Guidelines for Selection of Routes of Opioid Administration

Chapter 14


Guidelines for Selection of Routes of Opioid Administration



REGARDLESS of the type of pain being treated, opioids should be administered by the least invasive and safest route capable of producing satisfactory analgesia. The oral route is the most common and generally is selected before other routes because it is relatively safe, convenient, and inexpensive (Coyle, Cherny, Portenoy, 1995; Hanks, Cherny, Fallon, 2004; Stevens, Ghazi, 2000). The transdermal route is an accepted alternative for long-term therapy. If pain is severe and a rapid onset of analgesia is desired, the IV route can be used for rapid titration with close monitoring; the patient can be transitioned to the oral route when pain is under control.


Over time, it is often necessary to switch routes of administration (Hanks, Cherny, Fallon, 2004). For example, in a postoperative patient, the process of transitioning from IV or epidural to oral may require the use of both the old and the new routes to ensure continuous analgesia. For example, the patient may be started on the oral formulation while receiving PRN boluses by the IV route. When the oral route is established and at the approximate required dose, the IV route is discontinued.


In a survey of patients with cancer pain, more than half required more than one route of administration to maintain pain control during the last 4 weeks of life. This occurred usually when patients were unable to swallow. The routes used included rectal, SC, IV, and epidural. Sometimes patients required more than one route at a time (Coyle, Adelhardt, Foley, et al., 1990). Table 14-1 summarizes the advantages and disadvantages to some of the routes of opioid administration. This chapter presents most of the routes by which opioids are administered. The intraspinal routes are discussed separately in Chapter 15.



Table 14-1


Routes of Opioid Administration


image


image


image


ATC, Around-the-clock; CI, continuous infusion; FDA, Food and Drug Administration; PCA, patient-controlled analgesia.


Opioid analgesics can be administered by a wide variety of routes. This table summarizes the advantages and disadvantages to some of these. See text for detailed discussion.


From Pasero, C., & McCaffery, M. (2011). Pain assessment and pharmacologic management, pp. 369-370, St. Louis, Mosby. Data from Buxton, I. L. O. (2006). Pharmacokinetics and pharmacodynamics. The dynamics of drug absorption, distribution, action, and elimination. In L. L. Brunton, J. S. Lazo, & K. L. Parker KL (Eds.), Goodman & Gilman’s the pharmacological basis of therapeutics, ed 11, New York, mcgraw-Hill; Darwish, M., Kirby, M., Jiang, J. G., et al. (2008). Bioequivalence following buccal and sublingual placement of fentanyl buccal tablet 400 microg in healthy subjects. Clin Drug Investig, 28(1), 1-7.; Darwish, M., Kirby, M., Robertson, P. Jr, et al. (2007). Absolute and relative bioavailability of fentanyl buccal tablet and oral transmucosal fentanyl citrate. J Clin Pharmacol, 47(3), 343-350; Dale, O., Hjortkjær, R., & Kharasch, E. D. (2002). Nasal administration of opioids for pain management in adults. Acta Anaesthesiol Scand, 46(7), 759-770; Gordon, D. B. (2008). New opioid formulations and delivery systems. Pain Manage Nurs, 8(3, Suppl 1), S6-S13; Gutstein, H. B., & Akil, H. (2006). Opioid analgesics. In L. L. Brunton, J. S. Lazo, & K. L. Parker (Eds.), Goodman & Gilman’s the pharmacological basis of therapeutics, ed 11, New York, mcgraw-Hill; Hanks, G., Cherny, N. I., & Fallon, M. (2004). Opioid analgesic therapy. In D. Doyle, G. Hanks, N. I. Cherny, et al. (Eds.), Oxford textbook of palliative medicine, ed 3, New York, Oxford Press; Holmquist, G. (2009). Opioid metabolism and effects of cytochrome P450. Pain Med, 10(Suppl 1), S20-S29; Shelley, K., & Paech, M. J. (2008). The clinical applications of intranasal opioids. Curr Drug Deliv, 5(1), 55-58; Smith, H. S. (2003). Drugs for pain. Philadelphia, Hanley & Belfus; Stevens, R. A., & Ghazi, S. M. (2000). Routes of opioid analgesic therapy in the management of cancer pain. www.medscape.com/viewarticle/408974. Accessed January 9, 2009; Swarm, R. A., Karanikolas, M., & Cousins, M. J. (2004). In D. Doyle, G. Hanks, N. I. Cherny, et al. (Eds.), Oxford textbook of palliative medicine, ed 3, New York, Oxford Press; Vascello, L., & McQuillan, R. J. (2006). Opioid analgesics and routes of administration. In O. A. de Leon-Casasola (Ed.), Cancer pain. Pharmacological, interventional and palliative care approaches, Philadelphia, Saunders. Pasero C, McCaffery M. May be duplicated for use in clinical practice.



Oral


The oral route is the most commonly employed for patients with continuous cancer or noncancer pain, or mild to moderate acute pain (Fine, Portenoy, 2007; Hanks, Cherny, Fallon, 2004; Menefee, Katz, Zacharoff, 2007). The many oral formulations available provide convenience and flexibility (American Pain Society [APS], 2003). Given the potential to titrate the oral dose to whatever level is necessary, the most common reason for failure to achieve analgesia by this route is insufficient dose administration. There is wide interindividual variation in response to opioids, however, and if attempts to escalate the oral dose of opioid do not achieve the desired response or result in unacceptable adverse effects, switching to a different oral opioid should be considered, as unresponsiveness to one opioid does not predict response to others (Fine, Portenoy, 2007).


Most first-line mu agonists and dual-mechanism drugs are available in oral form; fentanyl is not. Of the agonist-antagonist opioids, only pentazocine is available orally. Oral opioids in tablet form can be taken by most patients. Capsules and liquids are available for some opioids. Liquids should be carefully measured using an oral medication syringe or graduated liquid measuring spoon. Both of these measuring devices are available free from most pharmacies. When prescribing, dispensing, and administering opioids, care should be taken to ensure that the correct concentration and milligram amount are specified. Liquids should be ordered by milligram amount, not just volume, to avoid serious dosing errors (Institute for Safe Medication Practices, 2007). Non–modified-release tablet formulations can be crushed and taken with soft foods or put into suspensions (APS, 2003). Modified-release tablets; however, should not be cut, crushed, or chewed because this destroys the release mechanisms and risks severe overdose by releasing the half-day or full-day dose all at once. Modified-release medications in capsules may be opened and sprinkled on soft food, such as applesauce, but should not be chewed or allowed to dissolve (APS, 2003). Small amounts of food should be used to ensure consumption of the entire dose.



Disadvantages of the Oral Route


Two major disadvantages of the oral route are that it has a slow onset of action (typically 30 to 45 minutes) (APS, 2003) and a relatively delayed peak time (60 to 120 minutes after ingestion, and longer in the case of some of the modified-release tablets) (Hanks, Cherny, Fallon, 2004). As a result of these kinetics, the oral route is not ideal when it is imperative to get severe pain under control quickly, such as for pain crisis related to malignancy or myocardial infarction (Moryl, Coyle, Foley, 2008).


