Opioid Analgesics
Cancer pain is often undertreated even in developed countries with abundant resources and easy access to oral, parenteral, and transdermal opioids.1 However, problems in developing nations are more complex, and these medications are often not readily available to the majority of patients in Latin and South America, Eastern Europe, Asia, and Africa.2 Furthermore, the ratio of cost of opioids to income is higher in developing countries.3 In spite of the efforts by the World Health Organization (WHO) and others to make oral opioids available, too little progress has been made in relieving cancer pain in developing countries. Unfortunately, developing countries account for 75% of the world’s population and bear more than half the global cancer burden.
Drug therapy is the cornerstone in the treatment of pain in the cancer patient. Opioids are the essential category of drug for use in most cancer patients with pain.4 In some situations, particularly with rapid opioid escalation due to either worsening pain or the development of opioid tolerance, the addition of a second opioid may have merit.5 Furthermore, because patients have significant and unpredictable variations in response to opioids (both in terms of pain relief and side effects), use of these medications must be largely governed by trial and error. As such, the clinician caring for cancer patients must be familiar with all the available drugs in this category. It is not sufficient to be familiar with one or two opioids. Rather, comprehensive care of the cancer patient with pain requires detailed knowledge of the pharmacology (both pharmacokinetics and pharmacodynamics) of a wide array of currently available opioids. Modifications in formulation have resulted in prolongation of activity over standard or IR formulations. These modifications have resulted in the availability of sustained-release (SR), controlled-release (CR), and extended-release (ER) products. These products include morphine (SR, ER, CR), oxycodone (CR), oxymorphone (ER), and fentanyl (transdermal). Traditionally, opioids are best administered orally. However, other modes of opioid drug delivery such as by implantable osmotic pump,6 by inhalation,7 by iontophoresis,8 or transmucosally9 are either under investigation or in clinical use.
For millennia, opium derived from secretions of Papaver somniferum seedpods have been utilized for analgesic purposes. Opium contains two chemical classes of alkaloids, phenantrenes and benzyl-isoquinolines. One of the phenantrene alkaloids, thebaine, present in 0.2% to 0.8% of the opium derived from Papaver somniferum and in 90% of that extracted from morphine-free Papaver bracteatum, is extremely toxic and lacks analgesic properties. Morphine, an opium alkaloid, was isolated in 1803 by Serturner and was later found to be primarily responsible for the analgesic properties of opium. The word “opioid” is a generic term for naturally occurring, semisynthetic, and synthetic drugs that combine with opioid receptors to produce physiological effects and which are stereospecifically antagonized by naloxone. For clinical purposes, opioids can be classified according to their receptor interactions (agonist, partial agonist, and agonist-antagonist). Pure (full) µ-agonists (most of the currently used opioids such as morphine, hydromorphone, oxycodone, hydrocodone) are conventionally used for moderate- to severe-intensity pain.10 Partial agonists, such as buprenorphine, are avidly bound to the µ-receptor such that reversal of effects with standard clinical doses of naloxone may be difficult.11 Agonist-antagonist opioids, such as pentazocine, butorphanol, and nalbuphine appear to exert their agonist analgesic effect through κ-receptors with an antagonist effect at µ-receptors.12
Insights into receptor biology, pharmacogenetics, and pharmacological antagonism help refine the use of established opioids and may result in the development of more selective drugs with improved clinical profiles. Opioids act on different receptors or receptor subtypes, and individual receptor profiles may influence the degree of pain relief attainable and the occurrence of opioid-related adverse events.13 There are at least three major types of opioid receptors identified on the basis of pharmacological response, in vitro radioligand binding affinities, and in vivo localization of labeled drug in tissue homogenates or sections. These receptors are µ (MOR), κ (KOR), and δ (DOR). Identification of receptors allowed opioids to be grouped according to similarities in the activation of their receptor types. These receptors have been identified on cell bodies in the dorsal root ganglion (DRG) and on central terminals of primary afferent neurons within the dorsal horn of the spinal cord.14 In the early 1990s, the opioid receptors were cloned.15 Although the receptor most commonly associated with pain relief is the µ-receptor, specific δ- and κ-agonists can also mediate antinociception at spinal and supraspinal sites. MOR is the primary target mediating analgesic, euphoric, and reinforcing effects of morphine.16 DOR agonists are associated with pain relief and euphoria, whereas KOR agonists produce pain relief, miosis, sedation, and dysphoria.
Individual variations to pain perception may in part be accounted for by variation in levels of µ-opioid receptor expression and responses to different opioids.17 In addition, variable patient responses to different opioids may be influenced by genetic variation and subtle differences in mechanism of action and potency.18 Basic science research is beginning to identify the allelic variants that underlie such antinociceptive variability using a multiplicity of animal models, and genetic approaches are being exploited to accelerate this process.19 Other factors that may explain
interpatient variability in opioid responsiveness include polymorphisms in the µ-receptor regulatory region,20 pharmacokinetic differences due to cytochrome P450 monooxygenase heterogeneity, and use of concomitant medications that may predispose to pharmacokinetic and pharmacodynamic drug interactions.
interpatient variability in opioid responsiveness include polymorphisms in the µ-receptor regulatory region,20 pharmacokinetic differences due to cytochrome P450 monooxygenase heterogeneity, and use of concomitant medications that may predispose to pharmacokinetic and pharmacodynamic drug interactions.
Opioids are small peptides primarily involved in nociception and immune responses;21 they act through specific receptors (µ, δ, and κ) expressed in nervous and immune systems, which are also targets of substances of abuse. Opioid and chemokine systems can reciprocally influence each other’s function at different levels; for example, µ-opioid ligands regulate expression and function of chemokine receptors in immune cells via heterologous desensitization.22, 23
Opioid receptors belong to the G protein-coupled receptor (GPCR) family and they signal via a second messenger (cyclic AMP) or an ion channel (K+). GPCRs regulate the function of ion channels, which play an essential role in the function of neurons by mediating and regulating of selective ion concentrations across the cell membrane.24 GPCRs are widely distributed in the nervous system, and mediate key physiological processes including cognition, mood, appetite, pain, and synaptic transmission.25 mRNA for all the opioid receptors have been demonstrated in the dorsal root ganglion and small-diameter primary afferent neurons. MOR, DOR, and KOR are members of the GPCR superfamily. A fourth major opioid receptor has been cloned—nociceptin/orphanin FQ receptor or opioid receptor-like 1 (ORL1).26 Its function is not clear. Opioids have different affinities to the µ opioid receptor and potency is sometimes classified as low (eg, codeine) or high (eg, fentanyl). µ-opioid receptors are found in the periphery (following inflammation), at pre- and postsynaptic sites in the spinal cord dorsal horn, and in the brain stem, thalamus, and cortex, in what constitutes the ascending pain transmission system. In addition, µ-opioid receptors are found in the midbrain periaqueductal gray, the nucleus raphe magnus, and the rostral ventral medulla, where they comprise a descending inhibitory system that modulates spinal cord pain transmission. At a cellular level, opioids decrease calcium ion entry, resulting in a decrease in presynaptic neurotransmitter release (eg, substance P release from primary afferents in the spinal cord dorsal horn). They also enhance potassium ion efflux, resulting in the hyperpolarization of postsynaptic neurons and a decrease in synaptic transmission. A third mode of opioid action is the inhibition of GABAergic transmission in a local circuit (eg, in the brain stem, where gamma-aminobutyric acid (GABA) acts to inhibit a pain-inhibitory neuron). This disinhibitory action of the opioid has the net effect of exciting a descending inhibitory circuit.
The administration of opioids results in a variety of effects including pain relief, miosis, bradycardia, sedation, hypothermia, insensitivity to various stimuli, and depression of flexor reflexes. Opioids can modulate endocrine processes27, 28 and can also affect the immune response.29 Although gender differences in opioid response have been reported in humans, with some studies reporting greater sensitivity in women30, 31, 32 and others reporting greater sensitivity in men,33, 34, 35 others have reported no differences.36, 37 Craft38 suggests that animal studies demonstrate gender differences in a variety of behavioral effects of opioids. This author suggests that µ-agonists are more potent and in some cases more efficacious in male than in female rats and that women were more sensitive than men to the reinforcing and locomotor stimulant effects of opioids. Furthermore, there also appears to be gender differences in opioid-related side effects such as respiratory depression, nausea, urinary retention, and altered immune function, as well as the rate at which opioid tolerance and dependence develop. Craft suggests that estradiol may be an important modulator of opioid effects and may be the primary mechanism by which adult women differ from adult men in opioid sensitivity. The anatomic and physiologic characteristics of the periaqueductal gray and its descending projections to the rostral ventromedial medulla may account for gender difference in morphine potency.39
The expression of opioid receptors on cells of the immune system was first implicated by the ability of opioids to alter immune function.40 Since then, pharmacologic, molecular, and, more recently, immunologic evidence for the expression of opioid receptors on immune cells have been reported.41, 42, 43 The regulation of cytokine, chemokine, and cytokine receptor expression may also be a critical component of the immunomodulatory activity of the opioids.44 Increased expression of chemokines is associated with a wide range of inflammatory diseases and pathologies. MOR activation by opioids results in altered transcriptional and protein regulation of several cytokines, chemokines, and chemokine receptors. By contrast with MOR, KOR activation exhibits a broad inhibitory influence on cytokine, chemokine, and chemokine receptor expression.44 Cytokines represent some of the principal mediators of immune function by mediating and regulating the innate and adaptive immunity and stimulating the growth and the differentiation of cells in the immune system. Proinflammatory cytokines can enhance neuronal excitability and perpetuate neuropathic pain. In addition, proinflammatory cytokines can suppress the ability of opioids to control pain and contribute to opioid tolerance and dependence/withdrawal.45 Acute and long-term administration of exogenous opioids is known to have inhibitory effects on antibody and cellular immune responses, natural killer (NK) cell activity, cytokine expression, and phagocytic activity.46 Opioid receptor signaling has been implicated in the regulation of cell proliferation and cell death in various cells expressing opioid receptors.47 The observed tumor-suppressive effects of morphine suggest the intriguing possibility that morphine might be useful as an adjunct in cancer therapy not only to reduce cancer pain but also tumor growth.48 Other opioids also appear to induce apoptosis. Methadone induced cell death not only in anticancer drug-sensitive and apoptosis-sensitive leukemia cells but also in doxorubicin-resistant, multidrug-resistant, and apoptosis-resistant leukemia cells.49 Several important pathways that control cell proliferation, survival, and apoptosis have been reported to be associated with the nonanalgesic effects of opioids, which may be mediated through both opioid receptor signaling and other nonopioid receptor molecular entity-mediated signaling.50 Opioid-induced general suppression of the immune system might jeopardize other potentially favorable outcomes. Although data are very limited in this area, one animal study suggests that chronic morphine treatment
may have resulted in accelerated tumor growth probably as a consequence of general immunosuppression.51 At this time, it is unknown whether the administration of opioids and the association with immunosuppression has clinical implications in cancer patients.
