Basic Principles of Cancer Pain Management
Acetaminophen and Nonsteroidal Anti-inflammatory Drugs
Opioids
        Opioid types
        Principles of opioid administration
        Route of administration
        Drugs and routes to be avoided
        Side effects of opioids
Adjuvant Drugs

Basic Principles of Cancer Pain Management

The World Health Organization (WHO) has described a three-step analgesic ladder as a framework for pain management.[1] It involves a stepped approach based on the severity of the pain. If the pain is mild, one may begin by prescribing a Step 1 analgesic such as acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID). Potential adverse effects should be noted, particularly the renal and gastrointestinal adverse effects of the NSAIDs. If pain persists or worsens despite appropriate dose increases, a change to a Step 2 or Step 3 analgesic is indicated. Most patients with cancer pain will require a Step 2 or Step 3 analgesic. Step 1 can be skipped in those patients presenting at the onset with moderate-to-severe pain in favor of Step 2 or Step 3. At each step, an adjuvant drug or modality such as radiation therapy may be considered in selected patients. WHO recommendations are based on worldwide availability of drugs and not strictly on pharmacology.

Analgesics should be given “by mouth, by the clock, by the ladder, and for the individual.”[1] This requires regular scheduling of the analgesic, not just as needed. In addition, rescue-doses for breakthrough pain need to be added. The oral route is preferred as long as a patient is able to swallow. Each analgesic regimen should be adjusted for each patient’s individual circumstances and physical condition.

NSAIDs are effective for relief of mild pain and may have an opioid dose–sparing effect that helps reduce side effects when given with opioids for moderate-to-severe pain. Acetaminophen is included with aspirin and other NSAIDs because it has similar analgesic potency, though it lacks peripheral anti-inflammatory activity.[2] Side effects can occur at any time, and patients who take acetaminophen or NSAIDs, especially elderly patients, should be followed carefully.[3-5] There is growing debate about whether NSAIDs are useful and have significant opioid-sparing effects. One meta-analysis [6] suggests that the usefulness of NSAIDs is limited and that they do not significantly spare opioid doses. Another study suggests that NSAIDs are useful and reduce the need for opioid dose increases; however, only patients with pain progression after 1 week of opioid stabilization were selected for the study.[7]

The coxibs are a subclass of NSAIDs designed to selectively inhibit cyclooxygenase-2 (COX-2).[8] Development of these drugs was based on the hypothesis that COX-2 was the source of prostaglandins E₂ and I₂, which mediate inflammation, and COX-1 was the source of the same prostaglandins in gastric epithelium, with the potential advantage over traditional NSAIDs of less gastrointestinal ulceration and bleeding and the absence of platelet inhibition. Direct comparisons between COX-2 inhibitors are few. A systematic meta-analysis of COX-2 inhibitors compared with traditional NSAIDs or different COX-2 inhibitors for postoperative pain suggests that rofecoxib, 50 mg, and parecoxib, 40 mg, are equipotent to traditional NSAIDs for postoperative pain after minor and major surgical procedures and have a longer duration of action after dental surgery. Rofecoxib was found to provide superior analgesic effect compared with celecoxib, 200 mg. There were insufficient data to comment on toxicity.[9]

There are three coxibs that were approved by the U.S. Food and Drug Administration (FDA): celecoxib, rofecoxib, and valdecoxib. On September 30, 2004, rofecoxib was withdrawn from the market after a study demonstrated that subjects in a colon cancer prevention trial taking the drug at higher-than-typical doses on a long-term basis had a significant increase in the incidence of serious thromboembolic complications. The question that remains unanswered is whether the increased risk applies to all COX-2 inhibitors, with the caution that the burden of proof rests with those who might claim that this is a problem for rofecoxib alone and does not extend to other coxibs.[8,10] On April 7, 2005, valdecoxib was withdrawn from the market. FDA is also asking manufacturers of all marketed prescription NSAIDs, including celecoxib (Celebrex) to revise the labeling (package insert) for their products to include a boxed warning, highlighting the potential for increased risk of cardiovascular events and/or the serious, potentially life-threatening gastrointestinal bleeding associated with use of these drugs.

Dosage

• Use patient response to determine the effective dosing interval for aspirin, acetaminophen, and other NSAIDs listed in the Dosing Recommendations for Acetaminophen and NSAIDs table. When pain relief is not attained with the maximum dosage of one NSAID, try other drugs within this category before abandoning NSAID therapy.

