- Email: [email protected]
Acetaminophen Overuse in the Ohio Medicaid Population
RESEARCH
Acetaminophen Overuse in the Ohio Medicaid Population Pamela C. Heaton, Robert J. Cluxton Jr., and Charles J. Moomaw
Objective: To examine patterns of use of acetaminophen in patients with and without risk factors for hepatotoxicity in the Ohio Medicaid population. Design: Retrospective, cross-sectional analysis of claims data. Setting: Ohio. Patients: Ohio Medicaid patients (n = 22,496) who received at least 6 prescriptions for acetaminophen from November 1998 through April 1999. Main Outcome
Measure: Overuse of acetaminophen, defined as an average daily dose (ADD) greater than or equal to 4 grams/day or an ADD of greater than or equal to 3 grams/day along with diagnosis codes suggesting underlying liver dysfunction. Results: We identified 687 patients (3.05%) who received either greater than or equal to 4 grams/day or greater than or equal to 3 grams/day and had diagnosis codes suggesting underlying liver dysfunction (n = 128). Conclusion: Although the number is relatively small, some Ohio Medicaid patients are receiving acetaminophen doses that exceed safety recommendations. Because acetaminophen overuse is the leading cause of liver failure, health care professionals should be alert to the possibility of acetaminophen overuse.
Keywords: Acetaminophen, adverse effects, hepatotoxicity, liver failure, Medicaid utilization, retrospective studies, database research. J Am Pharm Assoc. 2003;43:680–4.
Acetaminophen is one of the most commonly used drugs in the United States. In 1999 it was mentioned 36.3 million times in physicians’ offices, making it the most frequently mentioned generic medication, and it was prescribed 11.3 million times, ranking it eighth among the most often prescribed medications.1 It is a relatively safe drug, low in cost and widely available. However, each year intentional and unintentional acetaminophen overdoses do occur. Using data compiled from 1990 through 1999, the U.S. Food and Drug Administration (FDA) estimated that acetaminophen overuse results in an average of 458 deaths, 26,256 hospitalizations, and 56,680 emergency department (ED) visits each year. For this same period, FDA estimated that a yearly average of 100 deaths, 2,189 hospitalizations, and 13,036 ED visits occur because of unintentional acetaminophen overdoses.2 Produced by numerous manufacturers, acetaminophen is availReceived December 13, 2002, and in revised form May 30, 2003. Accepted for publication August 4, 2003. Pamela C. Heaton, RPh, PhD, is assistant professor; Robert J. Cluxton Jr., PharmD, is associate professor, Division of Pharmacy Practice, College of Pharmacy, University of Cincinnati, Cincinnati, Ohio. Charles J. Moomaw, PhD, is research associate, Institute for Health Policy and Health Services Research, University of Cincinnati Medical Center, Cincinnati, Ohio. Correspondence: Pamela C. Heaton, RPh, PhD, College of Pharmacy, University of Cincinnati, 3223 Eden Avenue, Cincinnati, OH 45267-0004. Fax: 513-558-0731. E-mail: [email protected].
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able in both over-the-counter (OTC) and prescription products. It comes in a wide range of doses and in various dosage forms. It is in part because of this wide availability that overdoses have occurred, either because patients took too much of a single product or combined multiple products containing acetaminophen. Multiplicity is a particular problem given the variety of OTC cough and cold products that contain acetaminophen. Acetaminophen is the most common drug to cause hepatotoxicity. In a study of 308 acute liver failure cases at 17 tertiary care centers participating in the United States Acute Liver Failure Study Group, 39% were linked to acetaminophen, whereas 13% were linked to all other medications.3 Although there have been case reports of patients with no risk factors taking chronic therapeutic doses who developed hepatotoxicity,4 the majority of cases have involved patients taking chronic high doses,5 alcoholic patients,6,7 patients with underlying liver disease,8 or patients taking medications that induce cytochrome P450 2E1 enzymes. Also, evidence exists that patients who are fasting or have a low nutritional status may also be at risk for developing hepatotoxicity.9 Alcoholic, fasting, and low nutritional status patients are at risk because they have low levels of stored glutathione. Recently, FDA recommended strengthening the warning concerning hepatotoxicity on the labels of OTC acetaminophen-containing products.10 Long-term use of acetaminophen may also lead to chronic renal disease.11,12 Recommended maximum daily doses for acetaminophen vary. Drug Facts and Comparisons states the maximum daily dose is
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4 grams.13 The Textbook of Adverse Drug Reactions recommends giving less than 2 grams a day to patients who drink more than 60 grams/day of ethanol.14 Since 1998 OTC labeling on acetaminophen products has warned that patients who have three or more alcoholic drinks daily should not take acetaminophen at all.