Although opioids tend to have a longer duration of action orally than parenterally, intervals between doses of short-acting preparations are relatively brief—commonly 4 hours. This requires the patient to take six to eight doses a day, a regimen that can interfere with patient activities, such as sleeping. The patient must remember to take all doses to maintain a constant level of analgesia.


A potential disadvantage for those opioids with active metabolites is that the ratio between the metabolite concentration and the parent compound is much higher when the drug is given orally and subjected to a larger first-pass effect through the liver than when it is given parenterally. This is true for morphine and its glucuronidated metabolites, for example (Lotsch, 2005). In most patients, this difference between oral and other routes is not clinically significant, but for some, particularly those with renal insufficiency, the relative concentration of the metabolites could be high enough to cause adverse effects.


The oral route is not an option for patients who are NPO (nothing by mouth), such as immediately after surgery. Some patients cannot tolerate the oral route because of GI obstruction or difficulty swallowing (Fine, Portenoy, 2007). Absorption by the oral route can be altered by a number of factors, including presence of food, gastric emptying time, and GI motility. Modified-release preparations appear to be less affected by the presence of food than short-acting preparations (see individual drugs later in this chapter, and see Chapter 13 for more).


The effectiveness of the oral route depends on patient compliance. Patients who must self-administer their medications but cannot adhere to the dosing regimen necessary to maintain stable effects are not good candidates for the oral route unless they are able to take formulations designed for once-a-day dosing (Lehne, 2004).


Finally, some oral medications, especially those in tablet or liquid form, have a bitter or unpleasant taste, to which most patients object. After administration, “chasers” of applesauce or lemon drops may be helpful in reducing the bitterness (Gardner-Nix, 1996).



Selected Oral Opioid Formulations


As mentioned, all of the first-line mu opioids except fentanyl are available in short-acting oral formulations, and several modified-release formulations exist. Opioids available in oral modified-release formulations in the United States include morphine (MS Contin, Oramorph SR, Kadian, Avinza, and generics), oxycodone (OxyContin), oxymorphone (Opana ER), hydromorphone (Exalgo), and tramadol (Ultram ER). Codeine is available as a modified-release product outside of the United States. Of the modified-release preparations, MS Contin has the smallest tablet, which is an important consideration in patients who have difficulty swallowing. MS Contin tablets are color-coded according to dose, as are Kadian and Avinza capsules, which may help prevent errors in dosing.


The modified-release opioid preparations have rendered the oral route more convenient than in the past by requiring only once- or twice-daily dosing. This may improve patient adherence to medication regimens and may also decrease the patient’s sense of being sick (APS, 2003; Fine, Portenoy, 2007; Gallagher, Welz-Bosna, Gammaitoni, 2007). These preparations simplify the regimen necessary to maintain relatively stable blood levels of the drug, potentially increasing their effectiveness for continuous pain (APS, 2003). Although unproven, some experts recommend modified-release products as one of the treatment strategies for patients at risk of opioid abuse because they may be less reinforcing of some drug-related behaviors and may be less likely to cause euphoria (Webster, Dove, 2007).


Patients should be observed closely for the need to shorten the recommended dosing interval of the modified-release agent. For example, although MS Contin and Oramorph were designed for 12-hour dosing, it is not unusual for patients to experience some end-of-dose failure (pain at the end of the dosing interval), which can be eliminated by switching to 8-hour dosing (Argoff, 2007). An observational cohort study found that 86% and 91% of patients taking modified-release morphine or oxycodone, respectively, required dosing more frequently than that recommended by the product’s manufacturers (Gallagher, Welz-Bosna, Gammaitoni, 2007). This underscores the importance of systematic assessment to determine the optimal dose interval as well as a need to develop modified-release formulations that provide satisfactory and sustained analgesia throughout the recommended dosing interval.


Although further research is warranted, the time of day that patients take their once-daily opioid dose does not appear to matter. A multicenter, randomized, placebo-controlled, cross-over study of patients with advanced cancer found essentially the same pain intensities when the once-daily dose of modified-release morphine was taken in the morning as when it was taken in the evening (Currow, Plummer, Cooney, et al., 2007). Patients can be told to find the time that works best to keep their pain under control.


Following is a discussion of the various oral formulations of morphine, oxycodone, oxymorphone, and hydromorphone. Formulations designed to deter abuse are also discussed.



Oral Morphine


Morphine is available in 15 and 30 mg short-acting tablets, and in 2, 4, 10, and 20 mg/mL solutions. These dose forms are used primarily when opioid therapy is initiated and for breakthrough pain (see Chapter 12 for more on breakthrough pain). MS Contin and Oramorph SR, modified-release formulations of morphine, are available in 15, 30, 60, and 100 mg tablets; MS Contin also is available in a 200 mg tablet. There are also generic products available at varying strengths. The recommended dosing interval is every 12 hours and no less than every 8 hours. There are two other modified-release morphine formulations, Kadian and Avinza, supplied as capsules that contain pellets which release drug at different rates. Kadian is available in 10, 20, 30, 50, 60, 80, 100, and 200 mg capsules and can be given every 12 or 24 hours. Avinza is available in 30, 45, 60, 75, 90, and 120 mg capsules and is approved for once-daily dosing. The Avinza prescribing information contains a black box warning that alcohol is not to be ingested while taking Avinza, as there is a risk of the pellets dissolving and the full daily dose of morphine being released at once (King Pharmaceuticals, 2008a). Kadian does not require such a warning (Alpharma Pharmaceuticals, 2008; Johnson, Wagner, Sun, et al., 2008), but alcohol can have additive CNS effects when ingested by a person taking any opioid and should be used with great caution. See Patient Education Form IV-9 (pp. 562-563) on short-acting morphine (includes concentrate), Form IV-10 (pp. 564-565) on modified-release 12-hour morphine, and Form IV-11 (pp. 566-567) on modified-release 24-hour morphine at the end of Section IV.


The pharmacokinetics of the modified-release formulations are complex because the time to steady state is determined by the half-life of absorption rather than the terminal elimination half-life. All of the modified-release formulations approach steady state in a 2- to 3-day timeframe. Like other oral formulations, the drugs are not preferable for rapid titration to address severe pain. Although patients can be titrated using the modified-release drug, an accepted alternative approach is to titrate first to a stable dose of short-acting morphine, then switch to the modified-release formulation (APS, 2003).


Co-administration of a short-acting opioid for breakthrough pain is conventional practice during the treatment of patients with pain related to active cancer or other types of serious illnesses; it is implemented on a case-by-case basis during the treatment of persistent noncancer pain based on a separate analysis of risk and benefit (Fine, Portenoy, 2007). Availability of a short-acting drug during dose titration of the modified-release formulation may facilitate dose finding and the comfort of the patient; the modified-release dose can be titrated every 24 to 48 hours (Twycross, Wilcock, 2007). The short-acting dose may or may not be continued after a stable dose of the modified-release drug is found. One study randomized 40 patients with uncontrolled cancer pain to titration with short-acting oral morphine given every 4 hours or titration with modified-release morphine (Kapanol, Kadian) given once daily (Klepstad, Kaasa, Jystad, et al., 2003). The mean time to achieve adequate pain control was 2.1 days with short-acting morphine and 1.7 days with modified-release morphine, and those taking the latter reported feeling less tired at the end of titration. No other differences in adverse effects, health-related quality of life functions, or satisfaction with treatment were noted.


