Medication Safety: Are OTC Medications Safer than Rx Medications?

Medication Safety: Are OTC Medications Safer than Rx Medications?

Kevin L. Zacharoff, MD

Disclosures Grant/Research Funding: Endo Pharmaceuticals, Actavis Salary: Inflexxion

Learning Objectives  Explain the use of OTC medications in the U.S  Interpret safety-related issues with respect to the use of OTC medications for the management of chronic pain  Describe patterns of use of opioids in the U.S. for the management of chronic pain  Contrast safety-related issues between OTC medications and opioids in the management of chronic pain  Explain guidelines and recommendations with respect to the use of OTC medications and opioids in the management of chronic pain

What is Medication Safety?  Health care provider perspective – Depends on who you ask • Medication errors

– Name – Dose indication

• Assessment of adherence (compliance) to regimen • Risk evaluation – Drug-drug interactions – Adverse effect profile – Inappropriate patient selection – Co-morbid conditions – Overdose/aberrant drug-related behaviors

• Conservative prescribing

What is Medication Safety? (cont’d)  Patient perspective

– Knowledge about medications • Name • Directions

– Dose – Timing – Other factors (eg, with or without food, what about vitamins?)

– Allergies – Side effects

• Prior history • Awareness

– Storage/Disposal

Medication Use in the United States  A Survey1 explored patterns of medication use in the US – In a given week, an average of 82% of adults in the U.S. are taking at least one medication (prescription or non-prescription drug, vitamin/mineral, herbal/natural supplement) • 29% are taking five or more

– The prevalence of use of medications overall and prescription drugs has not changed materially since the Survey began in 1998 – Polypharmacy has increased since 2000, from 23% to 29% for use of five or more medications, and from 6.3% to 12% for use of at least five prescription drugs 1. The Slone Survey. Patterns of Medication Usage in the United States: 2006

A Report from the Slone Survey. 2006

What is the Most Commonly Used Medication in the US?

“Acetaminophen continues to be the most

commonly used drug among U.S. adults. 19% of all Americans are taking it in a given week”

The Slone Survey. PATTERNS OF MEDICATION USE IN THE UNITED STATES 2006 A Report from the Slone Survey. 2006

Managing Chronic Pain Usually involves pharmacologic treatment –Over-the-counter (OTC) medications –Prescription medications

May involve other substances –Holistic treatments –Dietary supplements –Certain foods

Medications and Managing Chronic Pain  OTC – Acetaminophen – NSAIDs

 Prescription – Opioids – Adjuvant agents • Antidepressants • Anticonvulsants • Local anesthetics • Others

Managing Chronic Pain Safely  Includes considering a number of different variables – Risk vs. benefit

• Age • Physiology • Economics • Cognitive function • Substance abuse history • Other factors

– Informed consent – Patient history – Pain condition – Other factors

Medications and Managing Chronic Pain Considerations for medication safety need to include assessment of the likelihood of a patient presenting with chronic pain currently or previously taking an OTC –High or low probability?

–Which OTC medications are most commonly used?

–Short-term effects of OTCs? –Long-term effects of OTCs? –Other risks?

Pain Medication and Safety Acetaminophen –One of the most commonly used drugs in the United States for treating pain and fever1 –In 2005, consumers purchased more than 28 billion doses of products containing acetaminophen • Acetaminophen-containing Rx narcotics represented 11 billion doses • The hydrocodone–acetaminophen combination product has been the most frequently prescribed drug since 1997 Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002 Jan 16; 287(3) 337-44.