Route of administration

• Use readily available oral tablets, capsules, or liquid. During intervals of nausea and vomiting, use suppositories. Ketorolac tromethamine is the only NSAID available for parenteral use.

Contraindications

• Patients taking NSAIDs are at risk for platelet dysfunction that may impair blood clotting. The table below lists NSAIDs with minimal antiplatelet activity.

Other side effects

• Follow patients carefully for adverse effects, which range from mild gastrointestinal discomfort to more serious problems including the following:
  • Gastric ulceration.
  • Hepatic dysfunction.
  • Myocardial infarction.
  • Renal failure.

  Because both NSAIDs and other drugs (e.g., warfarin, methotrexate, digoxin, cyclosporine, oral antidiabetic agents, and sulfonamide-containing drugs) are highly protein-bound, there is potential for altered efficacy or toxicity when they are given simultaneously.

Opioids, the major class of analgesics used in management of moderate-to-severe pain, are effective, are easily titrated, and have a favorable benefit-to-risk ratio.

The predictable consequences of long-term opioid administration—tolerance and physical dependence—are often confused with psychological dependence (addiction) that manifests as drug abuse. This misunderstanding can lead to ineffective prescribing, administering, or dispensing of opioids for cancer pain. The result is undertreatment of pain.[11]

Clinicians may be reluctant to give high doses of opioids to patients with advanced disease because of a fear of respiratory depression. Many patients with cancer pain become opioid tolerant during long-term opioid therapy. Therefore, the clinician’s fear of shortening life by increasing opioid doses is usually unfounded.

Opioids are classified as full morphine-like agonists, partial agonists, or mixed agonist-antagonists, depending on the specific receptors to which they bind and their activity at these receptors. The benefits of using opioids and the risks associated with their use vary among individuals.

Morphine is the most commonly used opioid in cancer pain management, largely for reasons of availability and familiarity;[12] however, it is useful to be familiar with more than one type of opioid. Wide interindividual variability in response to both the analgesic and adverse effects of opioids is recognized.[13] Some patients may not experience adequate pain control despite appropriate dose adjustments, while others may develop intolerable adverse effects to one particular opioid (see below). Alternative opioids include hydromorphone, oxycodone, methadone, and fentanyl. Knowledge of several medications and formulations give the caregiver much more flexibility in tailoring a regime to a particular patient’s needs.

Short-acting opioids are generally recommended when opioid therapy is being initiated for the first time or when patients are medically unstable or the pain intensity is highly variable. Once stable, patients can be switched to a controlled-release or slow-release formulation. This is more convenient and promotes compliance. (Refer to the Approximate Dose Equivalents for Opioid Analgesics table in the Principles of Opioid Administration section of this summary.)

Full agonists

• Morphine, hydromorphone, codeine, oxycodone, hydrocodone, methadone, levorphanol, and fentanyl are classified as full agonists because their effectiveness with increasing doses is not limited by a ceiling. Full agonists will not reverse or antagonize the effects of other full agonists given simultaneously.

Morphine

• The most commonly used opioid, morphine, is readily available in several forms, including sustained-release (8–24 hours duration of effectiveness) formulations for oral administration.

Other agonists

• For the patient who experiences dose-limiting side effects with one oral opioid (e.g., hallucinations, nightmares, dysphoria, nausea, or mental clouding), other oral opioids should be tried before abandoning one route in favor of another.

Methadone

• Methadone has had a revival in interest for the management of cancer pain. Published reports have been in the form of case reports,[14-20] outcome surveys,[21-25] and reviews.[26-28]Success has been reported with oral, intravenous (IV), and suppository methadone use. Subcutaneous methadone has been reported to cause tissue irritation at the injection site but has been used effectively in some patients without clinically significant local toxicity.[29]

  Methadone is a synthetic opioid agonist that has been reported to have a number of unique characteristics. These include excellent oral and rectal absorption, no known active metabolites, prolonged duration of action resulting in longer administration intervals, and lower cost than other opioids. Methadone is available as a pill, an elixir, and for parenteral use. Methadone has an average oral bioavailability of approximately 80% (range, 41%–99%).[30]

