ADE – Adverse Drug Events – A Growing Problem;
Arthritis Painkillers Dominate Offenders

What’s an ADE and just how serious are the side effects from arthritis painkillers and other drugs?

An ADE is an occurrence called Adverse Drug Event or Adverse Drug Experience resulting in death, birth defect, disability, hospitalization or requiring intervention to prevent harm from post-marketed drugs, as defined by the Food and Drug Administration (FDA).[1]

Often, taking medicines incorrectly can result in serious drug side effects, including heart attacks, strokes, hypertension, seizures, liver problems and/or death. Serious ADEs have more than tripled between 1998 and 2010, the latest year from which statistics are available. according to the Institute for Safe Medication Practices (ISMP).[2]

The ISMP is a respected 35-year-old nonprofit organization devoted entirely to medication error prevention and safe medication use.

To monitor new adverse events and medication errors that occur, the FDA set up a computerized database, Adverse Event Reporting System (AERS)[3], as part of its safety surveillance program for all approved drugs. However, this system depends on voluntary reporting by manufacturers, health professionals and the public, which critics say is of poor quality and as low as 1% and not more than 30% compliant.

ISMP report: serious ADEs mushroom to 141,829 new cases in 2010

For the full calendar year of 2010, the ISMP identified 141,829 new cases of serious, disabling or fatal adverse drug events reported to the U.S. Food and Drug Administration (FDA), compared to 117,093 cases in 2009.

In its report dated October 6, 2011, the 2010 annual results also ranked the drugs most frequently associated with reports of serious injury. Prominent were opioid pain medications, blockers of tumor necrosis factor (TNF), acetaminophen pain reliever, the antibiotic levofloxacin (Levaquin), and the antipsychotic quetiapine (Seroquel).

The top 15 suspect drugs for reported serious events, which include five painkillers, are listed below (ingredient name, brand name, ADE cases, drug purpose):

1. bosentan, Tracleer, 4,665, high blood pressure
2. fentanyl, Duragesic, 3,035, painkiller
3. infliximab, Remicade, 2,500, autoimmune painkiller
4. etanercept, Enbrel, 2,446, autoimmune TNF blocker
5. teriparatide, Forteo, 2,375, osteoporosis
6. varenicline, Chantix, 2,028, smoking cessation
7. quetiapine, Seroquel, 1,585, anti-psychotic
8. zoledronic acid, Reclast, 1,542, osteoporosis
9. adalimumab, Humira, 1,530, autoimmune TNF blocker
10. acetaminophen, Tylenol, 1,281, painkiller
11. levofloxacin, Levaquin, 1,123, antibiotic
12. baclofen, Lioresal, 1,077, muscle relaxant
13. pregabalin, Lyrica, 1,077, neurologic painkiller
14. atorvastatin, Lipitor, 1,075, cholesterol
15. oxycodone, Oxycontin, 1,070, painkiller

Excludes special reporting drugs. **Other brand names may exist
The ISMP report concluded, “The annual standings illustrate that the biggest safety problems during 2010 span the entire spectrum of drug therapy” including the pain reliever “acetaminophen, which is nearly universally available but lethal in substantial overdose.”

2012 Study: FDA's Adverse Event Reporting System (AERS) is flawed

A 2012 study of major FDA safety actions during 2009 makes clear that the AERS plays an essential role in drug safety. It showed that adverse drug event reports were the predominant source of scientific information used to support 57% of major safety changes overall, and 76% of new “boxed warnings” (the sternest warning for doctors that the FDA can require). The study was published as The FDA and New Safety Warnings on January 9, 2012 in the journal Archives of Internal Medicine.[4]

Citing the above study in QuarterWatch January 12, 2012, the ISMP warns that if AERS data is relied upon for public health safety issues, the system is flawed and in need of upgrading because of weak voluntary reporting compliance and other issues.5]

The concern of the ISMP is the “known limitations of a volunatry ADE reporting system. The AERS combines reports originated by drug manufacturers with cases submitted directly by consumers and health professionals through the agency’s MedWatch program. The reporting rate for AERS is unknown, and published estimates range from around 1% to 15% in most cases, and up to 30% in unusual cases of enhanced reporting.”

