DRUG REVIEW
`Oxymorphone Extended-Release Tablets (Opana ER)
`For the Management of Chronic Pain
`A Practical Review for Pharmacists
`David S. Craig, PharmD, BCPS
`
`Key words: oxymorphone, opioid, chronic pain, opioid
` rotation, opioid switching
`
`INTRODUCTION
`Whether in a dedicated pain-management clinic or in a com-
`munity pharmacy, pharmacists can provide valuable education
`and treatment recommendations to patients and clinicians.
`Pain programs, jointly managed by pharmacists, nurse prac-
`titioners, specialists in behavioral medicine and functional
`restoration, and specialty pain physicians, can enhance the sat-
`isfaction of patients and health care professionals, improve
`clinical outcomes, and minimize the need for secondary pain
`referrals.1 Pharmacists who become knowledgeable in pain
`pharmacotherapy can facilitate safe, effective, and cost-bene-
`ficial equianalgesic opioid conversions in primary care set-
`tings.2
`Long-acting (LA) opioids are recommended for moderate-
`to-severe chronic cancer and non-cancer pain.3,4 In their most
`recent evidence review, the American Pain Society and Amer-
`ican Academy of Pain Medicine concluded that there is insuf-
`ficient evidence to recommend that LA opioids be used in
`place of short-acting opioids for chronic non-cancer pain, but
`they acknowledge that LA opioids might provide more con-
`sistent pain control, improve adherence, and reduce the risk
`of addiction or abuse.4 Additional research is needed to eval-
`uate these proposed advantages.5
`Differences among opioids influence individual patient re-
`sponse and tolerability, risks and benefits in specific disease
`states, the likelihood of drug interactions, and ease of moni-
`toring. Differences among patients with respect to genetic
`factors, age, sex, and the prior use of opioids also contribute
`to variability of response to individual opioids.6 Consequently,
`when selecting LA opioids, clinicians cannot reliably predict
`how a given patient will respond. Patients with chronic pain
`usually require consecutive trials of several LA opioids before
`they find one that provides adequate analgesia with acceptable
`tolerability.7–9 For this reason, it is essential to have multiple LA
`opioids from which to choose.
`In 2006, the FDA approved extended-release oxymorphone
`HCl (Opana ER, Endo) for the control of moderate-to-severe
`chronic pain. At that time, morphine (MsContin, Purdue);
`Oramorph SR, Xanodyne; oxycodone (OxyContin, Purdue);
`methadone (Dolophine, Roxane); and transdermal fentanyl
`(Duragesic, Ortho-McNeil-Janssen) were the only LA opioids
`
`Dr. Craig is a Clinical Pharmacist Specialist at H. Lee Moffitt
` Cancer Center and Research Institute in Tampa, Florida.
`
`Accepted for publication January 22, 2010.
`
`324 P&T® (cid:129) June 2010 (cid:129) Vol. 35 No. 6
`
`approved in the U.S., and they remain the primary alternatives
`to oxymorphone ER today. Some pain specialists do not con-
`sider LA tramadol (Ultram, PriCara) to be an equivalent
` alternative to these drugs because of its predominantly non-
`opioid mechanism of action10 and relatively weak analgesic
` potency, compared with other more potent opioids.
`LA hydromorphone (Palladone, Purdue) was withdrawn
`from the U.S. market in 2005 because of a potentially fatal
` interaction with alcohol.11 A new formulation (Exalgo, Covid -
`ien) has received FDA approval.12,13
`Transdermal buprenorphine (e.g., Transtec, Butrans, or
`Norspan in Europe) is being studied for the management of
`chronic pain. It will probably represent another LA opioid
`choice if it receives FDA approval.14
`Tapentadol (Nucynta, PriCara) combines mu-opioid recep-
`tor agonism with norepinephrine reuptake inhibition. It is
`available as an immediate-release (IR) tablet, and a long-acting
`preparation is being investigated.15 Tapentadol is featured in
`this month’s Drug Forecast column on page 330.
