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INTRODUCTION

More than 120 million people in the United States (U.S.) have chronic pain. Pain's financial cost to society is estimated to exceed $600 billion.^1,2 Although patients with chronic pain are more likely to use health care services, many patients report that their pain is undertreated.^1,2 Quality of life, ability to perform activities of daily living, employment, and mental health are disproportionately affected in this population.¹ Clinical guidelines have recommended the use of opioid therapy in patients with moderate to severe chronic cancer or noncancer pain who experience impaired functioning and/or poor quality of life.^3-5 Opioid analgesic prescribing has risen significant over the past 2 decades, with the number of prescriptions dispensed increasing from approximately 75 million in 1991 to more than 200 million in 2013.⁶ Furthermore, use of extended-release (ER) and long-acting (LA) opioid analgesics in chronic pain patients may offer many advantages including improved adherence and sustained analgesia.⁷

This increased focus on appropriate, aggressive pain management has created challenges and consequences, including increasing rates of opioid abuse, addiction, diversion, and overdose deaths. Studies suggest that up to one-third of patients with chronic pain who are prescribed opioid therapy may abuse them at some point during treatment.⁸ Admission to substance abuse treatment facilities for addiction to opioid analgesics has increased.⁹ The number of opioid analgesic-related emergency room visits has more than doubled since 2004,¹⁰ and in 2007, these medications accounted for more than one-half of unintentional drug overdose deaths in the US.¹¹ The rates of nonmedical opioid analgesic use for first-time drug users has also increased and are now almost comparable to marijuana use in this population.¹⁰ More recently, an outbreak of human immunodeficiency virus infection in a rural county of Indiana was determined to be related to intravenous oxymorphone abuse.¹² The rate of heroin abuse has also significantly increased, and a recent study found that abuse or dependence on opioid analgesics was the strongest risk factor for heroin abuse or dependence.¹³

In 2012, the U.S. Food and Drug Administration (FDA) implemented a Risk Evaluation and Mitigation Strategy (REMS) for the opioid analgesic class. Its goal is to reduce the serious adverse effects associated with ER/LA opioid analgesics use while maintaining patient access to these medications.¹⁴ This activity provides an overview of the ER/LA REMS and available ER/LA opioids, and will describe best practices related to proper patient selection, risk assessment, patient education, and monitoring.

ER/LA Opioids for Chronic Pain

An important goal of therapy for management of chronic pain is to provide sustained analgesia to reduce the patient's pain to a tolerable level, highlighting the importance of continuous administration of analgesics. The use of ER/LA opioids for chronic pain can offer several advantages over short-acting, immediate-release opioids. These may include consistent, prolonged drug plasma concentrations throughout the dosing period; improved adherence and decreased pill burden; fewer adverse effects; decreased risk of addiction; improvement in symptoms often associated with chronic pain such as poor sleep; and increased health-related quality of life.^7,15 Although there is a lack of evidence to suggest that ER/LA opioids provide better analgesia and improved outcomes compared to short-acting opioids,^16,17 availability of these products increases the opportunity to provide patient-centered, individualized pain management. Common ER/LA opioid products are briefly reviewed below and are summarized in (Table 1).