may have resulted in accelerated tumor growth probably as a consequence of general immunosuppression.51 At this time, it is unknown whether the administration of opioids and the association with immunosuppression has clinical implications in cancer patients.
TABLE 19.1 OPIOID CLASSIFICATION OF ACTIVE METABOLITES BASED ON CLINICAL RELEVANCE | ||||||||||||||||||||||||||||||||||||
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Opioid alkaloids are extensively metabolized, mainly in the liver, and predominantly excreted by the kidneys. All opioids are eliminated by hepatic metabolism, principally oxidation (catalyzed by CYP450) and conjugation (catalyzed by transferases such as UDP-glucuronyl transferase). In many cases the primary metabolites formed are then further metabolized via secondary pathways (phase I—functionalization followed by phase II—conjugation). Opioids, which are alkyl ethers at the 3-phenolic hydroxyl group, such as codeine, hydrocodone, and oxycodone, are subject to O-dealkylation; this reaction is catalyzed by CYP2D6 and is therefore subject to considerable genetic polymorphism. Many opioids are subject to Ndemethylation into nor-derivatives, including morphine, codeine, dihydrocodeine, oxycodone, and tramadol. Many analgesic and psychoactive drugs are metabolized by one of three P450 enzymes. The major cytochrome in humans is 3A4, which is involved in 50% of all microsomal drug metabolism and is responsible for the metabolism of methadone, fentanyl, and certain selective selective serotonin-reuptake inhibitors (SSRIs). Opioid Ndemethylation is also catalyzed mainly but not exclusively by CYP3A4. Glucuronidation reactions take place on free hydroxyl groups on opioids (eg, morphine, oxymorphone, nalbuphine). Overall, glucuronidation of opioids is mainly mediated by the UDP glucuronosyltransferase UGT2B7. About 90% of a morphine dose is converted into metabolites; principally the glucuronide conjugates morphine-3-glucuronide (M3G, 50%) and morphine-6-glucuronide (M6G, 10%).52, 53 M3G does not bind to opioid receptors and is not an agonist.54 M6G has analgesic efficacy and has a superior side effect profile compared with morphine. Several opioids have metabolites with activity comparable to or even greater than the parent drug, with the best example being the conversion to morphine from codeine (Table 19.1). This has clinical relevance, especially in the elderly and those with renal dysfunction, because many of the active metabolites are more renally eliminated than the parent opioid (eg, morphine and M6G).55 In other situations, the metabolites are analgesically inactive but have evidence of toxicity (eg, normeperidine and neurotoxicity, nordextropropxyphene, and cardiotoxicity). Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion; it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination.56 The hepatic metabolism of morphine, meperidine, pentazocine, and alfentanil is significantly reduced in patients with cirrhosis, leading to changes in drug disposition that should be considered in dosage regimens.57
Unexpected degree and duration of effect of morphine metabolites can occur in patients with severely impaired renal function given morphine or derivatives in whom there is accumulation of metabolites.58 The elimination half-life of M3G varied between 14.5 and 118.8 hours (mean 49.6 hours) in renal failure patients, which was distinctly different from the 2.4 to 6.7 hours (mean 4.0 hours) found in patients with normal kidney function.59 Hydromorphone is metabolized principally by conjugation with glucuronic acid to form hydromorphone-3-glucuronide (H3G). After repeated doses, the steady-state plasma concentrations of both H3G and M3G exceed the respective plasma concentrations of the parent opioids to a similarly large extent (20- to 50-fold) in both adults and children.60, 61, 62 Due to the polar nature of the glucuronide conjugates, these metabolites can accumulate relative to the parent opioid in patients with renal impairment such that plasma concentration ratios of 100:1 have been reported.62, 63 M3G has been shown to evoke a range of neuroexcitatory behaviors including altered body posture, myoclonic jerks, and seizures64, 65, 66 in a dose-dependent manner.67 M3G is considered the likely reason for neuroexcitatory behaviors (myoclonus, allodynia, and seizures) observed in some patients receiving high doses of
chronically administered systemic morphine for the treatment of cancer pain.68 There are also reports of myoclonus in cancer patients dosed chronically with hydromorphone with speculation that H3G may be the causative agent.69 In an experimental model, Wright et al.70 demonstrated that H3G produced dose-dependent behavioral excitation similar to M3G and that H3G was approximately 2.5-fold more potent than M3G. The authors suggested that if H3G crosses the blood-brain barrier with equivalent efficiency to M3G, then the myoclonus, allodynia, and seizures observed in some patients dosed chronically with large systemic doses of hydromorphone were almost certainly caused by the accumulation of sufficient H3G in the central nervous system (CNS) to evoke behavioral excitation.
chronically administered systemic morphine for the treatment of cancer pain.68 There are also reports of myoclonus in cancer patients dosed chronically with hydromorphone with speculation that H3G may be the causative agent.69 In an experimental model, Wright et al.70 demonstrated that H3G produced dose-dependent behavioral excitation similar to M3G and that H3G was approximately 2.5-fold more potent than M3G. The authors suggested that if H3G crosses the blood-brain barrier with equivalent efficiency to M3G, then the myoclonus, allodynia, and seizures observed in some patients dosed chronically with large systemic doses of hydromorphone were almost certainly caused by the accumulation of sufficient H3G in the central nervous system (CNS) to evoke behavioral excitation.
SELECTION OF OPIOID THERAPY
The effective clinical use of opioid drugs requires familiarity with drug selection, routes of administration, dosage guidelines, and potential adverse effects. Several factors must be considered if opioids are to be used effectively. These include:
The patient’s previous opioid exposure and preferences
Severity and nature of disease
Age of patient
Extent of cancer, particularly hepatic and renal involvement altering normal opioid pharmacokinetics (Table 19.2).
Concurrent disease
Available formulations
The specific pathogenic mechanism that underlies a patient’s cancer pain should not be a factor in deciding which opioid to use, because the mechanism of pain does not reliably predict the response to opioid therapy.71 This particularly applies to situations in which neuropathic mechanisms dominate the pain complaint. Opioids should be used as first-line therapy in such situations, particularly if the pain is considered moderate to severe in intensity.
Short-acting agents (eg, morphine IR, hydrocodone IR, hydromorphone IR, oxycodone IR, oxymorphone IR, transmucosal fentanyl) may be favored initially because they are easier to titrate than long-acting agents (eg, morphine controlled release [CR], oxycodone CR, oxymorphone extended release [ER], and transdermal fentanyl [TTS]). Short-acting opioids are characterized by a rapid rise and fall in serum opioid levels, whereas serum levels of long-acting opioids increase slowly to therapeutic levels, remain there for an extended period, and then slowly decline.72 In general, the clinical circumstance dictates the choice of a short- or long-acting opioid. For example, the treatment of acute or postoperative pain usually requires frequent titration, and short-acting opioids, with duration of action of 2 to 4 hours, are preferred. Conversely, the treatment of cancer pain or chronic, moderate to severe nonmalignant pain usually can be treated with a longacting oral agent, with a duration of action of 12 to 24 hours, with less need for titration. In patients being treated with long-acting agents, short-acting opioids are usually provided as rescue medication for breakthrough pain. Because of the substantial interpatient variability in opioid responsiveness, clinicians who prescribe opioids for the treatment of cancer pain should be familiar with at least three different opioids appropriate for the management of moderate to severe pain.73
TABLE 19.2 EFFECTS OF RENAL FAILURE ON OPIOID PHARMACOKINETICS | ||||||||||
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The opioids used most commonly in the treatment of cancer pain are listed in Table 19.3. During the past decade, several long-acting oral opioid formulations have been developed for once- or twice-daily administration, and a transdermal fentanyl patch is also available for administration every 72 hours. Long-acting formulations of opioids are recommended to provide around-the-clock pain relief. With appropriately prescribed long-acting opioids, patients do not typically experience a significant disruption in cognitive functioning but instead may experience moderate improvement of some aspects of cognitive functioning, as a consequence of pain relief and concomitant improvement of well-being and mood.74 In addition, patients are often able to improve sleep patterns, have increased control over their own pain management, become more independent of caregivers, and experience improved compliance with treatment strategies.75 Although most of the commonly used CR oral opioid formulations (eg, oxycodone CR, morphine CR) are recommended by the manufacturer to be given every 12 hours, many patients with chronic, moderate to severe pain need to use these agents more frequently than every 12 hours to achieve adequate, sustained pain relief.76
Opioids should be administered by the most comfortable and convenient route that meets the specific needs of the individual patient. The regimen for opioid medications should generally provide around-the-clock analgesia with provision for rescue doses for the management of exacerbations of the pain not covered by the regular dosage. At all times, uncontrolled pain should be addressed by gradual increase in the opioid dose until either pain control is achieved or intolerable and unmanageable adverse effects supervene. The management of pain with opioid analgesics demands frequent patient assessment and a readiness to reevaluate the therapeutic plan in the setting of either inadequate relief or adverse effects.
