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Pain Management

Overview of Oral Modified-Release Products for the Management of Chronic

Celene M Amabile and Bill J Bowman

OBJECTIVE: To evaluate pharmaceutical and pharmacotherapeutic differences in oral opioid modified-release products used in the management of chronic pain. DATA SOURCES: Searches of MEDLINE (1966–May 2006) and an extensive review of peer reviewed journals were conducted using the key search terms opioid, , , and . Supplemental information was gathered through the American Pain Society, and limited but relevant information was obtained from manufacturers’ labeling. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated. Information deemed relevant was included for this review if it introduced new or well supported concepts or clarified clinical practice issues. DATA SYNTHESIS: The recognition and treatment of pain has become a major focus of healthcare professionals. The Joint Commission on Accreditation of Healthcare Organizations mandates compliance with recommended standards, outcome measures, and other initiatives. A general review of and pharmacokinetic parameters are included. CONCLUSIONS: Oral modified-release products have enabled patients to better maintain pain control due to convenient dosing intervals and sustained blood concentrations. The differences between available oral modified-release products are half-life, cost, and formulation (excipients and drug-release properties). KEY WORDS: hydromorphone, morphine, opioid, oxycodone. Ann Pharmacother 2006;40:1327-35. Published Online, 25 Jul 2006, www.theannals.com, DOI 10.1345/aph.1G259 THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT ACPE UNIVERSAL PROGRAM NUMBER: 407-000-06-017-H01

he recognition and treatment of pain have become a fewest adverse drug effects (ADEs).1,2 However, this dos- Tmajor focus of healthcare professionals. have ing regimen often requires frequent administration, espe- become the drugs of choice for the treatment of moderate- cially for agents with a short elimination half-life. The in- to-severe chronic pain.1,2 The American Pain Society noted convenience associated with frequent dosing may be over- that, in most cases, the preferred route of delivery for opi- come by using modified-release drug products. These oids is oral administration because of its flexibility, conve- formulations may also ensure uninterrupted sleep and al- nience, and ability to maintain relatively steady blood con- low patients to focus on their daily activities rather than on centrations.3 For chronic pain, around-the-clock therapy their pain, which facilitates adherence and optimizes thera- provides the most effective analgesia and results in the py. Therefore, oral modified-release opioid products have become the standard of care for the management of mod- Author information provided at the end of the text. erate-to-severe chronic pain.1,2 www.theannals.com The Annals of Pharmacotherapy I 2006 July/August, Volume 40 I 1327 CM Amabile and BJ Bowman This review focuses on the oral modified-release opioid ginning of recorded history.4 The most important therapeu- products currently used to treat moderate-to-severe chronic tically active compounds found in the are the pain: morphine (Avinza, Kadian, Oramorph, MS Contin) and morphine (Figure 1A).4,5 Oxy- and oxycodone (OxyContin). These products vary in re- codone, , and hydromorphone are semisyn- gard to their active ingredient, dosage form, mechanism of thetic derivatives of these compounds, resulting from mi- drug release, dosing frequency, pharmacokinetic profile, nor chemical modifications with the characteristic phenan- and cost. To effectively manage chronic pain, healthcare threne nucleus of the natural opioids remaining intact providers must have a complete understanding of this class (Figure 1B and 1C).6 Other opioids, such as meperidine, of drug products. Modified-release opioid formulations , , and propoxyphene, are classified as have also been designed for other forms of administration synthetic opiate and lack the characteristic mor- (eg, transdermal fentanyl), and some oral modified-release phinan nucleus (Figure 1D).6 All of these opioid opioid products are delivered via alternate routes (eg, rec- modify sensory and affective aspects of pain by binding to tal administration of MS Contin tablets); however, this re- and activating µ-opioid receptors in the central nervous view focuses on orally administered products. Palladone system (CNS).7 The pharmacologic effect of these agents (hydromorphone), which was recently withdrawn from the is similar to that of the endogenous endorphin peptides.8 market due to safety concerns, and miscellaneous products in development are included in the discussion. PHARMACOKINETICS AND PHARMACODYNAMICS The delivery systems discussed here have been desig- Opioids are primarily metabolized by the liver through nated as extended-release, controlled-release, or sustained- dealkylation, conjugation, hydrolysis, and oxidation, and release. However, these terms do not have specific defini- their resulting metabolites undergo renal excretion.7 Opioids tions and have been used inconsistently within other pub- such as codeine, meperidine, and propoxyphene have phar- lished reports. One needs to examine each product to macologically active metabolites.6,9 Therefore, both hepatic determine its exact mechanism of drug release. The formu- and renal impairment may significantly influence the clini- lations in this review are generally referred to as modified- cal effects of many opioids. Drug interactions also occur release products. with some opioids. For example, codeine, oxycodone, and hydrocodone are major substrates of CYP2D6; therefore, General Review of Opioid Analgesics the blood concentrations of these opioids may be affected by agents that inhibit or induce this enzyme.9-11 MEDICINAL CHEMISTRY AND PHARMACOLOGY All of the µ-opioid agonists have different pharmacoki- The opium poppy, (), netic properties, but all are pharmacodynamically similar. is one of the oldest and most prevalent sources of opioid Blood concentrations of opioid agonists do not directly analgesics, which have been used medicinally since the be- predict response.12,13 However, an increase in

