Pain Management and drug Safety.
Food and Drug Administration (FDA) has been engaging physicians, pharmacy groups, patients, and other stakeholders in an ongoing effort to strike the right balance between two important goals: on one hand, providing access to pain medications for those who need them, and on the other hand, managing the variety of risks posed by analgesic drugs. Recent FDA advisory committee meetings and actions reflect this effort. Acetaminophen is one of the most commonly used analgesics. In 2008, approximately 25 billion doses were sold in the United States. Acetaminophen is marketed as a singleingredient drug but can also be found in a multitude of over-the-counter combination products, such as cough and cold medicines, as well as in prescription opioid–acetaminophen combination products (e.g., Vicodin, Abbott), Percocet (Endo Pharmaceuticals), and Darvocet (AAIPharma). Although acetaminophen, when used as labeled, is generally safe, the ubiquity of the drug and its relatively narrow therapeutic index create the potential for serious harm from both inadvertent and intentional overdoses. Approximately 30,000 hospitalizations are associated with acetaminophen overdose in the United States annually — approximately half of them resulting from unintentional overdose. Acetaminophen is also a leading cause of acute liver failure . In June 2009, the FDA held a 2-day public advisory committee meeting to discuss acetaminophen toxicity. The FDA presented multiple options for improving the management of acetaminophen-related risk. The top three recommendations of the committee were to reduce the maximum single dose of over-the-counter acetaminophen from 1000 mg to 650 mg or switch the 1000-mg single dose to prescription status, to standardize the range of overthe-counter liquid concentrations (to reduce dosing confusion), and to eliminate prescription.
acetaminophen combinations or require a boxed warning on the labels of these products. The first and third recommendations, in particular, could have a considerable effect on the use and availability of acetaminophen-containing products. The agency is currently considering its next steps . Strong opioid analgesics (e.g., morphine) are the drugs of choice for the management of moderate-to severe pain following surgery or trauma. However, there is considerable interpatient variability in opioid analgesic dosing requirements as well as opioid-related sideeffects with genetic factors proposed as a possible explanation by the FDA. In February 2009, the agency announced that it was initiating a process under the FDA Amendments Act (FDAAA) that would require manufacturers of high-potency opioids to institute riskevaluation and mitigation strategies (REMS) to address the risks of abuse, misuse, and the exposure of persons who are not opioid-tolerant. In one month in 2007, an estimated 5.2 million people 12 years of age or older used pain relievers non-medically. In 2006, there were approximately 57,000 emergency department visits for nonmedical use of hydrocodone or hydrocodone combinations, 65,000 for nonmedical use of oxycodone or oxycodone combinations, and 45,000 for nonmedical use of methadone. An analysis of poison-control data from 2003 through 2006 identified 9179 children who were inadvertently exposed to prescription opioids. The median age of the children was 2 years, and 92% of the poisonings occurred in the child’s home. Such data highlights the need for additional measures to limit the abuse and misuse of prescription opioids and prevent the accidental exposure of children . Although the risks of serious or fatal gastrointestinal bleeding from nonsteroidal Antiinflammatory drugs (NSAIDs) have long been recognized, additional safety concerns have also emerged about these agents. In April 2005, the FDA implemented the recommendation of an advisory committee to require a boxed warning on the labels of NSAIDs (except aspirin) about the risk of excess myocardial ischemia, particularly in patients with preexisting heart disease . Despite increased awareness of the harm resulting from the use of NSAIDs, acetaminophen, opioids, and other drugs for pain, it is likely that extensive prescribing and use of these drugs will continue. Given this reality, there is a need for more vigorous riskmanagement efforts by the FDA and other stakeholders in the health care system. The FDA cannot address these risks on its own; prescribers and users of analgesics must also participate in this effort. Any risk-management option must be considered in the light of its potential effect on the use of other analgesics, given that most analgesic drugs have substantial liabilities. The unintended consequences of shifting use from one drug class to another, for example, must be considered carefully . Although management of the risks posed by the current armamentarium will be a predominant theme for the foreseeable future, the FDA is also exploring ways to improve analgesic-drug development, primarily through research into better designs for pain trials, in the hope that highly effective drugs with more easily managed risks may be developed .