The ISMP QuarterWatch report further states: “The FDA has not addressed several important issues raised in QuarterWatch, notably weak, outdated, and inconsistent regulatory guidance for industry; poor quality reporting of patient deaths by drug manufacturers; and low participation by medical professionals in direct reports to the FDA.”

The report concluded that the “study underlines the fact that after decades of use without major change, the AERS remains central to postmarketing safety surveillance. This aging system suffers from management neglect, ambiguous and fragmented guidelines and regulation, and requirements that dilute the quality of the reporting. The FDA needs to assign a higher priority to improving the performance of this key safety system.”

Consumers are invited to report an adverse drug event to the FDA at: fda.gov/medwatch

2011 study: 4.5 million ambulatory visits each year are related to ADE

Perhaps an illustration to the weak voluntary reporting of ADE situations to the FDA's AERS is the contrast in patient numbers when using other data sources for study.

For example, an estimated 4.5 million visits occur each year related to ADEs, according to a study published in Health Services Research, May 10, 2011. The study, Adverse drug events in U.S. adult ambulatory medical care, was a first to estimate the incidence of ADEs associated with health care visits among U.S. adults across all ambulatory settings, including physician's offices.[6]

Analyzing data from two nationally representative probability sample surverys, the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey from 2005 to 2007, researchers found that 72% of adverse events occurred in outpatient practice settings, and the remainder in emergency departments. About 400,000 of these 4.5 million patients are subsequently hospitalized annually. There was an increased odds of an ADE-related visit with increased medication burden for six to eight medications per patient, compared with no medications, and to ages over 65.

The study concluded that a greater focus on ADE prevention and detection is warranted among patients receiving multiple medications in primary care practice.

In total, one-half of 1% of all ambulatory visits are related to adverse drug events, the study said. That may not seem like a lot, but the 4.5 million annual adult outpatient visits for medication problems exceed the numbers for conditions such as strep throat (4.4 million) and pneumonia (4.2 million), said Urmimala Sarkar, MD, MPH, lead author of the study.

"Those are things that we think of as common problems," said Dr. Sarkar, assistant professor of medicine in residence at the University of California, San Francisco School of Medicine's Division of General Internal Medicine. "We should think of this as a common problem too."[7]

2010 study: 4.3 million clinic/ER visits each year are related to ADE

Another statistical study covering eleven years was published in 2010 that showed adverse reactions from pharmaceutical drugs are responsible for 4,335,990 annual visits to outpatient clinics and emergency departments throughout the United States.

ADE visits increased over the study period between 1995 and 2005 from 9.0 to 17.0 per 1000 persons. Overall, 791,082 individuals seek emergency department care for ADEs annually and 14.5% require hospitalization. Outpatient ADEs resulted in 107,468 hospital admissions annually.[8]

Reserachers examined data not from the AERS but from the National Center for Health Statistics on U.S. patient visits to outpatient clinics and emergency departments.

ADEs are a common complication of medical care resulting in high morbidity and medical expenditure yet historical population level estimates are limited. Researchers measured the national annual estimates, risk factors and characterizations of outpatient ADEs requiring medical treatment.

Authors concluded that additional efforts are required to identify preventable ADEs and develop measures to monitor and prevent ADEs in the outpatient population. They further concluded that both patient age and multi pharmaceutical use are risk factors for ADE-related healthcare visits, which have substantially increased during the study period. The incidence of ADEs has particularly increased among patients 65 years and older with as many as 1 in 20 persons seeking medical care for an ADE.

The study was published in final edited form as Adverse Drug Events in the Outpatient Setting: An 11-Year National Analysis in the journal Pharacoepidemiology and Drug Safety in September, 2010.

Third study says “….we are losing ground in terms of drug safety, and that ought to be of great concern”

A study published in the September 10, 2007 issue of Archives of Internal Medicine shows 467,809 serious adverse events were reported to the FDA by consumers, health professionals and drug manufacturers during the eight years the study covered--a 2.6-fold increase.[9]

According to the study, Serious Adverse Drug Events Reported to the Food and Drug Administration, 1998-2005, there was an increase from 34,966 serious events in 1998 to 89,842 for the year 2005. And fatal adverse drug events increased 5,519 to 15,107 comparing the same two years.