Figure 1. Chemical structures for (A) morphine, (B) oxycodone, (C) hydromorphone, and (D) fentanyl. The structures of morphine, oxycodone, and hydromor- phone contain the characteristic phenanthrene ring system of the natural and semisynthetic opioids.

1328 I The Annals of Pharmacotherapy I 2006 July/August, Volume 40 www.theannals.com Overview of Oral Modified-Release Opioid Products for the Management of Chronic Pain dose typically results in greater analgesia with no limit to The manufacturer’s package inserts for the modified-re- the effect.14 Therefore, these agents do not have a defined lease preparation of oxycodone (OxyContin) also contains maximum dose, and the “ceiling” to analgesic effective- a conversion table based on multiplication factors (Table ness is imposed only by ADEs, which also increase with 2).12 This table has not been verified in well controlled, dose.14 Effective opioid blood concentrations are dependent multiple-dose trials and underestimates the conversion of on several factors including a patient’s age, medical condi- opioid dosages compared with the chart shown in Table 1. tion, and previous opioid use.12,13 The minimum effective It is also important to note that the dosing factors shown in concentration varies greatly, and dosing should be based on Table 2 can be used only when converting from an opioid clinical evaluation of the patient to achieve an optimal bal- to OxyContin (ie, not between the other opioids within the ance between therapeutic pain control and ADEs.12-14 table). For example, a daily oral morphine dose can be converted to an equipotent OxyContin dose using the fig- Dosing ures in Table 2, but morphine cannot be converted to meperidine using this table. There is considerable individual variability in the anal- gesic response to opioids and the development of ADEs.15 CROSS-ALLERGINICITY Patients who experience insufficient analgesia or excessive ADEs with one opioid are often switched to another in an The classification of opioid analgesics may be based on effort to improve clinical response. Clinicians refer to 3 different schemes: (1) analog class (phenanthrene, equianalgesic dosing charts to compare opioid regimens phenylpiperidine, diphenylheptane), (2) chemical source between oral and parenteral routes and/or between differ- (natural, semisynthetic, synthetic), and (3) the presence or ent opioids (Table 1). Several considerations should be in- absence of a morphine-related chemical structure with a 6- corporated into the clinical utilization of opioid conversion hydroxyl group. The phenanthrene analog class consists of tables. First, these tables are often estimates based on sin- morphine, codeine, hydromorphone, oxycodone, and hy- gle-dose parenteral studies. Second, there is considerable drocodone. Meperidine and fentanyl are in the phenyl- interpatient variability in the efficacy and safety response piperidine class; methadone and propoxyphene are in the to opioids due to tolerance and cross tolerance, pharma- diphenylheptane class. Morphine and codeine are the 2 cokinetic and pharmacodynamic variability, use of coanal- naturally occurring opioids, while hydromorphone, oxy- gesics and other CNS-active medications, and psychologi- codone, and hydrocodone are semisynthetic. Meperidine, cal variables. Third, clinicians should always use the same fentanyl, methadone, and propoxyphene are synthetic opi- equianalgesic table to standardize their dose calculations oids. Codeine is the only opioid that has a morphine-relat- between different opioids, which can minimize the risk of ed chemical structure that includes a 6-hydroxyl group. dose conversion errors. It is also important to remember True allergic and anaphylactic reactions to opioid anal- that, if the equianalgesic table (Table 1) is used as a refer- gesics are rare, and the risk of cross-sensitivity is low even ence for switching patients from one opioid to another, there between the natural and semisynthetic compounds. Avail- is not complete cross-tolerance. In other words, switching a able reports suggest that reactions to opioids are most often patient from intravenous hydromorphone to intravenous related to nonimmunologic effects (histamine release, im- morphine at equianalgesic doses may be an overestimate. proper dosing, or concomitant medications), and none of The tolerance that developed while the patient was receiving these cases describes cross-sensitivity.16 Histamine release hydromorphone is not the same level of tolerance that would has been linked to urticaria, pruritus, and sneezing in pa- be demonstrated when the patient is switched to morphine.

