Download Overview of Oral Modified-Release Opioid Products for

Pain Management
Overview of Oral Modified-Release Opioid Products for the
Management of Chronic Pain
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, morphine, hydromorphone, and oxycodone. 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 pain management 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
he recognition and treatment of pain have become a
major focus of healthcare professionals. Opioids have
become the drugs of choice for the treatment of moderateto-severe chronic pain.1,2 The American Pain Society noted
that, in most cases, the preferred route of delivery for opioids is oral administration because of its flexibility, convenience, and ability to maintain relatively steady blood concentrations.3 For chronic pain, around-the-clock therapy
provides the most effective analgesia and results in the
T
Author information provided at the end of the text.
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ACPE UNIVERSAL PROGRAM NUMBER: 407-000-06-017-H01
fewest adverse drug effects (ADEs).1,2 However, this dosing regimen often requires frequent administration, especially for agents with a short elimination half-life. The inconvenience associated with frequent dosing may be overcome by using modified-release drug products. These
formulations may also ensure uninterrupted sleep and allow patients to focus on their daily activities rather than on
their pain, which facilitates adherence and optimizes therapy. Therefore, oral modified-release opioid products have
become the standard of care for the management of moderate-to-severe chronic pain.1,2
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CM Amabile and BJ Bowman
This review focuses on the oral modified-release opioid
products currently used to treat moderate-to-severe chronic
pain: morphine (Avinza, Kadian, Oramorph, MS Contin)
and oxycodone (OxyContin). These products vary in regard to their active ingredient, dosage form, mechanism of
drug release, dosing frequency, pharmacokinetic profile,
and cost. To effectively manage chronic pain, healthcare
providers must have a complete understanding of this class
of drug products. Modified-release opioid formulations
have also been designed for other forms of administration
(eg, transdermal fentanyl), and some oral modified-release
opioid products are delivered via alternate routes (eg, rectal administration of MS Contin tablets); however, this review focuses on orally administered products. Palladone
(hydromorphone), which was recently withdrawn from the
market due to safety concerns, and miscellaneous products
in development are included in the discussion.
The delivery systems discussed here have been designated as extended-release, controlled-release, or sustainedrelease. However, these terms do not have specific definitions and have been used inconsistently within other published reports. One needs to examine each product to
determine its exact mechanism of drug release. The formulations in this review are generally referred to as modifiedrelease products.
General Review of Opioid Analgesics
MEDICINAL CHEMISTRY AND PHARMACOLOGY
The opium poppy, Papaver somniferum (Papaveraceae),
is one of the oldest and most prevalent sources of opioid
analgesics, which have been used medicinally since the be-
ginning of recorded history.4 The most important therapeutically active compounds found in the opium poppy are the
alkaloids codeine and morphine (Figure 1A).4,5 Oxycodone, hydrocodone, and hydromorphone are semisynthetic derivatives of these compounds, resulting from minor chemical modifications with the characteristic phenanthrene nucleus of the natural opioids remaining intact
(Figure 1B and 1C).6 Other opioids, such as meperidine,
fentanyl, methadone, and propoxyphene, are classified as
synthetic opiate agonists and lack the characteristic morphinan nucleus (Figure 1D).6 All of these opioid analgesics
modify sensory and affective aspects of pain by binding to
and activating µ-opioid receptors in the central nervous
system (CNS).7 The pharmacologic effect of these agents
is similar to that of the endogenous endorphin peptides.8
PHARMACOKINETICS AND PHARMACODYNAMICS
Opioids are primarily metabolized by the liver through
dealkylation, conjugation, hydrolysis, and oxidation, and
their resulting metabolites undergo renal excretion.7 Opioids
such as codeine, meperidine, and propoxyphene have pharmacologically active metabolites.6,9 Therefore, both hepatic
and renal impairment may significantly influence the clinical effects of many opioids. Drug interactions also occur
with some opioids. For example, codeine, oxycodone, and
hydrocodone are major substrates of CYP2D6; therefore,
the blood concentrations of these opioids may be affected by
agents that inhibit or induce this enzyme.9-11
All of the µ-opioid agonists have different pharmacokinetic properties, but all are pharmacodynamically similar.
Blood concentrations of opioid agonists do not directly
predict analgesic 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 hydromorphone contain the characteristic phenanthrene ring system of the natural and semisynthetic opioids.