`A Schedule II controlled substance (CII), oxymorphone ER
`is a selective mu-opioid agonist16 that is embedded in an ag-
`glomerated hydrophilic matrix to provide sustained activity
`over a 12-hour dosing interval.17 This article describes the
`agent’s pharmacology, pharmacokinetics, efficacy and safety,
`and clinical considerations of significance to pharmacists, cli-
`nicians, and members of P&T committees.
`
`PHARMACOLOGY AND PHARMACOKINETICS
`Oxymorphone has selective affinity for the mu-opioid
` receptor,16 whereas oxycodone has weaker mu-receptor affin-
`ity and greater kappa-receptor affinity.18 Oxymorphone has
`lower protein binding (10% to 12%) compared with morphine
`(30% to 35%) or oxycodone (45%).16 Its highly lipophilic prop-
`erties facilitate its transit across the blood–brain barrier.17
`The pharmacokinetic profile of oxymorphone ER is pre-
`dictable, linear, and dose-proportional.17,19 The technology
`used in the ER formulation, TIMERx (Penwest Pharmaceuti-
`cals), maintains steady plasma levels over a 12-hour period.17,19
`With a half-life of 9 to11 hours,17 oxymorphone ER maintains
`a low fluctuation index of less than 1 after achieving steady
`state, as do its two metabolites.17,19 Oxymorphone is metabo-
`lized primarily via hepatic glucuronidation17 to one active
`metabolite (6-OH-oxymorphone) and to one inactive metabo-
`lite (oxymorphone-3-glucuronide). It is neither metabolized by
`
`Disclosure. Dana Franznick, PharmD, and Nicole Strangman, PhD, of
`Complete Healthcare Communications, Inc., in Chadds Ford, Penn-
`sylvania, provided research and editorial assistance for the develop-
`ment of the submitted manuscript, with support from Endo Pharma-
`ceuticals, Inc., in Chadds Ford, Pennsylvania.
`
`ENDO - Ex. 2057
`Amneal v. Endo
`IPR2014-00360
`
`

`

`Oxymorphone Extended-Release Tablets (Opana ER)
`
` cytochrome P-450 (CYP) enzymes nor inhibited or induced by
`CYP substrates.20 Consequently, oxymorphone ER, along with
`morphine and hydromorphone, lacks significant potential for
`CYP-mediated drug interactions and is unaffected by genetic
`factors influencing these enzymes.20 By contrast, oxycodone,
`fentanyl, methadone, buprenorphine, and other opioids are
` metabolized by CYP enzymes and therefore have the potential
`for clinically important pharmacokinetic interactions with
`other drugs that share this metabolic pathway.6,21 Interest-
`ingly, the CYP 3A4 enzyme alone is responsible for the
` metabolism of more than 50% of currently available drugs.6
`The absence of CYP-mediated metabolism is also advanta-
`geous because genetic variations in the activity of CYP
` enzymes have been associated with altered opioid metabo-
`lism. For example, codeine and hydrocodone are metabolized
`by CYP 2D6 to more active metabolites (morphine and hy-
`dromorphone, respectively).6 Some patients who are poor CYP
`2D6 metabolizers (i.e., 5% to 10% of Caucasians) or ultra-rapid
`CYP 2D6 metabolizers (i.e., 1% to 7% of Caucasians) may
` experience reduced efficacy or an increase in adverse events
`(AEs) because of a reduced or accelerated production of
`metabolites.6,22–24 A small portion of oxycodone undergoes
`CYP 2D6 metabolism to oxymorphone, and increased AEs
`have been reported for poor CYP 2D6 metabolizers.22,24
`Although oxymorphone ER has minimal potential for phar-
`macokinetic interactions, its use with sedatives, tranquilizers,
`hypnotics, phenothiazines, and other central nervous system
`(CNS) depressants can produce additive effects. Hence, as with
`other opioids, vigilance is required in preventing pharmaco -
`dynamic interactions during therapy with oxymorphone ER.