Table 2. Multiplication Factors for Conversion to 12,a Table 1. Equianalgesic Dosing Chart15 Oral OxyContin OxyContin Equianalgesic Dose (mg) Conversion Opioid Oral Parenteral Factors Morphine 30 10 Prior Opioid Oral Parenteral Hydromorphone 7.5 1.5 Oxycodone 1 NA Fentanyl 0.1 Morphine 0.5 3 Oxycodone 20 Hydromorphone 4 20 Methadone 20 (acute) 10 (acute) Methadone 1.5 3 2–4 (chronic) 2–4 (chronic) Meperidine 0.1 0.4 Meperidine 300 (not recommended) 75 Codeine 0.15 NA Codeine 200 120 Propoxyphene 130–200 a(mg/day of prior opioid) × (conversion factor) = mg/day of OxyContin.

www.theannals.com The Annals of Pharmacotherapy I 2006 July/August, Volume 40 I 1329 CM Amabile and BJ Bowman tients receiving opioids. There are no clear guidelines for have the same mechanism of action, their physiochemical patients with a reported opioid allergy. It is best to evaluate and pharmacokinetic characteristics are more critical in deter- each case individually and is most often safe and necessary mining the appropriate and product to administer an opioid from a nonrelated source (semisyn- formulation to be used.1,2,7 For example, the short elimination thetic vs naturally occurring). Most of the histamine release half-life of opioids such as morphine, hydromorphone, and causes pruritus, which can be treated with around-the-clock oxycodone require that these agents be administered fre- antihistamine administration prior to administering opioid quently to achieve around-the-clock analgesia, which makes doses. Since most patients develop tolerance to the pruritus, them excellent candidates for modified-release formulations. the antihistamines can be discontinued when that occurs. In Conversely, methadone is a long-acting opioid (elimination some cases, changing to a different opioid may be neces- half-life ~30 h) and does not require frequent dosing. Fen- sary due to pruritus refractory to antihistamines. tanyl undergoes significant first-pass metabolism and lacks sufficient bioavailability after oral administration. ADVERSE DRUG EFFECTS Pharmacokinetic processes such as distribution, metabo- lism, and excretion are difficult to manipulate consistently The ADEs of opioids result from the binding and activa- and predictably so as to prolong the in vivo duration of ac- tion of µ-opioid receptors throughout the body (eg, CNS, tion of a therapeutic agent.2 Therefore, the only effective way gastrointestinal [GI] system). Opioids have a low inci- of controlling blood concentration profiles is to design prod- dence of organ toxicity, and the most common opioid-in- uct formulations that modify the absorption of active ingredi- duced ADEs include sedation, confusion, pruritus, ents into the body. Table 3 lists the brand name modified-re- and vomiting, respiratory depression, and . Af- lease opioid products available for the oral treatment of ter repeated dosing, patients usually develop tolerance to pain.12,13,17-19 Generic, AB-rated products are also available for opioid ADEs such as sedation, pruritus, and nausea and MS Contin controlled-release tablets (15, 30, 60, 100, 200 vomiting.15 Tolerance to respiratory depression is variable mg) and OxyContin controlled-release tablets (10, 20, 40, 80 because this ADE is also dose related. For example, opi- mg). All of these brand name and generic products are cate- oid-naïve patients are at a higher risk of experiencing res- gorized as Schedule II controlled substances. piratory depression; however, a patient receiving chronic All of the products listed in Table 3 may be taken with- opioid therapy may also experience this ADE if a signifi- out regard to meals. However, they are sensitive to alter- cantly higher dose is administered. In general, patients do ations that destroy their modified-release mechanisms. not develop tolerance to opioid-induced constipation. The Therefore, these products should be swallowed whole (ie, general approaches to managing opioid-induced ADEs in- not broken, chewed, crushed, or dissolved) due to the risk clude trying a different drug, changing the dose or route of of rapid opioid release and absorption of potentially fatal administration, adding a drug that counteracts the effect, doses. For patients experiencing difficulty swallowing, and considering nonpharmacologic actions. capsule products such as Avinza and Kadian may be opened and their entire bead contents sprinkled onto apple- 13,17 Oral Modified-Release Opioid Products sauce immediately prior to administration. The apple- sauce should be room temperature or cooler, and the entire Since all of the µ- agonists of choice for amount should be consumed without chewing, followed by the treatment of moderate-to-severe chronic pain (mor- rinsing and swallowing with water to ensure that all beads are phine, hydromorphone, fentanyl, methadone, oxycodone) ingested. The prescribing information for Kadian also indi-

Table 3. Available Oral Modified-Release Opioid Products12,13,17-19

Time to Wholesale Dosing Steady- Acquisition Product Dosage Form Strength Frequency F (%) State (days) Costa ($) Morphine sulfate Avinza extended-release capsules 30, 60, 90, 120 mg 24 h <40 2–3 5.12 Kadian sustained-release capsules 20, 30, 50, 60, 100 mg 12–24 h 20–40 ~2 8.88 Oramorph sustained-release tablets 15, 30, 60, 100 mg 8–12 h ~40 1–2 1.92 MS Contin controlled-release tablets 15, 30, 60, 100, 200 mg 8–12 h ~40 1 6.20 Oxycodone HCl OxyContin controlled-release tablets 10, 20, 40, 80, 160 mg 12 h 60–87 1–1.5 5.53

F = bioavailability. aPrices based on morphine 120 mg daily and rounding to the nearest tablet or capsule size according to equivalent dosing.

