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Supplements Use of Opioid Analgesics in Managed Care Practice: Challenges, Controversies, REMS, and Optimizing P

Implications of the Extended-Release/Long-Acting Opioid REMS for Managed Care

James B. Ray, PharmD, CPE
The intent of the Risk Evaluation and Mitigation Strategy for extended-release/long-acting (ER/LA) opioid analgesics is to reduce harm by teaching prescribers how to safely use opioid analgesics. Key concepts include appropriate selection of doses and formulations for individual patients, avoidance of drug interactions that contribute to opioid toxicity, and anticipation and management of adverse effects. Abuse-deterrent opioid formulations have the potential to reduce opiate abuse and overdose, but they create unique challenges for managed care organizations.

Am J Manag Care. 2015;21:S177-S187
Extended-release and long-acting (ER/LA) opioid formulations are designed to deliver stable plasma concentrations over the dosing interval and provide chronic pain patients with the convenience of regular and less frequent dosing intervals, especially at night.1 But higher doses and a long duration of action increase the risk of overdose when ER/LA formulations are misused, especially by opiate-naïve persons.2 In the United States, the use of ER/LA opioid analgesics has increased steadily since the first ER opioid formulation, MS Contin (morphine), was approved by the FDA in 1987. A nationwide survey of outpatient retail pharmacies found that the number of prescriptions for ER/LA opioid analgesics more than doubled over the last decade, increasing from 9.3 million prescriptions in 2000 to 22.9 million in 2009. ER/LA formulations account for only a small portion, 9%, of the opioid analgesic prescriptions during this period. The volume for immediate-release (IR) formulations increased from 164.8 million in 2000 to 234 million in 2009.3 Since 2010, the number of prescriptions for opioid analgesics has stabilized.4

A confluence of factors may have contributed to the increase in use of ER/LA opioids, including aggressive promotion from the pharmaceutical industry, efforts to address under-treatment of pain, and underestimation of the risk of opiate addiction during treatment of chronic pain.5,6 The liberal increase of opioid analgesic prescribing over the past 20 years has been accompanied by an epidemic of prescription opioid misuse, abuse, and overdose. The earliest sign of the impending public health crisis was an upswing in abuse, diversion, and addiction reported in 2000 with Oxycontin (oxycodone), which had received FDA approval only 4 years earlier.6 Between 2000 and 2009, the epidemic accelerated as opiate usage increased. Since 2010, the volume of opioid prescriptions has stabilized and rates of prescription opioid diversion, abuse, and deaths have plateaued.4 In response to the epidemic, the FDA implemented a Risk Evaluation and Mitigation Strategy (REMS) for ER/LA opioid analgesics. This article explores how the ER/LA opioid REMS impacts managed care clinicians, and applies REMS principles to the treatment of chronic pain patients in managed care.

ER/LA Opioid Analgesic REMS

In 2011, the Office of National Drug Control Policy (ONDCP) released the national prescription drug abuse plan to combat the prescription drug abuse epidemic in the United States.7 The plan, which focuses on opioid analgesics, has 4 components: education, tracking and monitoring, proper disposal, and enforcement. The key educational element of the plan is the FDA’s ER/LA opioid REMS. In 2007, legislation granted the FDA the authority to require pharmaceutical companies to develop and implement REMS programs.2 In 2009, the FDA started planning a classwide REMS to replace earlier voluntary Risk Minimization Action Plans for individual opiates like oxycodone and fentanyl. Meetings were held with stakeholders, including pharmaceutical companies, other government agencies, patient advocacy groups, and organizations representing prescribers, pharmacists, and insurance providers. The process culminated in the approval of the ER/LA opioid REMS in 2012.2 Table 18-24 summarizes the ER/LA opioids affected by the REMS.

The REMS requires drug manufacturers to develop educational materials and initiatives to train prescribers in the appropriate use of opioid analgesics, as well as educational materials for patients on the appropriate use and disposal of opiate analgesics.25 The REMS contains 2 components of patient education: a patient counseling document for clinician use, and a specific medication guide for each formulation. Although pharmacists are not the intended audience, they will likely play a key role in implementing the patient education component of the REMS.26 Pharmacist-delivered patient education to chronic pain patients has demonstrated a reduction in adverse effects and increased patient satisfaction, and may reduce pain.27,28

In response to the FDA requirement for a shared response, pharmaceutical companies formed a consortium, the REMS Program Companies, to fund development of continuing education (CE) programs by independent providers. An FDA blueprint outlines the required content for 2- to 3-hour CE programs aimed at opioid prescribers.29 Continuing education programs that meet the requirements of the FDA blueprint are available at The FDA established a performance goal for prescriber participation in these CE programs, expecting 60% of the 320,000 active schedule-II controlled-substance prescribers to begin participating in these programs within 4 years.25 Follow-up surveys will assess whether the REMS has negatively impacted access to opioid analgesics for legitimate patients.2 Proposed metrics for evaluating the effectiveness of REMS education include prescribing formulations to opiate-naïve patients when those formulations are intended only for opiatetolerant patients, filling prescriptions for ER/LA opioids early, the incidence of urine drug screening, use of ER/LA formulations for acute pain, high daily doses, and overlapping of opioid and benzodiazepine prescriptions.30,31

