Morphine

Morphine is the prototype mu agonist opioid (Fine, Portenoy, 2007) and is the standard against which all other opioid drugs are compared (Hanks, De Conno, Cherny, et al., 2001; Inturrisi, 2002; Knotkova, Fine, Portenoy, 2009). It is the most widely used opioid throughout the world (Andersen, Christrup, Sjøgren, 2003), particularly for cancer pain (Flemming, 2010). Its role is supported by extensive research, clinical experience with its use, the availability of formulations for multiple routes of administration, and early development of modified-release formulations. In 1984, the World Health Organization designated morphine as the preferred drug for cancer pain management (WHO, 1996), and still today it is referred to as the “gold standard” for opioid analgesics (Quigley, Wiffen, 2003). This characterization can be viewed as educational; as noted previously, it is not based on comparative effectiveness or safety data. Although some guidelines continue to advocate for morphine as the preferred first-choice “strong” opioid (Hanks, De Conno, Cherny, et al., 2001; Donnelly, Davis, Walsh, et al., 2002), others recognize the lack of evidence to support a preferred status and are less definitive, instead preferring to recommend mu agonist opioids as a class (American Pain Society [APS], 2003; National Comprehensive Cancer Network, 2008). A Cochrane Collaboration Review of 54 studies of oral morphine for cancer pain concluded that well-controlled research with large numbers of patients is lacking, but that existing studies generally confirm that morphine is effective, with the most common adverse effects being constipation, nausea, and vomiting (Wiffen, McQuay, 2007).

In addition to the large role that it plays in the worldwide treatment of cancer pain (Donnelly, Davis, Walsh, et al., 2002; Hanks, Cherny, Fallon, 2004), morphine has a long history as a primary drug for acute postoperative pain management (McCartney, Niazi, 2006) and has been used to treat a wide range of other painful conditions including severe angina pectoris (Mouallem, Schwartz, Farfel, 2000), AIDS-related pain (Kaplan, Slywka, Slagle, et al., 2000), and prehospital admission trauma and medical conditions (Ricard-Hibon, Belpomme, Chollet, et al., 2008). As part of a standard anesthetic regimen, IV morphine, but not IV fentanyl, suppressed several components of the inflammatory response to cardiopulmonary bypass in patients undergoing coronary artery bypass graft surgery (Murphy, Szokol, Marymont, et al., 2007).

Although opioids are not first-line analgesics for neuropathic pain, morphine has been shown to effectively treat this type of pain, particularly in combination with first-line adjuvant analgesics for neuropathic pain, such as the gabapentinoids (i.e., gabapentin and pregabalin) and the analgesic antidepressants (Dworkin, O’Connor, Backonja, et al., 2007; Gilron, Bailey, Tu, et al., 2005; Maier, Hildebrandt, Klinger, et al., 2002). One randomized, placebo-controlled, double-blind, cross-over study (N = 76) found that opioids (morphine or methadone) and tricyclic antidepressants (despiramine or nortriptyline) were effective in treating postherpetic neuralgia with a nonsignificant trend toward greater reduction in pain with opioids (Raja, Haythornthwaite, Pappagallo, et al., 2002). Even with a higher incidence of adverse effects such as nausea and constipation, patients preferred opioid treatment. Cognitive decline during opioid administration was not observed.

Morphine has been administered by several routes of administration: oral, intranasal, intrapulmonary, rectal, IV, SC, IM, intraspinal (epidural and intrathecal), intraarticular, vaginal, sublingual/buccal, and topical (Christensen, Cohen, Mermelstein, et al., 2008; Donnelly, Davis, Walsh, et al., 2002; Hanks, Cherny, Fallon, 2004; Lavelle, Lavelle, Lavelle, 2007; Stoker, Reber, Waltzman, et al., 2008). Poor lipid solubility precludes transdermal absorption and also complicates reliable delivery through mucous membranes, such as the sublingual/buccal route (Donnelly, Davis, Walsh, et al., 2002; Reisfield, Wilson, 2007). The evidence for vaginal administration of morphine is limited to case reports (Ostrop, Lamb, Reid, 1998). Topical application of morphine is reported for painful wounds, in which case it is presumed to have a primary local action; there is a dearth of systematic research on this use, and it should not be considered an approach for systemic analgesic therapy (Paice, Von Roenn, Hudgins, et al., 2008; Zeppetella, Porzio, Aielli, 2007). Nebulized morphine has been used for dyspnea; case reports suggest a favorable local action exists, but the data overall are mixed, and there are no research reports describing this route as a means to provide systemic analgesia (see Chapters 14 and 20).

