative pain but is not commonly used for chronic cancer pain management. Sublingual buprenorphine, a partial opioid agonist, is widely used outside of the United States in the second step of the WHO analgesic ladder. It provides adequate pain relief for patients with mild to moderate pain. Both fentanyl and methadone are well absorbed sublingually, as demonstrated in a study of normal volunteers.106 An oral transmucosal formulation of fentanyl (see above) has been demonstrated to be efficacious in treating breakthrough pain in cancer patients. Morphine is poorly absorbed sublingually but may be effective. Buccal tablets of morphine are effective but require prolonged exposure. Such absorption requires that the tablet remain in contact with the gum for a prolonged period (1 to 2 h) making this approach less practical for most patients.

Oxymorphone, hydromorphone, and morphine are available as rectal suppositories and are effective in managing chronic cancer pain. Studies of sustained-release morphine rectal suppositories in normal volunteers reported no significant differences in morphine absorption between the oral and rectal methods except that rectal absorption was delayed.107

The transdermal fentanyl patch offers a unique route of opioid administration (see above). In the setting of GI malignancy, this route may be especially desirable.

Intravenous Bolus and Infusions

The common use of permanent central catheters to provide intravenous access for patients receiving chemotherapy has expanded the use of this route of administration to manage the patient with chronic cancer pain who is unable to tolerate drugs by the oral route. Intravenous bolus doses of opioids provide the most rapid onset and shortest duration of analgesia. The time to peak effect correlates with the lipid solubility of the opioid and can range from 2 to 5 min for methadone to 10 to 15 min for morphine.108 This mode of administration allows for complete systemic absorption. Intravenous bolus injections are used to titrate opioid dosage in the patient with rapidly escalating pain.109 This approach is most useful in the patient in an acute painful crisis for rapid escalation or for the patient with far advanced disease in the terminal stages of his or her illness. In patients requiring frequent repeated intravenous boluses to maintain analgesia, a continuous infusion often provides a more practical approach. Continuous infusions provide more stable analgesia without the peak and trough effects seen with repeated boluses. Table 78-8 summarizes the specific guidelines for the use of continuous infusions that have been developed.109

Table 78-8

Guidelines for the Management of Continuous Intravenous Infusion of Opioids.

The goal for intravenous infusions in the dying patient needs to be clearly delineated to families and to staff to avoid any concern that such an approach is a form of “slow euthanasia.”110,111 The intent of continuous intravenous infusions in this setting is to provide patients with continuous relief of pain and suffering. However, continuous infusions should not be limited to use in only the dying patient. This approach has been widely used to manage patients with acute postoperative pain, as well as to manage patients with chronic cancer pain in the home setting.112 Patient-controlled pumps are often employed and are discussed below.

Intermittent or Continuous Subcutaneous Infusions

This approach has been particularly useful in obviating the pain management problems of patients who cannot take oral opioids because of nausea or vomiting, gastrointestinal intolerance, or obstruction.113 In patients lacking available venous access, with pain requiring continuous treatment, and with adverse effects from bolus injections, the use of continuous subcutaneous infusions obviates these practical problems and allows patients to be maintained in a hospital or discharged home with adequate pain control. By using a portable infusion pump attached to a 27-gauge butterfly needle, and rotating the subcutaneous sites, this approach has been useful in patients for periods of 24 h to 12 months in chronic cancer pain management.113 The intraclavicular and anterior chest sites provide the greatest freedom of movement for patients. The infusion site is changed every 5 to 7 days, and a wide variety of opioid analgesics, including morphine, hydromorphone, levorphanol, oxymorphone, heroin, and fentanyl, have been used safely and effectively with this approach. Subcutaneous administration of methadone is complicated by the development of cutaneous rashes and inflammatory lesions thought to be a hypersensitivity response. Limited pharmacokinetic studies demonstrate that the bioavailability of drug from subcutaneous sites at steady state varies from 78 to 100%.113