Although the various forms of modified-release morphine contain the same drug and are of the same dose strength, they may or may not be bioequivalent. MS Contin and Oramorph SR, for example, are pharmaceutically equivalent because they contain the same drug, have the same dose form, can deliver the same amount of drug, are both available in the same dose strengths, and are given by the same route; however, the two are not necessarily therapeutically equivalent because they use different modified-release mechanisms. This means that the same dose of each product may not affect the patient in the same way (McCaffery, Lochman, 1996). The FDA does not consider any of the modified-release dose forms to be therapeutically equivalent unless bioequivalence data have been submitted. Given the many choices now available, it is best not to assume that very similar products will behave the same in a given individual. It should be recognized, however, that the FDA and some state laws have allowed pharmacists, physicians and other prescribers, institutions, and health care plans to consider drugs containing the molecule to be therapeutically equivalent, even in the absence of confirmatory clinical data. If patients report a change in the outcomes associated with stable drug therapy, the clinician should assess whether the formulation may have been changed by the pharmacist (McCaffery, Lochman, 1996). Box 14-1 provides recommendations when switching from one pharmaceutically equivalent product to another.



Guidelines


Box 14-1


Switching from One Pharmaceutically Equivalent Product to Another




• Examples of pharmaceutically equivalent products are MS Contin, Oramorph SR, and Kadian at 100 mg each.


• Assume that some difference may exist in therapeutic effects between the products.


• Completely switch from one product to the other. Avoid having patients take more than one product at a time (except during the transition phase), and avoid switching back and forth between products. The same formulation should be used if the patient is moved from hospital to home and vice versa.


• Advise the patient and family that the new drug may not have the same effect as the previous drug and that the dose may need to be adjusted.


• Monitor pain and sedation. Use a flow sheet for documentation so that problems can be detected early.


• Instruct the patient and family about the different products (e.g., Oramorph SR tablets are white and about the size of an aspirin; MS Contin tablets are smaller, and each strength is a different color). Tell the patient to question anyone who attempts to substitute one brand for another.


Drugs can be pharmaceutically equivalent without being therapeutically equivalent. This is because the drugs use different modified-release mechanisms. This means that the same dose of each product may not affect the patient in the same way. Box 4-11 lists examples of drugs that are pharmaceutically equivalent but not therapeutically equivalent and guidelines for switching from one to another.


From Pasero, C., & McCaffery, M. (2011). Pain assessment and pharmacologic management, p. 373, St. Louis, Mosby. Data from McCaffery, M., & Lochman, C. (1996). Controlled release morphine products. Am J Nurs, 96(4), 65. Pasero C, McCaffery M. May be duplicated for use in clinical practice.



The first modified-release morphine formulations were Oramorph and MS Contin. Oramorph contains a simple matrix system; GI fluid penetrates the tablet, hydrates the matrix, and forms a gel layer that breaks down and dissolves gradually over the dosing period (Amabile, Bowman, 2006). MS Contin tablets contain morphine in a dual-control (hydrophilic and hydrophobic) polymer matrix that controls the release of morphine (Amabile, Bowman, 2006). This sophisticated hydrophilic/hydrophobic relationship is reported to provide a more constant and predictable release of morphine from the system than is possible with the simpler Oramorph release mechanism (Amabile, Bowman, 2006).


Avinza is a capsule containing both fast-acting and modified-release beads of morphine. The primary advantage of this combination is that the fast-acting component allows the morphine concentration to plateau rapidly (within 30 minutes), and the modified-release component maintains the plasma concentration throughout the dosing interval (Amabile, Bowman, 2006). Most patients obtain adequate pain relief with either 12- or 24-hour dosing of the drug (Argoff, 2007). A comparative steady-state analysis of once-daily Avinza and twice-daily modified-release morphine (MS Contin) found that the two formulations provide similar total systemic exposure of morphine and its metabolites throughout a 24-hour period but have distinct pharmacokinetic profiles due to divergent technologies (Portenoy, Sciberras, Eliot, et al., 2002). Avinza maintains morphine concentrations at or greater than 50% and 75% for a longer duration of time than MS Contin. This may help to explain why studies have shown that the two drugs appear to have similar efficacy, but that Avinza may offer some additional benefits. For example, Avinza produced analgesia and adverse effects comparable to MS Contin but with greater improvements in sleep in patients with osteoarthritis (OA) pain (Caldwell, Rapoport, Davis, et al., 2002; Rosenthal, Moore, Groves, et al., 2007). Another study in patients with a variety of types of noncancer pain showed improvements in pain relief and both sleep and physical functioning over the 3-month study period with Avinza (Adams, Chwiecko, Ace-Wagoner, et al., 2006). Patients with noncancer pain of various origins (including neuropathic) that was unresponsive to short-acting opioid regimens experienced reduced pain and improvements in depressive symptoms and cognitive functioning after taking Avinza for 4 weeks (Panjabi, Panjabi, Shepherd, et al., 2008).


Once-daily Avinza has also been shown to produce more consistent opioid plasma concentrations with less frequent dosing compared with twice-daily modified-release oxycodone (OxyContin, see the paragraphs that follow) in healthy volunteers (Eliot, Geiser, Loewen, 2001). A multicenter study randomized 392 patients with persistent back pain (including some with neuropathic pain) to receive either Avinza every 24 hours or modified-release oxycodone every 12 hours; supplemental ibuprofen was allowed (Rauck, Bookbinder, Bunker, et al., 2006). Following a titration period, 174 patients took their study drug at a fixed dose for four weeks followed by a four-week period during which the dose could be changed as needed. Those taking Avinza experienced better pain control with a lower daily opioid dose, consumed fewer breakthrough doses, and had better sleep quality than those taking modified-release oxycodone. Adverse effects were similar. Patient surveys were used to evaluate physical function and revealed improvements in both groups but no significant differences between the two; however, fewer patients were unable to work due to illness or treatment in the Avinza group than in the modified-release oxycodone group (Rauck, Bookbinder, Bunker, et al., 2007).


Kadian, the other once-daily morphine formulation, is available in a capsule containing polymer-coated modified-release pellets of morphine (Alpharma Pharmaceuticals, 2008; Amabile, Bowman, 2006). If differs from Avinza in that it does not contain a fast-acting component. Its time to maximum serum level (tmax) is the longest (approximately 9.5 hours) of any of the modified-release morphine formulations (Rosielle, 2007). An analysis of data on nearly 1042 patients with noncancer pain who were started on Kadian once daily and could switch after two weeks to 12-hour dosing if necessary (Nicholson, Ross, Weil, et al., 2006) was undertaken to determine factors that influenced the patients’ choice of dosing interval (Weil, Nicholson, Sasaki, 2009). At the end of the study, 56.8% were taking the drug once daily and 43.2% were taking it every 12 hours. Race and gender did not influence dosing, but those with higher baseline and 2-week pain intensities were more likely to switch to a 12-hour dosing schedule, and older patients were more likely to remain on the 24-hour dosing schedule. Those who switched to 12-hour dosing experienced improved pain control, and by week 4, efficacy was comparable between the two dosing schedules. A review of the data of 68 patients taking Kadian for persistent pain showed the drug to be safe and effective for long-term opioid therapy (mean treatment = 12 months) (Chao, 2005). Patients in the review had a variety of pain conditions including radiculopathy and neck, head, and back pain. The median daily dose was 60 mg (range 20 to 400 mg); pain intensity (0 to 10) was reduced from a mean baseline of 7.8 to 5.2; 29% were considered non-responders, but over one-third of the patients experienced a reduction to 2.9; and, as in the previous study, over one-half of the patients were maintained on once-daily dosing.