There is no single optimal or maximal dose of an opioid analgesic drug. In general, for progressive, tumorrelated pain, the appropriate dose of an opioid is one that relieves a patient’s pain throughout the dosing interval without causing unmanageable or intolerable adverse events.77 The initial dose may be based on the severity of pain and known response to previous analgesic therapy, if any.78 Aggressive upward titration to a stable dose (ie, one
that provides adequate pain relief throughout the dosing interval) is predicated on continuing assessment of the effectiveness of therapy. Patients rarely benefit from combinations of opioids given in suboptimal doses; ideally clinicians should prescribe a single opioid analgesic and titrate to a stable dose.78 However, it is important to recognize that there is significant interpatient variability with regard to responsiveness to different opioid drugs, and patients who respond poorly to one opioid may respond favorably to another.79 In situations in which pain is not related to the tumor or its progression, unlimited opioid dose escalation may be inappropriate and the concepts of pain management need to shift from those of cancer pain to chronic pain not caused by cancer.80
that provides adequate pain relief throughout the dosing interval) is predicated on continuing assessment of the effectiveness of therapy. Patients rarely benefit from combinations of opioids given in suboptimal doses; ideally clinicians should prescribe a single opioid analgesic and titrate to a stable dose.78 However, it is important to recognize that there is significant interpatient variability with regard to responsiveness to different opioid drugs, and patients who respond poorly to one opioid may respond favorably to another.79 In situations in which pain is not related to the tumor or its progression, unlimited opioid dose escalation may be inappropriate and the concepts of pain management need to shift from those of cancer pain to chronic pain not caused by cancer.80
TABLE 19.3 ORAL AND TRANSDERMAL OPIOIDS USED IN THE PRIMARY TREATMENT OF CANCER PAIN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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An ongoing opioid regimen should include provisions for rescue doses for the treatment of breakthrough pain.
The rationale for providing rescue medication instead of increasing the dose of the around-the-clock opioid is to prevent overmedication and associated adverse events. Often, there is a narrow therapeutic window between an opioid dosage sufficient to achieve pain relief and one that is associated with unacceptable adverse events.81 For patients treated with a long-acting opioid, an IR or shortacting opioid formulation (often the same drug) may be used as the rescue medication. We recommend that the rescue drug be started at a dose equivalent to approximately 10% of the 24-hour baseline dose and titrated upward to achieve adequate pain relief.82 The dosing frequency of the rescue drug depends on the time to peak effect and the route of administration; in general, we administer oral rescue doses as frequently as every 2 hours if needed, but typically tend to start at every 3 to 4 hours as needed.83 If breakthrough pain occurs frequently, we advocate increasing the dose or shorten the dosing interval of around-the-clock opioid or increase the dose of the rescue opioid. A key principle in treating breakthrough pain is to optimize the background pain control by appropriately adjusting the around-the-clock opioid regimen.
The rationale for providing rescue medication instead of increasing the dose of the around-the-clock opioid is to prevent overmedication and associated adverse events. Often, there is a narrow therapeutic window between an opioid dosage sufficient to achieve pain relief and one that is associated with unacceptable adverse events.81 For patients treated with a long-acting opioid, an IR or shortacting opioid formulation (often the same drug) may be used as the rescue medication. We recommend that the rescue drug be started at a dose equivalent to approximately 10% of the 24-hour baseline dose and titrated upward to achieve adequate pain relief.82 The dosing frequency of the rescue drug depends on the time to peak effect and the route of administration; in general, we administer oral rescue doses as frequently as every 2 hours if needed, but typically tend to start at every 3 to 4 hours as needed.83 If breakthrough pain occurs frequently, we advocate increasing the dose or shorten the dosing interval of around-the-clock opioid or increase the dose of the rescue opioid. A key principle in treating breakthrough pain is to optimize the background pain control by appropriately adjusting the around-the-clock opioid regimen.
Hanks et al.78 reported on the recommendations of the European Association for Palliative Care (EAPC) on the use of morphine and alternative opioids in cancer pain. These recommendations provide practical strategies for dealing with difficult situations. The opioid of first choice for moderate to severe cancer pain is morphine. The optimal route of administration of morphine is by mouth. Ideally, two types of formulation are required: normal-release (for dose titration) and modified-release (for maintenance treatment). The simplest method of dose titration is with a dose of normal-release morphine given every 4 hours with the same dose for breakthrough pain. This “rescue” dose may be given as often as required (up to hourly) and the total daily dose of morphine should be reviewed daily. The regular dose can then be adjusted to take into account the total amount of rescue morphine. If pain returns consistently before the next regular dose is due, the regular dose should be increased. In general, normal-release morphine does not need to be given more often than every 4 hours and modified-release (MR) morphine more often than 12 or 24 hours (according to the intended duration of the formulation). Patients stabilized on regular oral morphine require continued access to a rescue dose to treat “breakthrough” pain. Several countries do not have a normal-release formulation of morphine, though such a formulation is necessary for optimal pain management. A different strategy is needed if treatment is started with MR morphine. Changes to the regular dose should not be made more frequently than every 48 hours, which means that the dose titration phase will likely be prolonged. For patients receiving normal-release morphine every 4 hours, a double dose at bedtime is a simple and effective way of avoiding being woken by pain. Several MR formulations are available. There is no evidence that the 12-hourly formulations (tablets, or capsules) are substantially different in their duration of effect and relative analgesic potency. The same is true for the 24-hour formulations though there is less evidence to evaluate. If patients are unable to take morphine orally, the preferred alternative route is subcutaneous. There is generally no indication for giving morphine intramuscularly for chronic cancer pain because subcutaneous administration is simpler and less painful. The average relative potency ratio of oral morphine to subcutaneous morphine is between 1:2 and 1:3 (ie, 20 to 30 mg of morphine by mouth is equianalgesic to 10 mg by subcutaneous injection). In patients requiring continuous parenteral morphine, the preferred method of administration is by subcutaneous infusion. Intravenous infusion of morphine may be preferred in patients who already have an indwelling intravenous line; with generalized edema; who develop erythema, soreness, or sterile abscesses with subcutaneous administration; with coagulation disorders; or with poor peripheral circulation. The average relative potency ratio of oral to intravenous morphine is between 1:2 and 1:3.
The buccal, sublingual, and nebulized routes of administration of morphine are not recommended, because there is no evidence of clinical advantage over the conventional routes. Oral transmucosal fentanyl citrate (OTFC) is an effective treatment for “breakthrough pain” in patients stabilized on regular oral morphine or an alternative step 3 opioid. Successful pain management with opioids requires that adequate analgesia be achieved without excessive adverse effects. By these criteria the application of the WHO and the EAPC guidelines (using morphine as the preferred step 3 opioid) permit effective control of chronic cancer pain in the majority of patients. In a small minority of patients adequate relief without excessive adverse effects may depend on the use of alternative opioids, spinal administration of analgesics, or nondrug methods of pain control. A small proportion of patients develop intolerable adverse effects with oral morphine (in conjunction with a nonopioid and adjuvant analgesic as appropriate) before achieving adequate pain relief. In such patients a change to an alternative opioid or a change in the route of administration should be considered. Hydromorphone or oxycodone, if available in both normal release and MR formulations for oral administration, are effective alternatives to oral morphine. Methadone is an effective alternative but may be more complicated to use compared with other opioids because of pronounced interindividual differences in its plasma half-life, relative analgesic potency, and duration of action. Its use by nonspecialist practitioners is not recommended. Transdermal fentanyl is an effective alternative to oral morphine but is best reserved for patients whose opioid requirements are stable. It may have particular advantages for such patients if they are unable to take oral morphine, as an alternative to subcutaneous infusion. Spinal (epidural or intrathecal) administration of opioid analgesics in combination with local anesthetics or clonidine should be considered in patients who derive inadequate analgesia or suffer intolerable adverse effects despite the optimal use of systemic opioids and nonopioids.