Researcher Thomas J. Moore of the Institute for Safe Medication Practices (ISMP) in Huntingdon Valley, PA, who led the study, was quoted in an online article in WebMD Health News by Kathleen Doheny:[10] “The clear finding is that we are losing ground in terms of drug safety, and that ought to be of great concern.”

Researchers at Wake Forest University School of Medicine, along with selected colleagues, conducted the study, which also commented that the overall relative increase in ADEs was four times faster than the growth in the total U.S. outpatient prescriptions, which grew in the same period from 2.7 billion to 3.8 billion, an increase of 1.1 billion in the U.S. population in 8 years..

A comment in the study said that “among the most frequently reported drugs associated with fatal events, we observed a disproportionate contribution of pain medications and drugs that modify the immune system. An implication was written as follows: “This study shows that substantially growing numbers of patients are experiencing serious injuries from drug therapy.”

Study: Serious adverse drug events (ADEs) are an important public health problem

The above study also commented, “this growing toll of serious injury shows that the existing system is not adequately protecting patients and underscores the importance of recent reports urging far-reaching legislative, policy, and institutional changes.”

In total, the study reflected that 80,880 ADE cases (17.3%) reported a death outcome; 32 922 (7%) indicated permanent disability or birth defect; and the remainder (354 007 [75.7%]) had one or more of the other serious outcomes.

The patients were more frequently female (55.5%) than male (44.5%), and the sex imbalance was stable over time. A disproportionate share of adverse drug events occurred in elderly patients 65 or older. This age group constituted 12.6% of the total US population but accounted for 33.6% of the reported serious adverse events. After adjustment for more intensive medication use, the 33.6% of reported cases still exceeded the 23.6% expected.

Report for 2009: Top 15 drugs causing death from ADEs

In 2009, the FDA received 19,551 reports of patient deaths associated with ADEs, a 14% increase compared to the previous year and a three-fold increase over the past decade, according to ISMP's Executive Summary titled Reported Patient Deaths Increased by 14% in Year 2009, dated June 17, 2010.[11]

Since the The U.S. system for postmarketing safety relies on voluntary reports from consumers, health professionals and others, the report attributed this “striking increase in reported patient deaths” was contributed to by at least three factors: 1) Increased awareness. 2) Known risks continue unabated. 3) Compnay direct-to-consumer contact caused an over-reporting problem.

The report expressed concern that some high alert drugs—notably the most powerful opiod narcotics and acetaminophen/narcotic combinations—have been associated with patient deaths for many years without reduction. “This indicates little or no progress has been made managing the risks of these important but inherently difficult to use drugs,” the report said.

Here is the list of 15 drugs involved most often in death from ADEs for the year 2009 as reported to the FDA and included in the ISMP report (drug name, brand [if any], drug purpose, # of ADE deaths):

2. Rosiglitazone, Avandia , Anti-diabetic, 1354
3. Deferasirox, Exjade, Iron Overload, 1320
4. Digoxin, Heart, 506
5. Fentanyl. Painkiller, 397
6. Acetaminophen, Painkiller, 362
7. Acetaminophen-Hydrocodone, Painkiller, 273
8. Imatinib, Gleevec, Cacner, 261
9. Sunitinib, Sutent, Cancer, 252
10. Oxycodone, Painkiller, 251
11. Ibandronate, Boniva, Osteoporosis, 250
12. Quetiapine, Seroquel, Anti-psychotic, 248
13. Alprazolam, Anti-anxiety, 233
14. Capecitabine, Xeloda, Breast Cancer, 218
15. Sildenafil, Viagra,/Revatio, ED/PAH, 190
16. Tacrolimus, Prograf/Protopic, Anti-rejection, 180

Note that painkillers are the most prominent on the list.

Painkillers represent four of the top nine drugs causing ADE deaths in 2009

In the above ISMP study for the year 2009, four of the top nine medications causing deaths from ADE were painkillers: Fentanyl; acetaminophen; acetaminophen-hydrocodone; and oxycodone (OxyContin). Here’s a brief thumbnail of those four pain relief drugs:

1. 
   