  Morphine is the international gold standard for first-line treatment of cancer pain. Methadone, however, can be considerably less expensive than existing rapid-release or sustained-release morphine or other opioid options. A randomized trial of 103 patients compared the effectiveness and side effects of morphine and methadone as first-line treatments for cancer pain. The outcome of successful pain management was similar for both groups; however, there were significantly more opioid-related dropouts in the methadone group. This study did not demonstrate superior analgesic effectiveness or overall tolerability of methadone over morphine as a first-line treatment for cancer pain. Despite this finding, the authors of this report suggested that study limitations did not allow definitive conclusions that methadone could not be a useful first-line opioid. Further research exploring other doses and schedules of methadone should still be explored.[31]

  Because of its long and unpredictable half-life and relatively unknown equianalgesic dose as compared with other opioids, methadone has been generally used by pain specialists with experience in its use. The utility of methadone in cancer pain and difficult cancer pain syndromes such as neuropathic pain has become more widely appreciated and has gained increasing acceptance for use in hospital and hospice settings and by clinicians who are not pain specialists.[32] The methadone preparation widely used in the United States is a racemic mix of the d-isomer and l-isomer of methadone. The d-isomer has antagonist activity at the N-methyl-D-aspartate (NMDA) receptor and may be beneficial in controlling neuropathic pain.

  Another controversy related to methadone concerns possible prolongation of QTc interval, leading to torsades de pointes and ventricular arrhythmia. A number of studies have raised the concern that methadone may be associated with prolonged QT interval and may lead to torsades de pointes. Several retrospective case reports suggest that parenteral methadone or oral methadone in high doses could be associated with this adverse effect.[33-36] Chlorobutanol has been implicated; although this substance is present in parenteral solutions, it is not found in oral formulations.[37] Another series of 132 patients taking methadone revealed statistically significant mean increases in QTc of 10.2 to 13.2 milliseconds, yet no episodes of torsades de pointes were reported.[36] This result raises the issue of the clinical significance of this effect. In another retrospective review of 520 patients treated with methadone for cancer pain, no change in QTc was seen in the 56 patients who had electrocardiograms 3 months before and after starting methadone.[38,39] Avoidance of concomitant medications that prolong QT interval [37] or that share common metabolism pathways with methadone [38] is recommended. In high-risk situations, clinicians could consider electrocardiogram monitoring and other clinical precautions such as correcting electrolyte abnormalities.

  When converting from another opioid to methadone, the calculated equianalgesic dose ratio of methadone varies depending on the oral morphine-equivalent daily dose (MEDD) of the previous opioid.[40,22] One guideline for choosing an appropriate initial dose of methadone based on the oral MEDD of the previous opioid is shown in the table below. For example, a patient who has been using sustained-release morphine at 80 mg every 8 hours (240 mg/day) would be appropriately switched to methadone at a dose of 10 mg every 8 hours (30 mg/day, an 8:1 conversion ratio). In contrast, a patient who is taking sustained-release morphine at a total daily dose of 60 mg/day might be switched to an oral methadone dose of 5 mg every 8 hours (15 mg/day, a 4:1 conversion ratio).

  Method 1: Initial Methadone Dose Based on Oral MEDD*
  Enlarge

  Oral MEDD (mg/d)	Initial Dose Ratio (oral morphine:oral methadone)
  <30	2:1
  30–99	4:1
  100–299	8:1
  300–499	12:1
  500–999	15:1
  >1,000	20:1 or greater**

  
  

  *Reprinted with permission from Fisch and Cleeland [41]

  **Great caution must be used when converting to methadone when very high opioid doses have been used. Often, only a portion of the total opioid dose is converted initially, with further conversions taking place over several days to weeks.

  
  

  To be conservative, one might estimate that methadone is roughly twice as potent when administered via IV versus oral administration. Thus, a patient with well-controlled pain on a stable oral methadone dose of 10 mg every 8 hours might be given IV methadone at an initial dose of 5 mg every 8 hours if IV use is necessary. Subcutaneous use of methadone may cause skin irritation in some patients but has been used successfully.

  In addition to the method described in the table above, several methods of switching to methadone have been proposed.[42,22,43-46] Some rely on patient-controlled analgesia with fixed doses and flexible intervals, some require fixed intervals and fixed doses, while others stagger the conversion over a few days. Whatever method is chosen, this kind of switch can be safe and effective as long as regular assessments are provided over time, and there is an appreciation of the equianalgesic dose ratio of methadone to morphine in opioid-tolerant patients.