In summary, some studies have shown patient preference for one morphine product or another, but as long as one product is used consistently and titrated to effect, they should all provide equally effective analgesia with the same adverse effect profile (Rosielle, 2007). Key to this is ensuring that the optimal dosing interval is prescribed. As mentioned, a high percentage of patients require more frequent dosing intervals than are recommended by the manufacturer (Argoff, 2007; Gallagher, Welz-Bosna, Gammaitoni, 2007).



Oral Oxycodone


Oxycodone is used extensively by the oral route and is available in both short-acting and modified-release formulations. It is also available alone or in combination (2.5 to 10 mg) with varying amounts of acetaminophen, aspirin, or ibuprofen (see Table 13-9 on p. 351). Single-entity oxycodone is available in 5, 15, and 30 mg tablets (capsules in 5 mg) and in two solution strengths, 5 mg/5mL and a 20 mg/mL concentrate (see the safety considerations for liquid opioids earlier in the chapter). The short-acting dose forms typically are used for short-term acute pain and for breakthrough pain.


With the varying doses and dose types (tablet, capsule, liquid) available, there is potential for confusion on the part of both clinician and patient. Prescriptions must be carefully written for each individual, and it is prudent to have the patient bring in the prescription bottle if refills are needed.


A drawback to the use of oxycodone combinations is that the clinician must carefully monitor the dose of acetaminophen, aspirin, or ibuprofen to ensure that maximum safe levels are not exceeded. Increases in the dose of oxycodone for inadequate pain relief are limited by acetaminophen’s and aspirin’s recommended maximum daily dose of 4000 mg and ibuprofen’s limit of 3200 mg (see Section III). At the time of publication, the United States Food and Drug Administration (U.S. FDA) was considering the need to restrict the availability of a maximum dose/tablet of acetaminophen to 325 mg and eliminate analgesics with fixed combinations of opioids-nonopioids (e.g., oxycodone plus acetaminophen [Percocet, Vicodin]) because of concerns of overdose and resultant liver failure (U.S. FDA, 2009b; Harris, 2008).


Single-entity preparations have allowed broader use of oxycodone. Oxycodone is one of four opioid analgesics that are available in the United States in 12-hour modified-release form (OxyContin) for twice daily dosing; it is also approved for 8-hour dosing for patients who do not maintain pain relief for 12 hours (see Tamper-Resistant and Abuse-Deferrent Oral Opioid Formations on p. 378). OxyContin is available in 10, 15, 20, 30, 40, 60, 80, and 160 mg tablets. Doses of 60, 80 and 160 mg or any single dose of greater than 40 mg are approved for opioid-tolerant patients only. These are small tablets that are color-coded according to dose. See Patient Education Form IV-14 (pp. 572-573) on oxycodone with acetaminophen, Form IV-12 (pp. 568-569) on short-acting oxycodone, and Form IV-13 (pp. 570-571) on modified-release oxycodone at the end of Section IV.


OxyContin exhibits a biphasic release profile, with an initial peak at approximately 0.6 hours and a second peak at approximately 6.9 hours (Purdue Pharma, 2007). Analgesic onset occurs in most patients within 1 hour of administration, sooner than that produced by the delivery system in MS Contin (Kalso, 2005). The rapid-release phase of OxyContin has a half-life of 37 minutes and releases 38% of the total dose; the slower phase has a half-life of 6.2 hours and accounts for the remaining 62% of the dose (De Pinto, Dunbar, Edwards, 2006). The rationale for this formulation was to provide an extended duration of analgesia without significantly compromising the brisk onset of analgesia inherent in conventional short-acting products (Davis, Varga, Dickerson, et al., 2003). Early clinical trials demonstrated that patients with cancer pain or noncancer pain could be converted from other opioids and titrated to comfort using modified-release oxycodone as readily as with a short-acting opioid (Salzman, Roberts, Wild, et al., 1999).


The bioavailability of modified-release oxycodone is similar to short-acting oxycodone, and it is as effective at 12-hour dosing as the equivalent dose of short- acting oxycodone taken at 4-hour intervals (Davis, Varga, Dickerson, et al., 2003). A morphine to oxycodone ratio of 1.5:1 is considered equianalgesic.


Modified-release oxycodone has been found to be effective for a wide variety of types of pain (Riley, Eisenberg, Muller-Schwefe, et al., 2008) (see research below). Like modified-release morphine, it is used for continuous cancer pain and non–cancer-related pain of all types. It also has been used for treatment of some types of acute pain. The extensive literature on OxyContin includes the following types of pain:



• Acute postoperative pain (Blumenthal, Min, Marquardt, et al., 2007; Cheville, Chen, Oster, et al., 2001; de Beer, Winemaker, Donnelly, et al., 2005; Dorr, Raya, Long, et al., 2008; Ginsberg, Sinatra, Adler, et al., 2003; Kampe, Warm, Kaufmann, et al., 2004) (See also Trend in Oral Analgesics for Postoperative Pain in paragraphs that follow.)


• Cancer pain (Gralow, 2002; Pan, Zhang, Zhang, et al., 2007; Reid, Martin, Sterne, et al., 2006).


• Persistent noncancer pain (Portenoy, Farrar, Backonja, et al., 2007; Roth, Fleischmann, Burch, et al., 2000)


• Acute exacerbation of noncancer pain (Ma, Jiang, Zhou, et al., 2008)


• Neuropathic pain (Eisenberg, McNicol, Carr, 2006; Furlan, Sandoval, Mailis-Gagnon, et al., 2006; Gimbel, Richards, Portenoy, 2003; Watson, Moulin, Watt-Watson, et al., 2003).


Among the controlled trials conducted with OxyContin have been several demonstrating the potential utility of combination therapy. One randomized study of 338 patients with painful diabetic neuropathy, for example, found that those who took a combination of modified-release oxycodone and gabapentin required less rescue medication, experienced significantly better pain relief and sleep, and were less likely to discontinue treatment due to lack of therapeutic effectiveness than those who took gabapentin plus placebo (Hanna, O’Brien, Wilson, 2008). This finding was not surprising given data from another controlled trial (N = 87) demonstrating that modified-release oxycodone was more effective than gabapentin for relief of acute pain of herpes zoster (Dworkin, Barbano, Tyring, et al., 2009). Similarly, oxycodone has been included in multimodal postoperative pain treatment plans (see later in this chapter for trends in the use of oral opioids for postoperative pain).