Acetaminophen Hepatotoxicity –The mechanism of liver injury is related to the fact that small amounts of acetaminophen are converted to a toxic metabolite • The metabolite binds with liver proteins to cause cellular injury • The amount of metabolite produced and the ability of the liver to remove it before it binds to liver protein influences the extent of liver injury

Acetaminophen (cont’d) FDA News Release1 – January 13, 2011 –“The U.S. Food and Drug Administration is asking manufacturers of prescription combination products that contain acetaminophen to limit the amount of acetaminophen to no more than 325 milligrams (mg) in each tablet or capsule” –“The FDA also is requiring manufacturers to update labels of all prescription combination acetaminophen products to warn of the potential risk for severe liver injury” US Food and Drug Administration, FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm accessed 6/3/2012

Acetaminophen (cont’d)  “FDA is taking this action to make prescription combination pain medications containing acetaminophen safer for patients to use,” said Sandra Kweder, M.D., deputy director of the Office of New Drugs in FDA’s Center for Drug Evaluation and Research (CDER)  “Overdose from prescription combination products containing acetaminophen account for nearly half of all cases of acetaminophen-related liver failure in the United States; many of which result in liver transplant or death”

Acetaminophen (cont’d)  From 1998 to 2003, acetaminophen was the leading cause of acute liver failure in the United States1  Unchanged in 2007 CDC survey2  Most of the cases of severe liver injury occurred: – In patients who took more than the prescribed dose of an acetaminophen-containing product in a 24-hour period – Took more than one acetaminophen-containing product at the same time – Drank alcohol while taking acetaminophen products 1. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Lee WM et al. Acute Liver Failure Study Group (ALFSG).

Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005 Dec; 42(6):1364-72.

2. Bower WA, Johns M, Margolis, HS, Williams IT, Bell B. Population-based surveillance for acute liver failure. Am J Gastroenterology. 2007;102:2459-63.

Acetaminophen (cont’d) The CDC study in 20071 also corroborated earlier data from 1998-20032 finding that a high percentage of cases of acetaminophen liver injury were related to unintentional overdose

1. Bower WA, Johns M, Margolis, HS, Williams IT, Bell B. Population-based surveillance for acute liver failure. Am J Gastroenterology.

2007;102:2459-63.

2. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Lee WM et al. Acute Liver Failure Study Group (ALFSG). Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005 Dec; 42(6):1364-72.

Acetaminophen (cont’d)  Why do overdoses occur?

– Acetaminophen has a relatively narrow safety margin – Patient variability • The maximum daily amount of acetaminophen that can be safely tolerated may not be the same for all patients

– Symptoms associated with acetaminophen liver injury can be insidious, even in severe cases • Additionally, symptoms may be non-specific and mimic flu-like symptoms, actually resulting in the individual continuing to use the acetaminophen1 1.US Food and Drug Administration, Acetaminophen Overdose and Liver Injury — Background and Options for Reducing Injury http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyand RiskManagementAdvisoryCommittee/UCM164897.pdf accessed 6/3/2012

Acetaminophen (cont’d)  Overdoses (cont’d) – Many different types of OTC and Rx products exist in a wide range of doses for a variety of different indications • Consumers may attempt to treat different conditions or symptoms at the same time with more than one product containing acetaminophen and may not realize that acetaminophen is in each of those products

– People aren’t educated about risks – Difficult to identify (eg, APAP1)

1. N-acetyl-para-aminophenol

Pain Medications and Safety Non-steroidal Anti-inflammatory Drugs (NSAIDs) –One of the “mainstays” of treatment for arthritic conditions for more than three decades –Block the cyclooxygenase (COX) enzymes and reduce prostaglandins throughout the body • Commonly used to effect reduction of ongoing inflammation, pain, and fever • Prostaglandins that protect the stomach lining and support platelet function and blood clotting are also reduced

NSAIDs  More than 50% of Americans use on a frequent basis in both OTC and prescription formulations  More than 17 million Americans use various NSAIDs on a daily basis  One of the most commonly used drugs in the world  The Centers for Disease Control predicts that with the “aging” of the US population, there will be a significant increase in the prevalence of painful degenerative and inflammatory rheumatic conditions which will likely lead to a parallel increase in the use of NSAIDs

NSAIDs (cont’d)  Chronic NSAID use can be associated with significant risks including: – Renal function – Gastro-intestinal (GI) bleeding – Hepatic function – Cardiovascular complications • Myocardial infarction • Angina • Hypertension

NSAIDs (cont’d) A recent report has shown that 86% of osteoarthritis patients seen by rheumatologists are at increased GI risk and that almost half of them are at high cardiovascular risk1 –The same study reported that it found “a high proportion of

NSAID prescriptions that are not considered appropriate according to recommendations given by professional scientific societies and regulatory agencies” 1. Lanas A, Tornero J, Zamorano JL: Assessment of gastrointestinal and cardiovascular risk in patients with osteoarthritis who require NSAIDs: the LOGICA study. Ann Rheum Dis 2010, 69:1453-1458.