  • Method 2: Staggered or 3-day Switchover

    One approach calls for a gradual switch over 3 to 5 days to decrease the risk of relative overdosing. An equianalgesic dose of methadone is first calculated, using an equianalgesic dose ratio of morphine to methadone of 10:1 (i.e., methadone being approximately ten times more potent than morphine). The caveat in using a ratio of 10:1 is that variations in ratios have been noted, depending on the dose of the previous opioid. The ratio may be much higher (12:1 or even higher) in patients being switched from high doses of morphine to methadone. The following example is given to illustrate this method: A patient who is on the equivalent of 450 mg per day of oral morphine (quick-release morphine 75 mg orally every 4 hours) needs to be switched to methadone. Using a ratio of 10:1, the predicted equivalent daily oral dose of methadone, once the switch is completed, will be 45 mg. On day 1 of the switch, the daily morphine dose is reduced by one third to approximately 300 mg per day (morphine 50 mg orally every 4 hours) and one third of the predicted daily methadone dose is added, divided into three doses per 24 hours (i.e., methadone 5 mg orally every 8 hours). Morphine continues to be given for rescue doses. On day 2 of the switch the patient is reassessed, and if no problems have developed, the morphine dose is reduced by another third (i.e., morphine 25 mg orally every 4 hours) and the methadone dose is increased by another third (i.e., methadone 10 mg orally every 8 hours). On day 3, the patient is reassessed. If there are complications such as significant somnolence, but the pain is still not under good control, the methadone dose is increased to 15 mg every 8 hours and the morphine is discontinued. On day 3, methadone or a short half-life opioid is added as a rescue dose as needed. The rescue dose is calculated at 5% to 15% of the total daily dose. On day 3, if the patient has good pain control but shows signs of relative overdosing such as significant somnolence, the morphine is discontinued without any increase in the methadone dose (i.e., it remains at the day 2 level or may even be decreased if needed).

  
  
  
  • Method 3: Ad Libitum [42]

    This approach calls for the previous dose to be discontinued and a single fixed-dose of methadone to be given at the start, calculated using an equianalgesic dose ratio of morphine to methadone of 10:1 (i.e., morphine 10 mg being roughly equivalent to 1 mg of methadone), but to a maximum of 50 mg of methadone per dose. After the initial single priming dose, the same dose is administered every 3 hours as needed. The clinician observes the patient and when the demand for rescue doses reduces or stabilizes (indicating steady-state being reached), which is usually on day 4 to 7, the daily requirement is calculated and the dose is given every 8 to 12 hours.

  
  
  
  • Method 4: Initial Priming Followed By Variable Conversion [43]

    In this method, an opioid-naïve patient is started on 3 to 5 mg of methadone every 8 hours and a nonnaïve patient is started on a dose of methadone that is equivalent to 50% of the estimated daily morphine dose. These doses are initially given for 3 days. Once the patient has acceptable pain relief for 6 to 8 hours, the dose is changed to a single fixed-dose once a day and rescue doses are given as needed. This method is probably best suited for opioid-naïve patients (in relatively unlikely situations where more frequently used opioids such as morphine are not available) or patients who are, for one reason or another, being switched from relatively low doses of morphine or other opioids.

  
  
  
  • Method 5: German Model [45]

    This method is suggested when patients are being switched from high equivalent daily doses of morphine (>600 mg orally per day). The morphine or other opioid the patient is receiving is stopped. Methadone at a dose of 5 to 10 mg orally is started every 4 hours and rescue-doses of 5 to 10 mg every hour are allowed as needed. On the second to third days of the switch, the methadone dose is increased by up to 30% every 4 hours until sufficient pain relief is achieved and no significant adverse effects are noted. After exactly 72 hours following the switch to methadone, the dose is changed from every 4 hours to every 8 hours, and the interval of rescue doses is increased to every 3 hours as needed at the same single dose as established on days 2 to 3. The dose can then be increased by up to 30% if further upward titration is required.

  
  
  

  In some countries there are restrictions that do not apply to other opioids on the ability of physicians to prescribe methadone. In the United States, this pertains to methadone for maintenance of addiction. Methadone is not restricted when used for pain management; however, physicians should carefully document the use of methadone.[47] It should be noted that ratios are different for switching from methadone to a morphine-like opioid.[22]

Meperidine (Demerol)

• Useful for brief courses (a few days) to treat acute pain, meperidine is not recommended in treating persistent cancer pain because of its short duration of action (2.5–3.5 hours) and its neurotoxic metabolite, normeperidine. Accumulation of this metabolite, particularly when renal function is impaired, causes central nervous system (CNS) stimulation that may lead to delirium or seizures. Seizures are typically preceded by development of multifocal myoclonus, which can be used as a warning sign.

