Timeline of Selected FDA Activities and Significant Events Addressing Opioid Misuse and Abuse
This timeline provides chronological information about FDA activities and significant events related to opioids, including abuse and misuse. Included is a summary timeline of key events, followed by tabbed years that provide selected additional actions and more detail about the items listed in the summary.
View and print full timeline (PDF - 203KB)
1995. OxyContin (oxycodone controlled-release) approved; first formulation of oxycodone
that allowed dosing every 12 hours instead of every 4 to 6 hours.
1998. Actiq (fentanyl) approved; first pain medicine approved to treat cancer breakthrough
pain, but with additional safety measures.
Early 2000s. Reports of overdose and death from prescription pain drugs, especially OxyContin, began to rise sharply.
2001. OxyContin label was changed to add and strengthen warnings about the drug’s
potential for misuse and abuse.
2003. FDA issued a Warning Letter (PDF - 149KB) to OxyContin’s manufacturer for misleading advertisements.
2007. FDA Amendments Act granted FDA authority to require for certain drugs specified
safety measures known as Risk Evaluation and Mitigation Strategies (REMS).
FDA partnered with U.S. Substance Abuse and Mental Health Services Administration (SAMHSA) to launch an initiative to help ensure the safe use of the opioid methadone.
FDA launched the Safe Use Initiative to reduce preventable harm by medications, including opioids.
FDA began working with U.S. Drug Enforcement Administration (DEA) and others to help educate the public on safe disposal of opioids.
2010. FDA approved a new formulation of OxyContin designed to deter abuse.
FDA held joint advisory committee meeting to discuss its proposal for a class-wide REMS
for Extended-Release (ER)/Long acting (LA) opioids, such as OxyContin.
2011. FDA approved REMS for transmucosal immediate-release fentanyl (TIRF) products,
such as Actiq.
2012. FDA implemented the ER/LA opioids REMS program, which includes voluntary
training for prescribers.
2013. FDA issued a draft guidance document to assist industry in developing new formulations of opioid drugs with abuse-deterrent properties: Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling (PDF - 463KB).
FDA held a January 24-25 meeting of its Drug Safety and Risk Management Advisory Committee (PDF - 69KB) to discuss the public health benefits and risks, including the potential for abuse, of drugs containing hydrocodone either combined with other analgesics or as an antitussive.
FDA scheduled a public hearing (PDF - 63KB) for February 7 & 8, 2013, to obtain information, particularly scientific evidence, such as study data or peer-reviewed analyses, on issues pertaining to the use of opioid drugs in the treatment of chronic pain, Impact of Approved Drug Labeling on Chronic Opioid Therapy; Public Hearing; Request for Comments.
1911 to 1990s
Opioid pain medications were used primarily for acute pain and cancer pain. Studies showing inadequate treatment of chronic non-cancer pain by physicians lead to an increased use of opioids.
May: MS Contin, (morphine sulfate) approved; first formulation of an opioid pain medicine that allowed dosing every 12 hours instead of every 4 to 6 hours.
August: Duragesic (fentanyl transdermal system) approved; first formulation of an opioid pain medicine in a patch (sometimes referred to as a “skin patch”) that is changed every 3 days.
December: OxyContin (oxycodone controlled-release) approved; first formulation of oxycodone that allowed dosing every 12 hours instead of every 4 to 6 hours. OxyContin would soon become a focal point of opioid abuse issues that would continue to escalate into the late 2000s and beyond.
At the time of approval, FDA believed the controlled-release formulation of OxyContin would result in less abuse potential, since the drug would be absorbed slowly and there would not be an immediate “rush” or high that would promote abuse. In part, FDA based its judgment on the prior marketing history of a similar product, MS Contin, a controlled-release formulation of morphine approved by FDA and used in the medical community since 1987 without significant reports of abuse and misuse.
Also at the time of OxyContin’s approval, FDA product labeling warned of the danger of abuse of the drug and that crushing a controlled-release tablet followed by intravenous injection could result in a lethal overdose. There was no evidence to suggest at the time that crushing the controlled-release capsule followed by oral ingestion or snorting would become widespread and lead to a high level of abuse.