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Overview of Oral Modified-Release Opioid Products for the Management of Chronic Pain
dose typically results in greater analgesia with no limit to
the effect.14 Therefore, these agents do not have a defined
maximum dose, and the “ceiling” to analgesic effectiveness is imposed only by ADEs, which also increase with
dose.14 Effective opioid blood concentrations are dependent
on several factors including a patient’s age, medical condition, and previous opioid use.12,13 The minimum effective
concentration varies greatly, and dosing should be based on
clinical evaluation of the patient to achieve an optimal balance between therapeutic pain control and ADEs.12-14
Equianalgesic Dosing
There is considerable individual variability in the analgesic response to opioids and the development of ADEs.15
Patients who experience insufficient analgesia or excessive
ADEs with one opioid are often switched to another in an
effort to improve clinical response. Clinicians refer to
equianalgesic dosing charts to compare opioid regimens
between oral and parenteral routes and/or between different opioids (Table 1). Several considerations should be incorporated into the clinical utilization of opioid conversion
tables. First, these tables are often estimates based on single-dose parenteral studies. Second, there is considerable
interpatient variability in the efficacy and safety response
to opioids due to tolerance and cross tolerance, pharmacokinetic and pharmacodynamic variability, use of coanalgesics and other CNS-active medications, and psychological variables. Third, clinicians should always use the same
equianalgesic table to standardize their dose calculations
between different opioids, which can minimize the risk of
dose conversion errors. It is also important to remember
that, if the equianalgesic table (Table 1) is used as a reference for switching patients from one opioid to another, there
is not complete cross-tolerance. In other words, switching a
patient from intravenous hydromorphone to intravenous
morphine at equianalgesic doses may be an overestimate.
The tolerance that developed while the patient was receiving
hydromorphone is not the same level of tolerance that would
be demonstrated when the patient is switched to morphine.
The manufacturer’s package inserts for the modified-release preparation of oxycodone (OxyContin) also contains
a conversion table based on multiplication factors (Table
2).12 This table has not been verified in well controlled,
multiple-dose trials and underestimates the conversion of
opioid dosages compared with the chart shown in Table 1.
It is also important to note that the dosing factors shown in
Table 2 can be used only when converting from an opioid
to OxyContin (ie, not between the other opioids within the
table). For example, a daily oral morphine dose can be
converted to an equipotent OxyContin dose using the figures in Table 2, but morphine cannot be converted to
meperidine using this table.
CROSS-ALLERGINICITY
The classification of opioid analgesics may be based on
3 different schemes: (1) analog class (phenanthrene,
phenylpiperidine, diphenylheptane), (2) chemical source
(natural, semisynthetic, synthetic), and (3) the presence or
absence of a morphine-related chemical structure with a 6hydroxyl group. The phenanthrene analog class consists of
morphine, codeine, hydromorphone, oxycodone, and hydrocodone. Meperidine and fentanyl are in the phenylpiperidine class; methadone and propoxyphene are in the
diphenylheptane class. Morphine and codeine are the 2
naturally occurring opioids, while hydromorphone, oxycodone, and hydrocodone are semisynthetic. Meperidine,
fentanyl, methadone, and propoxyphene are synthetic opioids. Codeine is the only opioid that has a morphine-related chemical structure that includes a 6-hydroxyl group.
True allergic and anaphylactic reactions to opioid analgesics are rare, and the risk of cross-sensitivity is low even
between the natural and semisynthetic compounds. Available reports suggest that reactions to opioids are most often
related to nonimmunologic effects (histamine release, improper dosing, or concomitant medications), and none of
these cases describes cross-sensitivity.16 Histamine release
has been linked to urticaria, pruritus, and sneezing in pa-
Table 2. Multiplication Factors for Conversion to
Oral OxyContin12,a
Table 1. Equianalgesic Dosing Chart
15
OxyContin
Conversion
Factors
Equianalgesic Dose (mg)
Opioid
Oral
Parenteral
Morphine
Hydromorphone
Fentanyl
Oxycodone
Methadone
30
7.5
10
1.5
0.1
Meperidine
Codeine
Propoxyphene
www.theannals.com
20
20 (acute)
2–4 (chronic)
300 (not recommended)
200
10 (acute)
2–4 (chronic)
75
120
130–200
Prior Opioid
Oral
Parenteral
Oxycodone
Morphine
Hydromorphone
Methadone
Meperidine
Codeine
1
0.5
4
1.5
0.1
0.15
NA
3
20
3
0.4
NA
(mg/day of prior opioid) × (conversion factor) = mg/day of OxyContin.
a
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tients receiving opioids. There are no clear guidelines for
patients with a reported opioid allergy. It is best to evaluate
each case individually and is most often safe and necessary
to administer an opioid from a nonrelated source (semisynthetic vs naturally occurring). Most of the histamine release
causes pruritus, which can be treated with around-the-clock
antihistamine administration prior to administering opioid
doses. Since most patients develop tolerance to the pruritus,
the antihistamines can be discontinued when that occurs. In
some cases, changing to a different opioid may be necessary due to pruritus refractory to antihistamines.