Morphine’s effectiveness as an analgesic, therefore, is established for specific systemic routes of administration—oral and parenteral—and intraspinal routes. Of the parenteral routes, IM administration is not recommended for morphine or for any other drug because of the painful injection and unreliable absorption (APS, 2003) (see Chapter 14). Short-term and long-term parenteral use can be easily accomplished with the IV or SC routes. The oral formulations of morphine are available in liquids, tablets, and capsules and in both short-acting and modified-release preparations. (See Chapter 14 for a detailed discussion of oral morphine formulations.)

Morphine is metabolized primarily in the liver. It has two main metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) (Gutstein, Akil, 2006). M3G is the primary metabolite of morphine, but it is not active at the opioid receptor and does not produce analgesia (South, Smith, 2001; Andersen, Christrup, Sjogren, 2003); M6G is active at the opioid receptor and produces analgesia (Dahan, van Dorp, Smith, et al., 2008; Smith, Binning, Dahan, 2009; Vaughn, Connor, 2003). Both metabolites have been implicated in morphine toxicity in animals and in patients with advanced disease (Morita, Tei, Tsunoda, et al., 2002), but the studies in humans have not established a clear association (Andersen, Christrup, Sjøgren, 2003). The mechanism by which toxicity, which is evidenced most often by delirium or myoclonus, occurs has not been fully described, and it has been noted that these symptoms are also seen with other opioids (Harris, 2008; Okon, George, 2008) (see Chapter 19 for treatment). Renal insufficiency presumably increases the risk of morphine toxicity because both the parent compound and its major metabolites are renally excreted (Dean, 2004) and there is a direct correlation between creatinine clearance and morphine, M6G, and M3G serum levels.

Administration of M3G directly into the CNS has been shown to produce neuroexcitability and anti-analgesic effects in animals (Sharke, Geisslinger, Lotsch, 2005). This metabolite has been implicated as the cause of the neuroexcitability noted in some patients who receive large doses of morphine on a long-term basis (Inturrisi, 2002). Some have suggested that opioid-induced hyperalgesia (see Chapter 11) may be due in part to M3G activity (Hemstapat, Monteith, Smith, et al., 2003; South, Smith, 2001); however, further research in humans is needed to draw firm conclusions (Andersen, Christrup, Sjogren, 2003; Sharke, Geisslinger, Lotsch, 2005).

M6G is thought to produce at least some (e.g., 10%) of the analgesic effect of a dose of morphine, but potency and effectiveness studies in humans have produced mixed results (Andersen, Christup, Sjogren, 2003; Smith, South, 2001; Wittwer, Kern, 2006). M6G is absorbed and eliminated from the CNS more slowly than morphine, which may account for the observed increase in potency with long-term morphine administration (Donnelly, Davis, Walsh, et al., 2002; Smith, South, 2001). It may be that the adverse effect profile of M6G is better than that of morphine (Donnelly, Davis, Walsh, et al., 2002). Specific adverse effects that have been investigated include respiratory depression, sedation, nausea and vomiting, hyperalgesia, and myoclonus. A randomized study of 170 patients with moderate to severe postoperative pain demonstrated that M6G produced long-lasting, dose-related analgesia with minimal cardiorespiratory or opioid-like adverse effects (Smith, Binning, Dahan, 2009). In another study (N = 100), M6G was compared with morphine and was found to produce less sedation and respiratory depression, and to have a slower initial onset of effect, with no significant difference in mean pain intensity between groups at 24 hours, but higher pain intensities at 30 minutes and 1 hour after M6G administration (Hanna, Elliott, Fung, 2005). The various factors that influence blood levels of morphine, M6G, and M3G are listed in Table 13-2.

Morphine is hydrophilic (soluble in aqueous solution), which contributes to its slow onset and long duration of action compared with the more lipophilic (soluble in fatty tissue) opioid drugs, such as fentanyl and sufentanil. This is not relevant after steady state is reached during continuous dosing but may be important when intermittent boluses are used systemically or intraspinally (see Chapters 15 through 17). The longer time that it takes morphine to reach its analgesic site of action must be considered when determining how quickly to administer doses during titration (IV); adequate time must be allowed to assess response to one dose before administration of another (Lotsch, Dudziak, Freynhagen, et al., 2006). Morphine has a short half-life of 2 to 4 hours; the half-life of M6G is somewhat longer (Andersen, Christup, Sjøgren, 2003). It is estimated that approximately 20% to 30% of the given dose of oral morphine is available for therapeutic effect because of first-pass effect (De Pinto, Dunbar, Edwards, 2006; Gutstein, Akil, 2006) (see Chapter 11). This is why the recommended dose of morphine by the oral route is higher than that by the parenteral route (APS, 2003) (see Table 16-1 on pp. 444-446).