Table 1. ER/LA Opioids included in the REMS Program
Product Name	Available Doses	Dosing Interval
Avinza (morphine sulfate capsules)a,b	30, 45, 60, 75, 90,c 120c mg	Once daily
Butrans (buprenorphine transdermal system)	5, 7.5,c 10,c 15,c 20c mcg/hour	1 patch weekly
Dolophine (methadone HCl tablets)b	5, 10 mg	Every 8–12 hours
Duragesic (fentanyl transdermal system)b,c	12, 25, 50, 75, 100 mcg/hour	1 patch every 72 hours
Embeda (morphine sulfate and naltrexone HCl capsules)d	0/0.8, 30/1.2, 50/2, 60/2.4, 80/3.2, 100/4 mg	Once or twice daily
Exalgo (hydromorphone HCl ER tablets)d	8, 12, 16, 32 mg	Once daily
Hysingla ER (hydrocodone bitartrate ER tablets)c	20, 30, 40, 60, 80,c 100,c 120,c mg	Once daily (every 24 hours)
Kadian (morphine sulfate ER capsules)b	10, 20, 30, 40, 50, 60, 70, 80, 100,c 130,c150,c 200,c mg	Once or twice daily
Methadose (methadone HCl tablets)b	10 mg	Every 8–12 hours
MS Contin (morphine sulfate ER tablets)b	15, 30, 60, 100,c 200c mg	Every 8–12 hours
NucyntaER (tapentadol ER tablets)	50, 100, 150, 200, 250 mg	Every 12 hours
Opana ER      (oxymorphone HCl ER tablets)b	5, 10, 20, 30, 40 mg	Every 12 hours
Oxycontin (oxycodone HCl ER tablets)b,d,e	10, 15, 20, 30, 40, 60,c 80 mg	Every 12 hours
TarginiqER       (oxycodone HCL and naloxone HCl ER tablets)d,e	10/5, 20/10, 40/20 mg/mg	Every 12 hours
Zohydro ER      (hydrocodone bitartrate ER capsules)d,e	10, 15, 20, 30, 40, 50 mg	Every 12 hours
Abbreviations: ER, extended-release; HCl, hydrochloride aAvinza was discontinued in July 2015. bAvailable in generic formulations which are also included in the REMS program. cFor use in opioid-tolerant patients only. dFDA-approved abuse-deterrent claim in product labeling. eSingle dose ≥ 40 mg or total daily dose of 80 mg are for use in opioid-tolerant patients only.

ER hydrocodone (ZohydroER) is an oral ER tablet formulated to release hydrocodone over a 12-hour dosing interval.¹⁸ In January 2015, an updated formulation became available that features BeadTek, a technology encompassing an indistinguishable mix of inactive beads, active immediate-release hydrocodone beads, and active extended-release hydrocodone beads.¹⁹ The inactive beads dissolve independently of the active hydrocodone beads and do not change the 12-hour release properties of hydrocodone when taken as directed. However, when crushed and dissolved in liquids or solvents, the inactive beads form a viscous gel immediately. This change in formulation has resulted in an FDA-supported product labeling amendment that includes an abuse-deterrent claim.

ER hydromorphone (Exalgo) is an oral, once-daily formulation of hydromorphone that is formulated using the osmotic controlled-release oral delivery system (OROS) technology.²⁰ Its bilayer tablet core is surrounded by a semipermeable membrane and hard outer shell which results in a push-pull delivery system. The hard outer shell prevents this formulation from being crushed or chewed. Additionally, Exalgo contains polyethylene oxide, a nonionic, water-soluble, hydrophilic resin that limits the ability to abuse hydromorphone via intravenous administration.

Methadone is a pharmacologically LA opioid with unique analgesic properties. It is an agonist at mu-opioid receptors, an antagonist at the N-methyl-D-aspartate receptor, and inhibits the reuptake of serotonin and norepinephrine at the spinal cord level.²¹ It is available as a racemic mixture of stereoisomers. Methadone has an unpredictable pharmacokinetic profile with high variability in its elimination half-life which is influenced by patient factors such as age, gender, weight, genetics, and drug interactions. For pain management, it is often administered every 8 or 12 hours, and total daily doses are typically significantly lower in comparison to the once-daily treatment of opioid addiction.

ER morphine is available in several formulations. Avinzais an oral ER formulation with a hard gelatin capsule that contains 10% immediate-release (IR) and 90% ER beads of morphine sulfate. Using spheroidal oral drug absorption system (SODAS) technology, fumaric acid (an excipient) acts as an osmotic wick to draw gastrointestinal fluid into the beads. The beads' polymer coating then swells, creating pores that release morphine in a controlled manner over 24 hours.²² Kadianis an oral ER morphine capsule that is FDA-approved for once or twice daily dosing. Each capsule contains morphine-embedded polymer beads.²³ Embedais an oral ER capsule that contains morphine pellets surrounding a central core of sequestered naltrexone in a ratio of morphine to naltrexone of 100:1. An outer polymer layer allows for a sustained release of morphine while preventing the release of naltrexone.²⁴ The FDA has provided Pfizer with approval to label Embedaas an abuse-deterrent opioid (ADO) formulation. MS Continis an oral ER tablet that releases morphine over a 12-hour dosing interval.²⁵ There are currently generic formulations for Avinza, MS Continand Kadian. Pfizer discontinued Avinza, which is a non-ADO formulation, in July 2015 after acquiring Embedafrom King Pharmaceuticals.²⁶

ER oxycodone is available is two distinct formulations.