Objective No population-based studies have been conducted on the overuse of acetaminophen. Our objective was to examine patterns of acetaminophen use in patients with and without risk factors for hepatotoxicity in the Ohio Medicaid population.
Methods Design, Setting, and Patients This study was a retrospective cross-sectional analysis of Medicaid claims data obtained from the Ohio Department of Jobs and Family Services. The sample included all fee-for-service (FFS) Medicaid beneficiaries who received at least six acetaminophen-containing prescriptions between November 1, 1998 and April 30, 1999. At least one of these prescriptions must have been filled during the last 2 months of the study period. The reason for this restriction was that this information was ultimately to be used as data for a drug utilization review (DUR) for the Ohio DUR Committee, which was looking for “current” problems, not patients who had problems several months before. In fiscal year 1999, 1,387,581 Ohio residents were enrolled in Medicaid (i.e., determined eligible and issued a Medicaid card) and 1,230,510 individuals received services.15 Eligible persons can be grouped into two general categories: Covered Families and Children (CFC) and people who are Aged, Blind, or Disabled (ABD). CFC beneficiaries can opt to be in a capitated (health maintenance organization [HMO]) or fee-for-service (FFS) program. In 1999, of all eligible beneficiaries, 32% opted for an HMO and 68%, comprising both ABD (31%) and CFC (37%) beneficiaries, chose the FFS program. Capitated recipients cannot be included in the study sample because their claim records do not include billing details such as National Drug Code codes or International Classification of Diseases 9 (ICD.9.CM) codes. Acetam inophen U se Patterns For patients who met the selection criteria, we identified their most recent acetaminophen-containing prescription, counted back 180 days from the date of that prescription, and found within that 180-day window their oldest prescription. We then calculated average daily dose (ADD) as mg/day by dividing the total milligrams of acetaminophen dispensed during the 180-day window (excluding the amount dispensed at the most recent fill) by the number of days between the oldest and most recent prescriptions.
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RESEARCH
We identified patients who had an ADD of at least 4 grams per day; we also identified patients who had an ADD of as low as 3 grams per day if they also had a diagnosis suggesting possible liver dysfunction. Such patients were identified by screening institutional and medical claims for specific ICD.9.CM16 diagnosis codes (see Appendix 1). We did not go as low as 2 grams per day because we were concerned that level would generate too many false positives. All acetaminophen-containing products covered by the state of Ohio were included in the review. The majority of these products are prescription pain medications and prescription cough and cold medications. Medicaid covers some OTC cough and cold products that contain acetaminophen, such as Tylenol Severe Allergy (McNeil). However, OTC acetaminophen-only products, either in liquid, drops, or solid oral forms, are not covered. The only nonprescription acetaminophen-only products that are covered are rectal suppositories.
Analysis We used descriptive statistics to summarize the data. Frequency tables were generated for sex, ethnicity, and age groups. Means, standard deviations (SDs), medians, and ranges were calculated for the number of different pharmacy providers, number of different prescribing physicians, and number of ED visits.
Results We identified 22,496 patients who met the study inclusion criteria. These patients received 236,772 acetaminophen prescriptions during the 6-month period, visited a mean ± SD of 2.47 ± 1.95 (range 1-30; median = 2) different pharmacies; saw 4.07 ± 3.04 (range 1-38; median = 3) different physicians; and had a mean of 3.25 ± 3.96 (range 1-56; median = 2) ED visits. Among the 22,496 patients, 687 patients (3%), receiving a mean of 20.15 ± 10.92 (range, 6-84; median = 17) acetaminophen prescriptions over the 6-month period, met one or both of the criteria for acetaminophen overuse. About 5% of these prescriptions contained only acetaminophen; the remaining prescriptions were for combination products. Table 1 shows the distribution of acetaminophen-containing products. Almost 50% of these prescriptions contained propoxyphene. Demographically, 68% of the overusers were women; 85% were white, and 14% were African American. The overusers were significantly more likely to be men, white, and between the ages of 40 and 59, and less likely to have reached the age of 80. Table 2 shows the demographics of the sample. Of the 687 overusers, 606 patients, receiving a mean of 20.57 ± 10.97 (range, 6-84; median = 17.5) prescriptions, used acetaminophen at a rate exceeding 4 grams/day; among them, 47 patients also had an underlying liver problem. Another 81 patients with liver problems used acetaminophen at a rate of 3 grams/day
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to 4 grams/day over the 6-month study period. Thus, a total of 128 patients, receiving a mean of 18.35 ± 9.98 (range, 6-51; median = 16) prescriptions, had diagnoses suggesting liver problems. The distribution of grams per day average daily dose is detailed in Table 3. Table 4 delineates the type of disease contraindication and the distributions of ADD. Only the diseases associated with highutilizing patients are listed.