IV morphine has been observed to have an increased analgesic efficacy and longer duration of action in older patients than in younger patients for reasons that are thought to be multifactorial; slow, steady titration is recommended (Villesen, Banning, Petersen, et al., 2007). A general practice is to reduce the starting dose of morphine (and other opioids) in older patients because of physiologic changes associated with aging, such as diminished first pass effect, enhanced bioavailability, and 20% to 40% decrease in clearance (Aubrun, Marmion, 2007).

Codeine

Codeine is the prototypical “weak” opioid used primarily for short-term acute pain. It is usually prescribed as an oral combination product that also contains aspirin or acetaminophen. Codeine combination products may also include caffeine or a muscle relaxant.

Combination preparations that include codeine are not appropriate for moderate to severe or escalating pain because of the dosing limitations inherent in the nonopioid constituent. The ceiling on the maximum safe daily doses of acetaminophen (4000 mg) and aspirin (4000 mg) limits dose increases for inadequate pain control (see Section III). In addition, aspirin is contraindicated for patients with a number of underlying conditions, such as those with a bleeding disorder or history of asthma. See Patient Education Form VI-2 (pp. 547-548) on codeine with acetaminophen at the end of Section IV.

Although a single-entity codeine formulation could theoretically undergo dose escalation sufficient to manage severe persistent pain, this is not pursued in practice. At the customary doses used, codeine provides analgesia for mild to moderate pain. A common oral dose of 60 mg produces analgesia equal to 600 mg of aspirin (less than two 325 mg tablets) (Gutstein, Akil, 2006). A systematic literature search concluded that acetaminophen/codeine (e.g., 300 mg/30 mg) was less efficacious and associated with more adverse effects than NSAIDs (e.g., ibuprofen, naproxen) for postpartum and postlaparotomy analgesia (Nauta, Landsmeer, Koren, 2009). One double-blind study randomized patients to receive codeine (30 mg) plus acetaminophen (300 mg) and caffeine (15 mg) per dose or ibuprofen (400 mg) plus acetaminophen (325 mg) per dose four times daily for 7 days or until pain free following outpatient hernia repair or laparascopic cholecystectomy (Mitchell, van Zanten, Inglis, et al., 2008). Those who received ibuprofen plus acetaminophen had lower pain ratings and fewer adverse effects throughout the treatment period and were more satisfied and less likely to discontinue treatment due to adverse effects or ineffectiveness compared with those who received codeine. A Cochrane Collaboration Review concluded that single doses of dihydrocodeine, a synthetic opioid with structure and pharmacokinetics very similar to codeine, is not sufficient for postoperative pain relief and that 400 mg of ibuprofen was superior to 30 or 60 mg of dihydrocodeine (Edwards, McQuay, Moore, 2004).

There also is evidence that higher doses of codeine would be relatively less effective than other opioids. Doses above 65 mg have been described as providing diminishing incremental analgesia but continued increase in adverse effects (Miaskowski, Cleary, Burney, et al., 2005).

The IM route has been used to administer codeine, but absorption is unreliable and is associated with a five-fold variation in peak blood level; the peak occurs approximately 30 to 60 minutes after IM administration. Nine-fold differences in minimum effective analgesic concentration have been found by this route, and late respiratory depression can occur. These properties make the IM route unfavorable for use in postoperative pain management (Cousins, Umedaly, 1996). It has also long been regarded as inappropriate for IV administration, with low doses of IV morphine recommended instead (Semple, Macintyre, Hooper, 1993) (see Table 13-1).The dose ratio for total analgesic effect between IM and oral codeine is 0.6:1, and a comparison between parenteral codeine and oxycodone found an equianalgesic dose ratio of 10:1; however, its relative potency varies with the extent to which it is converted to its active metabolite (Knotkova, Fine, Portenoy, 2009).

Codeine is a prodrug and is approximately 60% bioavailable orally (as compared, for example, with morphine, which has oral bioavailability of 20% to 30%). This is because codeine, like levorphanol, oxycodone, and methadone, undergoes less first-pass metabolism than morphine (Gutstein, Akil, 2006) (see Chapter 11). Once absorbed, 10% of codeine is metabolized in the liver to morphine, its active form (Somogyi, Barratt, Coller, 2007), which probably provides the bulk of its analgesic effect. However, as with other opioids, extremely wide variations exist between individuals in terms of absorption and analgesic requirements of codeine.