November: Actiq (fentanyl) approved; first pain medicine approved to treat cancer breakthrough pain but with additional safety concerns. Actiq was approved with a restricted distribution program to try to prevent 1) accidental exposure in children because the product looked like a lollipop, and 2) potential abuse. This drug would later become part of a category of opioids now known as transmucosal immediate-release fentanyl (TIRF) products. Transmucosal means that the dose of the drug is delivered across mucous membranes, such as inside the cheek, under the tongue, or in the nose.
Reports of overdose and death from prescription drug products, especially opioids, began to rise sharply, with OxyContin at the center of the problem. For instance, the number of people who admitted to using OxyContin for non-medical purposes increased dramatically from approximately 400,000 in 1999 to 1.9 million in 2002 and to 2.8 million in 2003.
By 2009, about 1.2 million emergency department (ED) visits were related to misuse or abuse of pharmaceuticals, an increase of more than 98% since 2004 and more than the number of ED visits related to use of illicit drugs such as heroin and cocaine. Most prominent among these prescription drug-related deaths and ED visits were opioid pain relievers (OPR), especially OxyContin.
FDA had worked with sponsors for more than a decade to implement risk management programs for a number of opioid products. However, data demonstrated that these programs did not adequately manage the risks of misuse, abuse, addiction, and overdose. More was needed.
January: Beginning in 2001 and ongoing, inter-agency collaboration occurred to develop public education regarding prescription drug abuse. The involved agencies included FDA, SAMHSA, the Center for Substance Abuse Treatment (CSAT), and the National Institute on Drug Abuse (NIDA).
March: CSAT hosted a meeting with FDA and other federal agencies, including DEA, NIDA, and the Centers for Disease Control and Prevention (CDC).
July: Additional stronger warnings about the potential for misuse and abuse were added to the OxyContin label.
- To help prescribers choose patients who would benefit from using OxyContin, the indication for using the drug was changed from “moderate to severe pain where use of an opioid analgesic is needed for more than a few days” to “management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.”
- The label was also changed to say that OxyContin is not appropriate for “as needed” pain or in the immediate-post operative period if the pain is mild or not expected to persist for an extended period of time.
- A Boxed Warning was added to reinforce the most important warnings, and information in the DRUG ABUSE AND DEPENDENCE section was updated. OxyContin’s manufacturer, Purdue Pharma, agreed to implement a Risk Management Program (RMP) to try to reduce misuse and abuse of OxyContin and issued a Dear Healthcare Professional Letter (PDF - 108KB) about changes to the label.
January: Patient Package Insert (PPI) approved for OxyContin. This is a document written for patients that provides information about how to safely use the drug.
March: Inter-Agency Working Group Meeting held to discuss OxyContin and other extended-release opioids and their abuse and diversion. FDA, DEA, NIDA, and SAMHSA involved.
January: FDA issued a Warning Letter (PDF - 149KB) to OxyContin’s manufacturer, Purdue Pharma, for misleading advertisements. Among many other details, the warning specified that the ads left out and minimized the serious safety risks associated with OxyContin and promoted it for uses beyond those which had been proven safe and effective. Specifically, the letter pointed out that the advertisements failed to clearly present information from the product label’s Boxed Warning regarding the potentially fatal risks and the danger of abuse.
September: PPI for Actiq converted to a Medication Guide (MG) due to heightened safety considerations. The conversion was to better ensure that each patient prescribed the drug was fully informed of its serious risks. In contrast to PPIs, MGs are required to be given to each patient when they fill a prescription.
September: Fentora (fentanyl buccal tablets), the second TIRF product, approved with an MG and RMP but not restricted distribution.
September: FDA issued a Public Health Advisory for Fentora due to reports of medication errors resulting in adverse events and deaths.