ADVERSE DRUG EFFECTS
The ADEs of opioids result from the binding and activation of µ-opioid receptors throughout the body (eg, CNS,
gastrointestinal [GI] system). Opioids have a low incidence of organ toxicity, and the most common opioid-induced ADEs include sedation, confusion, pruritus, nausea
and vomiting, respiratory depression, and constipation. After repeated dosing, patients usually develop tolerance to
opioid ADEs such as sedation, pruritus, and nausea and
vomiting.15 Tolerance to respiratory depression is variable
because this ADE is also dose related. For example, opioid-naïve patients are at a higher risk of experiencing respiratory depression; however, a patient receiving chronic
opioid therapy may also experience this ADE if a significantly higher dose is administered. In general, patients do
not develop tolerance to opioid-induced constipation. The
general approaches to managing opioid-induced ADEs include trying a different drug, changing the dose or route of
administration, adding a drug that counteracts the effect,
and considering nonpharmacologic actions.
Oral Modified-Release Opioid Products
Since all of the µ-opioid receptor agonists of choice for
the treatment of moderate-to-severe chronic pain (morphine, hydromorphone, fentanyl, methadone, oxycodone)
have the same mechanism of action, their physiochemical
and pharmacokinetic characteristics are more critical in determining the appropriate route of administration and product
formulation to be used.1,2,7 For example, the short elimination
half-life of opioids such as morphine, hydromorphone, and
oxycodone require that these agents be administered frequently to achieve around-the-clock analgesia, which makes
them excellent candidates for modified-release formulations.
Conversely, methadone is a long-acting opioid (elimination
half-life ~30 h) and does not require frequent dosing. Fentanyl undergoes significant first-pass metabolism and lacks
sufficient bioavailability after oral administration.
Pharmacokinetic processes such as distribution, metabolism, and excretion are difficult to manipulate consistently
and predictably so as to prolong the in vivo duration of action of a therapeutic agent.2 Therefore, the only effective way
of controlling blood concentration profiles is to design product formulations that modify the absorption of active ingredients into the body. Table 3 lists the brand name modified-release opioid products available for the oral treatment of
pain.12,13,17-19 Generic, AB-rated products are also available for
MS Contin controlled-release tablets (15, 30, 60, 100, 200
mg) and OxyContin controlled-release tablets (10, 20, 40, 80
mg). All of these brand name and generic products are categorized as Schedule II controlled substances.
All of the products listed in Table 3 may be taken without regard to meals. However, they are sensitive to alterations that destroy their modified-release mechanisms.
Therefore, these products should be swallowed whole (ie,
not broken, chewed, crushed, or dissolved) due to the risk
of rapid opioid release and absorption of potentially fatal
doses. For patients experiencing difficulty swallowing,
capsule products such as Avinza and Kadian may be
opened and their entire bead contents sprinkled onto applesauce immediately prior to administration.13,17 The applesauce should be room temperature or cooler, and the entire
amount should be consumed without chewing, followed by
rinsing and swallowing with water to ensure that all beads are
ingested. The prescribing information for Kadian also indi-
Table 3. Available Oral Modified-Release Opioid Products12,13,17-19
Product
Morphine sulfate
Avinza
Kadian
Oramorph
MS Contin
Oxycodone HCl
OxyContin
Time to
SteadyState (days)
Wholesale
Acquisition
Costa ($)
Dosage Form
Strength
Dosing
Frequency
extended-release capsules
sustained-release capsules
sustained-release tablets
controlled-release tablets
30, 60, 90, 120 mg
20, 30, 50, 60, 100 mg
15, 30, 60, 100 mg
15, 30, 60, 100, 200 mg
24 h
12–24 h
8–12 h
8–12 h
<40
20–40
~40
~40
2–3
~2
1–2
1
5.12
8.88
1.92
6.20
controlled-release tablets
10, 20, 40, 80, 160 mg
12 h
60–87
1–1.5
5.53
F (%)
F = bioavailability.
a
Prices based on morphine 120 mg daily and rounding to the nearest tablet or capsule size according to equivalent dosing.
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Overview of Oral Modified-Release Opioid Products for the Management of Chronic Pain
cates that the entire capsule contents may be administered
through a 16 French gastrostomy tube.17 The prescribing information for Avinza makes no such mention.13 However, instructions for G-tube administration can be obtained from the
manufacturer (telephone 888/828-4692).