The metabolism of codeine to morphine depends on the presence of the enzyme cytochrome P450 2D6 (Fine, Portenoy, 2007) (see Chapter 11 for a detailed discussion of this enzyme system). There is population variation in phenotype of cytochrome P450 2D6, distinguishing patients intermediate, extensive (or rapid), ultra-rapid metabolizers, or poor metabolizers. Extensive metabolizers are the norm and are able to perform catalyzed biotransformation of codeine (and other drugs). Approximately 10% of Caucasians and varying frequencies in other ethnic groups are poor metabolizers. These individuals have a very limited ability to convert codeine to morphine, and as a consequence, are relatively less responsive to codeine’s analgesic effect (Palmer, Giesecke, Body, et al., 2005). In contrast, ultra-rapid metabolizers, who biotransform codeine more rapidly or more completely and most of the population, may have an exaggerated (i.e., toxic) response to codeine (Voronov, Przybylo, Jagannathan, 2007; United States Food and Drug Administration [U.S. FDA], 2007a; Palmer, Giesecke, Body, et al., 2005).

The impact of the biotransformation via P450 2D6 can vary according to circumstances. Although biotransformation at this isoenzyme occurs at the same rate in neonates and adults, neonates can develop toxicity from codeine because the clearance of morphine is relatively reduced and it can accumulate in the blood. In 2007, the U.S. FDA issued a warning that nursing mothers who are ultra-rapid metabolizers of codeine can transfer sufficient morphine to their breast-feeding infants to cause life-threatening or fatal adverse effects (U.S. FDA, 2007a) (see Chapter 20 for more on opioid use during breast- feeding). In adults, the efficiency of the enzyme can be affected by certain drugs, leading to changes in the production of morphine from codeine. Drugs such as paroxetine (Paxil) and fluoxetine (Prozac), for example, may inhibit cytochrome P450 2D6, and therefore, could potentially interfere with the metabolism of codeine. Case reports suggest that hydrocodone may be effective in CPY2D6 poor metabolizers for whom codeine was ineffective (Susce, Murray-Carmichael, de Leon, 2006).

Fentanyl

Fentanyl is the prototype in a subset of mu agonists which includes sufentanil, alfentanil, and remifentanil (see separate discussions for the latter three). All of these drugs are characterized by high potency and high lipophilicity (fat solubility). When administered parenterally to the opioid-naïve patient, the effects are characterized by rapid onset and short duration of action. The injectable formulations of these drugs are administered via the IV, epidural, and intrathecal routes and typically are used for acute pain in the perioperative and procedural settings, often in conjunction with anesthetic or sedating agents; they are the most commonly used opioids in anesthesia (Coda, 2006). They also may be administered transmucosally, e.g., by the buccal, sublingual, or intranasal routes (see Chapter 14).

As a class, fentanyl and comparable drugs are versatile, although none are commercially available in an oral or rectal formulation. There are pharmacologic and cost differences that are considered in drug selection for each therapeutic application. With rapid IV administration of high doses, these drugs can produce chest wall rigidity and subsequent difficult ventilation (Lalley, 2005; Fukuda, 2005); this is a concern when fentanyl is used for intraoperative anesthesia (see Chapter 16 for more on speed of injection). Likely related is cough, which has been reported as a complication of both fentanyl and sufentanil (Agarwal, Gautam, Nath, et al., 2007); this effect has been successfully suppressed with IV lidocaine 0.5 mg/kg (Pandey, Raza, Ranjan, et al., 2005).

Fentanyl differs in many ways from morphine. Its lipophilicity means that there is wide and rapid distribution after IV administration, as well as ready passage through the blood-brain barrier. When given as a single IV bolus, fentanyl’s onset (within 1 to 5 minutes) is faster and its duration (sometimes less than 1 hour) is shorter than morphine as the drug moves from blood to lungs, muscle, and fat (Taylor, 2005). It also is approximately 100 times more potent than morphine, so that a single IV bolus of 100 mcg produces roughly the same analgesia as morphine 10 mg; however, caution is recommended when converting to and from fentanyl as studies demonstrate considerable variability in conversion ratios (see Knotkova, Fine, Portenoy, 2009 for a discussion of this research).

The lipophilicity and potency of fentanyl makes it an excellent candidate for transdermal and oral transmucosal formulation. The fentanyl transdermal patch is commonly used in long-term pain treatment (see Chapter 14). Oral transmucosal fentanyl formulations are used in the treatment of breakthrough pain: oral transmucosal fentanyl and buccal fentanyl; a buccal patch was recently approved in the United States, and a sublingual formulation and an intranasal formulation are available in some other countries (see Chapter 14 for oral transmucosal formulations).