`Pharmacists can help prevent medication errors, particularly
`those that result in drug interactions. Patients receiving opi-
`oid therapy for chronic pain may have complex medical prob-
`lems, often requiring the involvement of their primary care
`physician, a pain specialist, and one or more medical or surgical
`specialists. Although each prescriber has an obligation to be
`aware of all of a patient’s prescription and over-the-counter
`medications, the pharmacist is in a unique position to monitor
`the patient’s medications from all sources.
`Pharmacists must recognize and be vigilant in guarding
`against potential drug interactions, redundancy, misuse, or
`evidence of abuse and must take action to advise prescribers
`and caution patients accordingly. In this regard, pharmacists
`can be most successful by developing a collegial, cooperative
`relationship with the prescribing physician.
`
`CLINICAL TRIAL PROGRAM
`The clinical trial program for oxymorphone ER has included
`more than 2,000 opioid-naive and opioid-experienced patients
`with chronic cancer pain and non-cancer pain. The duration
`of treatment ranged from two weeks to two years. Collec-
`tively, the trials demonstrated that oxymorphone ER was an
`effective, generally well-tolerated 12-hour opioid agent in con-
`trolling chronic pain.
`In long-term, open-label trials of cancer and non-cancer
`pain, analgesic effects were maintained over time, and in pa-
`tients with osteoarthritis and low back pain, the effects were
` accompanied by improvements in functional outcomes.
`
`Use of Oxymorphone ER in Opioid-Naive Patients
`In clinical trials, individualized gradual titration improved the
`tolerability of oxymorphone ER in opioid-naive patients with
`moderate-to-severe chronic low back pain.25 These patients
` underwent a flexible, tailored, open-label, dose-titration period
`consisting of oxymorphone ER 5 mg every 12 hours, titrated at
`increments of 5 and 10 mg every three to seven days. A well-
` tolerated mean dose of approximately 40 mg in 205 of 325
` patients (63%) was achieved. These responders (n = 205) entered
`a randomized, double-blind, placebo-controlled 12-week period.
`Rescue medication, consisting of oxymorphone IR, was used to
`manage breakthrough pain and to prevent withdrawal symp-
`toms in patients switching from oxymorphone ER to placebo
`for the double-blind treatment period.
`Outcome measures included pain intensity, as measured
`by a 100-mm Visual Analogue Scale (VAS) and by patient and
`physician global ratings of treatment. No functional outcome
`measures were assessed. The Adjective Rating Scale (ARS) for
`Withdrawal and the Clinical Opiate Withdrawal Scale (COWS)
`were administered to ensure that between-group differences
`were not a result of withdrawal by patients who switched from
`oxymorphone ER to placebo.
`Patients given oxymorphone ER were significantly more
`likely than placebo patients to complete the double-blind treat-
`ment period (68% vs. 47% respectively; P < 0.001) and were
` significantly less likely to stop treatment owing to a lack of effi-
`cacy (11% vs. 35%, respectively; P < 0.001). Discontinuations at-
`tributed to AEs occurred with similar frequency in the two
`groups (oxymorphone ER, 8.6%; placebo, 8%). Only one patient
`receiving oxymorphone ER and two patients receiving placebo
`discontinued treatment because of withdrawal symptoms.
`Patients who received oxymorphone ER in the double-blind
`period exhibited consistent statistically significant improve-
`ment in VAS-rated pain intensity relative to placebo-treated
` patients (P < 0.001). Before enrollment into the study, most
` patients (87%) had rated their previous pain regimen as poor
`or fair. After the trial, 97% of patients and 87% of physicians rated
`oxymorphone ER as good, very good, or excellent.
`In an open-label, six-month study of opioid-naive patients
`with osteoarthritis,26 a similar flexible, individualized titration
`period resulted in a stable, effective, and tolerable dose of
`oxymorphone ER in 94 of 126 patients (75%). Mean (SD)
` average pain intensity significantly declined from 6.2 (1.3) at
`screening to below 2.5 (1.6) at the end of titration, on a 10-point
`pain intensity scale. Measures of general activity, work,
` enjoyment of life, walking ability, sleep, mood, and relations
`with others also showed significant improvement. Sixty of the
`94 patients (64%) completed the titration phase successfully.