The FDA did not require prescriber education to be mandatory, out of concern that it might burden the healthcare system, impede patient access to LA opiates, and require registration of prescribers that would duplicate the existing Drug Enforcement Administration (DEA) registration system.2 The number of stakeholders involved makes the inclusion of mandatory requirements complicated. The REMS is estimated to affect approximately 700,000 DEA-registered prescribers of schedule II opioid analgesics, 4 million patients receiving ER/LA opioid analgesics, 20 pharmaceutical companies (including generics), and 30 products.32 Although prescriber education is not mandatory now, the ONDCP plan recommends passing legislation that requires mandatory training about appropriate opioid use as part of the DEA registration application process.33

The decision by the FDA to limit the opiate REMS to ER/LA formulations is controversial. These formulations account for only a small portion of opioid prescription volume, but a disproportionate number of emergency department (ED) admissions for nonmedical use of opioids.34 Critics argue that failing to include IR formulations could imply that they are safer, and could lead to a preference for prescribing IR formulations.35 Others consider the ER/LA opioid REMS a first step in the implementation of a REMS that includes all opioids. Although IR formulations are currently exempt, a REMS for the rapid-onset opiates, specifically transmucosal fentanyl, has more stringent requirements, including enrollment of wholesalers, prescribers, pharmacies, and patients, and access only through a restricted distribution program.36

Education is not the only component of the ER/LA opioid REMS. Additional FDA actions include labeling changes to strengthen warnings about abuse and addiction risk, specifying more clearly who should receive ER/LA opioids, and requiring postmarketing safety studies. In 2013, all ER/LA opioid analgesics received a new indication specifying use “for the management of pain severe enough to require daily, around-the-clock, longterm opioid treatment for which alternative treatment options are inadequate.”37 This differs dramatically from indications in early labeling, such as “for the management of moderate to severe pain where use of an opioid analgesic is appropriate for more than a few days.”34 A classwide black box warning was added for neonatal opioid withdrawal syndrome (NOWS; also referred to as neonatal abstinence syndrome [NAS] in the medical literature) as a consequence of the substantial increase in chronic opiate use during pregnancy.38,39 Between 2004 and 2013, newborn intensive care unit admissions for NAS increased from 7 cases per 1000 admissions to 27 cases per 1000 admissions.39 Infants with NAS have high rates of medical complications, including respiratory complications and low birth weight, prolonged hospitalization, and high resource utilization.39-41 Manufacturers are now required to complete postmarketing studies to estimate the incidence of misuse, abuse, addiction, overdose, and death during long-term treatment of chronic pain with ER/LA opioid analgesics (results expected in 2018).42 Another requirement is a clinical trial to evaluate the risk of opioid-induced hyperalgesia during long-term treatment of chronic pain (results expected in 2017). FDA actions outside of the REMS include the rescheduling of all hydrocodone products to schedule II controlled substances, facilitating rapid approval of naloxone as an antidote for opiate overdose, providing incentives for the development of new non-opioid analgesics, and facilitating the development of abuse-deterrent formulations (ADFs).7,33,43

Abuse-Deterrent Opioid Formulations

In April 2015, the FDA released long-awaited guidance to the pharmaceutical industry on requirements for approval of ADFs.44 The guidance has 4 categories of data required for ADF labeling claims: in vitro manipulation and extraction studies (Category 1); pharmacokinetic studies (Category 2); clinical abuse potential studies (Category 3); and postmarketing comparison studies (Category 4).44 The guidance does not require all new opioids to be ADFs; rather, a new product’s abusedeterrent properties will be evaluated against the range of available abuse-deterrent and non−abuse-deterrent products, including generics.44 Guidance on generic ADFs is still pending.45 ADF mechanisms address specific forms of abuse. When mixed with water, some formulations (Hysingla ER, Zohydro ER [hydrocodone], Oxycontin [oxycodone]) become a gel that is difficult to draw into a syringe for injection.9,12 Another mechanism involves sequestration of an opiate antagonist, either naloxone or naltrexone, that diminishes the desired opiate effects if the formulation is crushed for oral or intranasal administration.9,13 Table 210-13,46 summarizes the properties of ER/ LA opioids that were approved by the FDA as ADFs. Other ER/LA formulations that have tamper-resistant properties, but did not meet FDA requirements for ADF labeling, include Exalgo (hydormorphone), Nucynta (tapentadol), and Opana ER (oxymorphone).47

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