2. Fentanyl
   Duragesic is one of the brand names. Fentanyl is one of the most powerful synthetic opioid analgesics with a potency approximately 81 times that of morphine. The main use is for severe pain relief, or to manage post-surgery pain. It is sometimes used to treat chronic pain in people who are physically tolerant to opiates. It is often administered by a physician via injection, lozenge, or transdermal patch. The FDA alerts that patients must avoid exposing the patch to excessive heat as this promotes the release of fentanyl from the patch and increases the absorption of fentanyl through the skin which can result in fatal overdose.[12]
   
   
3. Acetaminophen
   Acetaminophen belongs to a class of drugs called analgesics (pain relievers) and antipyretics (fever reducers). It relieves pain by elevating the pain threshold, that is, by requiring a greater amount of pain to develop before a person feels it. Brand names include Tylenol and Anacin-3 Maximum Strength. It is lethal when overdosed. Those who drink more than three alcoholic beverages per day  or have ever had cirrhosis may not be able to take medication that contains acetaminophen.[13]
   
   
4. Acetaminophen-Hydrocodone
   Hydrocodone is in a group of drugs called narcotic pain relievers. It's also a cough suppressant, similar to codeine, that blocks the receptors on nerve cells in the brain that give rise to the sensation of pain. Acetaminophen is a less potent pain reliever and is described above. Brand names such as Vicodin, Lortab, Lorcet, Norco. The combination of acetaminophen and hydrocodone is used to relieve moderate to severe pain. Hydrocodone may be habit-forming and should be used only by the person it was prescribed for. Acetaminophen and hydrocodone should never be given to another person, especially someone who has a history of drug abuse or addiction. Keep the medication in a secure place where others cannot get to it. Abuse of the drug may lead to moderate or low physical dependence or high psychological dependence.[14]
   
   
5. Oxycodone
   OcyContin is the brand name of a time-release formula of the chemical oxycodone and is prescribed as a pain medication. It is three times more potent than morphine. Oxycodone is an opioid analgesic medication synthesized from thebaine. An opioid is a chemical substance that has a morphine-like action in the body. Instances of abuse of this drug have increased in recent years, according to the U.S. Drug Administration.[15]
   

   Study: Drugs now kill more people than motor vehicle accidents in the U.S.

   Drug overdoses and brain damage linked to long-term prescription drug abuse killed an estimated 37,485 people in 2009, surpassing the toll of traffic accidents by 1,201, according to the U.S. Centers for Disease Control and Prevention as reported by ABC News, September 20, 2011.[16]
   

   Dr. Leonard Paulozzi, medical epidemiologist at the CDC's division of unintentional injury prevention, said patients begin using prescription opioids for legitimate reasons, such as illness or injury. "Over time, they grow addicted," he said. "Around 25 percent of the adult population struggles with chronic pain such as back injuries and headaches," he commented.

   "There has been a dramatic increase in use of prescription drugs as physicians have become more liberal in prescribing them," said Paulozzi, adding that the bulk of drug-related deaths stems from accidental opioid painkiller overdoses. "And with the decrease in the motor vehicle crash mortality rate, drug-induced deaths have now passed motor vehicle crash deaths."

   This is first time that drugs have caused more deaths than motor vehicle accidents since the government started tracking drug-related deaths in 1979.

   Joel Saper, founder of the Michigan Headache and Neurological Institute in Ann Arbor, said the rise in drug-related deaths underscored the liberal "unleashed" prescription nationwide of opioid painkillers such as OxyContin, Vicodin, Percodan and methadone.

   "Pain is not provable. It all comes down to trust," said Saper. "That puts a very high burden on the physician to carefully assess every person he or she feels is in pain. That's just not happening in this country, and now we have a monster."