Oral Oxymorphone


Oxymorphone is available in short-acting (Opana) and modified-release (Opana ER) oral formulations. Short-acting oxymorphone is available in 5 and 10 mg tablets, and modified-release oxymorphone is available in 5, 7.5, 10, 15, 20, 30, and 40 mg tablets. The tablets are color-coded according to dose.


Oxymorphone is more lipophilic than morphine, which may account for the slightly faster onset of action of its short-acting formulation (30 to 45 minutes) (Smith, 2009). A mean time to peak effect of 30 minutes has been associated with all doses of short-acting oxymorphone (Smith, 2009). The oral bioavailability of oxymorphone is 10% (Prommer, 2006b), and consumption of food at the time of dosing, particularly food with a high fat content, can increase the plasma concentration of oral oxymorphone (short-acting and modified-release) by as much as 50%. Oxymorphone is extensively metabolized in the liver and produces clinically inert metabolites (Smith, 2009). Oxymorphone’s half-life (7 to 11 hours) is longer than morphine’s (2 to 4 hours) (Chamberlin, Cottle, Neville, 2007), and, as a consequence, the time required to approach steady state is longer (Smith, 2009). Oxymorphone is more potent than morphine and oxycodone, and has suggested oral conversion ratios of 3:1 and 2:1, respectively (Smith, 2009).


Depending on pain severity, the initial dose of short-acting oxymorphone usually is 5 to 10 mg in opioid-naïve patients (Endo, 2006). Because food can increase the plasma concentration of oral oxymorphone, the drug should be taken on an empty stomach (1 hour before or 2 hours after a meal), and alcohol should be avoided as co-ingestion can increase serum levels up to 270% (Chamberlin, Cottle, Neville, 2007; Guay, 2007; Smith, 2009). These are important considerations when selecting an opioid; oral oxymorphone would not be a good choice in those who are unable to follow these dosing restrictions.


The use of short-acting oral oxymorphone is similar to morphine, hydromorphone, and oxycodone formulations. It is most appropriate for treatment of acute pain, such as postoperative pain (Gimbel, Ahdieh, 2004), and cancer- and non–cancer-related breakthrough pain (Sloan, Slatkin, Ahdieh, 2005). A randomized, placebo- controlled, parallel-group trial in 331 patients following abdominal surgery demonstrated that oxymorphone 5 mg or 10 mg provided comparable pain relief to oxycodone 10 mg (Aqua, Gimbel, Singla, et al., 2007). Another randomized controlled trial administered 5 mg of short-acting oxymorphone or placebo hourly as needed for up to 8 hours to 122 patients with mostly moderate-intensity pain following outpatient knee arthroscopy (Gimbel, Walker, Ma, et al., 2005). Patients in the oxymorphone group had significantly better pain relief, required less rescue medication, and were more likely to rate their pain relief as very good or excellent.


Modified-release oxymorphone (Opana ER) was approved for use in the United States in 2006 for the treatment of moderate to severe persistent pain. Its unique formulation allows the release of oxymorphone dependent on the rate of penetration of water into a hydrophilic matrix. Modified-release oxymorphone is dosed every 12 hours, and, like short-acting oxymorphone, steady state is reached after 3 days of every-12-hour dosing (Smith, 2009). As mentioned, oxymorphone is more potent than oxycodone. One study explored the dose equivalency of modified-release formulations of oxymorphone and oxycodone and established an equianalgesic dose ratio of 2:1 (oxymorphone was twice as potent as oxycodone) (Gabrail, Dvergsten, Ahdieh, 2004). See Patient Education Form IV-15 (pp. 574-575) on short-acting oxymorphone and Form IV-16 (pp. 576-577) on modified-release oxymorphone at the end of Section IV.


Although it is common to titrate the opioid dose using the short-acting formulation, and then switch to the modified-release formulation, one study demonstrated that it is safe to start with the lowest modified-release oxymorphone dose (5 mg every 12 hours) in opioid-naïve patients with moderate to severe noncancer pain and titrate from there (Rauck, Ma, Kerwin, et al., 2008). Similar to other opioids, research has shown that fixed dosing and rapid titration resulted in a higher incidence of adverse effects than gradual titration of modified-release oxymorphone (Brennan, 2009).


Modified-release oxymorphone has been found to be effective in the treatment of a variety of types of persistent cancer and noncancer pain (Brennan, 2009; Prager, Rauk, 2004; Sloan, Barkin, 2008; Sloan, Slatkin, Ahdieh, 2005; Slatkin, Tormo, Ahdieh, 2004). One study that evaluated modified-release oxymorphone in patients with persistent low back pain found that positive effects were less profound for those aspects of the pain likely to be neuropathic in origin (and described as cold, itchy, sensitive, tingling, and numb) than pains that were inferred to be nociceptive (and were described as sharp, aching, and deep) (Gould, Jensen, Victor, et al., 2009). This study lends support to the conclusion that is applied to all opioid drugs, i.e., that opioids are effective for neuropathic pain but may be relatively less effective for some pains of this type than pains conventionally considered to be nociceptive. (See Section I for more on nociceptive pain and neuropathic pain.)


The number of clinical trials that evaluate modified-release oxymorphone in diverse types of acute and persistent pain has been increasing. Studies have appeared in the following types:



Oxymorphone has been shown to be safe for long-term therapy (McIlwain, Ahdieh, 2005; Prager, Rauck, 2004; Rauck, Ma, Kerwin, et al., 2008). A multicenter, open-label, nonrandomized study (N = 126) evaluated opioid-naïve patients with noncancer pain during a 6-month gradual dose-titration and stabilization phase followed by a 5-month maintenance phase and found that modified-release oxymorphone provided effective, well-tolerated, and stable analgesia in 75% of the patients (Rauck, Ma, Kerwin, et al., 2008).


Although further research in special populations is needed, plasma concentrations of the drug and its metabolites have been shown to be 40% (mean) higher in older adults; therefore, initial low doses should be used in these patients, and titration should proceed cautiously (Smith, 2009). As with short-acting oxymorphone, Guay (2007) recommends beginning with the lowest dose of modified-release oxymorphone, 5 mg every 12 hours. Dose adjustments of oxymorphone are also likely to be necessary in patients with moderate renal and hepatic disease (Smith, 2009). Guay (2007) recommends avoiding oxymorphone entirely in patients with moderate to severe hepatic impairment. The drug was shown in one study to be removed by hemodialysis (Smith, 2009). There appears to be a low risk for interaction with concurrent medications that are metabolized by the CYP450 enzyme system, which may be a significant benefit in patients who are poor metabolizers or those who take multiple medications that rely on this enzyme system for metabolism, such as some antidepressants, beta blockers, antipsychotics, chemotherapeutic agents, and some other opioids (Adams, Pieniaszek, Gammaitoni, et al., 2005; Chamberlin, Cottle, Neville, 2007; McIlwain, Ahdieh 2005; Smith, 2009) (see Chapter 11 for more on cytochrome P450 enzymes and drug-drug interactions). The reader is referred to a 2009 journal supplement devoted to content on oxymorphone: Pain Med 10(Suppl 1).