1330 I The Annals of Pharmacotherapy I 2006 July/August, Volume 40 www.theannals.com Overview of Oral Modified-Release Opioid Products for the Management of Chronic Pain cates that the entire capsule contents may be administered nent.17 The pellets are similar in general structure to the ex- through a 16 French gastrostomy tube.17 The prescribing in- tended-release beads in Avinza (Figure 2A). However, formation for Avinza makes no such mention.13 However, in- their polymer coating consists of an insoluble ethylcellu- structions for G-tube administration can be obtained from the lose base along with polyethylene glycol (PEG) and a manufacturer (telephone 888/828-4692). methacrylic acid copolymer. Both the PEG and In overdose situations, modified-release delivery sys- methacrylic acid copolymer are water soluble, but the wa- tems may continue to release their active ingredients; ter solubility of the methacrylic acid copolymer is pH de- therefore, the management of an overdose should be moni- pendent. After ingestion, the hard gelatin capsule shell tored accordingly. Evacuation of the gastric contents may quickly dissolves, releasing the drug-containing pellets. In be required to eliminate unabsorbed drug. In addition, the acidic pH of the stomach, the PEG component of the some of the excipients used to prepare oral modified-re- polymer coating dissolves and immediately creates pores lease opioid products, particularly talc, may lead to serious that allow GI fluid to enter the pellets and dissolve the complications if these products are parenterally abused. morphine sulfate, which can then diffuse and be absorbed into the body. Since only the PEG component can dissolve at that point, the pores are relatively small, limiting drug diffu- AVINZA EXTENDED-RELEASE CAPSULES sion. However, this does allow for some drug to be absorbed Avinza extended-release capsules contain morphine sul- quickly into the body. As the pellets enter and move through fate in both immediate and extended-release beads that are the intestines, the pH of the GI environment continues to in- 1–2 mm in diameter.13 The advantage of such a combina- crease, and the methacrylic acid copolymer begins to dis- tion is that the immediate-release component achieves solve as the PEG continues its dissolution. This increases the plateau morphine concentrations within 30 minutes while number and size of the pores in the polymer coating, which the extended-release component maintains these plasma increases the rate of morphine release. concentrations throughout the 24 hour dosing interval, which is longer than most other oral modified-release opi- ORAMORPH SUSTAINED-RELEASE TABLETS oid products are able to achieve. The SODAS (Spherical Oramorph sustained-release tablets differ from Avinza Oral Drug Absorption System) is used to produce the ex- and Kadian capsules in that they contain morphine sulfate tended-release component of the product. The extended-re- lease beads are prepared using sugar/starch spheres upon which a drug/excipient layer is coated, followed by an am- monio-methacrylate copolymer coating (Figure 2A). After administration and rapid dissolution of the hard gelatin capsule shell, the permeability of the ammonio- methacrylate copolymer coating allows GI fluid to enter the beads and solubilize the drug. The entrance of GI fluid is mediated by fumaric acid, which acts as an osmotic agent and local pH modifier within the drug/excipient lay- er. As a result, drug release is independent of the pH of the surrounding GI environment. After dissolving, morphine may then diffuse out of the beads at a predetermined rate. This entire process prolongs the in vivo dissolution of the drug and extends its absorption into the body. The immedi- ate-release beads are formed by utilizing the same sugar/starch core and drug/excipient layer, without the rate-limiting polymer coating, and contain approximately 10% of the respective dose.20 Dosing is limited to no greater than 1600 mg/day due to fumaric acid levels that may, theoretically, result in renal toxicity; however, fumar- ic acid has poor oral bioavailability.