Tramadol

• Tramadol can be considered an atypical opioid analgesic that has a dual action. It is a weak mu opioid agonist that also inhibits the reuptake of norepinephrine and serotonin.[48,49] It is believed that both mechanisms work synergistically to provide analgesic benefit with a potency that is approximately one-tenth that of morphine [50] and approximately equivalent to codeine. The most common side effects reported with tramadol are drowsiness, constipation, dizziness, nausea, and orthostatic hypotension.[48] There is also a risk of precipitating seizures in patients with a previous history or in patients who are receiving medications that could reduce the seizure threshold. The use of other serotonergic medications (e.g., selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]) together with tramadol has the potential to increase the risk of the serotonin syndrome. Tramadol is available in short- and long-acting formulations and in fixed combination with acetaminophen. The recommended starting dose of oral tramadol is 50 mg 1 or 2 times a day, with gradual titration up to a maximum of 400 mg per day.[48] There is also the option of using tramadol via the rectal or subcutaneous route in patients who are unable to tolerate oral medication.[51,52]

Partial agonists

• Partial agonists such as buprenorphine have less effect than full agonists at opioid receptors. They are subject to a ceiling effect and thus are less effective analgesics.

Mixed agonist-antagonists

• Mixed agonist-antagonists block or are neutral at one type of opioid receptor while activating a different opioid receptor. Mixed agonist-antagonists are contraindicated for use in the patient receiving an opioid agonist because they may precipitate a withdrawal syndrome and increase pain. Mixed agonist-antagonists include pentazocine (Talwin), butorphanol tartrate (Stadol), dezocine (Dalgan), and nalbuphine hydrochloride (Nubain). Their analgesic effectiveness is limited by a dose-related ceiling effect.

Most patients with cancer pain require fixed-schedule dosing to manage the constant pain and prevent the pain from worsening.[53] An Italian study of patients whose baseline pain was well controlled on morphine when admitted to a palliative care unit found that most episodes of breakthrough pain were rapidly controlled with IV morphine equivalent to 20% of the calculated equianalgesic total daily dose. Adverse effects were uncommon.[54] An as-needed rescue dose (breakthrough dose) should be combined with the regular fixed-schedule opioid to control the episodic exacerbation of pain, often referred to as breakthrough pain. When this pain is elicited by an action such as weight-bearing, breathing, or defecation, it is termed incident pain. Rescue or breakthrough doses can be given hourly or more frequently as needed, depending on route of administration, pharmacokinetic properties of the drug, and presence or absence of side effects. The breakthrough dose is generally calculated to be 10% to 20% of the total dose of the fixed schedule.[55] Adherence rates are improved when patients are prescribed around-the-clock opioids compared with as-needed prescribing.[56] Preliminary data suggest that the intensity of incident pain related to bone metastases may be diminished by increasing the dose of the scheduled opioid above that needed for control of baseline pain, while maintaining it below that associated with the development of limiting side effects.[57]

Dosage

• The appropriate dosing interval is determined by the opioid and formulation used. The analgesic effects of short-acting oral opioids such as morphine, hydromorphone, codeine, and oxycodone begin within a half hour after administration and last for approximately 4 hours. The dosing interval of these drugs is usually 4 hours. In patients given controlled-release formulations of morphine, hydromorphone, codeine, or oxycodone, relief should begin in 1 hour, peak in 2 to 3 hours, and last for 12 hours (controlled-release hydromorphone and codeine are not available in the United States); these formulations are usually prescribed in 12-hour intervals. A small group of patients, however (10%–20% of those on 12-hour controlled-release formulations), may require administration every 8 hours. The analgesic effect of transdermal fentanyl begins approximately 12 hours after the application of the patch, peaks in 24 to 48 hours, and lasts for approximately 72 hours. Patches are therefore changed every 72 hours. In a select group of patients who consistently experience end-of-dose failure despite increases in the patch doses, the dosing interval can be increased to every 48 hours (<10% of patients on fentanyl patches). Transdermal fentanyl is not recommended for control of acute pain or poorly controlled pain because there is a delayed onset of action until reaching steady-state either with new use or with a change in the dose. Patients receiving transdermal fentanyl may be switched to a continuous IV or subcutaneous infusion of fentanyl using a conversion ratio of 1:1 to facilitate more rapid titration.[58]