Epidural and Intrathecal Infusions

Although the vast majority of cancer patients receive adequate analgesia with oral opioids, patients who experience intolerable side effects, or who are unable to take medication by mouth, may receive significant relief from epidural and intrathecal infusions.114 Opioid receptor agonists bind to selective sites within the substantia gelatinosa of the spinal cord and produce analgesia without motor or sensory dysfunction.115 Data suggest that approximately 10% of cancer patients require this approach to provide adequate analgesia.116 The combination of low doses of local anesthetics with opioids has expanded the usefulness of this technique in patients with neuropathic pain.

The availability of patient-controlled devices that can be attached to subcutaneous reservoirs to which the epidural catheter is attached has allowed patients to be fully ambulatory when using this technique.117 The pharmacokinetics of epidural opioids suggest that a substantial amount of opioid (10 to 100 times the amount that would be there from a systemic injection) diffuses into cerebrospinal fluid from the epidural space. There is concurrent systemic uptake of the drug that is comparable to an intramuscular injection. Therefore, the epidural route is associated with cerebrospinal fluid as well as systemic uptake of the drug. In contrast, intrathecal administration is associated with significantly less systemic uptake of drug.118,119 The advantage of both these routes of administration is that smaller doses of opioids can be used, and the undesirable central effects, for example, somnolence and respiratory depression, of the opioids can be minimized. However, in a recently published 3-year retrospective outcome study on the use of epidural catheters in the management of chronic cancer pain, technical problems and infections, including epidural abscesses, occurred in a significant number of patients, suggesting that the epidural route may be most useful in patients with limited life expectancy.120 In Cherney's study cited above, of the 12% of patients who received an epidural or intrathecal catheter for cancer pain, the infusion was continued in only 4%.100 New evidence-based guidelines are available to assist with clinical decision-making, highlighting the need for large published controlled studies.121,122

Patient-Controlled Analgesia

This method of opioid administration employs the concept of individualization of analgesic dose in which the patient can titrate the analgesic doses to provide adequate relief. Patients taking oral medications who are instructed in how to titrate their dose are in fact using patient-controlled analgesia (PCA). This term has been more selectively used to describe the use of specifically designed infusion pumps that can deliver a continuous infusion with bolus doses by the intravenous, subcutaneous, or epidural routes. Each pump can be programmed to the needs of the individual patient with a set “lockout time” to prevent patients from overdosing themselves. This approach is most useful for managing the patient with continuous, as well as incident, pain who requires a bolus dose of opioid prior to movement. The availability of PCA pumps—from simple devices to sophisticated computerized systems—combined with the use of intravenous or subcutaneous administration, is a major advance in cancer pain management.123

Use Equianalgesic Dose When Switching to Alternative Routes

For patients who are stabilized on a continuous or subcutaneous route and who need to be converted to the oral dosing route, this is best done by slowly reducing the parenteral dose and substituting equianalgesic oral doses on a fixed schedule over a 2- or 3-day period. This obviates the problems that arise from changing from a route (IV) with a rapid onset of action to one (PO) with a slower onset. When converting a patient from the intramuscular to the intravenous route, we assume that the equianalgesic dose is the same for these two routes. When switching from high doses of morphine or hydromorphone to methadone, conversion ratios suggested by Ripamonti and Bruera, respectively, should be used (see above).79

Adjuvant Drugs

There is a series of adjuvant drugs that is used in patients with pain and cancer.124,125 These drugs have been developed and approved for clinical indications other than analgesia, including nausea, vomiting, anxiety, mania, depression, and seizures. Moreover, there are specific adjuvant drugs for the treatment of neuropathic pain and bone pain. The choice of the drugs must be individualized using the simplest but most potent of combinations.

