ABSTRACT: The management of cancer pain requires familiarity with a range of therapeutic strategies, including antineoplastic therapies, analgesic pharmacotherapy, and anesthetic, neurosurgical, psychological, and rehabilitation techniques. Successful pain management is characterized by implementation of the techniques with the most favorable therapeutic index for the prevailing circumstances, along with provision for repeated evaluations, so that a favorable balance between pain relief and adverse effects is maintained. For most patients, pain management involves the administration of specific analgesic approaches. In all cases, these analgesic treatments must be skillfully integrated with the management of other symptoms.
There is a wide consensus that analgesic pharmacotherapy is the mainstay of cancer pain management. A commonly recommended approach is the "three-step analgesic ladder" of the World Health Organization, which advocates three basic steps of therapy according to the severity of the presenting pain problem (Figure 1). This approach emphasizes the principle of using analgesics appropriate to the severity of the prevailing pain problem; it emphasizes the centrality of opioid pharmacotherapy. Combined with appropriate dosing guidelines, this approach provides adequate relief to 70% to 90% of patients.[2-7] Systemic Analgesic Pharmacotherapy Nonopioid Analgesics
The nonopioid analgesics (aspirin, acetaminophen, and the nonsteroidal anti-inflammatory drugs [NSAIDs]) are useful alone for mild to moderate pain (step 1 of the WHO analgesic ladder) and provide additive analgesia when combined with opioid drugs in the treatment of more severe pain. They are useful in a broad range of pain syndromes of diverse mechanisms, but there are no data to support therapeutic superiority to alternative options in any particular setting other than inflammation. Unlike opioid analgesics, the nonopioid analgesics have a "ceiling" effect for analgesia and produce neither tolerance nor physical dependence. The nonopioid analgesics constitute a heterogeneous group of compounds that differ in chemical structure but are all competitive blockers of cyclooxygenase. The relatively selective cyclooxygenase-2 drugs are equianalgesic with the non-selective inhibitors, and they are associated with less mucosal morbidity.[9-11] Despite the advances presented by the development of cyclooxygenase-2 selective agents, the coadministration of a conventional NSAID with a gastroduodenal protective agent (such as omeprazole (Prilosec), pantoprazole (Protonix), misoprostol (Cytotec), or high-dose famotidine remains a valid therapeutic option. With the administration of all of these agents, particular caution is required for patients at increased risk for adverse effects, including the elderly and those with predilection to peptic ulceration, impaired renal function, and concurrent corticosteroid therapy. Acetaminophen rarely produces gastrointestinal toxicity and there are no adverse effects on platelet function; hepatic toxicity is possible, however, and patients with chronic alcoholism and liver disease can develop severe hepatotoxicity at the usual therapeutic doses. Opioid Analgesics: Basic Pharmacology
A trial of systemic opioid therapy should be administered to all cancer patients with pain of moderate or greater severity regardless of the pain mechanism. Although both somatic and visceral pain appear to be relatively more responsive to opioid analgesics than neuropathic pain, a neuropathic mechanism does not confer opioid resistance; appropriate dose escalation will identify many patients with neuropathic pain who can achieve adequate relief.[14,15] Optimal use of opioid analgesics requires a sound understanding of the general principles of opioid pharmacology, the pharmacologic characteristics of each of the commonly used drugs, and principles of administration, including drug selection, routes of administration, dosing and dose titration, and the prevention and management of adverse effects. Important Principles in Opioid Drug Therapy
- Classification-Opioid compounds can be divided into agonist, agonist-antagonist, and antagonist classes based on their interactions with the various receptor subtypes (Table 1). In the management of cancer pain, the pure agonists are most commonly used. Recently, with the advent of a transdermal route of administration, there has been increased interest in the use of the partial agonist opioid buprenorphine in the management of moderate pain.
- Dose-Response Relationship- The pure agonist drugs do not have a ceiling dose. As the dose is raised, analgesic effects increase in a semilog- linear function until either analgesia is achieved or the patient develops dose-limiting adverse effects such as nausea, vomiting, confusion, sedation, myoclonus, or respiratory depression.
- The Equianalgesic Dose Ratio- Relative analgesic potency of opioid is commonly expressed in terms of the equianalgesic dose ratio. This is the ratio of the dose of two analgesics required to produce the same analgesic effect. By convention, the relative potency of each of the commonly used opioids is based upon a comparison to 10 mg of parenteral morphine. Equianalgesic dose information and dose conversion tables (Table 2) provide guidelines for dose selection when the drug or route of administration is changed.