Dose titration

• To date, dose titration is largely patient-driven, as determined by the balance of analgesia with side effects. For example, while morphine dose correlates with peak-and-trough plasma concentrations of a parent drug and its metabolites morphine-3-glucuronide and morphine-6-glucuronide, studies are conflicting with regard to the association between plasma levels of morphine and its metabolites versus analgesia as measured by pain scores.[59] The strong opioid agonists have no maximum dose or ceiling dose. The appropriate dose is the amount of opioid that controls pain with the fewest side effects. Dose titration should continue until good pain relief is achieved or intolerable side effects develop that cannot otherwise be controlled. The goal is to achieve a favorable balance between analgesia and side effects through gradual adjustment of the dose. If analgesic tolerance appears to be occurring, the dose can be increased or consideration given to switching the opioid, especially if higher doses are required.

  The severity of the pain and the opioid formulation chosen determine the rate of titration. The dose of immediate-release formulations can be increased on a daily basis if necessary until pain relief is adequate. Among patients receiving relatively low doses of opioids, those with uncontrolled moderate-intensity pain require daily increases of between 25% and 50% to their previous dose, while patients with severe uncontrolled pain may require a higher increase. At higher opioid doses, increases of 20% to 30% would be more prudent. Rapid dose escalation requires close monitoring for both efficacy and side effects. Preliminary data suggest that titration with sustained-release daily morphine is equivalent to titration with immediate-release morphine administered every 4 hours by an expert group of clinicians, but standard practice is to use a short-acting opioid for initial titration.[60]

  Occasionally, doses may need to be reduced or, rarely, stopped. This may occur when patients become pain free as a result of cancer treatment, including treatments such as nerve blocks and radiation therapy. Another time to consider reducing the dose is when a patient experiences significant opioid-related sedation that is accompanied by good pain control. In situations where interventions achieve complete pain relief, rapid opioid tapering rather than abrupt discontinuation is recommended and usually adequate.

Different types of opioids

• The debate regarding whether any individual opioid causes fewer side effects or is more effective is characterized by much speculation but little clinical evidence. These inconclusive findings have prompted expert working groups of the European Association of Palliative Care to recommend that there is currently little evidence of the clinical superiority of one opioid over another regarding the side-effect profile and/or analgesia.[12,13] Even constipation and other side effects may be positively affected by a switch. Compared with morphine, fentanyl may cause less constipation.[61,62] Studies suggesting that oxycodone and hydromorphone may cause less nausea and hallucinations than morphine [63] are juxtaposed with other studies that found no significant differences between them.[64-66] One study found that transdermal fentanyl was better tolerated than sustained-release oral morphine and equally effective.[67]

Tolerance

• Assume that patients actively abusing heroin or prescription opioids (including methadone) have some pharmacologic tolerance that will require higher starting doses and shorter dosing intervals.

Opioid therapy in special populations

• Health professionals should check current recommendations for opioid use in older people, children, people who are cognitively impaired, and known or suspected drug abusers.

Opioid switching

A series of case reports have demonstrated the clinical problem of inadequate pain control with escalating opioid doses in the presence of dose-limiting toxic effects, including hallucinations, confusion, hyperalgesia, myoclonus, sedation, and nausea.[17,23,68-70] It was suggested that these problems could be managed by switching to an alternative opioid, with the result being improved pain management and decreased toxic effects. The improvement with opioid switching, although predominantly demonstrated initially with morphine, has also been reported with other opioids.[71-74] A retrospective review over a 1-year period in a pediatric oncology center supports efficacy of this technique in children, with resolution of adverse opioid effects, largely pruritus, achieved in 90% of patients, while maintaining pain control.[75]

• Guidelines for switching from one opioid to another

  Guidelines for opioid switching are intended to reduce the risk of relative overdosing or underdosing as one opioid is replaced by another. These guidelines require a working knowledge of an equianalgesic-dose table.[13,76] The equianalgesic-dose table provides only a broad guide for dose selection when switching from one opioid to another. Wide ranges in interindividual responses to the various opioids have been noted.[76] Therefore, because of incomplete cross-tolerance in most cases, the calculated dose-equivalent of a new drug must be reduced by 25% to 50% to ensure safety. These figures are based on clinical experience rather than empiric data. The selection of an alternative opioid is largely empirical. There is little clinical evidence to indicate that one opioid has therapeutic superiority over another opioid. A patient, for example, who requires a switch from morphine to another opioid can be switched to hydromorphone, oxycodone, fentanyl, or methadone.[77-79] In one prospective study of 186 cancer patients being treated with morphine, 25% did not respond and required switching to another opioid (oxycodone). The primary reasons for switching included pain, confusion, drowsiness, nightmares, and nausea. Of the 47 patients who required switching to an alternative opioid, 37 (79%) obtained good relief. This result provides beginning evidence for the prevalence of the need to switch, as well as determining the success rate once switching occurs.[80] Patients should be followed closely after a switch and should be reassessed, and the new opioid dose should be adjusted according to the intensity of pain and lack or presence of adverse effects.