In overdose situations, modified-release delivery systems may continue to release their active ingredients;
therefore, the management of an overdose should be monitored accordingly. Evacuation of the gastric contents may
be required to eliminate unabsorbed drug. In addition,
some of the excipients used to prepare oral modified-release opioid products, particularly talc, may lead to serious
complications if these products are parenterally abused.
AVINZA EXTENDED-RELEASE CAPSULES
Avinza extended-release capsules contain morphine sulfate in both immediate and extended-release beads that are
1–2 mm in diameter.13 The advantage of such a combination is that the immediate-release component achieves
plateau morphine concentrations within 30 minutes while
the extended-release component maintains these plasma
concentrations throughout the 24 hour dosing interval,
which is longer than most other oral modified-release opioid products are able to achieve. The SODAS (Spherical
Oral Drug Absorption System) is used to produce the extended-release component of the product. The extended-release beads are prepared using sugar/starch spheres upon
which a drug/excipient layer is coated, followed by an ammonio-methacrylate copolymer coating (Figure 2A).
After administration and rapid dissolution of the hard
gelatin capsule shell, the permeability of the ammoniomethacrylate 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 layer. 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 immediate-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, fumaric acid has poor oral bioavailability.
nent.17 The pellets are similar in general structure to the extended-release beads in Avinza (Figure 2A). However,
their polymer coating consists of an insoluble ethylcellulose base along with polyethylene glycol (PEG) and a
methacrylic acid copolymer. Both the PEG and
methacrylic acid copolymer are water soluble, but the water solubility of the methacrylic acid copolymer is pH dependent. After ingestion, the hard gelatin capsule shell
quickly dissolves, releasing the drug-containing pellets. In
the acidic pH of the stomach, the PEG component of the
polymer coating dissolves and immediately creates pores
that allow GI fluid to enter the pellets and dissolve the
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 diffusion. However, this does allow for some drug to be absorbed
quickly into the body. As the pellets enter and move through
the intestines, the pH of the GI environment continues to increase, and the methacrylic acid copolymer begins to dissolve as the PEG continues its dissolution. This increases the
number and size of the pores in the polymer coating, which
increases the rate of morphine release.
ORAMORPH SUSTAINED-RELEASE TABLETS
Oramorph sustained-release tablets differ from Avinza
and Kadian capsules in that they contain morphine sulfate
KADIAN SUSTAINED-RELEASE CAPSULES
Kadian sustained-release capsules contain morphine sulfate in identical polymer-coated, sustained-release pellets;
the product does not contain an immediate-release compowww.theannals.com
Figure 2. Representation of (A) an extended-release bead formulation and
(B) a sustained-release matrix tablet prepared using a hydrophilic polymer.
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in a simple matrix system instead of a polymer-coated
reservoir (Figure 2B).19 This allows for the preparation of
tablet dosage forms rather than capsules. The drug and any
additional excipients are uniformly blended with a hydrophilic polymer (hydroxypropyl methylcellulose) and
then compressed into tablets. Upon ingestion, GI fluid penetrates the tablet and hydrates the hydrophilic hydroxypropyl methylcellulose matrix, causing it to swell and
form a viscous gel layer. The gel layer controls both the
diffusion of water into the system and the diffusion of drug
out of the system. Over time, this layer begins to break
down and dissolve. As this occurs, water penetrates deeper
into the matrix, forming a new viscous gel layer. This process continues until the entire hydrophilic matrix is dissolved. The gel matrix effectively traps the active ingredient and slows its release, which may occur by diffusion
through the gel layer or erosion of the gel matrix itself.
MS CONTIN CONTROLLED-RELEASE TABLETS
MS Contin controlled-release tablets contain morphine
sulfate in a dual-control polymer matrix (Contin) that consists of a hydrophilic polymer (hydroxypropyl methylcellulose) and a hydrophobic polymer (hydroxyethyl cellulose).19 To prepare these systems, the drug is blended with
the hydrophilic polymer, selectively hydrated with a polar
solvent, and fixed with a higher aliphatic alcohol.21 The
partition coefficients of the active ingredient with the hydrophilic and hydrophobic components of the formulation
control the release of drug from the tablet.22 The hydrophobic content is used to slow the diffusion of drug into the
aqueous phase, which limits diffusion into the GI tract and
absorption into the body. These hydrophilic/hydrophobic
relationships are used to provide a more constant and predictable release of drug from the system than that achieved
with Oramorph.