September: The Food and Drug Administration Amendments Act (FDAAA) became law, providing the Agency with a wide array of new authority designed to enhance drug safety. One of these is the authority to require Risk Evaluation and Mitigation Strategies (REMS) in order to ensure the benefits of the drugs continue to outweigh their risks. REMS are intended to require manufacturers to implement various safety measures for certain drugs. This new law helped provide the basis for a future comprehensive REMS program for all FDA-approved Extended-Release (ER)/Long Acting (LA) opioid products (see 2009 through 2012 below).
September: FDA announced it would require companies to stop marketing any unapproved drug containing the opioid pain medication hydrocodone bitartrate (the active ingredient in the opioid sold under the familiar trade name Vicodin).
Fentora’s manufacturer, Cephalon, requested an expansion of the drug’s indication to include patients with non-cancer breakthrough pain. An FDA Advisory Committee concluded that the existing RMP for the drug was not effective, and Cephalon was told that a REMS program would be required before the drug could be considered for a broader indication.
February: Fentora’s label and MG were revised to strengthen warnings.
February: FDA informed Cephalon that the RMP was not sufficient to ensure the safe use of Fentora for the already approved indication for treatment of breakthrough cancer pain and needed to be replaced by a REMS.
March: FDA met with manufacturers of ER/LA opioid pain medications to discuss the requirement for a class-wide, shared-system REMS, which is a single uniform program for all products in a drug class.
April: FDA partnered with SAMHSA to launch an initiative to help ensure the safe use of the opioid methadone, as this drug appeared to be responsible for a highly disproportionate number of overdoses and deaths in pain patients compared with all other opioids. (Methadone is best known as a treatment for addiction to and dependence on heroin and other narcotic pain medicines, but it is also prescribed to treat moderate-to-severe chronic pain.)
May: Among a variety of public and stakeholder meetings that occurred in 2009, FDA held a large public meeting on May 27-28 where more than 100 people provided comments on their experiences with opioid drugs along with suggestions for a REMS targeting ER/LA opioid products. Groups that participated included patient advocacy organizations, prescriber organizations, pharmacy organizations, insurance providers, and other government agencies. In addition, FDA solicited written comments through a public docket. (See summary of comments (PDF - 6MB).)
July: FDA approved Onsolis (fentanyl), the third TIRF for breakthrough cancer pain. It was approved with a REMS in place. At this point, FDA decided that a separate REMS for each TIRF product would create a great burden to patients, pharmacies, and prescribers and so began discussion of a single-shared REMs for all TIRF products.
FDA informed Cephalon in 2009 of the requirement to convert the RMP for Fentora and Actiq to a REMS.
August: Embeda (morphine sulfate and naltrexone extended-release tablets) approved. Naltrexone helps block the effects of opioids. Embeda was the first product approved combining an opioid pain medicine and opioid blocker since Talwin NX (pentazocine and naloxone) was approved in 1982. [Suboxone (buprenorphine and naloxone) sublingual tablets, approved in 2002, has an opioid blocker but is specifically for the treatment of opioid dependence, not for pain.]
October: Similar to actions in 2007 against makers of unapproved hydrocodone products, FDA warned companies they must stop marketing unapproved codeine sulfate tablets, a widely used opioid to treat pain.
November: FDA launched the Safe Use Initiative to create and facilitate public and private collaborations within the health care community, with a goal to reduce preventable harm from medication. Safe use of opioids is a primary focus of this ongoing effort.
November: The November 26, 2009, issue of The New England Journal of Medicine featured an article titled A Difficult Balance – Pain Management, Drug Safety, and the FDA by Janet Woodcock, M.D., director of FDA’s Center for Drug Evaluation and Research (CDER). In the article, Dr. Woodcock discussed FDA’s efforts to strike a balance between legitimate patient access to pain medications and managing the risks posed by various analgesics. She cited recent FDA actions on the over-the-counter pain reliever acetaminophen, the low-potency opioid propoxyphene, and high-potency opioids such as OxyContin.