`Analgesia and improvements in measures of function were
`maintained, and the mean daily dose of oxymorphone ER
` remained stable for the duration of the study. Rates of discon-
`tinuation resulting from AEs were low during the titration and
`maintenance phases (16% and 17%, respectively).
`
`Use of Oxymorphone in Opioid-Experienced Patients
`The safety and efficacy of oxymorphone ER in opioid-expe-
`rienced patients were assessed in a pivotal two-period study.27
`Opioid-experienced patients with moderate-to-severe chronic
`low back pain who were following a stable opioid pain regimen
`
`Vol. 35 No. 6 (cid:129) June 2010 (cid:129) P&T® 325
`
`

`

`Oxymorphone Extended-Release Tablets (Opana ER)
`
`at screening were switched to an equianalgesic dose of oxy-
`morphone ER twice daily based on established conversion
` ratios (Table 1). Outcome measures included pain intensity
`scores from a 100-mm VAS and both patient and physician sat-
`isfaction with treatment. No functional outcomes were assessed.
`After achieving adequate pain control, patients received
`oxymorphone ER or placebo in the 12-week double-blind pe-
`riod. Rescue medication (oxymorphone IR) was allowed for
`breakthrough pain and to prevent withdrawal symptoms after
`a switch from a previous opioid to oxymorphone ER during
`titration or from oxymorphone ER to placebo during double-
`blind treatment.
`Of 250 patients, 149 (60%) completed titration and were
` assigned to double-blind treatment with oxymorphone ER or
`placebo. After randomization, patients receiving oxymorphone
`(70%) were more likely to complete treatment compared with
`placebo patients (25%) (P < 0.001). A lack of efficacy led to dis-
`continuation of therapy in 53% of placebo patients and in 11%
`of oxymorphone patients, but discontinuations resulting from
`AEs were similar (for oxymorphone ER, 10%; for placebo,
`11%). Opioid withdrawal, as measured on the ARS and the
`COWS, was infrequent but nonetheless was the most common
`occurrence leading to discontinuation by the placebo patients
`(7%).
`Continuation of the individually titrated dose of oxymor-
`phone ER over the next 12 weeks maintained relief of chronic
`low back pain with little change, as measured via the VAS. Be-
`fore entering the trial, only 14% of patients had rated their pain
`regimen as excellent or very good. After the dose-titration pe-
`riod, 72% of patients and 68% of physicians rated oxymorphone
`ER as excellent or very good. The most common AEs (con-
`stipation, nausea, headache, and somnolence) were typical of
`opioid therapy.
`
`Table 1 Conversion Ratios of Daily Oral Opioid
`Doses to an Equivalent Dose of Oxymorphone
`Extended Release
`
`Approximate
`Equivalent Daily
`Oral Dose (mg)
`
`Oral
`Conversion
`Ratio*
`
`Oxymorphone
`Hydrocodone
`Oxycodone
`Methadone†
`Morphine
`
`10
`20
`20
`20
`30
`
`1.0
`0.5
`0.5
`0.5
`0.333
`
`* Ratio for conversion of an oral opioid dose to an approximate
`oxymorphone equivalent dose. The total daily dose for the opioid
`was summed and multiplied by the conversion ratio to calculate the
`oxymorphone total daily dose.