• FDA first approved OxyContinin 1995 as an oral tablet that could be manipulated for abuse through various routes of administration. It was reformulated in August 2010 with tamper-resistant properties, making it more difficult to crush, grind, or dissolve. It releases oxycodone in a biphasic manner.²⁷
• TarginiqER is an oral ER tablet that contains oxycodone and naloxone in a 2:1 ratio.²⁸ This ratio was determined to be most appropriate to balance analgesia with oxycodone- and naloxone-related adverse effects. Targiniq ER is also formulated to release both oxycodone and naloxone in a biphasic manner.

ER oxymorphone (OpanaER) is an oral ER tablet of oxymorphone that is embedded in a hard polymer matrix. This formulation is intended to be crush-resistant.²⁹ Based on pharmacokinetic studies, food increases oxymorphone's C_max by approximately 50%; therefore, this formulation should be taken on an empty stomach.

ER tapentadol (NucyntaER) is a multimodal analgesic with mu-opioid agonist and serotonin norepinephrine reuptake inhibition properties.³⁰ This oral tablet formulation's hard polymer matrix may decrease some forms of non-oral abuse.

Transdermal systems. Butransis a transdermal system containing buprenorphine, a partial opioid agonist, within a drug polymer adhesive matrix.³¹ Although Butransis available in five different strengths, each patch contains the same concentration of buprenorphine; however, the amount released from each system is proportional to the active surface area of the system applied to the skin. Transdermal fentanyl systems have been designed as both reservoir and drug matrix patches. Reservoir patches contain fentanyl within a hydroxycellulose gel contained between the backing of the patch and a release membrane.³² Abusers find this formulation of transdermal fentanyl attractive because the drug can be extracted from the reservoir and abused through various routes of administration. Very few formulations of the reservoir patch are currently available. Most fentanyl transdermal systems are now formulated as drug polymer adhesive matrix patches, as the pharmacokinetic profile and clinical effects have been found to be comparable.³³

Overview of the ER/LA Opioid REMS

The advent of REMS, which were created as a component of the FDA Amendments Acts of 2007, set a precedent for pharmaceutical manufacturing processes. REMS led to an increase in enforcement by the FDA with regard to authority and mandates, enhancing, and modernizing systems involved with drug safety. While the FDA stipulates REMS requirements, manufacturers are ultimately responsible for REMS development; they are tasked with designing programs that adequately mitigate risks while ensuring appropriate patient access. These programs are individualized to address each product’s unique risks and may include up to 5 components: medication guide, communication plan, elements to assure safe use (ETASUs), implementation system, and timetable for submission of assessments. There are currently more than 70 REMS, 6 of which are class-specific REMS including ER/LA opioids.¹⁴

The FDA announced the need for a class-wide REMS for ER/LA opioids in April 2011. It received approval in July 2012 and was most recently modified in June 2015 (Table 2). The goal of the ER/LA REMS is to ensure that therapeutic benefits continue to outweigh risks of adverse outcomes, such as addiction, unintentional overdose, and death. Designed to be a streamlined program, it addresses the risks of the entire medication class, and its uniformity is an attempt to minimize confusion and remove potential prescribing biases in favor of alternative medications not requiring a REMS.¹⁴

Table 2. Summary of ER/LA Opioid REMS
Approval Date	July 2012 (last modified June 2015)
Components	Medication Guide ETASU: Training and Awareness
Implementation System	Not required
Timetable for Submission of Assessments	Data must be submitted to FDA at 6 and 12 months after the initial REMS approval date and annually thereafter
Health Care Provider Requirements	None; education and training is encouraged but not required
Pharmacy Requirements	None