NSAIDs (cont’d)  It has been estimated that from approximately 5 to 7 percent of all hospital admissions are related to adverse effects of drugs – A UK study found 30% of these hospitalizations result from gastrointestinal, nervous system, renal, or allergic effects of aspirin or nonaspirin NSAIDs1

 An old survey estimated in 19992 that 16,500 patients with rheumatoid arthritis or osteoarthritis alone died of, and 103,000 were hospitalized because of NSAID-related GI bleeding the United States each year – This has largely remained unchanged 1. Pirmohamed M, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ. 2004;329(7456):15.

2. Singh G, Triadafilopoulos G: Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol. 1999;26(Suppl):18–24.

NSAIDs (cont’d)  NSAIDs are generally not recommended for people with a variety of common conditions: – Renal disease – Coronary artery disease • Prior MI

– Congestive heart failure – Cirrhosis – Patients on diuretic therapy – Aspirin allergy – Pregnant patients in 3rd trimester

NSAIDs – Are They Ever Safe?  The American College of Rheumatology1 recommends that NSAIDs should be avoided in people who: – – – – – – – – – – – – –

Have decreased kidney or liver function, or an uncontrolled or undiagnosed liver problem (e.g., hepatitis) Have had a recent ulcer, gastritis, or bleeding from the intestinal tract or have had these problems in the past Take blood thinners like warfarin, heparin, aspirin, or other anticoagulants Take steroids Have a low platelet count Have Crohn’s disease or ulcerative colitis Have a history of stroke, heart attack, hypertension, or congestive heart failure Have asthma or chronic lung disease Are allergic to aspirin or other NSAIDs, or have nasal polyps Have "reflux disease," indigestion or hiatal hernia Are pregnant, may become pregnant, or breast feeding Drink more than seven alcoholic drinks per week or more than two in a day Are over the age of 65 1. American College of Rheumatology. Information for Patients about NSAIDs. http://www.rheumatology.org/practice/clinical/patients/medications/nsaids.asp accessed 6/3/12.

Pain Medications and Safety  Opioids – Opioids have become the most commonly prescribed drug category in the United States1 – In primary and specialty care, chronic nonmalignant pain is common, with 20% to 40% of adults reporting chronic pain2 • If you include malignant pain, more than 1 of every 2 medical visits is pain related

– Opioids are the most common means of treatment for chronic pain1 • 15% to 20% of office visits in the U.S. now include the prescription of an opioid2 1. Grady et al. Opioids for Chronic Pain. Arch Internal Medicine Vol. 171 (No. 16), Sep 12, 2011 1426-1427 2. American Pain Society. Guideline for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain: Evidence Review. Glenview, IL: American Pain Society; 2009.

Opioids Do chronic pain patients expect a prescription? Do health care providers have the same expectation?

–“It is often impossible for patients and physicians alike to imagine ending a clinical encounter without a medication prescription • And for most doctors, it is equally unimaginable not to turn to the most up-to-date drugs in trying to do the right thing for the patient”1 1. Schiff et al. Principles of Conservative Prescribing. Arch Internal Medicine Vol. 171 (No. 16), Sep 12, 2011 1433-1440.

Opioid Analgesics “Pain reliever hydrocodone with acetaminophen (APAP) was the most widely prescribed individual medication, accounting for 124 million prescriptions in 2008�

Opioid Risk Old definition –The potential for opioid analgesia adverse effects • Constipation • Nausea/Vomiting • Dry mouth • Itching • Sweating

–Respiratory Depression

Opioid Risk New definition –Adverse effects –Aberrant drug-related behavior • Abuse • Misuse • Diversion • Addiction

– Unintended Deaths

Unintentional Overdose Deaths Involving Opioid Analgesics, Cocaine, and Heroin United States, 1999–2007