`† It is extremely important to closely monitor all patients who
`are switched from methadone to other opioid agonists. The conver-
`sion ratio of methadone to other opioid agonists may vary widely as
`a function of previous exposure, because methadone has a long half-
`life and tends to accumulate in the plasma.17
`Data from Opana ER, prescribing information.17
`
`326 P&T® (cid:129) June 2010 (cid:129) Vol. 35 No. 6
`
`Importance of Slow, Individualized Titration
`Outcomes are typically less successful for patients whose
`opioid doses are titrated on a fixed-dose schedule. More recent
`guidelines for the use of opioids in chronic non-cancer pain
` recommend individualized, flexible titration to minimize AEs
`and premature discontinuation of therapy.4
`This was the case in two earlier trials of oxymorphone ER.28,29
`In a two-week dose-ranging study,28 opioid-naive and opioid-
`experienced patients with moderate-to-severe osteoarthritis of
`the knee or hip received initial doses of oxymorphone ER
`10 mg twice daily or 20 mg twice daily during week 1, followed
`by 40 mg twice daily or 50 mg twice daily during week 2. In a
`fixed-dose, double-blind, placebo-controlled and active com-
`parator- controlled trial,29 opioid-naive and opioid-experienced
`patients with moderate-to-severe osteoarthritis pain initiated
`oxymorphone ER 20 mg or 40 mg twice daily.29 In the two tri-
`als combined, 225 of 521 patients (43.2%) receiving oxymor-
`phone ER discontinued therapy because of AEs.
`By contrast, a pooled analysis of two clinical trials of oxy-
`morphone ER in patients with chronic low back pain con-
`firmed the value of flexible titration.30,31 Of 575 patients, 348
`(60.5%) completed titration to an effective, well-tolerated oxy-
`morphone ER dose.30 Only 106 patients (18.4%) stopped ther-
`apy because of AEs. These results were consistent with
` outcomes for other LA opioids titrated during a flexible, indi-
`vidualized dosing schedule. For example, in a randomized,
`open-label trial by Rouck et al.,31 68% of LA opioid-naive patients
`(266 of 392) completed the opioid dose titration phase to ef-
`fective and generally well-tolerated doses of either once-daily
`morphine sulfate ER (Avinza, King) or twice-daily oxycodone
`CR (OxyContin, Purdue).
`After titration, the proportion of patients discontinuing dou-
`ble-blind treatment with oxymorphone ER (54 of 175 patients,
`or 30.8%) was nearly identical to the discontinuation rate re-
`ported in a systematic review of randomized controlled trials
`that evaluated other LA opioids in patients with chronic non-
`cancer pain (209 of 698 patients, or 29.9%).32
`
`ROLE OF THE PHARMACIST
`When initiating oxymorphone ER or other opioid agents,
`pharmacists can help patients understand essential informa-
`tion, such as instructions for taking medications. They can also
`advise patients about how to distinguish between AEs that
`are likely to resolve over time and those indicating the need
`for a medication switch, a dose reduction, or another inter-
`vention. Some patients who experience inadequate analgesia
`or bothersome AEs find it more convenient and less costly to
`consult with their pharmacist rather than their physician. How-
`ever, relationship building between patients and physicians is
`an important component of clinical care and may improve
`physician decision making and patient outcomes.
`Pharmacists are often placed in the position of managing
`over-the-counter treatments that are complementary to or fun-
`damental adjuncts to prescription therapy, such as a bowel reg-
`imen during chronic opioid therapy. Informing patients that the
`cause of opioid-induced constipation is impaired intestinal
`motility, pharmacists can recommend a stimulant laxative, but
`they should emphasize that a stool softener in the absence of
`a stimulant is ineffective and that bulk-forming laxatives may
`
`

`

`Oxymorphone Extended-Release Tablets (Opana ER)
`
`lead to intestinal obstruction.33 Elderly patients and those with
`complex medical conditions may also need to be steered away
`from osmotic laxatives and enemas, which raise the risk of
` dehydration, electrolyte imbalances, and renal dysfunction.33
`Ultimately, programs that optimize the relationship between
`patients and pharmacists may provide an opportunity to im-
`prove health care and reduce costs. Research suggests that
`pharmacist-intervention programs can improve pain manage-
`ment, reduce drug interactions and other AEs, enhance patient
`compliance, and identify unaddressed patient needs.1,34–36 For
`example,34 patients with chronic disease who participated in a
`primary care pharmacist-intervention program were signifi-
`cantly more likely than nonparticipants to address non -
`compliance with therapy and untreated conditions and to
` receive necessary medications. Costs were lower among
` program participants, although not significantly.