Note: The values that appear in the table below are NOT recommended starting doses. Opioid doses are highly variable and should be based on the individual’s previous responses and overall condition. Important cautions are contained in the footnotes.

It has been suggested that a less complicated approach than opioid switching would be reassessment of the clinical situation and use of adjuvant analgesics, decreasing the opioid dose if possible, use of medical management for opioid-related side effects, and correction of any contributing metabolic abnormalities.[81,82] Nevertheless, there does appear to be an emerging consensus that opioid switching does have a useful role when pain control remains inadequate with escalating opioid doses and opioid use results in unacceptable opioid-related side effects.[81-83]

Morphine, as the strong opioid of choice for the management of cancer pain, was used increasingly during the 1970s and 1980s.[84] Associated with this increasing experience was the clinical observation of the risk of accumulation of morphine metabolites, particularly in the presence of renal impairment. Morphine-6-glucuronide, an analgesic metabolite, was recognized as having a useful role in enhancing analgesia. A number of reports, however, have described seizures, cognitive impairment, nausea, and problems of myoclonus that were associated with accumulation of morphine-6-glucuronide.[84-91]

The potential role of morphine metabolites, in particular the ratio of 3-glucuronide to 6-glucuronide in the development of opioid-related toxicity, has been reported. The literature on this issue has been somewhat controversial. There is no disagreement that morphine metabolites increase in the presence of deteriorating renal function; however, there has been conflicting evidence regarding the role and ratios of the metabolites in patients exhibiting both a poor response to increasing morphine doses and associated toxicity.[92-96]

Switching from one opioid to another requires familiarity with a range of opioids and the use of opioid dose-conversion tables.[13,76] When using these ratios, it must be understood that the guidelines should be reviewed and the patients should be monitored more closely during the switching phase. A recent review has highlighted some important issues related to these tables.[76] Wide ranges in ratios are noted. In the case of methadone, it is much more potent than previously thought (on average ten times more potent), and its equianalgesic dose-ratio compared to other opioids changes according to the dose of the previous opioid; the higher the dose, the higher the ratio. (Note that potency does not denote more effectiveness but denotes the equivalent dose required to obtain the same effect.)

Oral administration is preferred in patients with intact gastrointestinal tracts because it is convenient and usually inexpensive. When patients cannot take oral medications, other less invasive routes (e.g., rectal or transdermal) should be offered. Parenteral methods should be used only when simpler, less demanding, and less costly methods are inappropriate, ineffective, or unacceptable to the patient. In general, assessing the patient’s response to several different oral opioids is advisable before abandoning the oral route in favor of anesthetic, neurosurgical, or other invasive approaches.

Rectal

• Use this safe, inexpensive, effective route for delivery of opioids as well as nonopioids when patients have nausea or vomiting. Rectal administration is inappropriate for the patient who has diarrhea, anal/rectal lesions, mucositis, thrombocytopenia, or neutropenia. The use of suppositories is not always culturally acceptable and may not be practical for patients who are obese, have fractures, are physically unable to place the suppository in the rectum, or prefer other routes. When changing from the oral to the rectal route, begin with the same dosage as had been given orally, then titrate as needed.

Transdermal (fentanyl)

• Patches currently available are formulated to provide analgesia lasting up to 72 hours. This preparation is not suitable for rapid dose titration and should be used for relatively stable analgesic requirements when rapid increases or decreases in dosage are not likely to be needed.[97,98] In the chronic setting, considerable inter- and intraindividual variability may exist in the rate of absorption of fentanyl from transdermal patches in patients receiving a stable dose of transdermal fentanyl.[99] Based on a case series, it has been proposed that conversion from transdermal to IV fentanyl using a 1:1 conversion ratio can be safe and effective during acute exacerbations of cancer pain.[58] Although other opioids are sometimes compounded into gel form for transdermal application, there is insufficient evidence to support this practice.