KADIAN SUSTAINED-RELEASE CAPSULES

Kadian sustained-release capsules contain morphine sul- fate in identical polymer-coated, sustained-release pellets; Figure 2. Representation of (A) an extended-release bead formulation and the product does not contain an immediate-release compo- (B) a sustained-release matrix tablet prepared using a hydrophilic polymer. www.theannals.com The Annals of Pharmacotherapy I 2006 July/August, Volume 40 I 1331 CM Amabile and BJ Bowman in a simple matrix system instead of a polymer-coated tablet matrix, it dissolves the entrapped drug, which slowly reservoir (Figure 2B).19 This allows for the preparation of diffuses out of the matrix pores. Oxycodone release from the tablet dosage forms rather than capsules. The drug and any tablets is pH independent, which allows for a uniform release additional excipients are uniformly blended with a hy- throughout the GI tract. Since the matrix is hydrophobic and drophilic polymer (hydroxypropyl methylcellulose) and does not dissolve, patients should be advised that they may then compressed into tablets. Upon ingestion, GI fluid pen- pass empty tablets or “ghosts” in the stool or via colostomy, etrates the tablet and hydrates the hydrophilic hydrox- and that this is not a concern since the active ingredient has ypropyl methylcellulose matrix, causing it to swell and already been released from the tablet. form a viscous gel layer. The gel layer controls both the diffusion of water into the system and the diffusion of drug PALLADONE EXTENDED-RELEASE CAPSULES out of the system. Over time, this layer begins to break down and dissolve. As this occurs, water penetrates deeper Palladone extended-release capsules were launched in into the matrix, forming a new viscous gel layer. This pro- February 2005 and marketed to a limited number of medi- cess continues until the entire hydrophilic matrix is dis- cal practitioners.24 The capsules were the first oral modi- solved. The gel matrix effectively traps the active ingredi- fied-release opioid product that contained hydromorphone ent and slows its release, which may occur by diffusion HCl. The product used an ATC (Around The Clock) ma- through the gel layer or erosion of the gel matrix itself. trix pellet formulation to achieve a biphasic release of drug that resulted in a relatively rapid rise to an initial peak con-

MS CONTIN CONTROLLED-RELEASE TABLETS centration, followed by a second broad peak with thera- peutic plasma concentrations maintained over the 24 hour MS Contin controlled-release tablets contain morphine dosing interval.14 During product development, results in- sulfate in a dual-control polymer matrix (Contin) that con- dicated that consuming ethanol while taking Palladone dis- sists of a hydrophilic polymer (hydroxypropyl methylcel- rupted the modified-release mechanism of the product and lulose) and a hydrophobic polymer (hydroxyethyl cellu- resulted in the absorption of a potentially fatal dose of hy- lose).19 To prepare these systems, the drug is blended with dromorphone.24 Peak blood concentrations increased ap- the hydrophilic polymer, selectively hydrated with a polar proximately 6 times with the consumption of 8 ounces of a solvent, and fixed with a higher aliphatic .21 The 40% (80 proof) ethanol solution, and approximately 2 partition coefficients of the active ingredient with the hy- times with the consumption of 8 ounces of a 4% ethanol drophilic and hydrophobic components of the formulation solution.25 These results were disclosed to the Food and control the release of drug from the tablet.22 The hydropho- Drug Administration (FDA), and Purdue had developed bic content is used to slow the diffusion of drug into the professional prescribing information and a patient medica- aqueous phase, which limits diffusion into the GI tract and tion guide with strong warnings, including a boxed warning absorption into the body. These hydrophilic/hydrophobic that clearly stated the risks of consuming alcohol when tak- relationships are used to provide a more constant and pre- ing Palladone.24 After launching the product, Purdue moni- dictable release of drug from the system than that achieved tored and collected data on medication use, abuse, and drug with Oramorph. diversion, which was reported to the FDA. However, in July 2005, the FDA advised Purdue that the risk of alcohol inter- OXYCONTIN CONTROLLED-RELEASE TABLETS action cannot be adequately managed with warnings alone and, at the request of the FDA, Purdue suspended all market- OxyContin controlled-release tablets contain oxycodone ing and sales of Palladone.24 The company has implemented HCl and are prepared using the AcroContin delivery sys- a plan to reformulate the product to reduce the risk of an al- tem, which is an improvement upon the Contin system.12 cohol interaction, and the FDA has agreed to consider a pro- The AcroContin system provides a biphasic absorption posal that would allow for the use of the drug in certain insti- profile due to both an immediate release of drug within tutional settings, such as hospitals and in-patient hospices, one hour, which cannot be achieved using the Contin sys- where access to alcohol-containing products is controlled. tem, and a prolonged release over 12 hours. This system uses a dual-controlled matrix consisting of 2 hydrophobic OTHER MODIFIED-RELEASE PRODUCTS polymers (ammonio methacrylate copolymer).3 After in- gestion, the GI fluid dissolves the tablet coating, exposing ALZA is developing an oral hydromorphone controlled- the hydrophobic acrylic matrix. An initial amount of oxy- release product that uses the OROS delivery system (Di- codone (~30– 40% of the respective dose23) is immediately laudid CR) for once-daily dosing.26 The product is current- released upon contact with the GI fluid, which begins ly in Phase III clinical trials. Endo has recently received channeling into the pores of the tablet matrix. This imme- approval from the FDA for an oral extend- diate-release component is much greater than that of Avin- ed-release formulation that is to be dosed every 12 hours.27 za (~10% of the respective dose).20 As GI fluid enters the Also, slow-release morphine sulfate or oxycodone HCl