`The pharmacist’s observation of patients’ use of over-the-
`counter medications may prompt interventions to increase
`the quality of opioid prescribing. One important area of con-
`cern is the use of short-acting combination opioids for chronic
`pain. The most frequently prescribed opioids for chronic pain
`are combination products that contain acetaminophen,37 which
`is hepatotoxic at doses of 4 g/day or greater.38
`Pharmacists should be aware that combination opioids,
`when used for chronic pain, pose risks for undertreatment of
`pain and acetaminophen toxicity. Clinical trials of oxymor-
`phone ER in opioid-experienced patients found that most
` patients who were switched from combination opioids had
`been taking the maximum dose of these products and reported
`low satisfaction with pain relief.30,39 Patients with undertreated
`pain may be tempted to self-medicate with over-the-counter
`medications containing acetaminophen in addition to their com-
`bination opioid, thereby risking liver toxicity. Patients may
` further increase their exposure if they are also using other non-
`prescription drugs, such as pain, cold, and allergy products.
`In addition to alerting patients to the danger of over-the-
`counter medications containing acetaminophen, pharmacists
`can help identify the inappropriate concomitant use of pre-
`scription and nonprescription agents. They might suggest that
`the physician consider substituting either a short-acting opioid
`that does not include aspirin or acetaminophen or, if appro-
`priate, a long- acting opioid.
`
`SWITCHING TO OXYMORPHONE ER
`Patients with chronic pain may have to endure switching to
`three or four opioids before they discover one that offers ef-
`fective analgesia with tolerable AEs. Patients may feel per-
`plexed when the efficacy or tolerability of an opioid wanes over
`time, so that rotation to a different opioid becomes necessary.
`Pharmacists must often explain why switching and rotation are
`sometimes necessary. Some of these reasons include:40,41
`
`(cid:129) development of tolerance.
`(cid:129) emergence of drug interactions when new medications
`are added.
`(cid:129) changes in hepatic or renal drug clearance, leading to
` intolerable side effects.
`(cid:129) differences in the patient’s response that may be related
`to age, sex, and genetic variability.
`
`Although genetic and other factors (e.g., renal or hepatic
`function) do influence the patient’s response to opioids in gen-
`eral, in a combined analysis of a cohort with chronic low back
`pain who completed initial titration to oxymorphone ER, age,
`sex, and previous opioid experience had no impact on the
` effectiveness and tolerability of oxymorphone ER.6,30 How-
`ever, completing this step was more challenging in several
` patient subgroups. Patients 65 years of age or older experi-
`enced more opioid-related AEs than younger patients and
`were more likely to discontinue treatment as a result. Similar
`proportions of opioid-naive and opioid-experienced patients
`completed titration; however, patients who took hydro -
`codone/acetaminophen (e.g., Vicodin, Abbott) as their previ-
`ous opioid were more likely to complete the titration phase suc-
`cessfully than patients who had previously used oxycodone.30,39
`Among patients switching from oxycodone, the success rate
`was higher among men (56.4%) than women (35%) and among
`patients 65 years of age or younger (47.8%) compared with
`those 65 years of age or older (33.3%).42 The initial starting dose
`of oxymorphone ER might have been lower than needed in
`women and in older patients because (1) oxycodone blood lev-
`els are 25% higher in women than in men; (2) they are 15%
`higher in older patients than in younger patients; and (3) con-
`version tables do not give sex or age recommendations based
`on pharmacokinetic differences in subpopulations.43
`Two studies suggest that patients who were successfully
`switched from hydrocodone to oxymorphone ER likely en-
`tered the study with undertreated pain.30,39 More than half of
`the hydrocodone-experienced patients required a daily dose of
`oxymorphone ER 65 mg or greater, which is more than the
`maximum dose of their prestudy combination agent, hydro -
`codone/acetaminophen, consisting of approximately 120 mg
`of hydrocodone and 4 g of acetaminophen.44 Patients previously
`taking oxycodone CR, with no dose maximum, might have en-
`tered the study with more satisfactory pain control and with
`less motivation to switch to oxymorphone ER.