After repetitive dosing or continuous infusion of fentanyl, a steady state is approached. Although some clinicians believe that fentanyl has a very short half-life, this is a misconception. When fentanyl or some other very lipophilic drug is administered to the patient who is not receiving regular dosing, the blood levels decline quickly as the drug redistributes into fatty tissue. This redistribution, or “alpha” phase, is associated with a short half-life and a brief duration of clinical effects. With fentanyl, it is typically only minutes long. In contrast, regular dosing of fentanyl or any other lipophilic drug eventually leads to a steady state in which there is equilibrium between the blood and fatty tissues. A bolus injection in this setting still has a redistribution phase, but most of the elimination time, the “beta” phase, results from metabolism and redistribution of drug from fat back into blood. As a result, the half-life, and the duration of effect after the bolus, is much longer. The so-called terminal elimination half-life is the half-life that is obtained after the redistribution has taken place.

Given these kinetics, the half-life of fentanyl varies in the literature depending on whether the study that yielded the value measured the decline in concentration in a steady-state situation or not. Although it has been reported that fentanyl has a terminal half-life of approximately 3 to 4 hours, it is much longer—four to five times longer—after steady state has been approached (Dershwitz, Landow, Joshi-Ryzewicz, 2003; Liu, Gropper, 2003). After steady state is achieved using transdermal fentanyl, half-life also is affected by continued absorption from the skin depot under the patch; the half-life is therefore even longer, typically over 24 hours (see Table 13-1).

Fentanyl’s lipophilicity and storage in fatty tissue has significant implications for obese patients in the perioperative setting. If perioperative dosing is based on body weight alone, obese patients are likely to receive too high a dose. Dosing based on a calculated “pharmacokinetic mass” (i.e., for patients weighing 140 to 200 kg, dosing weights of 100 to 108 kg are projected) has been shown in two clinical studies to provide safe and effective intraoperative and postoperative analgesia at lower doses than would be predicted by actual weight (Shibutani, Inchiosa, Sawada, et al., 2004, 2005). This is a result of a nonlinear relationship between total body weight and fentanyl clearance.

Fentanyl is metabolized in the liver, has no active metabolites, and produces minimal hemodynamic effects (Fukuda, 2005). These characteristics have made fentanyl a favorite in the critically ill, including older critically ill adults, and especially patients who are hemodynamically unstable or have renal failure (Graf, Puntillo, 2003; Jacobi, Fraser, Coursin, et al., 2002). It is recommended for patients with end-stage renal disease who need opioid analgesia (Dean, 2004; Johnson, 2007; Murtagh, Chai, Donohoe, et al., 2007). Though more research is needed, fentanyl appears safe in patients with hepatic dysfunction as well (Johnson, 2007).

When used for pain, fentanyl typically is given either parenterally (by the IV route usually) or intraspinally (see Chapter 15). Its rapid onset and short duration in the non–steady state situation make fentanyl the most commonly used opioid in combination with benzodiazepines for procedural analgesia and sedation. Along with morphine and hydromorphone, fentanyl has become a first-line choice for postoperative pain management via IV PCA in many institutions (Pasero, 2005) (see Chapter 17 for PCA dosing). There have been no randomized controlled trials comparing these drugs. A retrospective analysis of medical records compared adverse effects associated with morphine (N = 93), hydromorphone (N = 89), and fentanyl (N = 72) via postoperative IV PCA and found lower mean rates of nausea, pruritus, urinary retention, and sedation with fentanyl; there were no differences among the opioids in incidence of respiratory depression, headache, agitation, confusion, and hallucinations (Hutchison, Chon, Tucker, et al., 2006). However, well-controlled research is needed to draw conclusions regarding differences.

Parenteral fentanyl can be administered by SC infusion (Anderson, Shreve, 2004). A small study comparing continuous SC infusions of morphine followed by fentanyl (N = 13) and fentanyl followed by morphine (N = 10) in hospice cancer patients revealed that fentanyl is as efficacious as morphine with no differences in adverse effects except less constipation in patients receiving fentanyl (Hunt, Fazekas, Thorne, et al., 1999). The researchers recommended a conversion ratio of morphine 10 mg to fentanyl 150 mcg as appropriate but emphasized that further research is needed in this area.