1332 I The Annals of Pharmacotherapy I 2006 July/August, Volume 40 www.theannals.com Overview of Oral Modified-Release Opioid Products for the Management of Chronic Pain capsules that use a drug/Methocel hypromellose matrix are recommended that Avinza and Kadian capsules be opened often compounded by pharmacists in certain settings.28-30 and sprinkled onto applesauce for children even though it is an appropriate administration technique for adults.13 Clinical and Comparative Issues PREGNANT AND BREAST-FEEDING WOMEN The goal of managing chronic pain is to provide suffi- cient relief with minimal ADEs so that patients can func- All opioid analgesics reviewed here are pregnancy cate- tion at a desirable level.1 Short-acting opioid products are gory C. Opioid analgesic concentrations have been found used to rapidly titrate patients to an adequate dose or as in breast milk; therefore, the risk/benefit of using these breakthrough pain management if the patient is initiated on agents in nursing women should be considered. If patients modified-release opioids.31 Patients may be converted to a require chronic opioid therapy, the cessation of breast feed- long-acting opioid product to prevent baseline pain, with ing may be necessary to reduce the risk to the neonate or additional dosing of a short-acting product to treat break- infant. The amount of systemic absorption of the excipi- 1 through pain. Many of the available clinical trials involv- ents used in preparing the modified-release products has ing oral modified-release opioid products included a small not been formally evaluated. Therefore, the risk of these number of patients, an open-label study, or sponsorship by agents to the breast-feeding infant cannot be determined. pharmaceutical companies. The American Pain Society states that the choice of opi- ELDERLY PATIENTS oid is based on the clinician’s experience with an agent, since there are few data indicating a preferred agent. Clini- Elderly patients (aged ≥65 y) were incorporated into the cians also base their choice of opioid on a patient’s previ- clinical studies of the oral modified-release opioid prod- ous experience, since some patients will tolerate or re- ucts. However, subgroup analysis was not possible in these spond to particular agents better than to others.15 Because trials due to small sample sizes. It is recommended that con- there is also a great deal of interpatient variability that may servative doses be initiated in these patients due to their me- be due to genetic polymorphism, some patients may need tabolism differences, their sensitivity to CNS active agents, longer or shorter dosing intervals of a modified-release and the potential for decreased renal elimination of metabo- opioid. This may increase costs to the patient if the interval lites compared with that of younger patients. The use of must be decreased, resulting in more doses each day. In these agents is not contraindicated in this population if ap- such cases, it may be prudent to switch the opioid to use propriate monitoring and slow-dose titration are practiced. tolerance or agents with longer half-lives (Avinza or Kadi- an) to decrease the pill burden and cost to the patient. There are 3 commonly used modified-release formula- PATIENTS WITH PAST OR CURRENT tions of morphine (MS Contin, Kadian, and Avinza). Kadi- Opioid products are not contraindicated in patients ex- an and Avinza have smaller trough to peak fluctuations periencing past or current substance abuse if they are pre- 13,17 compared with MS Contin. This means these agents scribed with the intention of treating pain. Boundary set- have lower maximum and higher minimum concentrations ting, frequent assessment, and treatment plan development than MS Contin. The clinical benefit of these pharmacoki- are key components of opioid therapy in these patients. netic differences has not correlated with higher efficacy or Boundary setting methods include medication therapy safety in clinical studies when Kadian or Avinza has been agreements (opioid contracts) and developing clear goals compared with MS Contin.32,33 It has been hypothesized for the reduction of pain. Patients with an addictive disor- that reduced fluctuations in blood morphine concentrations der who are experiencing chronic pain should be referred may influence the rate of opioid tolerance. The trough to to a specialist in pain management or medicine. peak fluctuation hypothesis has not been confirmed by Opioids are used in detoxification and maintenance pro- controlled trials and should not be the reason for choosing grams within facilities licensed to administer these agents one morphine formulation over another. to patients. All of the labeling for the oral modified-release opioid products contains warnings and information about Special Population Considerations drug abuse and dependence. PEDIATRIC PATIENTS Summary The safety of oral modified-release opioid products has not been established in children younger than 18 years of Oral modified-release opioid products have enabled pa- age. Therefore, these products should not be used in this tients to better maintain pain control due to convenient group of patients. These products cannot be divided or dosing intervals and sustained blood concentrations. The crushed and are not available in liquid formulations. It is not consistent blood concentration reduces the peaks and www.theannals.com The Annals of Pharmacotherapy I 2006 July/August, Volume 40 I 1333 CM Amabile and BJ Bowman troughs of the drug and, therefore, can decrease ADEs and 18. Package insert. Oramorph (morphine sulfate). Columbus, OH: Roxane Laboratories, May 2001. periods of inadequate pain control. The differences be- 19. Package insert. MS Contin (morphine sulfate). Stamford, CT: Purdue tween available oral modified-release products are half- Fredrick, December 2004. life, cost, and formulation (excipients and drug-release 20. Wilkinson K. Cancer treatments. Clin J Oncol Nurs 2003;7:458-60. 