December: FDA held a stakeholder meeting on December 4 with the Industry Working Group (IWG), consisting of representatives from 22 pharmaceutical companies asked to help develop an effective opioid REMS program for a proposed class-wide opioid REMS. [IWG would be re-named REMS Program Companies (RPC) in August, 2011].
A significant percentage of deaths and overdose from opioids, especially from ER/LA opioids, results from theft of pain medicine from medicine cabinets and accidental exposure to the drugs. Since 2009, FDA has worked with DEA and other organizations to help educate the public on safe disposal of opioids when they are no longer needed for pain.
April: FDA approved a new formulation of OxyContin designed to deter abuse associated with crushing the tablet.
July: FDA held a joint meeting of its Anesthetic and Life Support Drugs Advisory Committee (ALSDAC) and the Drug Safety and Risk Management (DSaRM) Advisory Committee to discuss the Agency’s proposal for a class-wide REMS for ER/LA opioid analgesics (for complete background information discussed at this meeting, see the July 22-23, 2010, AC meeting entry).
September: To improve clinical studies of pain medicines with the goal of advancing the development of novel, less abusable, safer, and more effective pain medicines, FDA announced a plan to establish a public-private partnership to conduct multiple scientific projects under the umbrella of the Analgesic Clinical Trial Translation, Innovations, Opportunities, and Networks (ACTTION) Initiative. The University of Rochester (UR) was chosen for the contract to establish the infrastructure of the ACTTION PPP initiative and to establish relationships with the key experts and organizations in the field.
October: FDA held a joint Advisory Committee Meeting (PDF - 149KB) (ALSDAC and DSaRM) on studies for demonstrating effectiveness of abuse-deterrent formulations on addiction, overdose, and death, with OxyContin and Embeda featured.
October: FDA held a meeting with TIRF sponsors and informed them that in order to decrease the burden on the healthcare system, they must form a single-shared REMS for these products. The Agency committed to working with the firms to assist in the regulatory aspects of developing this program. Regular meetings followed, after which the firms formed a working group, the Transmucosal Immediate-release Fentanyl REMS Industry Group (TRIG).
November: Separate from the developing REMS program but connected to FDA’s overall effort toward safe use of opioids, FDA recommended voluntary market withdrawal of propoxyphene, sold under the familiar trade name Darvon. New data showed the drug could cause serious toxicity to the heart, even in therapeutic doses.
January: Abstral (fentanyl) approved; the fourth TIRF product. This product was approved with a MG and REMS in place.
April: FDA supported the White House Office of National Drug Control Policy (ONDCP) report Epidemic: Responding to America’s Prescription Drug Abuse Crisis (PDF - 306KB), a comprehensive action plan to address the national prescription drug abuse epidemic.
June: Lazanda (fentanyl) approved; the fifth TIRF product. This product was approved with a MG and REMS in place.
June: Oxecta (oxycodone hydrochloride) approved; the first immediate-release oxycodone tablet designed to deter abuse by resisting physical and chemical manipulation. It also includes a chemical to irritate the nose of abusers who try to snort the drug.
September: FDA provided funds through a one-year cooperative agreement grant to the University of South Carolina to develop a statewide collaboration to decrease rates of misuse, overuse, and abuse of opioids. This was to be accomplished through the detailing of information regarding prescription opioids and the use of state prescription drug monitoring programs (PDMPs) geared to individual physicians who are high volume prescribers of opioids.
October: As part of a three-year inter-agency agreement with the Department of Justice’s Bureau of Justice Administration and in collaboration with the CDC, FDA provided funding to support efforts by the Prescription Drug Monitoring Program Center of Excellence at Brandeis University. The effort was to develop a national database of state PDMP data to be used for surveillance of emerging problems or concerns with scheduled drugs and to examine the impact of national, state and community initiatives implemented to curb misuse, overuse, and abuse of opioids.
December: FDA announced the approval of a new formulation of the ER/LA opioid OPANA ER (oxymorphone hydrochloride), designed to deter abuse through resistance to physical and chemical manipulation of the drug.