Antidepressant Drugs

This class of drugs appears to be the most useful in the management of patients with neuropathic pain.126 Their analgesic effects are mediated in part by serotonergic and noradrenergic activity in the central nervous system. Controlled studies in migraine, postherpetic neuralgia, and diabetic neuropathy have demonstrated their efficacy. They appear to be equally useful in controlling chronic burning pain, continuous dysesthesia, and lancinating or shock-like pain common in patients with peripheral nerve injury. Amitriptyline is the most commonly used drug, but newer agents, such as venlafaxine, as well as nortriptyline, imipramine, desipramine, and paroxetine, reportedly are effective.127–129 The suggested dosing schedule for amitriptyline is to start at 10 to 25 mg in a single dose at bedtime with dosing increments of the same amount. Doses can be increased every 1 to 2 days, particularly when using 10 mg tablets. Compliance with the regimen, as well as establishing a therapeutic level, can be facilitated by the assessment of plasma levels. Upward titration should be considered if the levels are below a therapeutic range. The majority of patients will note some response within a week, but it may take 2 to 3 weeks to see an analgesic effect. Of interest, analgesia with amitriptyline is often achieved earlier and at lower dosages in the treatment of neuropathic pain, when compared with its use as an antidepressant. Of all the selective serotonin reuptake inhibitors on the market in the United States, paroxetine has demonstrated efficacy in diabetic neuropathy and has fewer side effects than amitriptyline.129 One study suggests that it may be particularly helpful in managing pruritus in the advanced-cancer patient.130

Anticonvulsant Drugs

Carbamazepine and gabapentin are anticonvulsant drugs that suppress spontaneous neuronal firing and represent the drugs of choice for treating trigeminal neuralgia and other neuropathic pain. In cancer patients, carbamazepine has been used specifically in managing the acute shock-like neuralgic pain in the cranial or the cervical distribution caused by tumor infiltration or surgical injury. This drug has also been effective in patients with stump pain secondary to traumatic neuroma and patients with lumbosacral plexopathy reporting acute lancinating pain. Patients should commonly start at 100 mg at bedtime, slowly titrating up to 400 to 800 mg/d. The minimal effective concentration for analgesia is not known, but evaluation of plasma levels of carbamazepine are helpful in determining compliance and evaluating drug absorption in the individual patient. Carbamazepine is contraindicated in patients with leukopenia because of its independent ability to produce leukopenia. Oxcarbazepine, a derivative of carbamazepine, lamotrigine, and topiramate, may be useful substitutions among other adjuvant agents.131,132

Gabapentin has been shown in controlled trials to be very useful in the treatment of neuropathic malignant and nonmalignant pain.99,133 Its excellent side-effect profile, lack of hepatic metabolism, and lack of any known drug-drug contraindications make it a prime choice. Although small numbers of patients report bothersome gastrointestinal side effects and mental clouding, overall, it is exceedingly well-tolerated up to 4,800 mg/d. Patients start on 100 mg three times a day and titrate upward as warranted. Gabapentin is highly effective for neuropathic pain in randomized, double-blind, controlled trials.133 Other adjuvant drugs for neuropathic pain with demonstrated efficacy include clonazepam, valproic acid, phenytoin, and lamotrigine.124 Promising reports regarding topiramate, a comparatively newer anticonvulsant, are now appearing, suggesting that further study of this agent in treating malignant neuropathic pain is warranted.

Phenothiazine Drugs

Methotrimeprazine has been shown to have definitive analgesic properties in single-dose studies in patients with postoperative pain and chronic cancer pain.134,135 A dose of 15 mg parenterally is equivalent to 15 mg of morphine parenterally. This drug is most useful in the patient who is opioid tolerant, providing temporary analgesia by a nonopioid receptor mechanism. It is most commonly used in the patient with bowel obstruction and pain to avoid the constipating effects of opioid drugs. In patients with pain and opioid-induced nausea and vomiting, it acts as both an analgesic and an antiemetic. In patients who are highly anxious, it is reported to have anxiolytic properties as well. Long-term administration of this drug in patients with cancer pain has not been fully assessed.