MORPHINE
Oral morphine was first recommended in England in the 1950s for the treatment of cancer pain. This was often in the form of a “Brompton Cocktail,” which contained cocaine and alcohol in addition to morphine or diamorphine. Although many compounds produce morphine-like pain relief and other effects, morphine is the standard
opioid against which all new analgesics are measured. Morphine, usually as the sulfate or hydrochloride salt, is available in four oral formulations—an elixir or solution, an IR tablet, a number of different preparations of MR tablets or capsules, and MR suspensions. Chronic subcutaneous infusions of morphine are used in cancer patients; however, significant intra- and interpatient variability in morphine, M6G, and M3G concentrations have been reported with chronic infusions.84 The reasons for this variability and its clinical implications are unknown. Subcutaneous administration of morphine results in less interpatient variability than oral morphine and smoother and more stable plasma concentrations.85 Oral absorption of IR morphine (tablets and solution) is almost complete. Peak plasma concentrations are 5 to 10 times lower than those obtained following parenteral administration.53,86, 87 Peak plasma concentrations usually occur within the first hour after oral administration of morphine in solution88 and slightly later with IR tablets.87 Both short-acting formulations have a rapid effect, and pain relief lasts for approximately 4 hours. By contrast, CR morphine tablets produce delayed peak plasma concentrations after 2 to 4 hours,89, 90 the peak is attenuated, and analgesia usually lasts for 12 hours.91 Following oral administration, there is rapid and extensive first-pass metabolism. The average bioavailability is 30% to 40%, but is quite variable (19% to 47%).53,92, 93 Although short-acting opioids are appropriate for immediate pain relief and dosage titration, long-acting opioids, generally indicated for once-daily (q24 hours) or twice-daily (q12 hours) dosing, are recommended for around-the-clock control in patients with moderate to severe chronic pain. Absolute bioavailability following administration of CR morphine is similar to other oral solutions and no dosage adjustment is required when converting between IR and CR formulations.86 The elimination half-life of CR morphine is similar to that of IR formulations. CR agents are specially formulated to control the rate of dissolution of opioid from the dosage form, enabling a slow release of the analgesic, followed by an increase to therapeutic level, plateau, and ultimate decline in concentration. This ER delivery system maintains blood levels of opioid within the therapeutic window with minimal fluctuation.
opioid against which all new analgesics are measured. Morphine, usually as the sulfate or hydrochloride salt, is available in four oral formulations—an elixir or solution, an IR tablet, a number of different preparations of MR tablets or capsules, and MR suspensions. Chronic subcutaneous infusions of morphine are used in cancer patients; however, significant intra- and interpatient variability in morphine, M6G, and M3G concentrations have been reported with chronic infusions.84 The reasons for this variability and its clinical implications are unknown. Subcutaneous administration of morphine results in less interpatient variability than oral morphine and smoother and more stable plasma concentrations.85 Oral absorption of IR morphine (tablets and solution) is almost complete. Peak plasma concentrations are 5 to 10 times lower than those obtained following parenteral administration.53,86, 87 Peak plasma concentrations usually occur within the first hour after oral administration of morphine in solution88 and slightly later with IR tablets.87 Both short-acting formulations have a rapid effect, and pain relief lasts for approximately 4 hours. By contrast, CR morphine tablets produce delayed peak plasma concentrations after 2 to 4 hours,89, 90 the peak is attenuated, and analgesia usually lasts for 12 hours.91 Following oral administration, there is rapid and extensive first-pass metabolism. The average bioavailability is 30% to 40%, but is quite variable (19% to 47%).53,92, 93 Although short-acting opioids are appropriate for immediate pain relief and dosage titration, long-acting opioids, generally indicated for once-daily (q24 hours) or twice-daily (q12 hours) dosing, are recommended for around-the-clock control in patients with moderate to severe chronic pain. Absolute bioavailability following administration of CR morphine is similar to other oral solutions and no dosage adjustment is required when converting between IR and CR formulations.86 The elimination half-life of CR morphine is similar to that of IR formulations. CR agents are specially formulated to control the rate of dissolution of opioid from the dosage form, enabling a slow release of the analgesic, followed by an increase to therapeutic level, plateau, and ultimate decline in concentration. This ER delivery system maintains blood levels of opioid within the therapeutic window with minimal fluctuation.
Sublingual and buccal administration of morphine appear to be equally efficacious as oral morphine and these routes may be suitable for patients who cannot take oral medications. However, these routes do not appear to offer any advantages in terms of speed of onset of the drug or more extensive absorption compared to other IR preparations. Rectal administration is often not a viable alternative because of the necessary frequency of administration of IR formulations and the lack of patient acceptance. The rectal route of administration shows similar plasma concentrations and bioavailability compared to the oral route.94 Elderly patients (>60 years of age) have reduced distribution volumes, which may result in higher peak plasma concentrations and reduced clearance of morphine.95, 96 Patients with impaired renal function have increased sensitivity to morphine and may experience severe and prolonged respiratory depression when treated with morphine.97, 98 Long-term treatment with escalating doses of morphine does not appear to change the pharmacokinetics of morphine or its metabolites, suggesting that escalating doses can be administered to cancer patients with disease progression or opioid tolerance.99
In a Cochrane review, Wiffen and McQuay100 reported that oral morphine is an effective analgesic in patients who suffer pain associated with cancer and remains the gold standard for moderate to severe pain. Morphine has a wide therapeutic range, is effective by different routes of administration, is available in most countries, and is relatively inexpensive. Furthermore, WHO recommends that oral morphine is part of the essential drug list. In this review it was not possible to demonstrate the superiority of one modified-release product over another, either by brand or by length of time release. Some preparations had the practical advantage of a formulation as microcapsules for those who cannot readily swallow tablets.
The standard for long-acting opioids is generally considered to be controlled-release morphine. In the United States, five preparations of controlled- or slow-release morphine are now available. These agents exist in either tablet or capsule form. Most tablet formulations adsorb morphine onto a hydrophilic polymer that is embedded in a hydrophobic matrix. Upon ingestion, gastrointestinal (GI) fluid dissolves the tablet surface and hydrates the hydrophilic polymer to produce a gel layer through which morphine is released at a rate determined by the type of hydrophilic polymer, hydrophobic matrix, or their ratio. MS Contin and Oramorph SR are produced in a resin matrix that dissolves and releases morphine over approximately a 12-hour period. The controlled-release form of morphine incorporates two different classes of macromolecules which provide gradual, measured release of morphine by dissolution and diffusion. One of these macromolecules is a cellulose polymer of variable branching and molecular weights. Slow release of morphine is related to binding of water as the polymer passes through the GI tract largely unchanged. The other macromolecule consists of aliphatic alcohols. Inclusion of both macromolecules results in both hydrophilic and hydrophobic molecular effects. This system regulates morphine release rate proportional to the hydrophilic and hydrophobic components. On aqueous contact, the drug-containing cellulose matrix becomes hydrated and relatively porous but otherwise remaining intact. Water absorption allows the drug to diffuse smoothly and evenly. Morphine release rate is determined by the size of the pores and by the barrier created by the aliphatic alcohol. The rate of release is not significantly altered by pH.
The efficacy and safety of MS Contin and Oramorph SR for patients with cancer pain has been confirmed by multiple studies. In a study comparing the pharmacokinetic profiles of MS Contin and Oramorph SR by administering a single 60-mg dose to 18 healthy volunteers, significant differences between the drugs for maximum plasma concentration (P < .001), area under the plasma concentration curve from zero to 12 hours (P < .01), and apparent elimination half-life (P < .001) were observed, indicating that the two morphine preparations were not bioequivalent.101 Patients should be instructed not to chew on or crush these preparations as this may result in a potentially toxic dose of morphine. Although the product insert for both MS Contin and Oramorph SR recommends using these drugs every 12 hours, we have found that it is frequently necessary to prescribe them
every 8 hours, particularly when higher doses (doses >200 mg/day) are required.
every 8 hours, particularly when higher doses (doses >200 mg/day) are required.
A form of CR morphine, Kadian, is available in clear capsules containing small polymer-coated pellets of drug and is recommended for once a day use. An individual capsule contains multiple pellets (eg, a 100-mg capsule contains on average 300 pellets). Each of the pellets contains a morphine sulfate-containing core that essentially functions as a separate drug reservoir. Kadian is available as 10, 20, 30, 50, 60, 80, 100, and 200 mg capsules. Following multiple doses of 100 mg capsules every 24 hours, the Tmax was approximately 10.3 hours. On a fixed dosing regimen to patients with chronic pain from malignancy, steady state is achieved in about 2 days. The nature of the core, the nature of the polymer coat, and the thickness of the coat collectively control the release of morphine from each pellet. The outer gelatin capsule rapidly dissolves in the stomach. The polymer coating has three components: an insoluble layer consisting of ethylcellulose, which has an enteric component (methacrylic acid copolymer, which is insoluble and relatively hydrophobic at pH 1.2); a water-soluble component (polyethylene glycol which is soluble and hydrophilic at pH 1.2); and a plasticizer (diethyl phthalate). As the core coating is partially soluble at an acidic pH, some release of morphine will occur in the stomach. As pH increases in the intestine, the remaining coating dissolves and significant drug absorption occurs in both the small and large intestines.
The pharmacokinetic profile of Kadian offers some advantages over MS Contin and Oramorph SR.102 MS Contin has a short time to Cmax with significant fluctuations in plasma concentrations at steady-state.103 Although Kadian and MS Contin administered every 12 hours have similar total plasma morphine concentrations (as measured by area under the curve), Kadian exhibited a significantly higher Cmin, less fluctuation in plasma morphine concentration throughout the dosing interval, a longer Tmax, and a greater time that the plasma morphine concentration was > 75% of Cmax.103 Another advantage of Kadian is its use by sprinkling (ie, breaking the capsule and sprinkling the pellets onto an easily ingested substance such as apple sauce or Guinness) which does not affect the time-release mechanism. Patients with swallowing difficulties may find Kadian a more suitable formulation as it can also be administered through a gastrostomy tube.