OXYCONTIN CONTROLLED-RELEASE TABLETS
OxyContin controlled-release tablets contain oxycodone
HCl and are prepared using the AcroContin delivery system, which is an improvement upon the Contin system.12
The AcroContin system provides a biphasic absorption
profile due to both an immediate release of drug within
one hour, which cannot be achieved using the Contin system, and a prolonged release over 12 hours. This system
uses a dual-controlled matrix consisting of 2 hydrophobic
polymers (ammonio methacrylate copolymer).3 After ingestion, the GI fluid dissolves the tablet coating, exposing
the hydrophobic acrylic matrix. An initial amount of oxycodone (~30– 40% of the respective dose23) is immediately
released upon contact with the GI fluid, which begins
channeling into the pores of the tablet matrix. This immediate-release component is much greater than that of Avinza (~10% of the respective dose).20 As GI fluid enters the
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tablet matrix, it dissolves the entrapped drug, which slowly
diffuses out of the matrix pores. Oxycodone release from the
tablets is pH independent, which allows for a uniform release
throughout the GI tract. Since the matrix is hydrophobic and
does not dissolve, patients should be advised that they may
pass empty tablets or “ghosts” in the stool or via colostomy,
and that this is not a concern since the active ingredient has
already been released from the tablet.
PALLADONE EXTENDED-RELEASE CAPSULES
Palladone extended-release capsules were launched in
February 2005 and marketed to a limited number of medical practitioners.24 The capsules were the first oral modified-release opioid product that contained hydromorphone
HCl. The product used an ATC (Around The Clock) matrix pellet formulation to achieve a biphasic release of drug
that resulted in a relatively rapid rise to an initial peak concentration, followed by a second broad peak with therapeutic plasma concentrations maintained over the 24 hour
dosing interval.14 During product development, results indicated that consuming ethanol while taking Palladone disrupted the modified-release mechanism of the product and
resulted in the absorption of a potentially fatal dose of hydromorphone.24 Peak blood concentrations increased approximately 6 times with the consumption of 8 ounces of a
40% (80 proof) ethanol solution, and approximately 2
times with the consumption of 8 ounces of a 4% ethanol
solution.25 These results were disclosed to the Food and
Drug Administration (FDA), and Purdue had developed
professional prescribing information and a patient medication guide with strong warnings, including a boxed warning
that clearly stated the risks of consuming alcohol when taking Palladone.24 After launching the product, Purdue monitored and collected data on medication use, abuse, and drug
diversion, which was reported to the FDA. However, in July
2005, the FDA advised Purdue that the risk of alcohol interaction cannot be adequately managed with warnings alone
and, at the request of the FDA, Purdue suspended all marketing and sales of Palladone.24 The company has implemented
a plan to reformulate the product to reduce the risk of an alcohol interaction, and the FDA has agreed to consider a proposal that would allow for the use of the drug in certain institutional settings, such as hospitals and in-patient hospices,
where access to alcohol-containing products is controlled.
OTHER MODIFIED-RELEASE PRODUCTS
ALZA is developing an oral hydromorphone controlledrelease product that uses the OROS delivery system (Dilaudid CR) for once-daily dosing.26 The product is currently in Phase III clinical trials. Endo has recently received
approval from the FDA for an oral oxymorphone extended-release formulation that is to be dosed every 12 hours.27
Also, slow-release morphine sulfate or oxycodone HCl
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Overview of Oral Modified-Release Opioid Products for the Management of Chronic Pain
capsules that use a drug/Methocel hypromellose matrix are
often compounded by pharmacists in certain settings.28-30
recommended that Avinza and Kadian capsules be opened
and sprinkled onto applesauce for children even though it is
an appropriate administration technique for adults.13
Clinical and Comparative Issues
The goal of managing chronic pain is to provide sufficient relief with minimal ADEs so that patients can function at a desirable level.1 Short-acting opioid products are
used to rapidly titrate patients to an adequate dose or as
breakthrough pain management if the patient is initiated on
modified-release opioids.31 Patients may be converted to a
long-acting opioid product to prevent baseline pain, with
additional dosing of a short-acting product to treat breakthrough pain.1 Many of the available clinical trials involving oral modified-release opioid products included a small
number of patients, an open-label study, or sponsorship by
pharmaceutical companies.
The American Pain Society states that the choice of opioid is based on the clinician’s experience with an agent,
since there are few data indicating a preferred agent. Clinicians also base their choice of opioid on a patient’s previous experience, since some patients will tolerate or respond to particular agents better than to others.15 Because
there is also a great deal of interpatient variability that may
be due to genetic polymorphism, some patients may need
longer or shorter dosing intervals of a modified-release
opioid. This may increase costs to the patient if the interval
must be decreased, resulting in more doses each day. In
such cases, it may be prudent to switch the opioid to use
tolerance or agents with longer half-lives (Avinza or Kadian) to decrease the pill burden and cost to the patient.