Haloperidol is the drug of choice in the management of patients with acute psychosis and delirium. Its role in pain management is to treat drug-induced psychosis, which may result from opioid drugs. Its specific indications are for the treatment of confusional states and hallucinations in patients receiving opioids. Animal studies demonstrate that haloperidol potentiates morphine analgesia. The doses of haloperidol in patients with acute delirium or acute psychotic reaction start with 0.5 to 1 mg orally at bedtime or 1 to 3 times a day, depending on the patient's symptomatology and ability to tolerate the drug.3,136 Olanzapine (Zyprexa) and risperidone (Risperdal) may be useful alternative agents as in some patients, they are associated with fewer parkinsonian side effects. Given its sedative properties, we often prescribe olanzapine, starting at 2.5 mg PO at bedtime, for patients who require both an anxiolytic and neuroleptic pharmacologic intervention.137

Antihistamine Drugs

Hydroxyzine has analgesic effects when combined with morphine or meperidine in doses of 100 mg parenterally.138 Hydroxyzine also has antiemetic and sedative properties, both of which can be desirable in patients with nausea and vomiting and acute anxiety. A recent report suggests that diphenhydramine also may be useful in managing refractory cancer pain.139

Corticosteroids

Corticosteroids are the most widely used general purpose adjuvant analgesics. They may ameliorate pain and produce beneficial effects on appetite, nausea, and mood. They provide analgesia from pain syndromes associated with raised intracranial pressure, acute spinal cord compression, superior vena cava syndrome, metastatic bone pain, neuropathic pain due to infiltration or compression by tumor, and hepatic capsular distention.140 Patients with advanced cancer who experience pain and other symptoms that may respond to steroids are usually given relatively small doses (dexamethasone, 1 to 2 mg twice daily). In patients with epidural spinal cord compression, high doses (dexamethasone, 100 mg IV followed by a slow taper) can be used to manage an acute episode of severe pain.35 Eighty-five percent of patients receiving 100 mg of dexamethasone as a part of a radiotherapy protocol reported significant relief associated with marked reduction in analgesic requirements within 24 h of administration of this dose. Several studies demonstrate prolonged survival times and reduced opioid doses in terminal cancer patients receiving steroids. In patients with prostate cancer, 30 mg of prednisone on a regular basis improves patients' quality of life and reduces their pain symptomatology.140–143 In a controlled study of oral methylprednisolone, patients with pain caused by advanced cancer reported analgesic effects that seemed to stabilize following the introduction of this treatment.144 Pain resulting from tumor infiltration of the brachial and lumbosacral plexus is often improved by the use of steroids. Steroids also improve the headache and radicular pain commonly seen in leptomeningeal disease. Corticosteroids may be particularly helpful in the patient who is admitted to the hospital with far advanced disease and diffuse pain in an acute painful crisis. We often use a large dose of steroids in this setting, 100 mg of dexamethasone intravenously, to stabilize the patient and to provide rapid symptom control. However, steroid psychosis can complicate steroid use and occur during dose escalation and withdrawal. Steroid-induced psychosis is frequently responsive to haloperidol.

Neurostimulant Drugs

Patients with cancer pain should not be inadequately treated due to opioid-induced sedation. We commonly add a neurostimulant agent to manage this side effect when it occurs. In a controlled, repeated-dose trial, oral methylphenidate reversed opioid-induced sedation and provided supplemental analgesia in a population of patients with cancer pain.145,146 Recent anecdotal evidence suggests that pemoline in starting doses of 18.5 mg/d may also be useful to counter opioid-induced sedation, but controlled studies are lacking. Pemoline is rarely associated with significant hepatic dysfunction and should be used with appropriate caution. Approved by the FDA for the management of narcolepsy, modafinil may also be useful at a starting dosage of 100 mg bid. As its site of action is more restricted to the hypothalamus than the older, amphetamine-derived agents, there is some evidence to suggest that it may be better tolerated.147 Other recent studies suggest that caffeine and the cholinergic agonist approved for patients with Alzheimer disease, donepezil (Aricept), may be useful in treating opioid-induced sedation.148,149