Avinza utilizes a combination of immediate- and extended-release beads. Upon ingestion, 10% of the beads release morphine immediately while the residual beads gradually release their morphine content over the next 24 hours. The fumaric acid component of the extendedrelease system of Avinza limits the daily dose to a maximum of 1600 mg because of the potential for renal toxicity from high doses of fumaric acid. Avinza is a oncedaily, extended-release oral morphine preparation. The controlled-release formulation utilizes SODAS (Spheroidal Oral Drug Absorption System) technology. This multiparticulate product is designed to provide a rapid onset of action together with a sustained therapeutic effect over 24 hours. Avinza is available in 30-, 60-, 90-, and 120-mg capsules. The capsule can be opened and the entire bead content sprinkled on a small amount of applesauce or put down a feeding tube. The beads should not be chewed or crushed. Within the GI tract, due to the permeability of the ammoniomethacrylate copolymers of the beads, fluid enters the beads and solubilizes the drug. This is mediated by fumaric acid, which acts as an osmotic agent and a local pH modifier. The resultant solution then diffuses out in a predetermined manner which prolongs the in vivo dissolution and absorption phases. It has a pharmacokinetic profile that exhibits less peak-to-trough fluctuation (%FI) in plasma concentration while providing analgesia statistically identical to that produced by MS Contin (CR morphine sulfate), OxyContin (oxycodone HCl controlled-release) and six doses of oral morphine sulfate administered every 4 hours. Compared to twicedaily controlled-release morphine, Avinza had a 19% lower maximum concentration (Cmax), a 66% higher minimum concentration (Cmin), and a 44% lower peak-totrough fluctuation over the 24-hour period. In addition, Avinza maintained concentrations above 50% and 75% of the Cmax longer than controlled-release morphine.104 In 2005, the Food and Drug Administration (FDA) issued a black box warning regarding alcohol use with Avinza suggesting that alcohol may cause dose-dumping.
Although some clinicians advocate the use of CR morphine when initiating morphine therapy in cancer patients, others suggest the best approach is to start treatment with an immediate-release preparation because dosage can be modified every 4 hours according to patients’ needs.78 Once the effective dosage is determined, it can be converted to a longer-acting preparation with the use of a short-acting opioid for breakthrough pain. De Conno et al. 105 reported on the use of immediate-release morphine (5 or 10 mg initial doses) given every 4 hours with a double dose given at bedtime and uptitrated according to response resulted in adequate pain control in 75% of 159 cancer patients during the first 5 days of treatment. Overall, 50% and 75% of patients achieved pain control within 8 and 24 hours after starting immediate-release morphine, respectively. The most commonly reported adverse events were somnolence (24%), constipation (22%), vomiting (13%), nausea (10%), and confusion (7%). The use of a double dose of IR morphine at bedtime instead of single doses repeated every 4 hours throughout the night has been recommended by EAPC.78 However, Dale et al.106 failed to find a significant difference between the two regimens, in terms of pain control.
The intracellular protein β-arrestin2 appears to be an important regulator of MOR desensitization. In β-arrestin2 knockout mice, morphine analgesia was increased and prolonged.107 Genetic variation in β-arrestin2 is associated with the need to switch from morphine to an alternative opioid, although variation in genes involved in MOR signaling may influence the clinical response to morphine in cancer patients.108 Catechol-omethyltransferase (COMT) inactivates dopamine, epinephrine, and norepinephrine in the nervous system. A common functional polymorphism (Val158Met) leads to a three- to fourfold variation in the COMT enzyme activity. The Val158Met polymorphism affects pain perception, and subjects with the Met/Met genotype have the most pronounced response to experimental pain. Genetic variation in the COMT gene may contribute to variability in the efficacy of morphine in cancer pain treatment.109
When we select morphine as the opioid of choice for the treatment of tumor pain, we usually use a long-acting
preparation for baseline pain control. Our preference is to use Avinza because of its exceptional duration of action. We commonly use a short-acting, immediate release opioid for the control of breakthrough pain; in most instances, this will be morphine sulfate, immediate release. Our standard dose for breakthrough medication is up to 10% of the 24-hour long-acting dose. Breakthrough medication dose intervals are based on the known duration of action of the drug (typically every 3 to 4 hours). The longacting medication dose is first adjusted to control the background pain. Once this is satisfactorily controlled, breakthrough medication is adjusted proportionally.
preparation for baseline pain control. Our preference is to use Avinza because of its exceptional duration of action. We commonly use a short-acting, immediate release opioid for the control of breakthrough pain; in most instances, this will be morphine sulfate, immediate release. Our standard dose for breakthrough medication is up to 10% of the 24-hour long-acting dose. Breakthrough medication dose intervals are based on the known duration of action of the drug (typically every 3 to 4 hours). The longacting medication dose is first adjusted to control the background pain. Once this is satisfactorily controlled, breakthrough medication is adjusted proportionally.
OXYCODONE
Oxycodone is a semisynthetic opioid that is a derivative of the opium alkaloid thebaine. It has been in use for over 80 years, mainly as the hydrochloride or terephthalate salt. Oxycodone has a lipid solubility similar to morphine.110 Oxycodone is a MOR-specific ligand with clear agonist properties. The µ-opioid receptor binding affinity of oxycodone is less than that of morphine or methadone.111 Oxycodone has been suggested to be a κ-opioid receptor agonist.112 This is not likely, as animal studies have shown that oxycodone and oxymorphone analgesia are fully antagonized by the µ-opioid receptor antagonist naloxone, whereas there was no antagonistic effect of the κ-opioid receptor antagonist norbinaltorphimine.113
Oxymorphone, the active metabolite of oxycodone that accounts for approximately 11% of the oxycodone metabolized, has a significantly higher MOR affinity.114 Kalso et al. suggested that the analgesic effect of oxycodone was due to the presence of pharmacologically active metabolites in circulation.115 Oxymorphone, although possessing analgesic activity, is present in the plasma only in low concentrations. The role of metabolites in the analgesic effects of oxycodone was investigated in healthy volunteers.114 The central opioid effects of oxycodone could be explained by the pharmacokineticpharmacodynamic of the parent drug alone. Although the potent active metabolite noroxymorphone was present at relatively high concentrations in the circulation, it did not appear to penetrate the blood brain barrier to a significant extent. Furthermore, other metabolites either demonstrated low potency or were present in circulation at very low levels. The main known metabolic pathways of oxycodone are through O-demethylation to oxymorphone and via N-demethylation to noroxycodone. Noroxycodone is a considerably weaker analgesic than oxycodone and does not appear to contribute to the analgesic effect of oxycodone.
The conversion of oxycodone to oxymorphone, as well as the conversion of noroxycodone to noroxymorphone is catalyzed by CYP2D6. The contribution of oxymorphone to the analgesic effect is controversial. Recently, Zwisler et al.116 suggested that oxycodone analgesia was dependent on both oxycodone and oxymorphone. In a human experimental model, differences in pain detection and tolerance thresholds were demonstrated between CYP2D6 poor metabolizers and extensive metabolizers with oxycodone administration. For single sural nerve stimulation, there was a less pronounced increase in thresholds on oxycodone in pain detection (9% vs. 20%, P = .02, a difference of 11%; 95% confidence interval [CI]: 2%-20%) and pain tolerance thresholds (15% vs. 26%, P = .037, a difference of 10%; CI: 1%-20%) for poor metabolizers compared with extensive metabolizers. In the cold pressor test, there was less reduction in pain AUC on oxycodone for poor metabolizers compared with extensive metabolizers (14% vs. 26%, P = .012, a difference of 12%; CI: 3%-22%).
Oxycodone and its metabolites are excreted primarily via the kidney and elimination is impaired by renal failure. Patients with renal dysfunction (creatinine clearance <60 mL/min) show peak plasma oxycodone and noroxycodone concentrations 50% and 20% higher, respectively, and AUC values for oxycodone, noroxycodone, and oxymorphone 60%, 50%, and 40% higher than normal subjects, respectively.117 Oxycodone is well absorbed, when orally administered. Approximately 60% of an oral dose (range: 50% to 87%) is bioavailable. With the controlled-release oxycodone tablets, 38% of the available dose is rapidly absorbed with a mean half-life of 37 minutes, providing a fast onset of pain relief, within 1 hour.118 Pharmacologic effects of oxycodone include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, and cough suppression, as well as pain relief. Common side effects associated with oxycodone (OxyContin or oxycodone IR) are constipation (23%), nausea (23%), somnolence (23%), dizziness (13%), pruritus (13%), vomiting (12%), dry mouth (6%), and sweating (5%).
After oral administration, oxycodone is rapidly absorbed to produce an initial peak plasma oxycodone in about 2 hours.115,119 Once peak plasma concentrations are reached, oxycodone concentrations decline, rapidly, with an apparent terminal half-life ranging from 3.0 to 5.7 hours.119, 120 The rapid absorption and quick elimination after oral administration of oxycodone (bioavailability of oxycodone is >60%), mandates frequent dosing to maintain plasma concentrations within the therapeutic analgesic range. The elimination half-life of CR oxycodone is 4.5 hours compared to 3.2 hours for IR oxycodone. Given the shortness of its half-life of elimination, steady-state of plasma concentrations is achieved within 24 to 36 hours of initiation of dosing with oxycodone CR. The higher oral-intravenous ratio of oxycodone (0.7) compared with that of morphine (0.31) reflects the greater oral bioavailability of oxycodone compared to morphine.121
Oxycodone was first introduced in the United States in fixed combination with acetaminophen, acetylsalicylic acid, or with nonsteroidal anti-inflammatory drugs (NSAIDs). It is now also available as a single agent in CR and IR formulations. CR oxycodone exhibits a biphasic absorption pattern with two apparent absorption halftimes of 0.6 and 6.9 hours. Thirty-eight percent of the available dose is rapidly absorbed, with a mean half-life of 37 minutes, providing onset of analgesia within 1 hour.118 The relative oral bioavailability of OxyContin to IR oral dosage forms is 100%. OxyContin administered per rectum produces an area under the curve (AUC) 39% greater and a Cmax 9% higher than tablets administered by mouth, suggesting an increased risk of adverse events with rectal administration.