The ER/LA Opioid REMS requires the following 3 components: (1) medication guide, (2) ETASUs, and (3) timetable for submission of assessments. This program emphasizes patient counseling; therefore, medication guides must be dispensed with each ER/LA opioid prescription.¹⁴ Although the medication guides include product-specific risks, they must also include information applicable to all prescribed ER/LA opioids. With patient-friendly guides for ER/LA opioids and consistent counseling, patients may understand the risks and benefits of prescription opioid medications better. To date, the effectiveness of these educational tools is unknown, but other medication guides have lacked impact.³⁴

The ETASUs for the ER/LA opioids REMS focus on prescriber education and patient counseling. Unlike other REMS programs, prescriber education, training, and assessment of knowledge of ER/LA opioids is encouraged but not required. This education is intended to:

1. Improve prescriber understanding of how to assess patients for treatment with ER/LA opioid analgesics;
2. Increase familiarity with how to initiate therapy, modify dose, and discontinue use of ER/LA opioids;
3. Enhance knowledge about how to manage ongoing therapy;
4. Increase ability to counsel patients and caregivers about the safe use of these products, including proper storage and disposal; and
5. Become familiar with general and product-specific drug information concerning ER/LA opioids.

Pharmaceutical manufacturers are required to ensure prescriber access to REMS training and conduct independent audits to confirm that the material covers all necessary components including assessment measures of knowledge. In addition to medication guides and ETASUs, the ER/LA opioids REMS includes a timetable for submission of assessments. The timetable requires manufacturers to evaluate program effectiveness to determine if modifications are needed. This includes surveys to assess patients' understanding of risks or adherence, medication use patterns (e.g. indication, length of therapy), and surveillance.¹⁴ Further details and documents related to the ER/LA opioids REMS are available on the following web site: www.ER-LA-opioidREMS.com.³⁵

Determining Appropriateness of ER/LA Opioid Therapy

Patient Selection

Opioids may be effective for most types of pain; however, these medications are not appropriate for all patients and/or chronic pain conditions. According to FDA-approved labeling, ER/LA opioids are indicated for the management of moderate to severe pain when a continuous, around-the-clock analgesic is needed for an extended period of time.^{18, 20-25, 27-32} Determining the medical necessity of opioid use for chronic pain should include consideration of the diagnosis, and implementation and response to nonopioid analgesics, nonpharmacologic therapies, and behavioral interventions.⁴ When considering opioid therapy, prescribers should evaluate the following factors prior to initiation: personal or family history of substance abuse, current substance abuse, patient age, medical comorbidities, organ function, medication allergies and intolerances, concomitant medications, and genetic polymorphisms.

All ER/LA opioids are labeled with boxed warnings that highlights the need for proper patient selection, noting an increased risk of opioid abuse in those with a personal or family history of substance abuse or mental illness.³⁵ Various medical comorbidities can increase the risk of opioid-related adverse effects including hepatic dysfunction, renal dysfunction, and cardiorespiratory impairments. Contraindications to use of ER/LA opioids include significant respiratory depression; acute or severe asthma in an unmonitored setting or in the absence of resuscitative equipment; known or suspected paralytic ileus; or hypersensitivity. Older adults may be at elevated risk for toxicity due to age-related changes in opioid pharmacokinetics and pharmacodynamics.

Most opioids undergo phase I metabolism mediated by cytochrome P-450 (CYP) enzymes, especially cytochrome P-450 3A4 (CYP3A4) and cytochrome P-450 2D6 (CYP2D6), which can increase the risk of drug-drug interactions. Hydromorphone, morphine, oxymorphone, and tapentadol undergo phase II hepatic metabolism via glucuronidation, bypassing CYP-mediated metabolism and reducing the risk of drug–drug interactions involving the CYP450 system. Additive central nervous system and respiratory depression can occur when opioids are combined with other centrally-active agents, especially benzodiazepines and alcohol; therefore, prescribers should review patients' medication and substance use carefully prior to administration. Combining alcohol with ER opioid formulations can also result in an increase in the rate of opioid release, resulting in absorption of a potentially fatal dose known as “dose dumping.”³⁵ Genetic polymorphisms related to opioid use involve polymorphisms of CYP isoenzymes and opioid receptor subtypes that may affect analgesic response and risk for adverse effects; however, genetic testing is not commonly performed likely due to the cost and availability of testing.³⁷