Oral Hydromorphone


Oral short-acting hydromorphone is available in 2, 4, and 8 mg tablets and in a 1 mg/mL oral solution. Modified-release formulations of oral hydromorphone are available in Canada and Europe, and a once-daily formulation (Exalgo) (8, 12, and 16 mg tablets) was approved in the United States in 2010 (Gupta, Sathyan, 2007). The formulation uses a novel bilayer tablet system, the OROS® Push-Pull™ technology, to release hydromorphone at a relatively constant rate during a 24-hour period (Gardner-Nix, Mercadante, 2010). The bilayer core within the semipermeable tablet consists of a single drug layer (the “pull” layer) and a hydrophilic expanding compartment (the “push” layer). After tablet ingestion, fluid from the gastrointestinal (GI) tract forms a drug suspension and causes the push layer to expand. This exerts force on the pull layer and pushes the suspended drug out of the tablet through a laser-drilled orifice in the tablet shell membrane (Gardner-Nix, Mercadante, 2010).


Research in 31 healthy volunteers demonstrated that the pharmacokinetics of modified-release hydromorphone are linear and dose proportional (Sathyan, Xu, Thipphawong, et al., 2007a). Median peak concentration was noted between 12 and 16 hours with a mean terminal half-life of approximately 11 hours, both independent of dose. Steady state is reached after 48 hours of dosing (Gupta, Sathyan, 2007). The presence of food has little effect on the bioavailability of the drug (Sathyan, Xu, Thipphawong, et al., 2007b), and alcohol does not cause immediate release (“dose dumping”) of the drug (Sathyan, Sivakumar, Thipphawong, et al., 2008). Drug release is independent of pH and agitation (Gupta, Sathyan, 2007).


A study of opioid-tolerant patients with persistent cancer pain (N = 73) or persistent noncancer pain (N = 331) stabilized the patients on their previous opioid, converted this dose to modified-release hydromorphone, then titrated to optimal dose using a stepwise approach, which was then maintained for 2 weeks (Palangio, Northfelt, Portenoy, et al., 2002). The majority of patients reached a stable dose of modified-release hydromorphone quickly (mean 12.1 days), and most required no or few steps to achieve it. The most common adverse effects were nausea and constipation. A morphine to hydromorphone conversion ratio of 5:1 was used, but the researchers reinforced the principle of decreasing the equianalgesic dose of the new opioid by 25% to 50% until research establishes differently (see Chapter 18). This study also suggested that direct conversion from another opioid to modified-release hydromorphone could be done without the intermediate step of titration with short-acting hydromorphone first. In other clinical trials, the once-daily hydromorphone has also been well tolerated with an adverse effect profile similar to other short- and modified-release opioid analgesics, such as morphine and oxycodone (Cousins, 2007; Gardner-Nix, Mercadante, 2010; Gupta, Sathyan, 2007; Hale, Tudor, Khanna, et al., 2007; Hanna, Thipphawong, 118 Study Group, 2008; Wallace, Thipphawong, 2007; Wirz, Wartenberg, Elsen, et al., 2006).


Long-term use of modified-release hydromorphone has been shown to be effective and safe. A multicenter open-label study (N = 388) administered modified-release hydromorphone for 274 days to patients with persistent cancer or noncancer pain (Wallace, Moulin, Rauck, et al., 2009). The median daily dose was 48 mg at 6, 9, and 12 months, with 75.9% of patients reporting overall treatment as good to excellent at 12 months. The most common adverse effects were nausea and constipation. A ratio of 5:1 (5 mg of morphine equivalents to 1 mg of hydromorphone) was used to convert opioid-tolerant patients with persistent noncancer pain from other oral opioids to modified-release hydromorphone without loss of efficacy or increase in adverse effects (Wallace, Rauck, Moulin, et al., 2007). (See Exalgo package insert for patient medication guide.)



Trend in Oral Analgesics for Postoperative Pain


With the current trend toward early discharge of patients after relatively major surgical procedures, consideration must be given to more aggressive pain treatment in the home setting than is possible with the traditional fixed combination opioid/nonopioid analgesics. The fixed dose of the nonopioid in these preparations limits the number of tablets that patients may take in a 24-hour period without exceeding the maximum safe daily dose (e.g., 4000 mg of acetaminophen). Single-entity opioids, such as morphine, oxycodone, and oxymorphone, are better choices if the anticipated severity or persistence of the pain increases the likelihood that dose titration will be needed.


Research has addressed the safety of early postoperative oral analgesia. A randomized controlled trial (N = 227) showed that early oral analgesia (first postoperative day) with scheduled 20 mg doses of short-acting morphine every 4 hours and an additional 10 mg dose every 2 hours PRN was safe and effective, producing similar analgesia as IV PCA with a basal rate after intraabdominal surgery (Pearl, McCauley, Thompson, et al., 2002). Others have found similar positive results with this approach following orthopedic surgery (Zaslansky, Eisenberg, Peskin, et al., 2006).


Modified-release opioids, used most often for patients with persistent cancer or noncancer pain, are increasingly prescribed in selected patients in the postoperative setting (Holt, Viscusi, Wordell, 2007; Pasero, McCaffery, 2007). The modified-release opioid formulations, e.g., MS Contin, OxyContin, and Opana ER, are FDA-approved for postoperative pain treatment in patients who were taking the particular opioid prior to surgery. They should also be considered for some opioid-naïve patients who are undergoing major surgeries that are associated with moderate to severe pain and are likely to require repeated doses of analgesics over several days. Modified-release opioids are not appropriate for pain that is mild or not expected to persist for an extended period of time.


Oxycodone (OxyContin) is the most widely studied modified-release opioid for treatment of postoperative pain. One study randomized 40 patients to receive either 20 mg of modified-release oxycodone or placebo preoperatively and every 12 hours postoperatively, in addition to IV morphine via PCA and IV acetaminophen (1 g) for 2 days following lumbar discectomy (Blumenthal, Min, Marquardt, et al., 2007). Those who received oxycodone consumed significantly less morphine; had significantly lower pain scores during rest, coughing, and with movement; experienced less nausea and vomiting and earlier recovery of bowel function; and reported higher satisfaction with their pain treatment than those who received placebo. Another study (N = 59) demonstrated that, compared with placebo, modified-release oxycodone given preoperative and every 12 hours postoperatively produced better pain relief, greater range of motion and quadriceps strength during physical therapy, and a shorter length of hospital stay by 2.3 days in patients following total knee arthroplasty (Cheville, Chen, Oster, et al., 2001). Others have found similar superior pain relief, reduced supplemental analgesic requirements, and cost savings with a range of doses (10 to 30 mg) of pre- and postoperative modified-release oxycodone following knee or hip replacement (de Beer, Winemaker, Donnelly, et al., 2005; Dorr, Raya, Long, et al., 2006) and breast surgery (Kampe, Warm, Kaufmann, et al., 2004).