Although fentanyl’s properties of high lipophilicity, rapid onset, and short duration in the non–steady state situation make it an attractive option for pain management in a variety of settings, populations, and conditions, these properties also necessitate careful patient selection, appropriate monitoring, and adherence to the safety warnings that accompany fentanyl products, especially the patches and oral transmucosal products. A number of fatalities have occurred due to improper prescribing and use. See Chapter 14 for specific information on indications, patient selection, administration, monitoring, and precautions for the various fentanyl products.

Hydrocodone

Hydrocodone is available in several proprietary products (e.g., Lortab, Vicodin, Lorcet, Hydrocet, and Norco) and generic preparations, and in several different fixed-dose combinations with acetaminophen, aspirin, and ibuprofen. Most are available in tablet form, while others are available in capsule or liquid form (Table 13-3). Combination drugs containing hydrocodone and a nonopioid drug can provide more effective relief than either drug alone. Ibuprofen combined with a variety of hydrocodone doses was shown to increase the effectiveness of hydrocodone seven-fold in animal research (Kolesnikov, Wilson, Pasternak 2003). See Patient Education Form IV-6 on hydrocodone with acetaminophen on pp. 556-557 at the end of Section IV.

Hydrocodone is not available in single-entity form. The dose is limited by the ceiling on safety and efficacy inherent in the nonopioid constituent. The dose limitation, in turn, typically means that the drug is useful for the management of mild to moderate pain in the opioid-naïve patient. Use in persistent pain (except for breakthrough dosing) should be carefully evaluated. Long-acting analgesics without a fixed dose co-analgesic are preferred for moderate to severe persistent cancer or noncancer pain. A modified-release (12-hour) oral formulation of hydrocodone 15 mg plus acetaminophen 500 mg has been studied in clinical trials but has not been approved in the United States (Coddings, Levinsky, Hale, et al., 2008; Golf, Robson, Pollak, et al., 2008).

Hydrocodone with acetaminophen is not only the most commonly prescribed analgesic in the United States, it is by far the most commonly prescribed medication in all classes (Lamb, 2008). In 2008, hydrocodone plus acetaminophen was first in the list of the 200 most commonly prescribed drugs (Drug Topics, 2008). It is critical to avoid prescribing or administering amounts that would exceed the daily maximum dose for acetaminophen (4000 mg), aspirin (4000 mg), or ibuprofen (3200 mg) and teach the patient the dangers of exceeding these amounts (see Section III).

Hydrocodone has an onset of action of approximately 20 minutes, reaches peak effectiveness by 60 minutes, and has a half-life of 3.8 hours (Gutstein, Akil, 2006). It is metabolized by the cytochrome P450 2D6 (CYP2D6) enzyme. Case reports suggest that hydrocodone may be effective in CPY 2D6 poor metabolizers for whom codeine was ineffective (Susce, Murray-Carmichael, de Leon, 2006). (See Chapter 11 for more on the cytochrome P450 enzyme system and drug-drug interactions.)

The adverse effects of hydrocodone are comparable to that of other opioids. It has been shown to have similar efficacy (when titrated to effect) and a lower incidence of adverse effects compared with tramadol and codeine (Rodriguez, Bravo, Castro, et al., 2007; Rodriguez, Castillo, Del Pilar Castillo, et al., 2007). Several cases of an unusual adverse effect (hearing loss) have been reported in patients taking hydrocodone and in hydrocodone abusers (Ho, Vrabec, Burton, 2007). No causative mechanism, if it exists, has been identified for this association.

To ensure safety, it should be specifically noted that the name hydrocodone is similar in appearance and sound to oxycodone, oxymorphone, and hydromorphone. An increased level of alertness is required to prevent medication errors with these opioids.

Hydromorphone

Hydromorphone is often considered an alternative to morphine, especially for acute pain (Chang, Bijur, Meyer, et al., 2006; Rapp, Egan, Ross, et al., 1996). Although there are few head-to-head studies, morphine and hydromorphone appear to provide equivalent analgesic effects and very similar adverse effect profiles (Ripamonti, Bandieri, 2009; Quigley, Wiffen, 2003); there is some evidence that hydromorphone may be associated with less nausea and pruritus (Chang, Bijur, Meyer, et al., 2006).

IV hydromorphone is a first- or second-choice opioid (after morphine) for postoperative pain management via PCA (Quigley, 2002). When given IV as a bolus, its onset of action is 5 minutes, its peak effect occurs in 8 to 20 minutes, and its duration is approximately 4 hours (Sarhill, Walsh, Nelson, 2001).