Risk Assessment

Opioid misuse is defined as use of an opioid for a medical purpose other than as directed or as indicated, whether willful or unintentional, and whether it results in harm or not.³⁸ Taking opioids other than as directed can have dire consequences and can increase the risk for abuse and addiction. Screening for the risk of opioid misuse and abuse is highly recommended in all patients. As part of a universal precautions approach to the management of chronic pain, clinicians should conduct a comprehensive psychologic assessment, including identification of risk factors, along with baseline urine drug testing, before starting patients on opioid therapy.³⁹

Risk factors for opioid abuse and addiction include a personal or family history of substance abuse, current substance abuse, psychiatric disease, and history of physical or sexual abuse.⁴⁰ Numerous screening and assessment tools can identify patients who may be at risk for abuse and addiction and assist with risk stratification to determine which patients may require closer monitoring.⁴¹ Examples of validated tools include the Opioid Risk Tool (ORT), Screener and Opioid Assessment for Patients with Pain—Revised (SOAPP-R), and the Diagnosis, Intractability, Risk, Efficacy (DIRE) tool. Urine drug testing at baseline can confirm illicit or nonmedical prescription drug use. Limitations of this testing should be considered including cost, protocols for obtaining urine samples (eg, observed, unobserved with tests that assess for tampering), and variations in results interpretation including window of detection and cross-reactivity.⁴²

A comprehensive risk assessment for ER/LA opioids should also consider include physical dependence and tolerance, overdose, inadvertent exposure/ingestion, abuse, diversion by household contacts, and risk of neonatal withdrawal syndrome with prolonged use during pregnancy. Most states now have prescription monitoring programs, and prescribers and pharmacists should review these data for all patients being considered for treatment and before subsequent prescription refills.

Initiation, Modification, and Discontinuation of ER/LA Opioid Therapy

Initiating Therapy–Clinical Considerations

Patients who are deemed appropriate candidates for opioids should provide informed consent, sign a written treatment plan (e.g., patient-provider treatment agreement), and should be initiated on a trial that is individualized with regard to both dose and formulation. It is important to note that most ER/LA opioids are recommended in patients who are opioid-tolerant, especially ER hydromorphone and transdermal fentanyl. However, some products are formulated in strengths that may be appropriate for select opioid-naïve patients.Of note, patients are considered opioid tolerant if they are taking at least 60 mg of oral morphine per day, 25 mcg of transdermal fentanyl per hour, 30 mg of oral oxycodone per day, 8 mg of oral hydromorphone per day, 25 mg of oral oxymorphone per day, or an equianalgesic dose of another opioid for 1 week or longer.^{18,20-25,27-32} Methadone should be initiated with caution and prescribed by health care professionals who are familiar with its unique pharmacokinetic and adverse effect profile. The use of abuse-deterrent ER opioid formulations may be considered in specific clinical scenarios including when patients and/or their household contacts may be at risk for abuse/diversion.⁴³

Prescribers should use opioid equianalgesic conversion tables or calculators as guides to determine appropriate starting doses. Incomplete cross-tolerance and inter-patient variability should be accounted for, with appropriate percent reductions in the calculated new total daily dose to ensure conservative dosing with further titration as needed based on patient response.