In the treatment of cancer-related pain, the oral requirement for oxycodone is less than morphine, but
oxycodone is less potent intravenously.115,121 According to Beaver et al.,122, 123 twice the amount of oxycodone in milligrams is required orally than intramuscularly for equianalgesia; intramuscular oxycodone is two thirds as potent as intramuscular morphine. IR oxycodone is well-tolerated in steady-state pharmacodynamic studies.120-121,124 Kalso and Vainio121 utilized oxycodone hydrochloride and morphine in a double-blind crossover study of 20 patients who were experiencing severe cancer pain. No major differences in the side effects between the two opioids were observed, although morphine led to more nausea than oxycodone and hallucinations occurred only during morphine treatment. Maddocks et al.125 stated that morphine-induced delirium in cancer patients was ameliorated when they were changed to oxycodone.
oxycodone is less potent intravenously.115,121 According to Beaver et al.,122, 123 twice the amount of oxycodone in milligrams is required orally than intramuscularly for equianalgesia; intramuscular oxycodone is two thirds as potent as intramuscular morphine. IR oxycodone is well-tolerated in steady-state pharmacodynamic studies.120-121,124 Kalso and Vainio121 utilized oxycodone hydrochloride and morphine in a double-blind crossover study of 20 patients who were experiencing severe cancer pain. No major differences in the side effects between the two opioids were observed, although morphine led to more nausea than oxycodone and hallucinations occurred only during morphine treatment. Maddocks et al.125 stated that morphine-induced delirium in cancer patients was ameliorated when they were changed to oxycodone.
OxyContin, a CR preparation of oxycodone, is now available in strengths of 10, 15, 20, 30, 40, 60, and 80 mg. Mandema et al.118 showed that the pharmacokinetics of the CR dosage form permitted 12-hourly dosing. Oxycontin absorption is characterized by a rapid initial component (t½abs = 37 min) accounting for 38% of the available dose and a slower component (t½abs = 6.2 hours) accounting for 62% of the available dose.
Steady-state pharmacodynamic profiles of Oxycontin and MS Contin were compared in 27 patients with chronic cancer pain in a double-blind, randomized, crossover design.126 When oxycodone was given initially, the total opioid consumption ratio of oxycodone to morphine was 2:3; when given after morphine, it was 3:4. Patients reported similar adverse experiences but significantly more vomiting occurred with morphine, and constipation was more common with oxycodone. The two opioids provided comparable pain relief in this study. Reid et al.127 evaluated the efficacy and tolerability of oxycodone in cancer-related pain in a systematic review of randomized controlled trials. The authors found no clinically important differences between the analgesic efficacy and the adverse effect profile of oxycodone compared with morphine. In essence, the efficacy and tolerability of oxycodone was similar to morphine, supporting its use as an opioid for cancer-related pain.
We use oxycodone routinely in the management of pain in the cancer patient. It is usually well tolerated and easy to titrate. The availability of a wide variety of dosing formats (in both tablet and liquid) facilitates the use of this medication. However, we are concerned about the relatively large immediate dose available in the CR formulation (30%) and its euphoric effects. This may be problematic in patients who are at risk to abuse opioid medications.
OXYMORPHONE
Oxymorphone is a semisynthetic µ-opioid agonist that has been available in parenteral form since 1959. It is a pyridine-ring unsubstituted pyridomorphinan. Structurally, oxymorphone is more closely related to hydromorphone. It is available as a hydrochloride salt. It has a greater analgesic potency than morphine. It is available as parenteral injection, suppository and oral formulations (Table 19.4).
TABLE 19.4 FORMULATIONS OF OXYMORPHONE | |||||||||||||||
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The antinociceptive effects of oxymorphone are mediated predominantly through µ- and δ-receptors.128 The oral bioavailability of oxymorphone is approximately 10%. The half-life is influenced by the route of administration. The recommended dosing has been every 6 hours, which is longer than most IR opioids. Steady-state conditions are achieved after 3 to 4 days. Oxymorphone is subject to hepatic first-pass effects and is renally excreted. Oxymorphone undergoes extensive hepatic metabolism via conjugation with glucuronic acid to create oxymorphone 3-glucuronide, and the keto group is reduced to form 6-OH-oxymorphone. Hale et al.129 found a 2:1 dose ratio for oxycodone (CR) relative with oxymorphone (ER). Oxymorphone IR reaches Tmax at 0.5 hrs after single doses (5, 10, or 20 mg) with a terminal elimination half-life of approximately 7.3 to 9.4 hours in healthy volunteers.130 Ingestion of food along with oxymorphone increases the Cmax by 38% to 50% and it may be advisable to take the drug on an empty stomach. Oxymorphone ER is a tablet formulation that utilizes the proprietary TIMERx technology (Penwest Pharm) which allows 12-hour dosing. This CR technology inserts the opioid into an agglomerated hydrophilic matrix which releases the drug (as water penetrates the matrix) to sustain plasma levels during the 12-hour dosing interval. The elimination half-life of oxymorphone ER is similar to the half-life of oxymorphone IR. Steady-state conditions were achieved after 3 days of 12-hour dosing and Tmax occurred at 1.5 to 3.5 hours.130 Consumption of alcohol with oxymorphone ER may increase release of oxymorphone by 31%. The absolute oral bioavailability is approximately 10% suggesting that patients may be switched from parenteral to oral oxymorphone by giving 10 times the parenteral doses in divided doses. Oxymorphone should be considered a more potent opioid than morphine with no reported CYP450 system interactions131 and an otherwise similar profile to that of other available opioids. As with other opioids, renal and hepatic impairment require monitoring and dose adjustment.
Sloan et al.132 compared oxymorphone ER and oxycodone CR in patients (N = 86) with moderate to severe cancer pain. Patients were first stabilized for 3 days or longer on morphine CR or oxycodone CR. Those who attained stable pain relief for at least 3 days (three or fewer rescue doses of opioid per day) entered the first 7-day treatment period (period 1) at the stabilized dose of the titrated medication with no dosage adjustments. All patients who were treated for 7 days at their stabilized dose of either morphine CR or oxycodone CR were then
crossed over to oxymorphone ER at an estimated equianalgesic dosage and treated for an additional 7 days (period 2). During periods 1 and 2, the oral IR formulation of the study medication was available as rescue medication. Each dose of rescue medication was approximately 10% of the total daily dose of scheduled medication. Similar daily pain intensity scores during the last 2 days of the initial treatment phase (morphine CR or oxycodone CR) compared with those during the last 2 days of the oxymorphone ER treatment phase indicate that equivalent analgesia was achieved after patients had been rotated to oxymorphone ER. This also suggests that the long-acting formulation can maintain drug levels in a stable fashion. Patients taking oxymorphone ER needed less breakthrough medication than patients taking morphine CR. The tolerability/safety profiles (eg, nausea, drowsiness, and somnolence) were similar between the two drugs. There were no significant differences in daily pain intensity scores between oxymorphone ER and either morphine or oxycodone. Gabrail et al.133 noted that 47 adult patients with cancer who were taking oxycodone CR were readily converted to oxymorphone ER and required half the milligram dose to stabilize their pain. Within 72 hours, most patients achieved a stable dose that provided adequate relief with similar opioid adverse events.
crossed over to oxymorphone ER at an estimated equianalgesic dosage and treated for an additional 7 days (period 2). During periods 1 and 2, the oral IR formulation of the study medication was available as rescue medication. Each dose of rescue medication was approximately 10% of the total daily dose of scheduled medication. Similar daily pain intensity scores during the last 2 days of the initial treatment phase (morphine CR or oxycodone CR) compared with those during the last 2 days of the oxymorphone ER treatment phase indicate that equivalent analgesia was achieved after patients had been rotated to oxymorphone ER. This also suggests that the long-acting formulation can maintain drug levels in a stable fashion. Patients taking oxymorphone ER needed less breakthrough medication than patients taking morphine CR. The tolerability/safety profiles (eg, nausea, drowsiness, and somnolence) were similar between the two drugs. There were no significant differences in daily pain intensity scores between oxymorphone ER and either morphine or oxycodone. Gabrail et al.133 noted that 47 adult patients with cancer who were taking oxycodone CR were readily converted to oxymorphone ER and required half the milligram dose to stabilize their pain. Within 72 hours, most patients achieved a stable dose that provided adequate relief with similar opioid adverse events.
We have found oxymorphone to be a useful drug in the oncology population. The drug is generally well tolerated in our patient population. It has a similar pharmacokinetic profile to other CR opioids such as MS Contin and OxyContin, but it does not have the immediaterelease component associated with latter.
