Minimizing the Risks Associated with Opioids

Phoenix—In the past 22 years, the number of opioid prescriptions dispensed by retail pharmacies has nearly tripled, according to data from the Department of Health & Human Services. There were 207 million opioid prescriptions in 2013, down from a peak of 219 million in 2011 but up from 76 million in 1991.

Although opioids are commonly used in pain management, they are sometimes associated with abuse, misuse, and diversion. During a session at the AAPM meeting, speakers discussed the importance of weighing the risks and benefits of opioids and recommended a multifaceted approach to treating chronic pain.

More than 100 million people in the United States have chronic pain, resulting in an estimated $635 billion in annual direct medical costs and lost productivity, according to Steven Simon, MD, assistant clinical professor, physical medicine and rehabilitation, Kansas University Medical Center.

Treatment Options
In addition to opioids, other treatment options include acetaminophen, skeletal muscle relaxants, nonsteroidal anti-inflammatory drugs, and adjuvant therapy, as well as nonpharmacologic options, such as acupuncture, cognitive behavior therapy, physical therapy, spinal manipulation, transcutaneous electrical nerve stimulation, yoga, and surgery. The World Health Organization recommends patients begin with a nonopioid with or without adjuvant therapy. However, patients can use opioids for mild-to-moderate pain and moderate-to-severe pain and continue to take nonopioids.

Although Dr. Simon said opioids are “absolutely essential” as a treatment option, he added that healthcare professionals should be careful when prescribing opioids and should monitor patients. He cited a report from the Centers for Disease Control and Prevention that found nearly 60% of drug overdose deaths were attributed to pharmaceutical drugs. Of the pharmaceutical overdose deaths, nearly 75% (n=16,651) were attributed to opioid analgesics, including oxycodone, hydrocodone, and methadone. There were 6497 overdose deaths attributed to benzodiazepines yet <4000 overdose deaths due to heroin and cocaine.

However, Dr. Simon said an evidence-based review found that 3.27% of patients who receive opioids to treat nonmalignant, chronic pain have a high likelihood of abusing the drugs or becoming addicted. The authors evaluated 67 studies, including 24 that examined abuse and addiction rates (n=2507 patients), 17 that examined aberrant drug-related behaviors (n=2466 patients), and 5 that examined urine test results (n=1965 patients). The rate of abuse and addiction was 25 times lower in patients without a prior history of abuse or addiction.

Among people who use opioids for nonmedical purposes, approximately 60% receive the drugs from family or friends during days 1 to 29, according to Dr. Simon. However, when individuals continue using opioids for nonmedical purposes, they are more likely to obtain them from physicians. Dr. Simon said doctors should be mindful when prescribing opioids and treating patients with chronic pain. “We are not policemen, yet we are responsible for this,” he said.

Educating Providers and Patients
Christopher Gharibo, MD, medical director, pain medicine, New York University Hospital, said opioid abuse and misuse could be mitigated through educating providers on appropriate prescribing, screening, monitoring, and patient management. He also suggested teaching patients about adherence, storage, and disposal of opioids and recommended healthcare professionals, patients, states, the federal government, and industry participants work together to ensure safe and effective pain management.

Healthcare professionals have numerous ways to screen patients for potential issues with opioids, including the Opioid Risk Tool, Current Opioid Misuse Measure, revised Screener and Opioid Assessment for Patients with Pain, and the Pain Assessment and Documentation Tool. They can also monitor adherence by utilizing random drug screening and prescription drug monitoring programs.

Dr. Gharibo said patients should be responsible for:
• Taking medications as prescribed
• Understanding the risks of opioids
• Being aware of inappropriate use
• Keeping opioids hidden or locked to avoid access by family and friends
• Not sharing opioids with others
• Disposing of medications through community-sponsored take-back programs or environmentally friendly programs consistent with the Office of Drug Control National Policy recommendations

In September, Eric Holder, US attorney general, announced a take-back program and regulation from the Drug Enforcement Administration (DEA) for pharmacies, hospitals, clinics, and other authorized collectors of unused prescription drugs. In a news release, Mr. Holder said more than half of the 41,300 unintentional drug overdose deaths in the United States were attributed to prescription drugs. Furthermore, during the past 4 years, the DEA and other organizations have collected >4.1 million lbs of prescription drugs.