Prescribers should consider prescribing take-home intramuscular or intranasal naloxone to reverse potential opioid overdose in patients at high risk for overdose. Risk increases in patients receiving 50 mg or more of morphine equivalent per day; concomitant use of benzodiazepine and/or alcohol; comorbid respiratory, hepatic, renal, or cardiac dysfunction; and/or patients who have difficulty accessing emergency medical services.⁴⁴

Once an appropriate opioid dose has been selected, titration should be based on efficacy and tolerability, and dose increases should not occur sooner than 3-7 days after initiation of therapy. Guidelines suggest an initial trial and dose adjustment phase of several weeks to months.^3-5

Education and Counseling for Patients and Caregivers

General Information

Patients should be educated on product-specific information including drug name, formulation, dose, route of administration, and frequency. Emphasis should be placed on taking the opioid exactly as prescribed. Risks of misuse, abuse, and formulation tampering should be reviewed, including the risk of overdose or addiction. Common and serious adverse effects should be discussed in detail, and a management plan should be in place to be used if such events should occur. Counseling on appropriate use of any medications implemented to manage opioid-related adverse effects (e.g., laxatives, antiemetics) should be included.

Since it is highly recommended that a review of concomitant medications be conducted prior to initiating an ER/LA opioid, any necessary therapy changes should be reviewed to minimize the potential for drug interactions. Patients should be told not to dicontinue ER/LA opioids abruptly, and signs and symptoms of opioid withdrawal should be discussed. Safe, secure storage of the ER/LA opioid should be addressed to ensure that it is kept away from children, family members, household visitors, and pets. Additionally, patients should understand how these medications are regulated as controlled substances and be counseled on not sharing or diverting them. The ER/LA opioid REMS includes a Patient Counseling Document. It is meant to facilitate discussion with regard to the safe and appropriate use of these medications.⁴⁵ This document reviews the “DOs” and “DON’Ts” of therapy and includes space for patient-specific messages. Key education and counseling points are summarized in (Table 3).

Table 3. Recommended Patient Counseling Points for ER/LA Opioids Drug Name and Formulation Dosing Initial dosing with explanation on importance of adherence Titration (e.g., titrated to a dose that provides adequate analgesia while minimizing adverse effects) Discontinuation The importance of tapering, importance of not stopping therapy abruptly, signs/symptoms of opioid withdrawal. Product-specific instructions regarding administration Solid oral dosage forms (e.g., swallowing tablets or capsules whole, which capsules can be opened) Transdermal dosage forms (e.g., proper placement, rotating application sites, avoiding exposure to heat) Adverse effects Common adverse effects including constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, cognitive impairment that may affect driving and work safety (e.g., adjunctive medications to reduce common side effects) Severe adverse effects such as respiratory depression, signs/symptoms of overdose Potential for misuse, abuse, and addiction Product-specific adverse effects (e.g., methadone and QTc prolongation, application site reactions with transdermal patches Drug interactions Alcohol, CNS depressants, anticholinergic drugs, CYP450 enzyme-mediated inhibitors/inducers/substrates, P-glycoprotein inhibitors Safe storage Drug disposal

Select Product-Specific Information

Oral ER Opioid Formulations

Morphine Sulfate ER Capsules (Kadian)
The dosing interval for this formulation is once or twice daily. Capsules can be opened and sprinkled on applesauce for patients who can swallow without chewing.²³

Morphine Sulfate/Naltrexone HCL Capsules (Embeda)
The dosing interval for this formulation is once or twice daily. Patients should swallow capsules whole, but can separate the capsules and sprinkle the pellets on applesauce only, then swallow entire portion of applesauce immediately without chewing if necessary. The applesauce must not be saved or divided into separate doses. Patients should rinse their mouths to ensure that all pellets have been swallowed. Crushing, dissolving or chewing the capsule causes rapid release of medication, resulting in a potentially fatal morphine dose and withdrawal symptoms from naltrexone in opioid-tolerant patients.²⁴

Tapentadol ER Tablet (NucyntaER)
The dosing interval for this formulation is every 12 hours, and the maximum total daily dose is 500 mg.³⁰ Patients should take tablets one at a time and swallow them whole with plenty of water. This medication can increase the risk of serotonin syndrome.