Patients have been rapidly converted from IV opioids to modified-release oxycodone following major surgery. A multicenter, open-label study of 189 patients who were receiving IV PCA opioid for 12 to 24 hours following abdominal, orthopedic, or gynecologic surgery were given an initial dose of modified-release oxycodone at 12 hours postoperatively (Ginsberg, Sinatra, Adler, et al., 2003). The initial dose of oxycodone was calculated by multiplying the amount of IV morphine used in the previous 24 hours by a conversion factor of 1.2 to determine the daily dose of oxycodone, which was then divided by 2 to determine the every-12-hour dose of oxycodone (matched with available tablet strengths). This calculated amount of modified-release oxycodone plus breakthrough doses of NSAIDs or short-acting oxycodone every 4 hours PRN was well tolerated and provided satisfactory pain control for seven days postoperatively.


Though further research is needed, positive results were found with the use of modified-release oxymorphone for postoperative pain. One study randomized patients to receive modified-release oxymorphone 20 mg every 12 hours or placebo following knee arthroplasty (Ahdieh, Ma, Babul, et al., 2004). IV oxymorphone PCA was used for rescue analgesia. Patients who received modified-release oxymorphone had significantly better pain control and used significantly less rescue analgesia than those who received placebo. Treatment was well tolerated.



Tamper-Resistant and Abuse-Deterrent Oral Opioid Formulations


Several oral opioid formulations designed to be tamper-resistant and deter abuse were in various phases of investigation, development, and approval at the time of publication (Fleming, Noonan, Wheeler, et al., 2008; Jones, Johnson, Wagner, et al., 2008; Katz, Adams, Chilcoat, et al., 2007; Katz, Sun, Fox, et al., 2008; King Pharmaceuticals, 2008b; Medical News Today, 2008). A unique modified-release formulation (ALO-01, EMBEDA) contains pellets of morphine and sequestered naltrexone, an opioid antagonist (Johnson, Sun, Stuaffer, et al., 2007). Embeda was approved in 2009 and is available in capsules containing morphine/naltrexone in the following strengths: 20 mg/0.8 mg, 30 mg/1.2 mg, 50 mg/2 mg, 60 mg/2.4 mg, 80 mg/3.2 mg, and 100 mg/4 mg (King Pharmaceuticals, 2009). When taken as directed, the naltrexone remains sequestered in a pellet core and passes through the GI tract without significant absorption; however, if the product is crushed, chewed, or dissolved, the naltrexone is released and free to reverse opioid effects. A phase II multicenter, randomized-controlled, cross-over trial of 113 patients with moderate to severe OA pain was conducted to compare ALO-01 and modified-release morphine (Kadian) (Katz, Sun, Fox, et al., 2008). After a washout period to induce pain flare, patients were titrated to comfort with Kadian then randomized to receive either Kadian or ALO-01 for 14 days. Patients were then treated with Kadian for 7 days followed by a cross-over to the other study medication (either Kadian or ALO-01) for 14 days. Most of the patients (Kadian, 80% and ALO-01, 92%) rated the analgesics as good to excellent. Morphine exposure at steady state was similar, and plasma naltrexone levels were below quantification and had no effect on analgesia in those who took ALO-01. Adverse effects were similar and typical of opioids. A crossover study randomized 113 patients with moderate-to-severe OA pain to receive modified-release morphine (Kadian) or ALO-01 and demonstrated similar morphine exposure at steady state with the two formulations, and again the sequestered naltrexone had no effect on pain scores (Katz, Sun, Johnson, et al., 2009). When tested in recreational opioid users, crushed ALO-01 reduced euphoria due to naltrexone absorption and was no more desirable than intact morphine (Jones, Johnson, Wagner, et al., 2008).


OxyContin (12-hour modified-release oxycodone) is available in a novel abuse-deterrent formulation. The drug is contained within a hard gelatin capsule designed to resist tampering, such as crushing or dissolving in alcohol; other similar oxycodone formulations are in development (Fleming, Noonan, Wheeler, et al., 2008; Gordon, 2008; King Pharmaceuticals, 2008b). Research in healthy volunteers demonstrated that the technology successfully protected the drug from rapid release in various tampering simulations, such as chewing (Fleming, Noonan, Wheeler, et al., 2008). Plasma levels were lower when the drug was taken in a fasted state.



Oral Transmucosal


The oral mucosa functions similar to the skin as a barrier to dangerous substances. It differs from the skin in that it is significantly more vascular, more permeable to drugs with similar properties, and has a lower drug depot (storage) effect than the skin. Although mucosal drug absorption also involves hydrophilic pathways, absorption is optimized with drugs that are lipid soluble, such as fentanyl, buprenorphine, and methadone (Reisfield, Wilson, 2007). Three areas within the mouth can be used for oral transmucosal drug delivery: the sublingual, buccal, and gingival areas. These areas usually are regarded as separate routes of administration and are studied and discussed separately. Drug development for oral transmucosal routes of delivery has focused on acute pain management, primarily breakthrough pain, because a relatively rapid onset of effect can be achieved using these formulations.



Sublingual


Use of the sublingual route involves placing the drug under the tongue for absorption through the oral mucosa into the systemic circulation. Because the drug is absorbed directly into systemic circulation, the first-pass effect is avoided (Zhang, Zhang, Streisand, 2002). Of all the areas within the mouth for oral transmucosal drug administration, the sublingual area appears to be the highest in drug permeability. It is only 25% as thick as the buccal mucosa and, unlike the gingival mucosa, is nonkeratinized (Reisfield, Wilson, 2007). The sublingual route is an alternative when oral, parenteral, and rectal routes are unavailable or impractical (Reisfield, Wilson, 2007).


Few opioids have been administered by the sublingual route. Hospice nurses report success with morphine by the sublingual route (Robinson, Wilkie, Campbell, 1995), but it is thought that this is related to the fact that the drug is eventually swallowed; sublingual absorption of morphine and other hydrophilic drugs is poor (Hanks, Cherny, Fallon, 2004; Reisfield, Wilson, 2007).


The effects of lipid solubility, oral cavity pH, and drug contact time on sublingual absorption of various opioids and naloxone have been studied. Normal saliva pH is 6.5, but can vary with mouth breathing, nutritional status, food or beverage consumption, vomiting, stomatitis, and decreased salivary flow. Salivary pH also varies by region of the mouth (Reisfield, Wilson, 2007). Absorption of drugs is improved with high lipid solubility and an alkaline environment. Compared with morphine at pH 6.5 (18% absorption), the more lipophilic opioids—buprenorphine (55%), fentanyl (51%), and methadone (34%)—were absorbed to a significantly greater extent, whereas levorphanol, hydromorphone, oxycodone, heroin, and the opioid antagonist naloxone were not (Weinberg, Inturrisi, Reidenberg, et al., 1988). At a pH of 8.5, methadone absorption increased to 75%. Drug absorption was not affected by concentration, but was affected by contact time. Sixty percent of the maximum methadone and fentanyl absorption at 10 minutes was seen at 2.5 minutes of contact time; maximum buprenorphine absorption was complete by 2.5 minutes of contact time. Adverse effects were minor (bitter taste, burning sensation, lightheadedness), with fentanyl and buprenorphine associated with the lowest incidence.