Topical and Systemic Local Anesthetics

Topical drugs are most useful in the management of painful cutaneous and mucosal lesions and as a premedication prior to skin puncture. Controlled studies have demonstrated the effectiveness of a eutectic mixture of local anesthetics (EMLA) of 2.5% lidocaine and 2.5% prilocaine in reducing pain associated with venipuncture, lumbar puncture, and arterial puncture.150,151 Viscous lidocaine is frequently used in the management of oropharyngeal ulceration.152 A topical lidocaine patch has also been approved by the FDA for the management of postherpetic neuralgia.153

Oral local anesthetic drugs have been studied in the management of neuropathic pain. Mexiletine is the safest of these drugs with dosing starting at 100 to 150 mg/d. One open-label study demonstrated efficacy in patients with diabetic neuropathy.154 If side effects do not occur, the dose can be increased by 100 mg every few days until a maximum dose of approximately 300 mg three times per day is reached. Cardiac monitoring should be used during dose escalation.

Adjuvants for Bone Pain

Bisphosphonate drugs, pamidronate (Aredia), zoledronate (Zometa), clodronate, and etidronate (Didronel), bind to bone hydroxyapatite inhibiting osteoclast activity and are highly effective in the management of metastatic disease to the bone and in multiple myeloma. Recent large, randomized, double-blind studies have demonstrated their efficacy for relieving bone pain as well as for reducing skeletal complications.155–157 Pamidronate, given as a 90 mg monthly infusion, was recently shown to be safe and effective for as long as 2 years.158 While the currently available bisphosphonates may not affect overall survival, they are very useful palliative agents. Recent studies suggest that bisphosphonates also may inhibit bony attachment of cancer cells, decrease cytokine production, and induce apoptosis of tumor cells.159,160 The new generation of bisphosphonates may be useful not only for pain and reduction of skeletal complications but also for improved survival.

Strontium-89, among other radiopharmaceuticals, reportedly is effective in patients with bone pain secondary to widely metastatic disease.161,162 Because this treatment can compromise marrow reserve and irreversibly lower platelet counts, its use is not recommended if future myelosuppressive chemotherapy is under consideration, or if significant thrombocytopenia is present. Typically, pain relief develops within 6 weeks and is sustained for a median duration of 6 months.

A prospective nonrandomized trial of subcutaneous salmon calcitonin demonstrated significant efficacy in treating pain secondary to bone metastases.163 Further controlled studies with larger populations are needed.

Other Adjuvants

The oral antitussive dextromethorphan is an NMDA receptor antagonist as well as a calcium channel blocker. In experimental models, dextromethorphan prevents and reverses the development of tolerance.164,165 In a cancer population, however, dextromethorphan given at 30 mg three times a day was found to be ineffective in providing analgesia when compared to conventional therapies based upon the WHO analgesic ladder.166

Octreotide, a somatostatin analog with analgesic and palliative effects, inhibits pancreatic, gastric, and intestinal secretions, and facilitates water and electrolyte absorption.167,168 It may be useful for pain, particularly in the setting of bowel obstruction.

Epidural clonidine may be useful in cancer patients with severe pain unable to be optimally managed on opiates because of side effects.169 In a randomized, placebo-controlled trial in the setting of intractable cancer pain, 45% of patients received analgesia versus 21% in the placebo group.170 Clonidine was especially useful in patients with neuropathic pain. Given its properties as an α2-adrenergic agonist, blood pressure and heart rate must be continuously monitored.

Anticipate and Treat Side Effects

A number of side effects associated with opioid analgesics can, depending upon the circumstance, be characterized as desirable or undesirable. Respiratory depression, sedation, confusion, nausea, vomiting, constipation, and multifocal myoclonus are the most common side effects encountered in the clinical use of opioids.