HYDROMORPHONE
Hydromorphone (Dilaudid) is a short-half-life opioid that is versatile because of its many routes of administration. Hydromorphone is a semisynthetic opioid agonist and is a hydrogenated ketone analogue of morphine. It was synthesized in Germany in 1921 and introduced into clinical medicine in 1926. It is commercially available in most countries as the hydrochloride salt. Absorption of oral hydromorphone is mainly from the upper small intestine. Onset of action is within 30 minutes and the duration of action is approximately 4 hours. Bioavailability is low owing to extensive presystemic liver elimination. The mean proportion of the oral dose absorbed is 62 ± 33%, but variability is wide.134 Low oral bioavailability and interindividual variation determine the oral-parenteral relative milligram potency ratio, which is 5:1 with repeated administration.134, 135 Hydromorphone is metabolized in the liver and undergoes conjugation to H3G. Hydromorphone also undergoes reduction to dihydromorphine and dihydroisomorphine. H3G can produce dose-dependent behavioral excitation if it crosses the blood brain barrier.70 In renal failure the mean ratio of H3G to hydromorphone may increase to 100:1, perhaps producing neuropsychological effects including cognitive impairment.63,136
The short elimination half-life of hydromorphone requires at least q4hr administration of the drug to maintain adequate plasma levels. Equianalgesic dose equivalence of hydromorphone to morphine is approximately 1:5. Quigley137 concluded that hydromorphone was a potent analgesic, as predicted for a µ-opioid receptor agonist and its efficacy was dose related. The adverse effect profile of hydromorphone was also predictable and similar to other µ-opioid agonists. Hydromorphone has no clinical superiority over other opioid analgesics. An ER form called Palladone was available for a short time in the United States before being voluntarily withdrawn from the market when an FDA advisory released in July 2005 warned of a high overdose potential if taken with alcohol (“dose dumping”).
Oral hydromorphone use in our patient population is limited because of the current unavailability of a longacting oral preparation. We do use it in the management of breakthrough pain.
METHADONE
Methadone is a synthetic opioid and is a phenylheptylamine structure. It is a potent µ- and δ-opioid receptor agonist. In animal studies, it also has antagonist activity at N-methyl-D-aspartic acid (NMDA) receptors, resulting in some interest in the use of this drug for various neuropathic pain syndromes.138
Methadone is an attractive alternative opioid for the management of cancer pain because of its analgesic efficacy, good oral bioavailability, and lack of known neuroactive metabolites. Unfortunately, the substitution of methadone for another opioid is not simple. Clinically, methadone has large interindividual pharmacokinetic variability, a potential for delayed toxicity and a widely varying dose ratio when switching from different opioids. Methadone is available as the lipophilic hydrochloride powder that can be used for the preparation of oral, rectal, and parenteral solutions and is available commercially in a variety of preparations. It is commonly available as a racemic mixture of two isomers, levorotatory (L) methadone and dextrorotatory (D) methadone, although pure L-methadone is available in some countries. Clinical effects of the racemic mixture are pain relief, meiosis, respiratory depression, antidiuresis and suppression of the abstinence syndrome in opioid addicts. L-methadone is the much more potent isomer in man and is believed to be almost entirely responsible for the analgesic properties.
Methadone is well absorbed by all routes. Oral administration is followed by rapid gastrointestinal absorption with measurable plasma levels at 30 minutes. Methadone is rapidly absorbed from the stomach, with little absorption occurring beyond the pylorus.139 The peak plasma levels after an oral dose occur at four hours and begin to decline 24 hours after dosing. The analgesic effect of an oral dose begins within 30 to 60 minutes and generally lasts for 4 to 6 hours.140 Oral bioavailability is high, generally more than 85%. The recommended dose to be given parenterally is between 50% and 80% of the oral dose.141 Significant interindividual variation in half-life has been observed in practice, with an average half-life of approximately 24 hours but a range of 13 to 100 hours141, 142 (Table 19.5). This has significant clinical implications with such variability at steady state dosing and often results in the accumulation of methadone in tissues with
chronic administration. This can lead to significant toxicity. Methadone is metabolized almost exclusively by the liver by type I CYP450 group of enzymes. Elimination of methadone is mediated by hepatic oxidative biotransformation, renal N-demethylation, and urinary and fecal clearance. Methadone is predominantly excreted in the feces. It does not accumulate in renal failure and does not appreciably filter during hemodialysis. Chronic administration results in increased metabolite to methadone ratios, suggesting that autoinduction of hepatic microsomal enzymes does occur. Renal impairment is not thought to impair clearance.143
chronic administration. This can lead to significant toxicity. Methadone is metabolized almost exclusively by the liver by type I CYP450 group of enzymes. Elimination of methadone is mediated by hepatic oxidative biotransformation, renal N-demethylation, and urinary and fecal clearance. Methadone is predominantly excreted in the feces. It does not accumulate in renal failure and does not appreciably filter during hemodialysis. Chronic administration results in increased metabolite to methadone ratios, suggesting that autoinduction of hepatic microsomal enzymes does occur. Renal impairment is not thought to impair clearance.143
TABLE 19.5 KEY PHARMACOKINETIC PARAMETERS FOR METHADONE | |||||||||||||||||||||
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Methadone has several advantages, including excellent oral and rectal absorption (oral bioavailability varies from 41% to 99%), no known active metabolites, high potency, high lipid solubility, low cost, and longer administration intervals. It may also offer enhanced pain relief due to incomplete cross-tolerance with other µ-opioid receptor agonist drugs.144, 145, 146, 147
The potency of methadone is much greater than previously recognized, especially with repeated-dose administration.146, 147, 148, 149 Standard equianalgesic tables underestimate methadone versus hydromorphone potency.150 This mandates a highly individualized and cautious approach when rotating patients with cancer pain from any other opioid to methadone. At the initiation of treatment, repeated doses of methadone at fixed intervals may lead to its accumulation and overdose effects. This has raised concerns about its use in cancer pain, particularly in situations that require rapid dose escalation.151
There are large interindividual variations in methadone pharmacokinetics with rapid and extensive distribution phases (t½α = 2 to 3 hours; t½β = 15 to 60 hours). Considerably longer elimination half-lives, even extending to 120 hours, have been reported.152 Relatively high daily doses of methadone (40 to 50 mg/day) have been used in patients with chronic renal disease.143
Concomitant administration of CYP3A4 inducers will increase methadone metabolism, potentially causing a reduction in methadone plasma concentrations. This may result in the need for larger doses of methadone during the period of interaction. In addition, doses of methadone may need to be reduced when a CYP3A4 inducer is discontinued. Known inducers of CYP3A4 include rifampin, rifabutin, carbamazepine, phenytoin, phenobarbital, and abacavir. The commonly used dietary supplement for depression, St. John’s wort, has also been shown to lower the plasma concentrations of methadone.153 Many methadone-related deaths may be caused by drug interactions rather than administration of methadone alone.154 Drugs that potentially interact with methadone include inhibitors of CYP3A4 and CYP2D6. Drugs that inhibit CYP3A4 include fluconazole, fluvoxamine, fluoxetine, paroxetine, HIV-1 protease inhibitors, and likely erythromycin and ketoconazole. In addition to CYP3A4 inhibitors affecting methadone’s clearance, methadone itself acts as a CYP3A4 inhibitor and therefore has the potential to interact with other CYP3A4 substrates.155
Unexpected deaths have been associated with the use of methadone.156, 157 The presumed mechanism of death in these cases was once thought to be respiratory depression from overdose. However, evidence now suggests that methadone administration is associated with prolongation of QTc interval and cases of torsades de pointes (TdP) ventricular arrhythmia.158, 159, 160 Torsades de pointes is most often caused by drugs that block the rapidly activating component of the delayed rectifier potassium current (Ikr) channels in cardiac myocytes. The human ether-a-go-go related gene (HERG) encodes for a major subunit of the Ikr channel.161 In vitro studies have revealed that methadone can block the cardiac HERG potassium channel.158, 159, 160, 161, 162 In addition, methadone has negative chronotropic properties163 and it has been observed that drug-induced TdP is often triggered during periods of bradycardia.164 Women have a slightly longer QTc interval than men; a prolonged QTc interval may be defined as >450 ms for men and >470 ms for women. Although there is disagreement over the exact risk QTc prolongation confers, measurements over 500 ms significantly increase the risk for torsades de pointes.165 Additionally, increases in the QTc interval > 40 over baseline also increase this risk.165, 166 Pearson and Woosley167 reported on adverse events associated with methadone to the FDA MedWatch program from 1969 to 2002 and noted the occurrence of torsades de pointes and QT prolongation to be 0.78% and 0.29%, respectively. The mean dose of methadone was 410 ± 349 mg/day, range 29 to 1680 mg/day. Female gender, interacting medications, hypokalemia, hypomagnesemia, and structural heart disease were identified as potential risk factors. Most adverse events required hospitalization or resulted in prolonged hospitalization; 8% were fatal. Krantz et al. 168 provided cardiac safety consensus recommendations for physicians prescribing methadone (Table 19.6). Electrocardiograph (ECG) screening may be performed on an individual basis in patients receiving methadone with multiple risk factors for QTc prolongation, including a family history of long QTc syndrome or early sudden cardiac death or electrolyte depletion, and on initiation of therapy with a CYP450 inhibitor or other QTc interval-prolonging drug, including cocaine. Moreover, urgent evaluation that includes ECG screening is warranted for patients receiving methadone with unexplained syncope or generalized seizures; if marked QTc interval prolongation is present, torsade de pointes should be suspected and methadone discontinued.