Oxymorphone HCl ER Tablets (OpanaER)
The dosing interval for this formulation is every 12 hours. Patients should take tablets one at a time and swallowed whole with plenty of water. This medication should be administered on an empty stomach, at least 1 hour before or 2 hours after eating.²⁹

Oxycodone HCl ER Tablets (OxyContin)
The dosing interval for this formulation is every 12 hours. Patients should take these tablets with enough water to ensure complete swallowing to prevent choking, gagging, or regurgitation.²⁷

Oxycodone HCl/Naloxone HCL ER Tablet (TarginiqER)
The dosing interval for this formulation is every 12 hours, and the maximum total daily dose is oxycodone 80 mg/naloxone 40 mg. Patients should swallow tablets whole; tampering may lead to either overdose from oxycodone or withdrawal from naloxone.

Methadone

This medication may be started at a lower dose to reduce the risk of overdose and death.^21,49 Doses must be titrated slowly, with increases no more frequent than a minimum of every 7 days because of the high variability in how methadone is metabolized. Methadone can increase the risk of arrhythmia, and baseline and periodic electrocardiogram monitoring may be performed.

Transdermal Systems

Transdermal Buprenorphine Patches (Butrans)

The dosing interval for this formulation is one application every 7 days. The process starts with removing the protective liner, and applying the patch to intact, non-irritated skin on the upper outer arm, upper chest, upper back or the side of the chest. Patients should not use soaps, alcohol, oils, lotions, or abrasive devices prior to application. Patients or their caregivers should rotate application sites, and avoid using the same site for at least 21 days.³¹ Patients should not cut or apply heat to the patches. They should wash their hands after each application. If the patch does not adhere appropriately, first aid tape can be applied to the edges of the patch only, or a biocclusive film such as Tegadermcan be placed over the entire patch. The patch can be worn while bathing, showering, or swimming.

Fentanyl Patches

The dosing interval for this formulation is one application every 72 hours. The initial application process is similar to that described for transdermal buprenorphine patches above (remove protective liner; apply to intact, nonirritated skin on the chest, back, flank [sides of the waist], or upper arm in a place where there is no hair; avoid soaps, alcohol, oils, lotions, or abrasive devices prior to application). Patients or their caregivers should press the patch onto the chosen skin site with the palm of the hand, and held there for at least 30 seconds to make sure it adheres. Hands should be washed after each application. If the patch falls off immediately after applying, it should be thrown away and a new one applied to a different skin site. If the patch does not adhere appropriately, first aid tape can be applied to the edges of the patch only, or a biocclusive film such as Tegadermcan be placed over the entire patch. The patch can be worn while bathing, showering, or swimming.

Disposal of ER/LA Opioids

The availability of local drug take-back programs and Drug Enforcement Agency (DEA)–authorized collectors has increased over the past few years. When these options are unavailable, FDA has recommended that ER/LA opioids be flushed down a sink or toilet due to consequences of accidental exposures.⁴⁶ Patients should dispose of used transdermal patches by folding the adhesive side of the patch to itself, then flushing the patch down the toilet immediately upon removal. Unused patches should be removed from their pouches, the protective liners removed, the patches folded so that the adhesive side of the patch adheres to itself, and immediately flushed down the toilet.

Transdermal buprenorphine patches are packaged with a Patch-Disposal Unit, and the closed disposal unit, with the patch sealed inside, may be discarded in the trash.

Currently, evidence linking health risks with environmental medication exposure is lacking.⁴⁷ Nonetheless, patients should be encouraged to employ other disposal methods whenever possible. An additional disposal option includes removing the medication from its original container, mixing it with substances such as coffee grounds, dirt, or kitty litter, and placing the mixture in a sealable bag or container to prevent the medication from leaking out in the disposal receptacle. This package is then placed in the trash receptacle immediately before it is emptied by the trash truck.

Monitoring Strategies

Assessment of treatment response should include level of analgesia, function, adverse effects, and aberrant behaviors. Health care providers should monitor these parameters closely at the beginning of therapy and at each return visit. The interval for follow-up should be individualized and may be based on the patient’s risk for negative outcomes including misuse and abuse. Guidelines recommend that patients at high risk require close and frequent monitoring.^3,4,48 Pill counts, urine drug testing, prescription monitoring programs, and screening tools such as the Current Opioid Misuse Measure and the Addiction Behaviors Checklist, should be used routinely (Table 4). Additionally, reassessment of the pain diagnosis, comorbid conditions, and presence of substance use disorders should be performed periodically to ensure that the benefits of treatment outweigh risks and that there is a continued need for opioid therapy.