Table 1. Distribution of Acetaminophen-Containing Products DEA Schedule
Drug
Frequency
%
Codeine and dihydrocodeine oral
5
14
0.10
Pentazocine
4
142
1.03
Codeine and dihydrocodeine oral
3
550
3.97
NA
735
5.31
Acetaminophen only Oxycodone oral
2
1,637
11.83
Hydrocodone oral
3
4,286
30.97
Propoxyphene oral
4
6,477
46.79
DEA = Drug Enforcement Administration; NA = not applicable.
Discussion A relatively small number of patients were taking more than 4 grams of acetaminophen per day. It is striking, however, that these overusers received an average of 20 prescriptions containing acetaminophen over a 6-month period. Most of these prescriptions were combination products containing narcotics. One possible explanation could be that particular patients were “drug shopping” and intended to sell medications they received; however, this is a sizeable number of prescriptions to obtain without a physician or pharmacist becoming aware of a problem. The total amount of acetaminophen these patients were receiving is probably underestimated. It is also conceivable that patients were taking OTC acetaminophen concomitantly with their prescription products. For example, patients taking chronic doses for osteoarthritis might be unaware that cough and cold products they take for their cold symptoms also contain acetaminophen. This problem is of particular concern for elderly patients.17 Only 128 patients appeared to have an underlying liver problem. This number, too, is most likely an underestimate. Only patients whose physicians had documented a problem with a diagnosis code could be identified. The federal Substance Abuse and Mental Health Services Administration estimates that 104 million people (46.6%), almost half of all Americans age 12 or older, currently drink alcohol. The agency also reports that 46 million people (26.6%) participated in binge drinking at least once in the 30 days
Table 2. Patient Demographics % All Patients (n = 22,496)
% Acetaminophen Overusers (n = 687)
% Acetaminophen Nonoverusers (n = 21,809)
Men
26.75
32.02
26.59
.0019 b
Ethnicity White African American Other
80.30 18.59 1.12
85.15 13.83 1.02
80.15 18.74 1.12
.0009 b .0010 b 1.0
Age, years < 40 40–59 60–79 80
19.99 42.71 24.66 12.64
19.21 52.55 23.00 5.24
20.01 42.40 24.71 12.88
.6283 < .0001 b 0.3,228 < .0001 b
Characteristic
Pa
a Two-sided Fisher exact test. b Significant at P < .01.
Table 3. Overuse of Acetaminophen
No. of Recipients
No. of Acetaminophen Prescriptions
4–5.99
510
9,823
19.26 ± 9.47 (16.5)
6–7.99
78
2,067
26.50 ± 13.42 (25.0)
8–9.99
12
295
24.58 ± 16.13 (23.0)
10–11.99
1
65
>12
5
215
43.00 ± 23.18 (35.0)
606
12,465
20.57 ± 10.97 (17.5)
Use in 180-Day Period (grams/day)
Total
Acetaminophen Prescriptions Mean ± SD (Median) per Recipient
65.00 ± 0
SD = standard deviation.
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Table 4. Type of Disease Contraindication Versus Acetaminophen Use 3–3.99 Grams/Day
4–5.99 Grams/Day
6–7.99 Grams/Day
8–9.99 Grams/Day
10–11.99 Grams/Day
> 12 Grams/Day
Other disorders of liver (573)
26
13
1
—
—
—
40
Alcohol dependence syndrome (303)
26
12
1
—
—
1
40
Chronic liver disease and cirrhosis (571)
25
10
2
1
—
—
38
Viral hepatitis (070)
Disease (ICD-9 Code)
Total
25
10
2
—
—
—
37
Hepatomegaly not otherwise specified (789.1)
3
6
1
—
—
—
10
Alcoholic psychoses (291)
2
2
—
—
—
—
4
Liver abscess and sequelae of chronic liver disease (572)
2
1
1
—
—
—
4
Acute and subacute necrosis of liver (570)
1
—
—
—
—
—
1
81
38
7
1
0
1
128
Total (per unique recipient)a
ICD = International Classification of Diseases. a Thirty-five recipients appear in multiple disease categories.