Oral short-acting hydromorphone is available in 2, 4, and 8 mg tablets and in a 1 mg/mL oral solution. It is approximately 60% bioavailable with an onset of action of 30 minutes via the oral route (Kumar, Lin, 2007) and a duration of approximately 3 to 4 hours; maximum plasma concentrations are reached within 1 hour of dosing (Gupta, Sathyan, 2007). Modified-release formulations of oral hydromorphone are available in Canada and Europe and most recently on the U.S. market (Gupta, Sathyan, 2007) (see Chapter 14 for modified-release hydromorphone). See Patient Education Form IV-3 on short-acting hydromorphone at the end of Section IV.

Hydromorphone also has been administered via a variety of other routes. Its greater potency compared with morphine, as well as its availability in concentrated parenteral form (10 mg/mL), has made it attractive for SC administration, especially when high doses are needed. It was found to be comparable to morphine by SC continuous infusion for persistent cancer pain in terminally ill patients (Miller, McCarthy, O’Boyle, et al., 1999). Absorption via the IM route is erratic and not recommended (Golembiewski, 2003). The epidural and intrathecal routes have been utilized for acute and persistent cancer and noncancer pain (DuPen, DuPen, Hillyer, 2006). Hydromorphone given rectally (3 mg suppository) is as effective as by the oral route; it is not, however, absorbed well by the oral mucosa (Kumar, Lin, 2007; Sarhill, Walsh, Nelson, 2001) (see Table 13-1).

Hydromorphone is metabolized in the liver and eliminated via the kidneys (Sarhill, Walsh, Nelson, 2001). It has a neuroexcitatory metabolite, hydromorphone-3-glucuronide (H3G), and it may be speculated that neurotoxicity at high doses is related to this molecule (Thwaites, McCann, Broderick, 2004; Wright, Mather, Smith, 2001; Smith, 2000). Although neurotoxic symptoms can occur in advanced disease and decreased renal clearance, hydromorphone appears to be a safer choice than morphine under these conditions (Dean, 2004). Hydromorphone is often recommended as the first alternative for opioid rotation when these symptoms occur during morphine administration (Hanks, Reid, 2005). Some clinicians will use hydromorphone in older adults as a first-line opioid instead of morphine because of the theoretically improved tolerance in the presence of decreased renal function; however, this practice has not been studied and has not been recommended by published guidelines. A prospective, randomized study (N = 50) comparing morphine and hydromorphone via postoperative IV PCA found no difference in efficacy, adverse effects, or patient satisfaction (Hong, Flood, Diaz, 2008). A retrospective analysis of medical records found the mean rates of nausea, pruritus, urinary retention, and sedation with postoperative IV PCA hydromorphone to be similar to that of IV PCA morphine and more common than with IV PCA fentanyl; there were no differences among the three opioids in incidence of respiratory depression, headache, agitation, confusion, and hallucinations (Hutchison, Chon, Tucker, et al., 2006). Well-controlled research is needed to draw conclusions regarding differences among the various opioids.

The equianalgesic dose conversion between morphine and hydromorphone is unclear and likely varies with the length of time a patient has been on one drug or the other (Berdine, Nesbit, 2006; Knotkova, Fine, Portenoy, 2009). Published equianalgesic tables typically show oral hydromorphone to be 5 times more potent than oral morphine. This is the most common ratio used when preparing equianalgesic solutions for PCA administration (e.g., 0.2 mg hydromorphone per 1 mL solution is considered approximately equal to 1 mg morphine per 1 mL solution) (Golembiewski, 2003). However, these data are generally derived from acute pain treatment in opioid-naïve patients or healthy volunteers (APS, 2003). An early study of morphine-hydromorphone equivalence showed that after a week of PCA treatment, the ratio was 3:1 (morphine 10 mg to hydromorphone 3.3 mg) (Dunbar, Chapman, Buckley, et al., 1996). Subsequent research found that when switching from long-term dosing of either oral or parenteral morphine to hydromorphone, the ratio was approximately 5.5:1 (morphine 10 mg to hydromorphone 2 mg) (Lawlor, Turner, Hanson, et al., 1997). However, when switching from hydromorphone to morphine, the ratio was 3.7:1 (morphine 10 mg to hydromorphone 2.7 mg). Still others suggest that an equianalgesic dose conversion of parenteral morphine to hydromorphone for long-term dosing is probably 4:1 (morphine 10 mg to hydromorphone 2.5 mg) (Hanks, Cherny, Fallon, 2004). A systematic review of hydromorphone for various types of pain concluded that there is insufficient evidence to recommend specific ratios of hydromorphone (Quigley, Wiffen, 2003) (see also Knotkova, Fine, Portenoy, 2009). (See Table 16-1).