   Study: Prescription pain reliever abuse rose 400% between 1998 and 2008

   The proportion of all substance abuse treatment admissions of those aged 12 and older involving abuse of prescription pain relievers rose by over 400 percent from 2.2 percent in 1998 to 9.8 percent in 2008 according to a new study by the Substance Abuse and Mental Health Services Administration (SAMHSA).[17]
   
   
   Researchers found that the large increases in the percentage of admissions reporting pain reliever misuse was seen among all age, gender, rade, ethnic groups as well as in all regions of the country. The study was released in July, 2010 by the Office of National Drug Control Policy (ONDCP).
   
   Experts say the nation is in the grip of a prescription drug-abuse epidemic--especially when it comes to opioids painkillers. The problem has so escalated that effective on Sept. 1, 2010 Texas Legislation was enacted that requires pain management clinics to be certified by the Texas Medical Board and run only by physicians with unrestricted licenses.[18]
   

   Asprin and ibuprofen among top 10 drugs that cause ADE treatment in a hospital emergency department

   Aspirin and ibuprofen, along with acetaminophen and hydrocodone-acetaminiphen, dominate the ten most commonly implicated drugs in ADEs requiring treatment in a hospital emergency department, as reported in an article by Kathryn L. Hahn emanating from the American Pharmacists Association Annual Meeting, March 16-19, 2007 referencing an ISMP study released the same month that identified all ten suspect drugs.[18]. The four painkillers are:

   2. acetaminophen
   3. hydrocodone-acetaminophen
   4. aspirin
   5. ibuprofen
   
   Acetaminophen and hydrocodone-acetaminiphen are both covered in a paragraph above. Aspirin and ibuprofen are both non-steroidal anti-inflammatory drugs (NSAIDs). See their thumbnails below:

   • Aspirin
     Brand names include Bayer, Bufferin, Empirin, St.Joseph and others. Aspirin was the first-discovered member of the class of drugs known as non-steroidal anti-inflammatory drugs (NSAID). Today, aspirin is one of the most widely used medications in the world, with an estimated 40,000 metric tons of it being consumed each year.

   • Ibuprofen
     Brand names containing ibuprofen include Advil, Genpril, Ibu-200, Midol, Motrin, and Nuprin. Ibuprofen is also a NSAID and works by reducing hormones that cause inflammation and pain such as headache, toothache, back pain, arthritis, menstrual cramps, or minor injury.

   Both aspirin and ibuprofen are available in over-the-counter (OTC) preparations. However, the FDA warns that NSAIDS are designed for short-term use, and overdosing the recommended daily maximums can result in serious, sometimes fatal, side effects.[19]
   

   NSAIDs are not limited to non-prescription drugs—they include prescription medications such as Celebrex®.

   Unintentional overdoses make up 40% of ER visits

   In her article, The Top 10 Drug Errors and How to Prevent Them,, Hahn writes: “unintentional overdoses made up 40% of these ED visits, representing the most prevalent mechanism of injury by far. Other mechanisms included side effects and allergic reactions. Some of the drugs on this list are especially common (eg, hydrocodone and amoxicillin), so the sheer volume of prescriptions written is a major factor.

   The elderly also play a key role in this issue, as they account for 34% of all written prescriptions.

   Common misuses that lead to adverse drug events are taking incorrect or excessive doses, taking doses at the wrong times, forgetting to take doses, or stopping the medication too soon (all nonadherence issues).

   The article continued, “An example of commonly misused medications can be seen with arthritis therapies. Seventy million Americans suffer from arthritis and joint pain, which translates into 30 million people taking nonsteroidal anti-inflammatory drugs, either prescription or OTC. Misuse of these drugs leads to 103,000 hospitalizations and 16,000 deaths per year. Unnecessary use of nonsteroidal anti-inflammatory drugs also increases avoidable side effects, such as dyspepsia, peptic ulcer, and gastrointestinal bleeding.”

   Other drugs on the list of ten were insulin, warfarin, amoxicillin, trimethoprim-sulfamethoxazole, cephalexin and penicillin.