Table 4. Patient Monitoring Strategies to Ensure Opioid Drug Safety and Efficacy Efficacy Analgesia Activities of daily living Achievement of treatment goals Adherence to therapy Safety Adverse effects Laboratory tests / procedures Periodic testing of renal and hepatic function Electrocardiogram (methadone) Affect/mood changes Aberrant drug-related behaviors Pill counts Urine drug testing Prescription monitoring program data Assessment tools (e.g., Current Opioid Misuse Measure, Addiction Behaviors Checklist) Drug storage/risk for diversion

Health care providers should perform medication reconciliation on a regular basis to evaluate for drug interactions that may increase risk for significant adverse effects including respiratory depression and organ dysfunction.

A joint guideline by the American Pain Society, College on Problems of Drug Dependence, and the Heart Rhythm Society recommends monitoring of QTc interval prolongation in patients managed with methadone. Monitoring includes follow-up ECGs be based on baseline ECG findings, methadone dose changes, and other risk factors for QTc interval prolongation.⁴⁹

Additionally, immediate methadone dose reduction or opioid rotation should be implemented in patients with QTc intervals ≥ 500 milliseconds.

Transdermal buprenorphine has been shown to prolong the QTc interval in patients treated with double the maximum daily dose (40 mcg/hour). When used within the appropriate dose range, consensus on the need for routine electrocardiograms is lacking; therefore, electrocardiograms should only be considered in patients with risk factors.

In April 2014, the FDA released updated safety information within REMS related to the monitoring of ER/LA opioids which included emphasis on the following boxed warnings: risk of misuse, abuse, or addiction, serious life-threatening or fatal respiratory depression, accidental ingestion especially in children, risk of neonatal withdrawal syndrome with use during pregnancy, and concomitant use of CYP 3A4 inhibitors.³⁵

Efforts to safeguard against prescription theft and diversion are an important prescriber and pharmacist responsibility. Pharmacists should verify prescription information with the prescriber as necessary and should contact the nearest DEA field office to provide information if suspicious prescription activities occur. Prescribers should routinely document adherence to treatment and assessment of achievement of therapeutic goals, while pharmacists should maintain comprehensive records pertaining to the dispensing and counseling of ER/LA opioids.

Discontinuation of Therapy

The evidence to support the long-term use of ER/LA opioid therapy is lacking.⁵⁰ The decision to discontinue therapy is often made based on several factors including patient response to treatment and the presence of concerning behavior related to ER/LA opioid use. For patients who experience treatment failure and/or adverse effects, opioid therapy should be discontinued through a slow taper (e.g., 10%-25% of total daily dose per week over 6 to 8 weeks). A more rapid taper can be considered in patients who have violated their treatment agreements (e.g., misuse, inappropriate urine drug tests, illicit substance use) or those who fail to adhere to the treatment plan. Symptoms of opioid withdrawal can be managed with medications such as alpha agonists (e.g. clonidine), muscle relaxants, antiemetics, antispasmodics, and antidiarrheals. In cases of suspected diversion or prescription forgery, therapy should be discontinued immediately without tapering.

Conclusion

Management of chronic pain can be complicated and complex. The availability of ER/LA opioids can have a significant impact on several key therapeutic goals, improving patients' quality of life and general well-being. However, opioids can have devastating consequences without proper patient selection, education, and monitoring. Appropriate implementation of ER/LA opioid therapy is a team effort involving numerous stakeholders. The development of a REMS program has been an important step forward to improve the safe use of ER/LA opioids; however, this program's impact on reducing adverse effects while ensuring access to care remains to be seen. Provider and patient education is an important component of this program; therefore, pharmacists can serve as an invaluable resource in any health-system setting to promote the safe and effective use of ER/LA opioids. Additionally, pharmacists can promote and facilitate close monitoring of therapy to ensure adherence to therapy and improve the identification of patient-related factors that may contribute to serious adverse effects.

REFERENCES

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