Several principles are critical in interpreting the data presented in such tables. The commonly quoted values do not reflect the substantial variability that is observed in both single-dose and multidose crossover studies. Numerous variables may influence the appropriate dose for the individual patient, including pain severity, prior opioid exposure (and the degree of cross-tolerance this confers), age, route of administration, level of consciousness, and genetically determined metabolic or receptor heterogeneity. For most opioids the equianalgesic dose relationship to morphine is linear. For methadone, however, the relationship appears to be curvilinear, with the equianalgesic dose ratio falling as the dose of prior morphine increases: at low doses of morphine (30 to 300 mg oral morphine) the equianalgesic ratio for oral methadone to oral morphine is 1:4 to 1:6 and at high doses (> 300 mg oral morphine) it is 1:10 to 1:12. Selecting an Appropriate Opioid
The factors that influence opioid selection in chronic pain states include pain intensity, pharmacokinetic and formulatory considerations, previous adverse effects, and the presence of coexisting disease. Traditionally, patients with moderate pain have been conventionally treated with a combination product containing acetaminophen or aspirin plus codeine, dihydrocodeine, hydrocodone, oxycodone, and propoxyphene. The doses of these combination products can be increased until the maximum dose of the nonopioid coanalgesic is attained (eg, 4,000 mg acetaminophen). Recent years have witnessed the proliferation of new opioid formulations that may improve the convenience of drug administration for patients with moderate pain. These include controlledrelease formulations of codeine, dihydrocodeine, oxycodone, morphine, and tramadol in dosages appropriate for moderate pain, and most recently, patches of buprenorphine. Patients who present with strong pain are usually treated with morphine, hydromorphone, oxycodone, oxymorphone, fentanyl, or metha-done. Of these, the short half-life opioid agonists (morphine, hydromorphone, fentanyl, oxycodone, or oxymorphone) are generally favored because they are easier to titrate than the long half-life drugs that require a longer period to approach steady-state plasma concentrations. If the patient is currently using an opioid that is well tolerated, it is usually continued unless difficulties in dose titration occur or the required dose cannot be administered conveniently. A switch to an alternative opioid is considered if the patient develops dose-limiting toxicity that precludes adequate relief of pain without excessive side effects, or if a specific formulation, not available with the current drug, is either needed or may substantially improve the convenience of opioid administration. Some patients will require sequential trials of several different opioids before a drug which is effective and well tolerated is identified.[18,19] This strategy has been variably labeled opioid rotation, or opioid switching. The existence of incomplete cross-tolerance to various opioid effects (analgesia and side effects) may explain the utility of these sequential trials. It is strongly recommended that clinicians be familiar with at least three opioid drugs used in the management of severe pain and have the ability to calculate appropriate starting doses using equianalgesic dosing data when switching between drugs. Selecting the Appropriate Route of Sytemic Opioid Administration
Opioids should be administered by the least invasive and safest route capable of providing adequate analgesia. The oral route is usually preferred. Alternative routes are necessary for patients who have impaired swallowing or gastrointestinal dysfunction, those who require a very rapid onset of analgesia, and those who are unable to manage either the logistics or side effects associated with the oral route. Transdermal fentanyl (Duragesic) often provides a convenient and noninvasive alternative to oral administration. Transdermal patches capable of delivering 25, 50, 75, and 100 ?g/h are available. The dosing interval for each patch is usually 72 hours, but some patients require a 48-hour schedule. Data from controlled studies suggest that the transdermal administration of fentanyl is associated with a lesser incidence of constipation than oral morphine.[22-24] Other noninvasive routes are less commonly used. Rectal suppositories containing oxycodone, hydromorphone, oxymorphone, and morphine have been formulated, and controlledrelease morphine tablets can also be administered per rectum.[25,26] The potency of opioids administered rectally is approximately equivalent to that achieved by the oral route. The sublingual route has limited value due to the lack of formulations, poor absorption of most drugs, and the inability to deliver high doses or prevent swallowing of the dose. An oral transmucosal formulation of fentanyl (Actiq), which incorporates the drug into a candy base, has been approved for use in the management of breakthrough pain.[28,29]
- Invasive Routes-A parenteral route may be considered when the oral route is precluded or there is a need for rapid onset of analgesia or a more convenient regimen. Repeated parenteral bolus injections, which may be administered by the intravenous (IV), intramuscular (IM), or subcutaneous (SC) routes, provides the most rapid onset and shortest duration of action. Parenteral boluses are most commonly used to treat very severe pain, in which case doses can be repeated at an interval as brief as that determined by the time to peak effect until adequate relief is achieved. Repeated bolus doses without frequent skin punctures can be accomplished through the use of an indwelling IV or SC infusion device such as a 25- to 27-gauge infusion device (a "butterfly") that can be left under the skin for up to a week.
- Changing Routes of Administration- The switch between oral and parenteral routes should be guided by knowledge of relative potency (Table 2) to avoid subsequent overdosing or underdosing. In calculating the equianalgesic dose, the potencies of the IV, SC, and IM routes are considered equivalent. In recognition of the imprecision in the accepted opioid dose conversion tables and the risk of toxicity from potential overdose, a modest reduction in the calculated dose is prudent.
Continuous parenteral infusions are useful for many patients who cannot be maintained on oral opioids. Longterm infusions may be administered IV or SC. In practice, the major indication for continuous infusion occurs in patients who are unable to swallow or absorb opioids. Continuous infusion is also used in some patients whose high opioid requirement renders oral treatment impractical. Ambulatory patients can easily use continuous SC infusion. A range of pumps are available, varying in complexity, cost, and ability, to provide patient-controlled "rescue doses" as an adjunct to a continuous basal infusion.[ 31] There are data indicating that when available, Teflon- or Vialoncoated nonmetal cannulae are preferred to butterfly needles. Opioids suitable for continuous SC infusion must be soluble, well absorbed, and nonirritating. Extensive experience has been reported with heroin, hydromorphone, oxymorphone, morphine, and fentanyl. Methadone appears to be relatively irritating and is generally not recommended. To maintain the comfort of an infusion site, the SC infusion rate should not exceed 3 to 5 mL/h. Patients who require high doses may benefit from the use of concentrated solutions such as hydromorphone at 10 mg/mL or morphine tartrate, which is available in some countries as an 80 mg/mL solution.
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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