December: FDA approved a single-shared REMS system for all TIRF products (the “go-live” date would be March 2012). The industry working group (TRIG, see above) was encouraged to continue working to complete its single-shared TIRF REMS system. The Agency continued to provide regulatory input and review of TRIG’s proposals throughout the year.
December: FDA began working to streamline the process for managing the TIRF single-shared REMS.
January: Subsys (fentanyl sublingual spray) approved; the sixth TIRF product. It was approved directly into the single-shared TIRF REMS in anticipation of its upcoming “go live” date.
January: FDA awarded a Center of Excellence in Research Science and Innovation grant to the University of Maryland to examine the use and utility of Patient Prescriber Agreements in reducing prescription opioid abuse.
March: The single-shared TIRF REMS went “live,” and FDA began work with TRIG to address patient access issues.
April: FDA hosted a scientific workshop to initiate a public discussion about the potential value of making naloxone available in the community to reduce the number of opioid overdose fatalities. In simple terms, naloxone, marketed under the trade name Narcan and others, reverses the effects of opioids.
May: FDA and the National Institutes of Health (NIH) Pain Consortium held a meeting on May 30-31, called Assessment of Analgesic Treatment of Chronic Pain: A Scientific Workshop, to review available data on the effectiveness of pain medications in the treatment of chronic non-cancer pain.
September: FDA awarded funding for up to three years for three cooperative agreement grants to examine strategies and interventions and their potential to impact opioid analgesic misuse and abuse. The following research topics were funded:
Examine the prescribing habits of physicians who prescribe doses of opioids above 100 mg morphine equivalents per day and/or prescribe opioids in combination with benzodiazepines. Those prescribers will be targeted for educational and informational mailings, and the PDMP data will be examined for changes in prescribing habits post-education and over time.
Examine the clinical use of different tools that can guide a clinician in prescribing opioids and reduce patient misuse, overuse, and abuse of opioids. All of the risk reduction strategies described are currently in use. They include 1) screening, brief intervention, and referral to treatment (SBIRT), 2) PDMPs, 3) REMS, 4) health insurer initiatives, and 5) treatment contracts. The study will survey approximately 1,300 prescribers (1,000 internists, 200 pain specialists and 100 addiction specialists) to gain an understanding of the knowledge, use, and perceptions of utility of these strategies.
Estimate the incidence of urine drug testing (UDT) during the year following initiation of chronic opioid therapy (COT) and identify demographic, clinical, provider, and facility variables associated with the use of UDT within the national Veterans Affairs (VA) healthcare system. Use qualitative interviews with primary care providers to explore perceptions of barriers to UDT, appropriate care for patients who misuse opioids, and opportunities to coordinate treatment with substance abuse specialty care. Describe current clinical practice following an aberrant UDT result, including rates of follow-up assessments and treatment changes among patients who initiate COT for chronic pain.
June: The Randomized Enrollment Study of Opioid Long-term use to eValuate Efficacy (RESOLVE) working group, under the auspices of ACTTION (see September 2010 above), was established. Formation of this group was initiated based on the FDA-sponsored meeting held at NIH in May (see directly above) and on plans to develop protocols for clinical trials to assess the effectiveness of long-term use of opioid pain medicines.
July: FDA approved the ER/LA opioids class REMS program. This program included new product labeling for ER/LA opioids and a requirement for manufacturers to develop and offer opioid training programs that prescribers can take on a voluntary basis.
August: ACTTION established the Consortium for Addiction Research on Efficacy and Safety (CARES) to address challenges in addiction drug trials. The Abuse Liability Evaluation for Research, Treatment, and Training (ALERTT) project was also initiated under ACTTION. This project was initiated with the intent to create a classification scheme and a risk assessment tool for use in clinical trials and for post-marketing adverse event reports to help identify incidents of drug abuse or emergence of drug addiction.
October: FDA and ACTTION hosted a scientific workshop October 24-26 to discuss preclinical models and clinical study issues to find ways to improve analgesic drug discovery and development.