In addition, Dr. Gharibo said 48 of 50 US states have prescription drug monitoring programs, which are electronic databases with information on substances dispensed in each state and accessible to authorized personnel. He said the benefits of the programs are that they support legitimate access to controlled substances; identify and deter drug abuse and diversion; provide use and abuse data; and educate individuals about use, abuse, and diversion. However, Dr. Gharibo said the programs are limited because they lack real-time data and integration between states.

Dr. Gharibo also mentioned the Medicaid lock-in program, a federal law that allows Medicaid to restrict patients who overuse Medicaid services to designated providers. The program restricts some high-risk opioid users from receiving treatment and prescriptions from a designated primary care physician and/or pharmacy. Dr. Gharibo said the program allows a single provider to coordinate care, reduces doctor and pharmacy shopping, limits drug diversion, and decreases healthcare utilization and pharmacy costs. He added that other government payers and insurance companies might adopt lock-in programs as well.

There are also Risk Evaluation and Mitigation Strategies (REMS) programs for opioids, including medication guides and patient package inserts. The REMS programs differ depending on the class of opioids. For instance, healthcare professionals and manufacturers are required to participate in REMS programs for transmucosal immediate release fentanyl products, but they are not mandated to participate in REMS programs for extended-release (ER) and long-acting opioids.

In July 2012, the FDA announced labeling changes for ER and long-acting opioids, noting that they are indicated for managing pain severe enough to require daily, around the clock, long-term treatment with opioids. The FDA also said ER and long-acting opioids should only be used in patients for whom other treatments are ineffective, not tolerated, or are otherwise inadequate for pain management. Manufacturers of these drugs are now required to conduct post-marketing studies to assess the risks of misuse, abuse, hyperalgesia, addiction, overdose, and death. These drugs must also carry a Boxed Warning alerting patients that using the drugs during pregnancy could lead to neonatal opioid withdrawal syndrome.

Abuse-Deterrent Opioids
Jeffrey A. Gudin, MD, director, pain management and palliative care, Englewood Hospital and Medical Center, New Jersey, said pharmaceutical manufacturers and healthcare professionals are taking various approaches to develop and promote the use of abuse-deterrent opioids. They are developing products that prevent the chewing, crushing, cutting, grating, or grinding of opioids; combining agonists and antagonists to curb the euphoria when formulations are compromised; and utilizing drug release designs or different methods of drug delivery to deter people from abusing the drugs.

In January 2013, the FDA issued draft guidance documents to help companies develop formulations of opioids with abuse-deterrent properties. The document recommends studies be conducted to demonstrate that formulations have abuse-deterrent properties and provides information regarding how the studies should be evaluated.

The FDA suggested 4 categories of studies: (1) laboratory manipulation and extraction studies to evaluate how easily the formulation can be manipulated; (2) pharmacokinetic studies to evaluate in vivo pharmacokinetic profiles of manipulated and intact drugs versus comparators; (3) clinical abuse potential studies to assess the impact of the drugs on abusers; and (4) post-marketing studies to determine if the formulations result in lower levels of abuse compared with nondeterrent formulations.

Once-daily hydrocodone bitartrate, a long-acting narcotic painkiller, is the most recently FDA-approved abuse-deterrent opioid, which was approved in November and is manufactured by Purdue Pharma L.P. It is the second ER pure hydrocodone drug approved by the FDA, following the controversial approval of hydrocodone bitartrate ER capsules in October 2013, which is not abuse-deterrent. Once-daily hydrocodone bitartrate is the fourth FDA-approved abuse-deterrent opioid as of press time. A fifth abuse-deterrent opioid manufactured by Pfizer Inc., is expected for approval in early 2015, as the FDA recently approved abuse-deterrent labeling for morphine sulfate and naltrexone hydrochloride.

Although Dr. Gudin said the abuse-deterrent formulations “are not fool-proof technologies,” he predicted that all opioids in 5 to 10 years would be abuse-deterrent.—Tim Casey