There are 3 commonly used modified-release formulations of morphine (MS Contin, Kadian, and Avinza). Kadian and Avinza have smaller trough to peak fluctuations
compared with MS Contin.13,17 This means these agents
have lower maximum and higher minimum concentrations
than MS Contin. The clinical benefit of these pharmacokinetic differences has not correlated with higher efficacy or
safety in clinical studies when Kadian or Avinza has been
compared with MS Contin.32,33 It has been hypothesized
that reduced fluctuations in blood morphine concentrations
may influence the rate of opioid tolerance. The trough to
peak fluctuation hypothesis has not been confirmed by
controlled trials and should not be the reason for choosing
one morphine formulation over another.
Special Population Considerations
PREGNANT AND BREAST-FEEDING WOMEN
All opioid analgesics reviewed here are pregnancy category C. Opioid analgesic concentrations have been found
in breast milk; therefore, the risk/benefit of using these
agents in nursing women should be considered. If patients
require chronic opioid therapy, the cessation of breast feeding may be necessary to reduce the risk to the neonate or
infant. The amount of systemic absorption of the excipients used in preparing the modified-release products has
not been formally evaluated. Therefore, the risk of these
agents to the breast-feeding infant cannot be determined.
ELDERLY PATIENTS
Elderly patients (aged ≥65 y) were incorporated into the
clinical studies of the oral modified-release opioid products. However, subgroup analysis was not possible in these
trials due to small sample sizes. It is recommended that conservative doses be initiated in these patients due to their metabolism differences, their sensitivity to CNS active agents,
and the potential for decreased renal elimination of metabolites compared with that of younger patients. The use of
these agents is not contraindicated in this population if appropriate monitoring and slow-dose titration are practiced.
PATIENTS WITH PAST OR CURRENT SUBSTANCE ABUSE
Opioid products are not contraindicated in patients experiencing past or current substance abuse if they are prescribed with the intention of treating pain. Boundary setting, frequent assessment, and treatment plan development
are key components of opioid therapy in these patients.
Boundary setting methods include medication therapy
agreements (opioid contracts) and developing clear goals
for the reduction of pain. Patients with an addictive disorder who are experiencing chronic pain should be referred
to a specialist in pain management or addiction medicine.
Opioids are used in detoxification and maintenance programs within facilities licensed to administer these agents
to patients. All of the labeling for the oral modified-release
opioid products contains warnings and information about
drug abuse and dependence.
PEDIATRIC PATIENTS
The safety of oral modified-release opioid products has
not been established in children younger than 18 years of
age. Therefore, these products should not be used in this
group of patients. These products cannot be divided or
crushed and are not available in liquid formulations. It is not
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Summary
Oral modified-release opioid products have enabled patients to better maintain pain control due to convenient
dosing intervals and sustained blood concentrations. The
consistent blood concentration reduces the peaks and
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CM Amabile and BJ Bowman
troughs of the drug and, therefore, can decrease ADEs and
periods of inadequate pain control. The differences between available oral modified-release products are halflife, cost, and formulation (excipients and drug-release
properties). Since there are no data supporting superior efficacy of any one of these opioids compared with the others, selection should be based on other features. Initiating
the opioid with which the clinician is most comfortable or
the opioid to which the patient has responded in the past
should be the first step in drug selection. Cost should also be
a consideration in the choice, since most of these products are
expensive. Patients will respond differently to opioids due to
differences in pain tolerance, drug metabolism, and control of
ADEs. The oral modified-release opioid products have been
an innovative addition to the treatment of chronic pain.
Celene M Amabile PharmD BCPS, Clinical Coordinator/Residency Program Director, Gaston Memorial Hospital, Gastonia, NC
Bill J Bowman BSPharm PhD, Assistant Professor of Pharmaceutical Sciences, Department of Pharmaceutical Sciences, College
of Pharmacy—Glendale, Midwestern University, Glendale, AZ
Reprints: Dr. Amabile, Gaston Memorial Hospital, 2525 Court Dr.,
Gastonia, NC 28053-1747, fax 704/834-3030, [email protected]
References
1. Vallerand AH. The use of long-acting opioids in chronic pain management. Nurs Clin North Am 2003;38:435- 45.
2. Gourlay GK. Sustained relief of chronic pain: pharmacokinetics of sustained release morphine. Clin Pharmacokinet 1998;35:173-90.
3. Reder RF. Opioid formulations: tailoring to the needs in chronic pain.
Eur J Pain 2001;5(suppl A):109-11.