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   References/sources

   [1] Guidance for Industry, Postmarketing Adverse Event Reporting for Nonprescription Human Drugs, U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2009. Accessed March 20, 2012 www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/-ucm171672.pdf
   [2] Report, QuarterWatch, October 6, 2011, 2010 Annual Summary, Institute for Safe Medication Practices (ISMP) http://www.ismp.org/quarterwatch/pdfs/2010Q4.pdf
   [3] Publication, Adverse Event Reporting System (AERS), FDA, accessed online, March 20, 2012 http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/surveillance/adversedrugeffects/default.htm
   [4] Moore TJ, Singh S, Furberg CD (2012) The FDA and New Safety Warnings; Arch Intern Med; January 9, 2012; 172(1): 78–80. http://archinte.ama-assn.org/cgi/content/extract/172/1/78 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/22232155
   [5] Report, QuarterWatch, January 12, 2012, Monitoring FDA MedWatch Reports Institute for Safe Medication Practices (ISMP). www.ismp.org/QuarterWatch/pdfs/2011Q1.pdf
   [6] Sarkar, U, et.al. Adverse drug events in U.S. adult ambulatory medical care, Epub May 10, 2011, Health Services Research,  2011 Oct;46(5):1517-33. doi: 10.1111/j.1475-6773.2011.01269.x. http://www.ncbi.nlm.nih.gov/pubmed/21554271
   [7] O'Reilly, K; article Quantifying adverse drug events: Med mishaps send millions back for care, amednews.com, posted June 13, 2011 http://www.ama-assn.org/amednews/2011/06/13/prl20613.htm
   [8] Bourgeois, FT et al: Adverse Drug Events in the Outpatient Setting: An 11-Year National Analysis. Journal Pharmacoepidemiology and Drug Safety, September, 2010, Vol. 19, Issue 9, pg 901-910. PMC free full text archive September 1, 2011, U.S. NIH/NLM http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2932855/ PubMed: http://www.ncbi.nlm.nih.gov/pubmed/20623513
   [9] Moore, TJ et. al.; Serious Adverse Drug Events Reported to the Food and Drug Administration, 1998-2005; Archives of Internal Medicine, Sept. 10, 2007; vol 167: pp 1752-1759 http://134.147.247.42/han/JAMA/archinte.ama-assn.org/cgi/content/full/167/16/1752
   [10] Doheny, K; article Reports of adverse drug effects up: Increase is 'cause for alarm', researchers say, WebMD Health News Archive, accessed March 21, 2012 http://www.webmd.com/news/20070910/reports-of-adverse-drug-effects-up
   [11] Report, QuarterWatch, June 17, 2010, Reported Patient Deaths Increased by 14% in 2009 Institute for Safe Medication Practices (ISMP) http://www.ismp.org/quarterwatch/2009Q4.pdf
   [12] FDA Alert July 15, 2005; Update December 21, 2007: Fentanyl Transdermal System (marketed as Duragesic) Information http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm114961.htm
   [13] FDA Q&A for Consumers: Acetaminophen and Liver Injury. Accessed online March 22, 2012 http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm168830.htm
   [14] Drug Information, acetaminophen and hydrocodone bitartrate 750 mg accessed drugs.com March 21, 2012 http://www.drugs.com/imprints/m360-10139.html
   [15] Jayawant, S, Balkrishnan, R, The controversy surrounding OcyContin abuse:issues and solutions, Ther Clin Risk Manag, June 2005: 1(2): 77-82. PubMed http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1661612/
   [16] Moisse, K; article Drug Deaths Exceed Traffic Deaths, ABC News, September 20, 2011 http://abcnews.go.com/Health/Drugs/drug-deaths-exceed-traffic-deaths/story?id=14554903#.T2vhpMVum5I
   [17] Monthly column, Texas Medical Board Adops New Rules, November 30, 2009 (law effective September 1, 2010) Houston Medical Journal, accessed online March 22, 2012 http://www.mjhnews.com/texas-medical-board-adopts-new-rules.html
   [18] Hahn, KL; article The Top 10 Drug Errors and How to Prevent Them, March, 2007, Medscape Education from Medscape Pharmacists. Accessed March 22, 2012 http://www.medscape.org/viewarticle/556487
   [19] News Release, FDA requires new labels for over-the-counter painkillers, CNN.com, April 29, 2009, accessed April 8, 2017 www.cnn.com/2009/HEALTH/04/28/fda.warning.tylenol.nsaids/ target="_blank"
   

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