Source: CDC Public Health Grand Rounds 2.18.2011 Data from the National Vital Statistics System. http://wonder.cdc.gov, multiple cause dataset

Public Health Impact Of Opioid Analgesic Use: For Every 1 Overdose Death There Are Abuse treatment admissions

9

ED visits for misuse or abuse

35

People with abuse/dependence

161

Nonmedical users

461 0

50

100 150 200 250 300 350 400 450 500

Slide from CDC Grand Rounds 2.18.11. Treatment admissions are for primary use of opioids from the Treatment Exposure Data Set. Abuse dependence and nonmedical use are from the Natl Survey on Drug Use and Health https://dawninfo.samhsa.gov/default.aspEmergency department (ED) visits are from DAWN (Drug Abuse Warning Network)

Dependent on Prescription Drugs, Even Before Birth

By ABBY GOODNOUGH and KATIE ZEZIMA New York Times Published: April 9, 2011

Safe and Appropriate Use What does this mean?

–Risk factors •What does risk mean?

–Prior experiences –Comfort level of all parties involved –Education –The Law

Opioid REMS  Prescription opioids continue to be an increasing problem with respect to adverse events & abuse  Prescription opioid abuse contributes to crime & violence  Inadequate patient supervision following prescription of opioids, leading to: – Overdose – Iatrogenic addiction – Continued dosing in patients who no longer need treatment – Recreational use (including high school and college students)

The REMS Rationale “The FDA believes that establishing a REMS for opioids will reduce these risks, while still ensuring that patients with legitimate need for these drugs will continue to have appropriate access” “The REMS would be intended to ensure that the benefits of these drugs continue to outweigh certain risks”

Safety and Opioids  A comprehensive assessment is an important part of the process to guide therapeutic decision making for safe and appropriate use of opioids and includes: – History and physical examination – Patient’s and Family’s substance abuse history – Pain assessment – Appropriate testing – Assessment of risk potential for: • Substance abuse • Misuse • Addiction

Substance Abuse History  Substance abuse history is the strongest predictor of abuse, misuse, or other aberrant drug-related behavior1 – Should include: • Personal and Family history of: – Substance abuse or addiction – Alcohol – Tobacco

• Patient’s history of taking prescription and non-prescription pain medications • Any legal history related to substance abuse – Arrests or imprisonment – DUI convictions 1. Edlund MJ, Steffick D, Hudson T, Harris KM, Sullivan M: Risk factors for clinically recognized opioid abuse and dependence among veterans using opioids for chronic non-cancer pain. Pain 129:355-362, 2007

Roles and Responsibilities Health care provider responsibilities –Consider patient needs • A number of factors related specifically to the chronic pain condition can impact patient needs, including: –Type of pain –Quality of pain –Duration and intensity –Affected area(s) –Prognosis –Coexisting conditions (e.g., Cancer, Depression) –Other factors

Roles and Responsibilities (cont’d) Health care provider responsibilities (cont’d) –Assess risk •Drug-drug interactions •Physiology •Adherence •Aberrant behavior –Including misuse

Roles and Responsibilities (cont’d) Health care provider responsibilities (cont’d) –Consider patient’s OTC use •Inquire about it –High likelihood of use

•Assess impact (e.g., renal function) •Reinforce communication about OTC use and non-painrelated conditions and hazards of unintended overdose

Roles and Responsibilities (cont’d) Health care provider responsibilities (cont’d) –When it comes to opioids follow a reproducible framework •Universal Precautions •Opioid Risk Assessment •APS/AAPM Guidelines •State Guidelines (e.g., Utah) •Documentation, Documentation, Documentation

Roles and Responsibilities (cont’d)  Health care provider responsibilities (cont’d) – Patient education including: • Medication safety – Recognition of adverse effects – “Take as directed” – Informed consent » Whatever works – Agreements when appropriate » Recommended for opioids – Storage – Sharing prescription medications and legal issues

Roles and Responsibilities (cont’d)  Patient responsibilities – Active role vs. passive one – Safe practices • Storage • Disposal • Sharing • Abuse/misuse • OTC use

Medication Safety and Managing Pain