4. Simpson BB, Ogorzaly MC. Medicinal plants. In: Prancan KM, Barter
PW, Luhrs M, eds. Economic botany. 2nd ed. New York: McGraw-Hill,
1995: 376-406.
5. Evans WC. Alkaloids. In: Evans WC, ed. Trease and Evans’ pharmacognosy. 14th ed. London: WB Saunders, 1999:340-408.
6. Hanson GR. Analgesic, antipyretic, and anti-inflammatory drugs. In:
Gennaro AR, ed. Remington: the science and practice of pharmacy. 20th
ed. Baltimore, MD: Lippincott Williams & Wilkins, 2000:1444-63.
7. Gutstein HB, Akil H. Opioid analgesics. In: Hardman JG, Limbard LE,
eds. Goodman & Gillman’s the pharmacologic basis of therapeutics.
10th ed. New York: McGraw-Hill, 2001:569-620.
8. Brase D, Dewey WL. Pain control with narcotic analgesics. In: Wingard
LB, Brody TM, Larner J, Schwartz A, eds. Human pharmacology:
molecular to clinical. St. Louis, MO: Mosby-Year Book, 1991:383-99.
9. Jackson KC, Lipman AG. Opioid analgesics. In: Lipman AG, ed. Pain
management for primary care clinicians. Bethesda, MD: American Society of Health-System Pharmacists, 2004:71-90.
10. Ripamonti C, Bianchi M. The use of methadone for cancer pain. Hematol Oncol Clin North Am 2002;16:543-55.
11. Lacy CF, Armstrong LL, Goldman MP, Lance LL. Drug information
handbook. 12th ed. Hudson, OH: Lexi-Comp, 2004.
12. Package insert. OxyContin (oxycodone). Stamford, CT: Purdue Pharma
L.P., February 2004.
13. Package insert. Avinza (morphine sulfate). San Diego: Ligand Pharmaceuticals, February 2003.
14. Package insert. Palladone (hydromorphone). Stamford, CT: Purdue Pharma L.P., November 2004.
15. Principles of analgesic use in the treatment of acute pain and chronic
pain. 5th ed. Glenview, IL: American Pain Society, 2003.
16. Paddock R, Beer EG, Bellville JW, Ciliberti BJ, Forrest WH Jr, Miller EV.
Analgesic and side effects of pentazocine and morphine in a large population of postoperative patients. Clin Pharmacol Ther 1969;10:355-65.
17. Package insert. Kadian (morphine sulfate). Piscataway, NJ: Alpharma
Branded Products Division, November 2004.
1334
n
The Annals of Pharmacotherapy
n
18. Package insert. Oramorph (morphine sulfate). Columbus, OH: Roxane
Laboratories, May 2001.
19. Package insert. MS Contin (morphine sulfate). Stamford, CT: Purdue
Fredrick, December 2004.
20. Wilkinson K. Cancer treatments. Clin J Oncol Nurs 2003;7:458-60.
21. Leslie S. The Contin delivery system: dosing considerations. J Allergy
Clin Immunol 1986;78:768-73.
22. Boroda C, Miller RB, Leslie ST, Nicol EG, Thomson I. Comparison of
the bioavailability of aminophylline in a conventional base and in a continuous-release base. J Clin Pharmacol 1973;13:383-7.
23. Kaplin M, Miliman A, Kaplan L, Collins M. Comparative clinical efficacy and abuse potential of oral long acting opioids in a chronic pain outpatient center (abstract 868). American Pain Society Annual Meeting,
Vancouver, BC, Canada, 2004.
24. Purdue Pharma L.P. suspends marketing of Palladone capsules. Purdue
Pharma press release. www.pharma.com/pressroom/news/20050713-01.
pdf (accessed 2005 July 21).
25. Hydromorphone hydrochloride extended-release capsules: alcohol–Palladone interaction. FDA alert for healthcare professionals. www.fda.gov/
cder/drug/InfoSheets/HCP/hydromorphoneHCP.pdf (accessed 2005 July
21).
26. ALZA announces 2000 first quarter financial results. ALZA press release. www.alza.com/alza/pr_966278856 (accessed 2005 Jul 20).
27. Penwest announces that Endo reports receiving final FDA approval for
oxymorphone ER. PR Newswire. www.prnewswire.com/cgi-bin/stories.
pl?ACCT=109&STORY=/www/story/06-23-2006/0004385962&
EDATE= (accessed 2006 Jun 27).
28. Bogner RH, Szwejkowski J, Houston A. Release of morphine sulfate
from compounded slow-release capsules: the effect of formulation on release. IJPC 2001;5:401–5.