When using equianalgesic dosing to switch a patient from another opioid to hydromorphone, the general condition of the patient and the severity of pain must be considered when choosing a starting dose (Fine, Portenoy, the Ad Hoc Expert Panel on Evidence Review and Guidelines for Opioid Rotation, 2009). In general, it is safest to use a conservative conversion ratio then titrate to effect. No matter what ratio or method for conversion is used, it is vital to take into account that hydromorphone is significantly more potent than morphine, there is great interindividual variability (Murray, Hagen, 2005), and individualization and monitoring are essential elements of prescribing and administering these agents. Deaths have occurred because of confusion between the two agents and a failure to take their inherent differences into account (Institute for Safe Medication Practices, 2004a).

It also should be noted that the name hydromorphone is similar in appearance and sound to oxycodone, oxymorphone, and hydrocodone. An increased level of alertness is required to prevent medication errors with these opioids.

Levorphanol

Like methadone, levorphanol (Levo-Dromoran) is considered a second-line drug for cancer pain (Hanks, Cherny, Fallon, 2004). It has not been widely used clinically since the modified-release formulations of morphine and oxycodone became available in the 1990s (McNulty, 2007). Most clinicians are unfamiliar with its pharmacology, which is somewhat different than the more commonly used opioids (McNulty, 2007; Prommer, 2007a; Prommer, 2007b). It is an agonist at both the mu and kappa opioid receptor sites and, like methadone, it also is an N-methyl-d-aspartate (NMDA) antagonist. In addition, it is an inhibitor of serotonin and norepinephrine reuptake (see Section I).

Levorphanol is available for oral (2 mg/tablet) and parenteral administration (2 mg/mL) and has a parenteral-to-oral ratio of 1:2 (Prommer, 2007a). Its metabolism is similar to morphine’s. It undergoes glucuronidation in the liver and is not affected by the CYP 450 system. For this reason, it has fewer potential drug-drug interactions than methadone but is subject to the effects of inducers and inhibitors of glucuronidation (Prommer, 2007a).

Levorphanol’s duration of analgesia is reported to range from a low of 3 hours to a high of 15 hours (Fine, Portenoy, 2007; Hanks, Cherny, Fallon, 2004; Prommer, 2007a) with both IV and oral dosing. Importantly, levorphanol has a longer half-life (15 hours) than morphine (2 to 4 hours), and it is likely that at least some patients can attain sustained analgesia with a relatively long dosing interval. Like methadone, the discrepancy between analgesic duration and half-life can predispose levorphanol to accumulation. Although outliers with half-lives that can extend to as much as 30 hours (Prommer, 2007a) are likely to pose substantial risk, accumulation overall appears to be less of a problem than it can be with methadone (Hanks, Cherny, Fallon, 2004). Excretion is by the kidneys.

A study using levorphanol at two dose levels established that neuropathic pain is responsive to opioid treatment (Rowbotham, Twilling, Davies, et al., 2003). In fact, all types of neuropathic pain responded to levorphanol except central poststroke pain in the study. In the higher-dose arm (mean was approximately 9 mg/day) apparent CNS toxicity occurred (irritability, mood changes, confusion, weakness). The reasons and risk factors for these changes were unknown. Close monitoring as well as dose and interval changes are indicated for older adults and those with impaired renal function.

Levorphanol is available in the United States orally only in 2 mg tablets, which can make titration difficult. It is no longer available in the United Kingdom or Canada (Hanks, Cherny, Fallon, 2004). (See Table 16-1 on pp. 444-446.)

Meperidine

Meperidine (Demerol) was once the most widely used opioid analgesic. In recent years, it has been either removed from or severely restricted on hospital formularies, the result of concerted efforts to improve patient safety during opioid use (Gordon, Jones, Goshman, et al., 2000; Raymo, Camejo, Fudin, 2007) (see the paragraphs that follow). The Beers Criteria of inappropriate medication use in older individuals, originally developed in 1991 (Beers, Ouslander, Rollingher, et al., 1991), described meperidine as having many disadvantages and continues to advise against the use of the drug in older adults (Beers, 1997; Fick, Cooper, Wade, et al., 2003) (Table 13-4). A refinement of the 1996 Medical Expenditure Panel Survey designated the drug as one to “always avoid” in older adults (Zhan, Sangl, Bierman, et al., 2001). Meperidine has some positive attributes, but it continues to be overused (Kornitzer, Manace, Fischberg, 2006) and misused (Hubbard, Wolfe, 2003) because of lack of knowledge about its pharmacology. Numerous misconceptions about meperidine persist (Table 13-5).