Sublingual oxycodone and hydromorphone have been studied to a very limited degree (Reisfield, Wilson, 2007). An alkalinized oxycodone sublingual spray had a bioavailability of 70% in an animal model. Hydromorphone in healthy volunteers had a bioavailability of only 25%. The injectable forms of sufentanil and alfentanil have been used sublingually for breakthrough pain, but have not been studied (Gardner-Nix, 2001a; Hanks, Cherny, Fallon, 2004); with their high lipophilicity and potency (which exceeds fentanyl), they are a good theoretical choice, but the lack of commercially available products makes them impractical (Reisfield, Wilson, 2007). Fentanyl and methadone are well absorbed sublingually, but no preparations are commercially available (see the following discussion on oral transmucosal fentanyl) (Hanks, Cherny, Fallon, 2004); a sublingual fentanyl tablet now is available in some countries (Lennernas, Hedner, Holmberg, et al., 2005). A sublingual buprenorphine wafer has been approved for use in treatment of opioid addiction (Heit, Gourlay, 2008). A buprenorphine liquid product is available in other countries and may provide relief of mild to moderate pain. Sublingual buprenorphine absorption occurs within 3 to 5 minutes, bioavailability is 51%, and peak plasma concentrations generally occur at approximately 60 minutes (Johnson, Fudala, Payne, 2005).


An advantage of the sublingual route is that administration requires little expertise, preparation, or supervision (Reisfeld, Wilson, 2007; Stevens, Ghazi, 2000). Unfortunately, the sublingual route currently has limited value for the administration of most opioids because formulations are lacking, absorption is poor for most opioids, and high doses cannot be given. In addition, proper administration is seldom possible because the drug must be in contact with the oral mucosa at least 5 minutes, a length of time most patients find intolerable (Reisfield, Wilson, 2007).




Oral Transmucosal Fentanyl for Breakthrough Pain


Breakthrough pain (sometimes called pain flare, episodic pain, or transient pain) is defined as a transitory exacerbation of pain in a patient who has relatively stable and adequately controlled baseline pain (Portenoy, Forbes, Lussier, et al., 2004) (see Chapter 12 for a detailed discussion of breakthrough pain). The ideal medication for breakthrough pain has been described as one with a fast onset, relatively short duration of action, and minimal adverse effects (Zeppetella, 2008). Transmucosal delivery of a lipophilic and potent drug such as fentanyl meets these characteristics. Fentanyl had been incorporated into three products approved in the United States for the treatment of breakthrough cancer pain at the time of publication; numerous others are in development. Although indicated for cancer-related breakthrough pain, these products are widely used for breakthrough pain in noncancer pain syndromes as well (Prime Therapeutics, 2007).


Oral transmucosal fentanyl citrate (OTFC, Actiq®) is provided as a solid matrix or lozenge on a plastic stick (Figure 14-1, A). The medication is intended to be dissolved by saliva and absorbed through all oral mucosal surfaces. An effervescent fentanyl buccal tablet (FBT, Fentora®) is designed for placement against the buccal mucosa—between the upper gum and cheek—until it is dissolved (Figure 14-1, B). The newest formulation, BEMA (BioErodible MucoAdhesive; Onsolis) is a microadhesive polymer disk, about the size of a nickel, that contains fentanyl and is designed to stick to the oral mucosa (inside of the cheek) and dissolve within 15 to 30 minutes (Blum, Breithaupt, Hackett, et al., 2008).



The safety guidelines for the oral transmucosal products are strict, and the titration recommendations are conservative (see the following). Although safe use in opioid-naïve patients with severe persistent noncancer pain has been described (Collado, Torres, 2008), these products have been approved for treatment of breakthrough pain in opioid-tolerant cancer patients only (Cephalon, 2007, 2008), and they should not be prescribed to patients with minimal or no existing opioid treatment unless appropriate monitoring is available. Titration usually should begin at the lowest dose (Cephalon, 2007, 2008). Despite using the same drug by a similar route, OTFC and FBT are not equivalent or interchangeable. These are important drugs for the treatment of breakthrough pain and are safe when used as directed; however, their potency must be respected, and clinicians, patients, and families must be well-versed in safe utilization.


OTFC is available in 200, 400, 600, 800, 1200, and 1600 mcg strengths (Cephalon, 2007). Individual titration, usually beginning with the lowest dose (200 mcg), is necessary. Dose adjustment on the basis of age alone is not required (Kharasch, Hoffer, Whittington, 2004), although elimination in older adults is prolonged (Gordon, 2006). To administer OTFC, the patient is instructed to hold onto the stick and place the lozenge between the gum and cheek. The stick is used to move and twirl the lozenge around the oral mucosa, particularly between the gums and cheek and above and below the tongue, so that it dissolves in the saliva. Patients should be told not to suck on the lozenge as one would suck on a candy lollipop; this will result in much of the drug being swallowed (oral route), negating the benefits of exposure to direct systemic circulation that the oral transmucosal route offers. Further, clinicians should not refer to OTFC as a lollipop, sucker, or popsicle, as this is not only misleading but can result in family members, particularly children in the home, misunderstanding that this is a medication (not candy) that should be consumed by the patient only. Biting or chewing will cause a greater proportion to be swallowed, also resulting in decreased effectiveness. It has been suggested that the patient swish the fentanyl-containing saliva around the mouth prior to swallowing to enhance oral mucosal absorption (Gordon, 2006). If pain relief is insufficient after 15 to 25 minutes and the entire lozenge has been consumed, a second lozenge may be used; there are no published data about the use of more than two lozenges successively, and this is not recommended (Cephalon, 2007) (see Box 14-2 for complete dosing recommendations). See Patient Education Form IV-4 (pp. 551-552) on oral transmucosal fentanyl at the end of Section IV.



Guidelines


Box 14-2


Dosing of Oral Transmucosal Fentanyl Citrate (Actiq)



Initial dose



1. The initial dose of Actiq to treat episodes of breakthrough pain is 200 mcg.


2. Instruct the patient to place the Actiq unit in the mouth between the cheek and lower gum and to occasionally move the drug matrix from one side to the other using the handle. The Actiq unit should be sucked and not chewed. Chewing the matrix could result in lower peak concentrations and efficacy.


3. The Actiq unit should be consumed over a 15-minute period. Longer or shorter consumption times may produce less efficacy than reported in clinical trials.


4. Tell the patient that if pain relief occurs or signs of excessive opioid effects such as sedation appear before the unit is consumed, the dose unit should be removed from the patient’s mouth immediately, disposed of properly (see below), and subsequent doses should be decreased.


5. From this initial dose, closely follow the patient and change the dose level until the patient reaches a dose that provides adequate analgesia using a single Actiq dose unit per breakthrough episode.


6. Ask patients to record their use of Actiq over several episodes of breakthrough pain and review their experience with their prescriber to determine if a dose adjustment is warranted.

< div class='tao-gold-member'>

Related posts:

  1. Perioperative Nonopioid Use
  2. Adjuvant Analgesics for Persistent (Chronic) Bone Pain
  3. Initiating Opioid Therapy
  4. Switching to Another Opioid or Route of Administration

Stay updated, free articles. Join our Telegram channel
Tags:
Jun 24, 2016 | Posted by in PHARMACY | Comments Off on Guidelines for Selection of Routes of Opioid Administration

Full access? Get Clinical Tree
Get Clinical Tree app for offline access