29. Webster KD, Al-Achi A, Greenwood R. In vitro studies on the release of
morphine sulfate from compounded slow-release morphine-sulfate capsules. IJPC 1999;3:409–11.
30. Glowiak DL, Green JL, Bowman BJ. In vitro evaluation of extemporaneously compounded “slow release” capsules containing morphine sulfate or oxycodone hydrochloride. IJPC 2005;9:157-64.
31. Cherny NI, Portenoy RK. Practical issues in the management of cancer
pain. In: Wall PD, Melzack R, eds. Textbook of pain. 4th ed. London:
Churchill Livingstone, 1999:1479-523.
32. Broomhead A, Kerr R, Tester W, et al. Comparison of a once-a-day sustained release morphine formulation with standard oral morphine. J Pain
Symptom Manage 1997;14:63-73.
33. Portenoy RK, Sciberras A, Eliot L, Loewen G, Butler J, Devane J.
Steady-state pharmacokinetic comparison of a new, extended-release,
once-daily morphine formulation, Avinza, and a twice-daily controlledrelease morphine formulation in patients with chronic moderate-to-severe pain. J Pain Symptom Manage 2002;23:292-300.
EXTRACTO
OBJETIVO: Evaluar las diferencias farmacéuticas y farmacoterapéuticas
entre los distintos productos que contienen opioides de liberación
controlada utilizados en el tratamiento del dolor crónico.
FUENTES DE DATOS: Se realizó una búsqueda en MEDLINE (1966–mayo
2006) y una revisión extensiva de publicaciones revisadas por pares
utilizando los términos: opioid, morphine, hydromorphone, y oxycodone.
Se obtuvo información complementaria a través de la American Pain
Society e información limitada pero relevante a partir del etiquetado de
los medicamentos.
SELECCIÓN DE LOS ESTUDIOS Y EXTRACCIÓN DE LOS DATOS: Se evaluaron
todos los artículos identificados a partir de las mencionadas fuentes. La
información que se estimó relevante se incluyó en esta revisión si
introducía conceptos nuevos o bien fundamentados o si clarificaba
cuestiones relacionadas con la práctica clínica.
SÍNTESIS DE DATOS: El reconocimiento y tratamiento del dolor se ha
convertido en uno de los principales centros de interés de los
profesionales sanitarios. La Joint Commission on Accreditation of
Healthcare Organizations establece la necesidad de adherirse a los
estándares recomendados, realizar mediciones de los resultados y otras
iniciativas. Se incluye una revisión general del tratamiento del dolor y de
los parámetros farmacocinéticos.
2006 July/August, Volume 40
www.theannals.com
Overview of Oral Modified-Release Opioid Products for the Management of Chronic Pain
Los productos de liberación modificada han permitido a
los pacientes mantener un mejor control del dolor ya que permiten
ajustar los intervalos de dosificación y mantener las concentraciones
plasmáticas. Las diferencias entre los distintos productos son: vida
media, coste y formulación (los excipientes y las propiedades de
liberación del medicamento).
CONCLUSIONES:
Juan del Arco
RÉSUMÉ
OBJECTIF: Évaluer les différences pharmaceutiques et
pharmacothérapeutiques des préparations orales d’opioïdes utilisées
dans le traitement de douleur chronique.
REVUE DE LITTÉRATURE: Une recherche informatisée Medline couvrant la
période de 1966 à mai 2006 ainsi qu’une revue extensive de journaux
revisés par les pairs furent effectuées utilisant les mots clés anglais
suivants: opioid, morphine, hydromorphone, et oxycodone. Des
informations supplémentaires furent obtenues de la American Pain
Society ainsi que des monographies officielles.
Tous les articles identifiés à
partir de la revue de littérature furent évalués. L’information jugée
pertinente fut inclue si elle apportait de nouveaux concepts ou supportait
des concepts connus ou finalement si elle clarifiait des éléments
cliniques importants.
RÉSUMÉ: La reconnaissance et le traitement de la douleur sont devenus
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,
aux mesures d’efficacité et autres initiatives. Une revue du traitement de
la douleur et des paramètres pharmacocinétiques est inclue.
CONCLUSIONS: Les produits oraux à libération prolongée ont permis aux
patients d'obtenir un meilleur soulagement de la douleur grâce à une
administration quotidienne peu fréquente et à des concentrations
sanguines soutenues. Les différences entre les divers produits à
libération prolongée résident en la demi-vie, les coûts et la formulation.
SÉLECTION DES ÉTUDES ET DE L’INFORMATION:
Marc M Perreault
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