21. Leslie S. The Contin delivery system: dosing considerations. J Allergy properties). Since there are no data supporting superior ef- Clin Immunol 1986;78:768-73. ficacy of any one of these opioids compared with the oth- 22. Boroda C, Miller RB, Leslie ST, Nicol EG, Thomson I. Comparison of ers, selection should be based on other features. Initiating the bioavailability of aminophylline in a conventional base and in a con- tinuous-release base. J Clin Pharmacol 1973;13:383-7. the opioid with which the clinician is most comfortable or 23. Kaplin M, Miliman A, Kaplan L, Collins M. Comparative clinical effica- the opioid to which the patient has responded in the past cy and abuse potential of oral long acting opioids in a chronic pain out- patient center (abstract 868). American Pain Society Annual Meeting, should be the first step in drug selection. Cost should also be Vancouver, BC, Canada, 2004. a consideration in the choice, since most of these products are 24. Purdue Pharma L.P. suspends marketing of Palladone capsules. Purdue expensive. Patients will respond differently to opioids due to Pharma press release. www.pharma.com/pressroom/news/20050713-01. pdf (accessed 2005 July 21). differences in pain tolerance, , and control of 25. Hydromorphone hydrochloride extended-release capsules: alcohol–Pal- ADEs. The oral modified-release opioid products have been ladone interaction. FDA alert for healthcare professionals. www.fda.gov/ cder/drug/InfoSheets/HCP/hydromorphoneHCP.pdf (accessed 2005 July an innovative addition to the treatment of chronic pain. 21). 26. ALZA announces 2000 first quarter financial results. ALZA press re- Celene M Amabile PharmD BCPS, Clinical Coordinator/Residen- lease. www.alza.com/alza/pr_966278856 (accessed 2005 Jul 20). cy Program Director, Gaston Memorial Hospital, Gastonia, NC 27. Penwest announces that Endo reports receiving final FDA approval for Bill J Bowman BSPharm PhD, Assistant Professor of Pharma- oxymorphone ER. PR Newswire. www.prnewswire.com/cgi-bin/stories. ceutical Sciences, Department of Pharmaceutical Sciences, College pl?ACCT=109&STORY=/www/story/06-23-2006/0004385962& of Pharmacy—Glendale, Midwestern University, Glendale, AZ EDATE= (accessed 2006 Jun 27). Reprints: Dr. Amabile, Gaston Memorial Hospital, 2525 Court Dr., 28. Bogner RH, Szwejkowski J, Houston A. Release of morphine sulfate Gastonia, NC 28053-1747, fax 704/834-3030, [email protected] from compounded slow-release capsules: the effect of formulation on re- lease. IJPC 2001;5:401–5. 29. Webster KD, Al-Achi A, Greenwood R. In vitro studies on the release of References morphine sulfate from compounded slow-release morphine-sulfate cap- sules. IJPC 1999;3:409–11. 1. Vallerand AH. The use of long-acting opioids in chronic pain manage- 30. Glowiak DL, Green JL, Bowman BJ. In vitro evaluation of extempora- ment. Nurs Clin North Am 2003;38:435-45. neously compounded “slow release” capsules containing morphine sul- 2. Gourlay GK. Sustained relief of chronic pain: pharmacokinetics of sus- fate or oxycodone hydrochloride. IJPC 2005;9:157-64. tained release morphine. Clin Pharmacokinet 1998;35:173-90. 31. Cherny NI, Portenoy RK. Practical issues in the management of cancer 3. Reder RF. Opioid formulations: tailoring to the needs in chronic pain. pain. In: Wall PD, Melzack R, eds. Textbook of pain. 4th ed. London: Eur J Pain 2001;5(suppl A):109-11. Churchill Livingstone, 1999:1479-523. 4. Simpson BB, Ogorzaly MC. Medicinal plants. In: Prancan KM, Barter 32. Broomhead A, Kerr R, Tester W, et al. Comparison of a once-a-day sus- PW, Luhrs M, eds. Economic . 2nd ed. New York: McGraw-Hill, tained release morphine formulation with standard oral morphine. J Pain Symptom Manage 1997;14:63-73. 1995: 376-406. 33. 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St. Louis, MO: Mosby-Year Book, 1991:383-99. OBJETIVO: Evaluar las diferencias farmacéuticas y farmacoterapéuticas entre los distintos productos que contienen opioides de liberación 9. Jackson KC, Lipman AG. Opioid analgesics. In: Lipman AG, ed. Pain controlada utilizados en el tratamiento del dolor crónico. management for primary care clinicians. Bethesda, MD: American Soci- ety of Health-System Pharmacists, 2004:71-90. FUENTES DE DATOS: Se realizó una búsqueda en MEDLINE (1966–mayo 10. Ripamonti C, Bianchi M. The use of methadone for cancer pain. Hema- 2006) y una revisión extensiva de publicaciones revisadas por pares tol Oncol Clin North Am 2002;16:543-55. utilizando los términos: opioid, morphine, hydromorphone, y oxycodone. 11. Lacy CF, Armstrong LL, Goldman MP, Lance LL. Drug information Se obtuvo información complementaria a través de la American Pain handbook. 12th ed. Hudson, OH: Lexi-Comp, 2004. Society e información limitada pero relevante a partir del etiquetado de 12. Package insert. OxyContin (oxycodone). Stamford, CT: Purdue Pharma los medicamentos. L.P., February 2004. SELECCIÓN DE LOS ESTUDIOS Y EXTRACCIÓN DE LOS DATOS: Se evaluaron 13. Package insert. Avinza (morphine sulfate). San Diego: Ligand Pharma- todos los artículos identificados a partir de las mencionadas fuentes. La ceuticals, February 2003. información que se estimó relevante se incluyó en esta revisión si 14. Package insert. Palladone (hydromorphone). Stamford, CT: Purdue Phar- introducía conceptos nuevos o bien fundamentados o si clarificaba ma L.P., November 2004. cuestiones relacionadas con la práctica clínica. 15. Principles of analgesic use in the treatment of acute pain and chronic SÍNTESIS DE DATOS: El reconocimiento y tratamiento del dolor se ha pain. 5th ed. Glenview, IL: American Pain Society, 2003. convertido en uno de los principales centros de interés de los 16. Paddock R, Beer EG, Bellville JW, Ciliberti BJ, Forrest WH Jr, Miller EV. profesionales sanitarios. La Joint Commission on Accreditation of Analgesic and side effects of and morphine in a large popula- Healthcare Organizations establece la necesidad de adherirse a los tion of postoperative patients. Clin Pharmacol Ther 1969;10:355-65. estándares recomendados, realizar mediciones de los resultados y otras 17. Package insert. Kadian (morphine sulfate). Piscataway, NJ: Alpharma iniciativas. Se incluye una revisión general del tratamiento del dolor y de Branded Products Division, November 2004. los parámetros farmacocinéticos.