Respiratory Depression

Respiratory depression is potentially the most serious adverse effect. The morphine-like agonists act on brainstem respiratory centers to produce, as a function of dose, increasing respiratory depression to the point of apnea. In man, death from an overdose of a morphine-like agonist is nearly always a result of respiratory arrest. Therapeutic doses of morphine may depress all phases of respiratory activity: rate, minute volume, and tidal exchange. However, as carbon dioxide accumulates, it stimulates central chemoreceptors resulting in a compensatory increase in respiratory rate, which masks the degree of respiratory depression.

At equianalgesic doses, all the morphine-like agonists produce an equivalent degree of respiratory depression. Respiratory depression most commonly occurs in opiate-naïve patients after acute administration of an opioid and is typically associated with other signs of central nervous system (CNS) depression, including sedation and mental clouding. Tolerance develops rapidly to this effect with repeated drug administration, allowing the opioid analgesics to be used in the management of chronic cancer pain without significant risk of respiratory depression. If respiratory depression does occur, it can be rapidly reversed by the administration of the specific opioid antagonist, naloxone. The use of naloxone should be based on the prior opioid exposure of the patient. In patients who chronically receive opioids and who develop respiratory depression, the standard 4 mg naloxone dose should be diluted in 10 cc of saline to 0.4 mg/mL and slowly titrated in the patient to reverse respiratory depression. This approach prevents the patient from experiencing excruciating pain with reversal of the analgesic effects of the current opioid while providing improved respiratory function.

Patients who take drugs with a long half-life, such as methadone or levorphanol, or who take a slow-release morphine preparation, or who use a transdermal patch may require a continuous infusion of naloxone to maintain a stable respiratory pattern. The dose of naloxone used continuously should be calculated from the initial dose used to reverse depression. Commonly, 1.2 mg of naloxone is diluted in 250 mL of saline and slowly titrated to the needs of the individual patient. Before administering naloxone to a comatose patient, an endotracheal tube should be placed to prevent aspiration given the possibility of respiratory compromise, excessive salivation, and bronchial spasm. In patients who are receiving meperidine chronically, naloxone may precipitate seizures by blocking the depressant action of the meperidine and allowing the convulsant activity of the active metabolite, normeperidine, to be manifest. Therefore, in respiratory depression from meperidine, naloxone must be administered with extreme caution, and diazepam or lorazepam should be available for intravenous injection to treat any potential seizures.

Patients who develop respiratory depression while receiving opioids must be evaluated comprehensively to assure that the proper cause for the clinical change is understood. Naloxone has been administered inappropriately by physicians who assumed that the clinical change they were observing was a consequence of opioids when, in fact, it was a result of other critical diagnoses (eg, sepsis, brain herniation, subarachnoid hemorrhage).171

In general, naloxone should be reserved for use in hemodynamically unstable patients. If a patient's respirations are slowed but other vital parameters are stable, we recommend vigorously stimulating the patient, lowering the rate of the opioid infusion, and reconsidering substituting alternative analgesic agents.

Sedation

This side effect is particularly bothersome for the patients who are trying to maintain their normal daily activities of work and social activities. Tolerance develops to this effect within several days. In patients who are excessively sedated but obtaining adequate analgesia, the use of caffeine, modafinil, dextroamphetamine, or methylphenidate may counteract this effect (Table 78-9).

Table 78-9

Algorithm for the Management of Persistent Opioid-Induced Sedation.

Confusion and Hallucinations

Cognitive impairment can result from opioid administration and should be clearly defined and separated from opioid sedative effects. Confusion, hallucinations, and acute psychosis may result from single or multiple opioid doses. All patients with mental status changes on opiates must receive a complete medical and neurologic evaluation to ascertain the etiology of the problem. If opiates are the culprit, tolerance develops to these effects. Dose adjustment, use of additional agents to counteract side effects, and rotation to another opioid may be very useful strategies (Table 78-10).