Methadone is actively used as a potent analgesic for cancer pain, with the advantages of a long half-life, lack of known active metabolites, high lipid solubility, good oral
and rectal bioavailability, low cost, and theoretical benefit over other opioids in the setting of neuropathic pain. Bruera et al.169 compared the effectiveness and side effects of methadone and morphine as first-line treatment with opioids for cancer pain. During a 4-week period, patients were randomly assigned to receive methadone (7.5 mg orally every 12 hours and 5 mg every 4 hours as needed) or morphine (15 mg sustained release every 12 hours and 5 mg every 4 hours as needed). A total of 103 patients were randomly assigned to treatment (49 in the methadone group and 54 in the morphine group). The groups had similar baseline scores for pain, sedation, nausea, confusion, and constipation. Patients receiving methadone had more opioid-related drop-outs (11 of 49; 22%) than those receiving morphine (three of 54; 6%; P = .019). The opioid escalation index at days 14 and 28 was similar between the two groups. More than three fourths of patients in each group reported a 20% or more reduction in pain intensity by day 8. The proportion of patients with a 20% or more improvement in pain at 4 weeks in the methadone group was 0.49 (95% CI: 0.34-0.64) and was similar in the morphine group (0.56; 95% CI: 0.41-0.70). The rates of patient-reported global benefit were nearly identical to the pain response rates and did not differ between the treatment groups. The authors concluded that methadone did not produce superior analgesic efficiency or overall tolerability at 4 weeks compared with morphine as a first-line strong opioid for the treatment of cancer pain. In a Cochrane review, Nicholson170 concluded that methadone was no more effective than morphine for cancer-related nerve related pain and that methadone had a similar side effect profile, but these side effects may be more apparent with repeated dosing.
and rectal bioavailability, low cost, and theoretical benefit over other opioids in the setting of neuropathic pain. Bruera et al.169 compared the effectiveness and side effects of methadone and morphine as first-line treatment with opioids for cancer pain. During a 4-week period, patients were randomly assigned to receive methadone (7.5 mg orally every 12 hours and 5 mg every 4 hours as needed) or morphine (15 mg sustained release every 12 hours and 5 mg every 4 hours as needed). A total of 103 patients were randomly assigned to treatment (49 in the methadone group and 54 in the morphine group). The groups had similar baseline scores for pain, sedation, nausea, confusion, and constipation. Patients receiving methadone had more opioid-related drop-outs (11 of 49; 22%) than those receiving morphine (three of 54; 6%; P = .019). The opioid escalation index at days 14 and 28 was similar between the two groups. More than three fourths of patients in each group reported a 20% or more reduction in pain intensity by day 8. The proportion of patients with a 20% or more improvement in pain at 4 weeks in the methadone group was 0.49 (95% CI: 0.34-0.64) and was similar in the morphine group (0.56; 95% CI: 0.41-0.70). The rates of patient-reported global benefit were nearly identical to the pain response rates and did not differ between the treatment groups. The authors concluded that methadone did not produce superior analgesic efficiency or overall tolerability at 4 weeks compared with morphine as a first-line strong opioid for the treatment of cancer pain. In a Cochrane review, Nicholson170 concluded that methadone was no more effective than morphine for cancer-related nerve related pain and that methadone had a similar side effect profile, but these side effects may be more apparent with repeated dosing.
TABLE 19.6 CARDIAC SAFETY RECOMMENDATIONS FOR METHADONE USE | ||||||||||||
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As with other potent opioids, caution must be exercised in elderly patients, in patients with encephalopathy or a major organ failure, in those who are difficult to monitor, and in patients who are noncompliant with treatment regimens. In addition, caution is suggested in situations where rapid control of severe pain is required. Substantial interindividual variation in the relationship between changes in plasma concentration and pain relief can occur in patients with chronic pain receiving methadone.171 Information about interpatient variation in pain perception has led to the concept of individualization of methadone dosing in the management of cancer pain.
We commonly prescribe methadone for the treatment of cancer pain. We use this medication in either a “pain cocktail” or tablet format. We are very cautious in converting to or from this drug with other opioids. We typically do not prescribe this drug to patients who have been noncompliant with opioid instructions. Compared to other opioids commonly used in the management of cancer pain, we believe that methadone is a unique drug that should be used cautiously, particularly by the inexperienced prescriber. The possibility of a life-threatening cardiac arrhythmia with this drug as well as the possibility of drug accumulation in a relatively short time period is particularly concerning. We recommend obtaining an ECG (for QTc measurement) before starting this drug and at yearly intervals thereafter if methadone treatment is continued. We believe that methadone is a useful and probably unique drug in the management of cancer pain. Its role is well established but it clearly has hazards that remain to be accurately defined.
LEVORPHANOL
Although structurally related to morphine, levorphanol has high affinity for a number of receptor subtypes, including both κ1 and κ3.172 Levorphanol infusions resulted in tolerance to both morphine and levorphanol, whereas morphine infusions selectively produced tolerance to morphine, suggesting that the unidirectional tolerance of morphine may occur because of the selectivity of morphine for µ receptors compared to levorphanol’s ability to interact more potently with other receptor subtypes.173 Levorphanol (levo-3-hydroxy-N-methyl morphinan) should be considered an agonist to µ1-, κ3-, and δ-opioid receptors.174, 175 In addition, it also appears to have NMDA receptor antagonist effects176 and also a monoamine reuptake inhibitor.177 Leorphanol is the levoenantiomer of dextromethorphan. Levorphanol has a long half-life (12 to 16 hours), and is available in both
oral and parenteral formulations. It is not well absorbed sublingually from the buccal mucosa.178 Levorphanol is metabolized in the liver to produce a 3-glucuronide metabolite and is renally excreted.179 Drug concentrations peak 30 minutes after parenteral injection and 1 hour after oral dose.179 The duration of pain relief ranges from 6 to 15 hours. With repeated dosing, the half-life can be as long as 30 hours.179 The initial oral dose should be 2 mg and can be repeated every 6 hours. The parenteral dose is approximately one half the oral dose. With repeated dosing, drug accumulation and accidental overdose may occur. Strategies for use of levorphanol are similar to those suggested for methadone. Levorphanol may be considered 4 to 8 times as potent as morphine, but a sliding scale for conversion from morphine to levorphanol has been suggested.180 To convert oral morphine equivalent doses <100 mg, use a conversion ratio of 12:1; from 100 to 299 mg, a ratio of 15:1; from 300 to 599 mg, a ratio of 20:1; and from 600 to 799 mg, a ratio of 25:1.
oral and parenteral formulations. It is not well absorbed sublingually from the buccal mucosa.178 Levorphanol is metabolized in the liver to produce a 3-glucuronide metabolite and is renally excreted.179 Drug concentrations peak 30 minutes after parenteral injection and 1 hour after oral dose.179 The duration of pain relief ranges from 6 to 15 hours. With repeated dosing, the half-life can be as long as 30 hours.179 The initial oral dose should be 2 mg and can be repeated every 6 hours. The parenteral dose is approximately one half the oral dose. With repeated dosing, drug accumulation and accidental overdose may occur. Strategies for use of levorphanol are similar to those suggested for methadone. Levorphanol may be considered 4 to 8 times as potent as morphine, but a sliding scale for conversion from morphine to levorphanol has been suggested.180 To convert oral morphine equivalent doses <100 mg, use a conversion ratio of 12:1; from 100 to 299 mg, a ratio of 15:1; from 300 to 599 mg, a ratio of 20:1; and from 600 to 799 mg, a ratio of 25:1.
We have rarely used this drug for cancer pain. It is often not available in our local pharmacies. We do not see unique advantages to this drug over methadone.
FENTANYL
Fentanyl is a synthetic µ agonist derivative of phenylpiperidine and is a chemical congener of the reversed ester of meperidine. It has a short duration of action: 30 to 60 minutes after a single intravenous bolus of 100 µg, mainly due to its large volume of distribution and redistribution and uptake into fatty tissues. It is characterized by high potency and lipophilicity and is 75 to 100 times more potent than morphine on a molar basis. Transdermal, transmucosal/buccal, and parenteral formulations are available. At steady-state conditions after parenteral administration, half-life is primarily determined by redistribution which results in a short duration of effect. The combination of high potency, low molecular weight, and high lipid solubility makes fentanyl an ideal medication for transdermal administration.181
Transdermal Fentanyl
Fentanyl patches have been in use since the early 1990s. The original patch (which is described as a reservoir patch) consists of a backing layer to protect the patch from the environment, a liquid drug reservoir, a membrane which controls the rate of drug transfer, and an adhesive layer to secure the patch to the skin surface. The drug reservoir contains fentanyl (2.5 mg/10 cm2 of system size) and ethanol (alcohol) [0.1 ml/10 cm2 system size] gelled with hydroxyethyl cellulose. The surface area of the patch determines the amount of fentanyl released. However, a significant amount of fentanyl remains in a transdermal system after 3 days of continuous use. Adequate policies for patch disposal have not been established.182 Abuse of reservoir fentanyl patches is not restricted to transdermal application and there are reports of I.V. injection of patch contents183, 184 as well as oral / transmucosal administration,185, 186, 187 rectal insertion,188 and inhalation.189 New transdermal-fentanyl systems that have an adhesive matrix but no drug reservoir or rate-controlling membrane are available. D-TRANS Matrix delivery system has fentanyl dissolved in a polyacrylate adhesive to form a drugin-adhesive layer, which in conjunction with the stratum corneum provides the rate-controlling element. The matrix adheres directly to the skin without adhesive edges or layers. This system compared with established reservoir and matrix fentanyl patches appears to be equivalent in terms of efficacy190
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