1334 I The Annals of Pharmacotherapy I 2006 July/August, Volume 40 www.theannals.com Overview of Oral Modified-Release Opioid Products for the Management of Chronic Pain

CONCLUSIONES: Los productos de liberación modificada han permitido a SÉLECTION DES ÉTUDES ET DE L’INFORMATION: Tous les articles identifiés à los pacientes mantener un mejor control del dolor ya que permiten partir de la revue de littérature furent évalués. L’information jugée ajustar los intervalos de dosificación y mantener las concentraciones pertinente fut inclue si elle apportait de nouveaux concepts ou supportait plasmáticas. Las diferencias entre los distintos productos son: vida des concepts connus ou finalement si elle clarifiait des éléments media, coste y formulación (los excipientes y las propiedades de cliniques importants. liberación del medicamento). RÉSUMÉ: La reconnaissance et le traitement de la douleur sont devenus Juan del Arco des éléments importants de tous les professionnels de la santé. L’organisation américaine (The Joint Commission on Accreditation of Healthcare Organizations) exige de se conformer aux standards reconnus, RÉSUMÉ aux mesures d’efficacité et autres initiatives. Une revue du traitement de la douleur et des paramètres pharmacocinétiques est inclue. OBJECTIF: Évaluer les différences pharmaceutiques et pharmacothérapeutiques des préparations orales d’opioïdes utilisées CONCLUSIONS: Les produits oraux à libération prolongée ont permis aux dans le traitement de douleur chronique. patients d'obtenir un meilleur soulagement de la douleur grâce à une administration quotidienne peu fréquente et à des concentrations REVUE DE LITTÉRATURE: Une recherche informatisée Medline couvrant la période de 1966 à mai 2006 ainsi qu’une revue extensive de journaux sanguines soutenues. Les différences entre les divers produits à revisés par les pairs furent effectuées utilisant les mots clés anglais libération prolongée résident en la demi-vie, les coûts et la formulation. suivants: opioid, morphine, hydromorphone, et oxycodone. Des Marc M Perreault informations supplémentaires furent obtenues de la American Pain Society ainsi que des monographies officielles.

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