October: FDA scheduled a meeting of the Drug Safety and Risk Management Advisory Committee for October 29-30 to discuss the public health benefits and risks, including the potential for abuse, of drugs containing hydrocodone, either combined with other analgesics or as a cough suppressant. This meeting was postponed due to Hurricane Sandy.
November: FDA scheduled a meeting November 28-29 for ACTTION’s ALERTT project working group for stakeholders to discuss consensus recommendations and research studies on definitions, measures, and prediction tools for abuse liability.
December: FDA held a December 7 meeting of the Anesthetic and Analgesic Drug Products Advisory Committee to discuss the risks and benefits of new drug application, for hydrocodone bitartrate extended-release capsules, which would be the first single-entity hydrocodone-containing drug product. The committee voted against approval.
January: FDA issued a draft guidance document, January 9, to assist industry in developing new formulations of opioid drugs with abuse-deterrent properties. The document, entitled Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling (PDF - 463KB), explains FDA’s current thinking about the studies that should be conducted to demonstrate that a given formulation has abuse-deterrent properties, how those studies will be evaluated by the agency, and what labeling claims may be approved based on the results of those studies.
January: FDA held a January 24-25 meeting of its Drug Safety and Risk Management Advisory Committee (PDF - 69KB) to discuss the public health benefits and risks, including the potential for abuse, of drugs containing hydrocodone either combined with other analgesics or as an antitussive. The Department of Health and Human Services (HHS) received a request from the Drug Enforcement Administration (DEA) for a scientific and medical evaluation and scheduling recommendation for drugs containing hydrocodone either combined with other analgesics or as an antitussive, in response to a citizen petition citing increasing reports of abuse related to these products. Currently, these products are Schedule III drugs under the Controlled Substances Act (CSA), and DEA is considering whether to reschedule the products to Schedule II, which would subject the products to more stringent requirements regarding storage, record keeping, and prescribing, such as limitations on oral prescriptions and refills. The committee voted in favor of rescheduling hydrocodone products from Schedule III controlled substances to Schedule II controlled substances.
February: FDA scheduled a public hearing (PDF - 63KB) for February 7 & 8, 2013, to obtain information, particularly scientific evidence, such as study data or peer-reviewed analyses, on issues pertaining to the use of opioid drugs in the treatment of chronic pain. The meeting was announced in a December 19, 2012 Federal Register notice titled, Impact of Approved Drug Labeling on Chronic Opioid Therapy; Public Hearing; Request for Comments.
Updated as of 2/28/2013
ACTTION Analgesic Clinical Trial Translation, Innovations, Opportunities and Networks
ALERTT Abuse Liability Evaluation for Research, Treatment, and Training
ALSDAC Anesthetic and Life Support Drugs Advisory Committee
CARES Consortium for Addiction Research on Efficacy and Safety
CDC Centers for Disease Control and Prevention
CDER Center for Drug Evaluation and Research
COT Chronic Opioid Therapy
CSAT Center for Substance Abuse Treatment
DEA Drug Enforcement Administration
DSaRM Drug Safety and Risk Management (Advisory Committee)
ER Extended Release
FDA Food and Drug Administration
FDAAA Food and Drug Administration Amendments Act
IWG Industry Working Group
LA Long Acting
MG Medication Guide
NIDA National Institute on Drug Abuse
ONDCP Office of National Drug Control Policy
OPR Opioid Pain Relievers
PDMP Prescription Drug Monitoring Program
PPI Patient Package Insert
REMS Risk Evaluation and Mitigation Strategies
RESOLVE Randomized Enrollment Study of Opioid Long-term use to evaluate Efficacy
RMP Risk Management Program
SAMHSA Substance Abuse and Mental Health Services Administration
SBIRT Screening, Brief Intervention and Referral to Treatment
TIRF Transmucosal Immediate-Release Fentanyl
TRIG Transmucosal Immediate-Release Fentanyl REMS Industry Group
UDT Urine Drug Testing
VA Veterans Affairs