Table 78-10

Algorithm for the Management of Confusion/Delirium in Cancer Patients Receiving Opioids.

Nausea and Vomiting

Nausea and vomiting can occur from opioid analgesics by their action on the medullary chemoreceptor trigger zone (CTZ). The incidence of nausea and vomiting is markedly increased in ambulatory patients, suggesting that the opioid drugs also alter vestibular sensitivity. The ability of an opioid analgesic to produce nausea and vomiting appears to vary with the drug and the patient so that some advantage may result from switching to an equianalgesic dose of another opioid. Alternatively, an antiemetic may be useful in combination with the opioid. Commonly used drugs for control of nausea and vomiting associated with opioids include prochlorperazine, metoclopramide, scopolamine, lorazepam, dexamethasone, and the 5-hydroxytryptamine3 (5-HT3) antagonists, ondansetron and granisetron. Tolerance to this side effect generally develops within 2 to 3 days.

Constipation

Constipation is the most common adverse effect of the opioid analgesics. These drugs act at multiple sites in the gastrointestinal tract and spinal cord to produce a decrease in intestinal secretions and peristalsis, resulting in a dry stool and constipation. Tolerance develops slowly, if at all, to the smooth muscle effects of opioids so that constipation usually persists when these drugs are used for chronic pain.

Provision for a regular bowel regimen that includes cathartics and stool softeners should be instituted to diminish this effect. A wide number of approaches have been suggested.172 A high-fiber diet alone or in combination with a bulk laxative containing bran, methylcellulose, or psyllium may be tried; however, most patients who require opioids for pain control will require both a stool softener such as docusate sodium (Colace) and a laxative such as senna (Senokot) on a daily basis. If ineffective in 2 to 3 days, and depending upon the patient's medical status, the use of an osmotic cathartic such as lactulose should be the next step. Whatever approach is taken, it should be used regularly and aggressively to prevent the onset of bowel obstruction and, secondarily, induced pain.

Multifocal Myoclonus

High doses of all the opioid analgesics can produce multifocal myoclonus. This complication is most prominent with the use of repeated administration of large parenteral doses of meperidine (250 mg or more per day), but can occur from escalating doses of all opioid-based analgesics. One approach is to switch the patient to an alternative opioid. If myoclonus is a complication of high-dose opioids in a dying patient, the use of anxiolytics such as clonazepam (Klonopin) to suppress the myoclonic jerks offers an alternative approach. The use of intravenous benzodiazepines, barbiturates, and anticonvulsants has been reported anecdotally to be of some value in managing this symptom.173,174

Tolerance

Tolerance is a pharmacologic effect characterized by the fact that, with repeated administration, increasing doses are necessary to provide the same effect. Dose escalation in the cancer patient most often is a sign of disease progression and should prompt a thorough medical investigation.175 Tolerance develops at different rates for the various opioid effects. Tolerance to respiratory depression, as discussed above, develops rapidly in contrast to slow tolerance to the constipating effects. The first sign of analgesic tolerance is the patient's report that the duration of analgesic effect is reduced from its initial interval. The patient reports the shorter duration of pain relief and is often labeled as a clock-watcher, a sign that is often misinterpreted by healthcare professionals as an early sign of addiction. From studies in cancer patients, it is now well recognized that although tolerance does occur, it is not the sole or even overriding factor in the dose escalation that occurs in the use of opioids in patients with pain and cancer. Rather, it is often progression of disease that dictates the need for escalating doses of drugs, which implies that it is change in the pain stimulus requiring an increase in the dose of the drug. It is common for patients to increase their dose of opioid analgesic during the titration phase until they have reached steady state and are stabilized on a dose. This stabilized dose may increase over a 2 to 4 week period, but the increase tends to be slow, by one-tenth to one-fifth of the daily dose of the drug. When the pain stimulus changes, either increases or decreases, there is a rapid change in the patient's requirements for analgesics. It is critical to remember that in patients with increasing pain, the degree of relief of pain and its analgesic effect are based on a log-dose relationship; consequently, doubling the dose may be necessary to provide adequate analgesia. In patients who have effective pain control, it is always useful to try to expand the time interval between the doses to determine whether the patient can reduce his/her analgesic requirements.