`Alternatively, differences in the pharmacokinetics of oxy -
`codone CR and oxymorphone ER could have contributed to a
`perceived lack of efficacy with oxymorphone ER, compared
`with oxycodone CR, which undergoes biphasic release with
` absorption peaks at 0.6 and 6.9 hours after the dose is given.43
`Patients experience a rapid onset of effect with the first peak
`and then continuous analgesia thereafter.
`By contrast, oxymorphone ER’s TIMERx technology en-
`ables steady drug release throughout the 12-hour dosing
` interval.17 It is possible that oxycodone CR–experienced
` patients who switched to oxymorphone ER did not believe
`that they were receiving comparable analgesia because they
`did not experience an initial rapid onset of effect. Whether the
`absence of a rapid-onset phase is a disadvantage for oxymor-
`phone ER is debatable, because this phase can be associated
`with increased euphoria and abuse potential.45
`ADVERSE EVENTS AND SAFETY
`CONSIDERATIONS
`As previously mentioned, one of the most common AEs ob-
`served in clinical trials of oxymorphone ER is constipation.
`Pharmacists should be aware that failure to include an effec-
`tive bowel regimen during chronic opioid therapy produces
`
`Vol. 35 No. 6 (cid:129) June 2010 (cid:129) P&T® 327
`
`

`

`Oxymorphone Extended-Release Tablets (Opana ER)
`
`constipation and myriad associated signs and symptoms that
`augment pain. Lack of a bowel regimen can be debilitating and
`can lead to poor adherence with treatment, impair quality of
`life, and create complications such as hemorrhoids, impaction,
`ileus, and rectal prolapse.46 The pivotal trials with oxymor-
`phone ER that demonstrated favorable tolerability incor porated
`an effective bowel regimen as part of the study protocol.25,27,28
`This is an area in which pharmacists can assist in the patient’s
`pain-management plan.
`As with other opioids, oxymorphone ER should not be taken
`with alcohol. The package labeling for the drug includes a
`boxed (black-box) warning for patients not to consume alco-
`holic beverages, or prescription or nonprescription medica-
`tions containing alcohol, while they are receiving oxymor-
`phone ER. In pharmacokinetic studies, there was a significant
`rise in maximum drug concentration when 40% alcohol was
` ingested with oxymorphone.17 However, the area under the
`concentration (AUC) versus time curve did not change, indi-
`cating no change in overall drug exposure. This is important
`because in vitro, the TIMERx delivery system does not release
`oxymorphone more rapidly (i.e., no dose dumping occurs) in
`solutions of up to 40% ethanol. The rapid absorption of oxy-
`morphone ER occurring with alcohol coadministration in vivo
`may be a result of increased splanchnic blood flow.
`Vigilance in identifying opioid abuse or the diversion of opi-
`oids is a duty of prescribers and pharmacists. Urine monitor-
`ing of oxymorphone is facilitated by the drug’s lack of metabo-
`lites, which can be mistaken for other prescribed opioids.
`Oxymorphone tablets may contain up to 1% oxycodone, de-
`pending on the method of production, but urine testing by
` liquid chromatography or tandem mass spectrometry usually
` reports more than 99% oxymorphone.16 Interpretation of urine
`monitoring tests is more complicated when the prescribed
`opioid has metabolites that are identical to other prescription
`opioids. For example, codeine produces morphine and hydro -
`codone, morphine produces hydromorphone, oxycodone pro-
`duces oxymorphone, and hydrocodone produces hydromor-
`phone.6,43,47–49
`Although pharmacists are valuable in detecting and pre-
`venting drug abuse and diversion, a survey conducted by the
`National Center on Addiction and Substance Abuse indicated
`that fewer than 50% of pharmacists receive training in this
`area.50 Checking the legitimacy of a prescription is an essen-
`tial first step; the pharmacist should evaluate the prescription
`itself, the patient, licensing information about the prescribing
`physician, and the state’s prescription drug-monitoring pro-
`grams if applicable. The pharmacist should also be aware of
`other ongoing drug-diversion programs in the jurisdiction.