Transmucosal/Buccal (fentanyl)

• Oral transmucosal fentanyl citrate is used for the relief of breakthrough pain. The lipid solubility of fentanyl allows rapid onset of pain relief. In open-label studies, 72% to 92% of patients found a dose that provided relief from breakthrough pain. Side effects in these studies were consistent with other opioid therapies, including sedation, constipation, stomatitis, and nausea.[100,101] There is growing interest in the use of rapidly acting, highly lipophilic opioids such as fentanyl for the management of difficult breakthrough pain syndromes. An oral transmucosal fentanyl citrate compound for buccal administration has become available for this purpose.[102,103] A double-blind, randomized, placebo-controlled study included 77 patients assigned to dose sequences of fentanyl buccal tablets (FBT). Results demonstrated that FBT was efficacious and safe in treating cancer-related breakthrough pain.[104] Other opioids such as morphine, hydromorphone, and oxycodone are not very lipophilic and therefore not suited for buccal or sublingual administration. In the home setting, opioids are sometimes administered buccally or sublingually with erratic absorption that is likely via the lower gastrointestinal tract.

Parenteral: IV and subcutaneous

• IV administration provides a rapid onset of analgesia within 2 to 10 minutes. The duration of action after a bolus dose may be shorter than with other routes. This route may be useful if a patient cannot swallow and IV access is established.



• The subcutaneous route is as effective as the IV route.[12,105] In some situations, it may even be more convenient, especially if patients are being cared for at home or in a hospice. To facilitate administration via this route, a 25- or 27-gauge butterfly needle can be inserted subcutaneously and left in place for up to 7 days at a time. The anterior thighs, abdomen, upper arms, subclavicular area, and upper back are possible areas for needle insertion. The site should be monitored for signs of infection or irritation and should be changed if these are noted.



• The bioavailability of parenterally administered opioids (morphine, hydromorphone, oxycodone, and codeine) is generally 2 to 3 times that of the oral route. The dose therefore needs to be halved or decreased by a third when switching from the oral to the subcutaneous and IV routes, respectively (refer to the Approximate Dose Equivalents for Opioid Analgesics table). Opioids administered parenterally may be given either intermittently (usually every 4 hours) or by a continuous infusion. With some exceptions, these two methods appear to be similarly effective.

Other routes

• Some studies suggest that the use of inhaled opioids for the management of pain and cancer-related shortness of breath are, with some exceptions, not more effective than systemic administration.[106,107] Their absorption via this route is unpredictable.



• The intramuscular administration of opioids is not recommended.

Patient-Controlled Analgesia

• Patient-controlled analgesia (PCA) may be used to determine the opioid dose needs when initiating opioid therapy. Once the pain is well controlled, a regular opioid dose can be instituted on the basis of the PCA doses required. This method is contraindicated in patients with cognitive impairment or patients with significant psychological undercurrents to their pain experience.

Intraspinal

• The intraspinal administration of opioids (epidural or intrathecal), especially when combined with a local anesthetic, can be helpful in a very small select group of patients with intractable pain. Use of the epidural or intrathecal route requires skill and expertise that may not be available in all settings. The table below presents the advantages and disadvantages of intraspinal administration. Although intrathecal opioid therapy has been FDA approved since 1991, the utility of an implantable drug delivery system (IDDS) to deliver spinal opioids was only recently compared with comprehensive medical management (CMM) (based on the Agency for Health Care Policy and Research 1994 cancer pain management guidelines) in a randomized trial. There were 202 patients enrolled in this unblinded study. Of the 101 patients randomized to the IDDS, 51 actually received this therapy. Sixteen of these patients (31%) had serious adverse effects. Patients using the IDDS experienced more than 20% reduction in both pain and opioid toxicity more often than the CMM group (P = .02). These data and further analysis in follow-up reports [108,109] suggest that the use of an IDDS delivery system may offer benefit for some cancer patients. More research is needed to determine which subsets of patients will benefit the most from this device, and what the proper timing should be for a trial of intrathecal opioids.[110,111] An open-label study demonstrated that patients with refractory cancer pain experienced better pain relief, fewer opioid-associated side effects, and decreased systemic opioid use when managed with patient-activated intrathecal delivery of morphine via an implanted delivery system. The device was implanted in 119 patients. There were 7 serious adverse events related to the device and 55 serious adverse events related to the implant and delivery-system refill procedures. The FDA denied the application for market approval of this system.[78]

The following two tables present data on drugs and routes of administration not recommended for the management of cancer pain.