In the clinical realm, it is important to recognize that there is no limit to tolerance. A wide range of opioid requirements in individual patients has been reported, with average requirements of patients with advanced disease in the last 4 weeks of life between 400 and 600 mg of morphine equivalents per 24 h.105 As many as 10% of patients require very large doses of opioids in the range of greater than 5,000 mg of morphine per 24 h.105

In their landmark study, in 1991, Trujillo and Akil demonstrated that the NMDA receptor antagonist MK-801 attenuated the development of morphine-associated tolerance and dependence without affecting morphine analgesia.176 Other noncompetitive NMDA antagonists have also inhibited the development of opioid tolerance, suggesting a possible role in the treatment of chronic pain.177 Through the release of substance P and glutamate, NMDA receptors facilitate and prolong nociceptive impulses and may participate in critical functions of the central nervous system including memory and long-term potentiation, neuronal degeneration, and excitotoxic injury.178 Both the d and l isomers of methadone, unlike the other available opioids, bind as noncompetitive antagonists to the NMDA receptor and animal studies show that d-methadone provides analgesia through a nonopioid mechanism.179 Ongoing research as to the role of the NMDA in potentiating analgesia and tolerance is currently being done in laboratory and clinical trials.180,181

Differentiate Physical Dependence from Psychological Dependence

Physical dependence describes the phenomenon of withdrawal when an opioid is abruptly discontinued or when a opioid-mixed agonist-antagonist or antagonist (eg naloxone) is administered. The severity of this withdrawal is a function of the dose and the duration of prior opioid administration. Prior exposure to an opioid agonist can greatly increase a patient's sensitivity to an antagonist. To prevent acute withdrawal, patients receiving opioids should be tapered off their drug. Twenty-five percent of the previous daily dose will prevent signs and symptoms of withdrawal. This dose is also referred to as the detoxification dose and is given in four divided doses. The initial dose is given for 2 days and then decreased by one-half, administered in four divided doses for 2 days, until the total daily dose of 10 to 15 mg/d (for morphine) is reached. After 2 days on this dose, the opioid can be discontinued. The degree of physical dependence is related to the opioid dose and the time of opioid exposure.

In contrast to physical dependence, psychological dependence describes a behavioral pattern of drug use characterized by continued craving for an opioid for effects other than pain relief. An overwhelming involvement with drug use and procurement as compulsive traits are the salient features of this type of dependence. Cancer patients chronically receiving opioids become physically but not psychologically dependent on their drugs. Patients' and physicians' fears of addiction are a major barrier to adequate cancer pain management.182–184 Patients with poorly managed and/or undertreated pain may mimic the signs of psychological dependence, displaying a behavioral pattern known as “pseudoaddiction.”185 The prevalence of true psychological dependence among patients receiving opioids for chronic medical illness is extremely rare. The Boston Collaborative Drug Surveillance Study reported an incidence of 0.4%.186 A better understanding of the legal restrictions to opioid use, coupled with broad educational programs beginning with governmental initiatives as part of the WHO Cancer Pain Relief Program, has helped to clarify some of these issues and identify the proper role of opioid analgesics in cancer pain management.187

Which drug is used as a palliative treatment for a client with tumor and do spinal cord compression?

Which drug is used as a palliative treatment for a client?

Which medications should the nurse caution the client about taking while receiving an opiod analgesic?

Which method of medication administration provides the client with the greatest first pass effect oral sublingual intravenous subcutaneous?