`Errors included in a written prescription may call into ques-
`tion its legitimacy, but mistakes alone do not mean that a pre-
`scription is forged or fraudulent. A forged prescription may be
`attributed to a fictitious physician, or the script might contain
`errors in a physician’s name, address, telephone number, or
`license number. The drug name might be misspelled, or a
`drug may be ordered in an unavailable dose or an unusual
`quantity. There might be refill orders for a Schedule II
` controlled substance (CII). The pharmacist should check for
`evidence of tampering, such as photocopying; an absence of
`safety features, such as watermarks; obscured, unclear, or
`
`328 P&T® (cid:129) June 2010 (cid:129) Vol. 35 No. 6
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`obliterated content; erasures; and correction fluid or tape.
`Pharmacists should be alert for suspicious patient behavior,
`such as impatience, anxiety, or hostility. One red flag might be
`an insured patient who pays with cash, because insurers usu-
`ally have systems in place to identify redundant prescriptions.50
`A simple safeguard against diversion is to request identification
`and to telephone the patient when a third party arrives to pick
`up medication for a patient said to be “too sick to come in.”
`Familiarity with the surrounding community can be helpful
`in identifying potential abusers. Increased vigilance is warranted
`in areas of frequent drug abuse, but prescribers should keep in
`mind that abusers sometimes travel outside their community to
`find a pharmacy with less experience in dealing with those who
`aim to engage in illegal activities. Asking why a patient is filling
`a prescription far from home is a legitimate action.
`The patient’s relationship to the prescribing physician is
`also important. It is unusual for a physician to prescribe opi-
`oids to a person working in his or her office, and it is unethi-
`cal to prescribe opioids to a family member.
`A questionable prescription that appears to have been le-
`gitimately written by a physician may represent an honest
`mistake or an error in judgment, or it might have been writ-
`ten under duress. It is appropriate for the pharmacist to ques-
`tion the prescribing physician about the therapeutic need for
`the medication—is it for trauma, palliative care, or chronic
`pain? The pharmacist might also ask about the physician’s
`level of familiarity with the patient—is this the patient’s primary
`physician or a physician at a walk-in clinic?
`When in doubt, the pharmacist should phone the physician,
`focusing on the specific reasons for concern. The pharmacist
`should also notify all prescribers if it is evident that a patient is
`receiving opioids from multiple prescribers. It is common for
` patients who are prescribed opioids on a long-term basis to
`enter into a patient–prescriber agreement typically including lan-
`guage stating that if a patient knowingly accepts or solicits
` opioids from another prescriber, this would result in termina-
`tion of the agreement and the patient–provider relationship.
`The pharmacist should ensure that any prescription written
`for a controlled substance complies with the requirements of
`the Controlled Substances Act. Prescriptions for Schedule II
`drugs must be received in writing (except in an emergency)
`and cannot be refilled. Schedule III and IV drugs can be pre-
`scribed in writing or by telephone and refilled up to five times
`within six months of the original prescription.51 However, state
`laws may differ from federal law and may impose additional lim-
`its, such as the quantity of medication or time permitted to
`elapse between writing and refilling prescriptions.
`When there is a discrepancy between state and federal laws,
`the more restrictive legislation is observed. For example,
` Virginia sets no limit on the quantity for a Schedule II drug pre-
`scription and allows up to six months for the prescription to be
`filled. By contrast, New Hampshire limits the quantity to 100
`dosage units and Hawaii requires Schedule II prescriptions to
`be filled within seven days.52 These differences may mean
`that a patient who travels out of state to see a specialist could
`return with a prescription that cannot be filled as written.
`Awareness of these potential differences can help prevent
` misunderstandings and reduce patient distress.
`After a prescription is filled, pharmacists can help in moni-
`
`

`

`Oxymorphone Extended-Release Tablets (Opana ER)
`
`toring the correct use of the drug. Signs of medication misuse
`and abu