before they took the survey. Of all Americans age 12 or older, 12.6 million (5.6%) are heavy drinkers. The estimates for 2000 were almost identical to the 1999 estimates.18 Despite the risk of hepatotoxicity with high doses of acetaminophen, annual toxicity deaths from nonsteroidal antiinflammatory drugs exceed those caused by acetaminophen.19 Our results show only a small number of patients receiving high chronic doses of acetaminophen, with most (84%) of these high users receiving between 4 grams and 6 grams per day, which is less likely to be toxic than higher doses. Risk of acetaminophen-related toxicity may be minimized because primary care physicians’ overall knowledge of acetaminophen toxicity is excellent20 and pharmacists are well trained to provide patients with the necessary information to improve health outcomes and reduce potential problems. Action from governmental drug agencies may also help control toxicity risk. In the United Kingdom, for example, acetaminophen must be packaged in blister packs, which limits the total number of tablets that can be dispensed.21,22 In the United States, as recently as September 2002, FDA suggested that increased education of consumers is warranted to lessen the risk for unintentional hepatotoxicity from acetaminophen.23
cific codes, changing codes, or outcomes poorly defined by ICD9 codes. Despite these potential biases, observational studies clearly depict actual utilization patterns, which reflect patient as well as prescriber behavior. Medicaid pharmacy claims are perhaps the most reliable and valid data source for Medicaid patients; in one validation study, the correspondence between medical records and Medicaid pharmacy claims was 94%.25 Another limitation is that the study design rested on the assumption that a prescription filled is a prescription consumed. Thus, we were possibly overestimating an already small number of acetaminophen overusers.
Limitations
The authors declare no conflicts of interest or financial interest in any product or service mentioned in the article, including grants, employment, gifts, stock holdings, or honoraria.
This study is limited by the classic concerns that arise from large claims database analysis, such as selection bias and misclassification bias.24 Selection bias may occur because patients whose information is in retrospective, observational databases cannot be randomized to receive or not receive certain interventions or medications. Misclassification bias may occur through the use of nonspe-
This project was funded by a grant through an interagency agreement between the Ohio Department of Jobs and Family Services (ODJFS) and the Ohio Board of Regents (OBR) through the Medicaid Technical Assistance and Policy Program (MEDTAPP), Grant #A-98-07-001. The conclusions and opinions expressed do not necessarily represent the official views or opinions of ODJFS, OBR, or MEDTAPP.
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Conclusion Acetaminophen is a relatively safe drug that is prescribed extensively. Acetaminophen overuse, however, is the leading cause of liver failure. In the Ohio Medicaid population, only about 3% of patients who filled at least 6 acetaminophen-containing prescriptions in a 6-month period received greater than 4 grams per day. Despite these small numbers, health care professionals should be alert to the possibility of acetaminophen overuse leading to avoidable hepatotoxicity.
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References 1. Fast Stats A to Z. Therapeutic Drug Use. 1999. National Center for Health Statistics Web site. Avalable at: www.cdc.gov/nchs/ fastats/drugs.htm. Accessed October 1, 2003. 2. Parivash N, Ahmad SR, Karwoski CB. Safety analysis of acetaminophen (APAP)-associated hepatotoxicity. Presented at: Nonprescription Drugs Advisory Committee meeting; Bethesda, Md. September 19, 2002. Available at: www.fda.gov/ohrms/dockets/ac/02/slides/3882S1_05_ Nourjah-Ahmad-Karwoski.pdf. Accessed October 1, 2003. 3. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med. 2002;137:947-54. 4. Kwan D, Bartle WR, Walker SE. Abnormal serum transaminases following therapeutic doses of acetaminophen in the absence of known risk factors. Dig Dis Sci. 1995;40:1951-5. 5. Barker JD, DeCarle DJ, Anuras S. Chronic excessive acetaminophen use and liver damage. Ann Intern Med. 1977;87:299-301. 6. Leist MH, Gluskin LE, Payne JA. Enhanced toxicity of acetaminophen in alcoholics: report of three cases. J Clin Gastroenterol. 1986;7:55-9. 7. McClain CJ, Kromhout JP, Peterson FJ, Holtzman JL. Potentiation of acetaminophen hepatotoxicity by alcohol. JAMA. 1980;244:251-3. 8. McClain CJ, Holtzman J, Allen J, et al. Clinical features of acetaminophen toxicity. J Clin Gastroenterol. 1988;10:76-80. 9. Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA. 1994;272;1845-50. 10. Fored CM, Ejerblad E, Linbblad P, Fryzek JP. Acetaminophen, aspirin and chronic renal failure. N Engl J Med. 2001;345:1801-8. 11. Acetaminophen safety. Med Lett Drugs Ther. October 28, 2002:91. 12. Perneger TV, Whelton PK, Klag MJ. Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs. N Engl J Med. 1994;331:1675-9. 13. Drug Facts and Comparisons. St. Louis, Mo: Facts and Comparisons; 2001:827. 14. Davies DM, Ferner RE, de Glanville H, eds. Textbook of Adverse Drug Reactions. 5th ed. New York, NY: Chapman & Hall Medical; 1998:282. 15. Ohio Medicaid Report. 3rd edition. Columbus, Ohio: Ohio Department of Job and Family Services; 2001. Available at: www.state.oh.us/odjfs/ ohp/bhpp/reports/omr1999/omr1.pdf. Accessed October 1, 2003. 16. International Classification of Diseases, Ninth Revision, Clinical Modification. 4th ed. Los Angeles, Calif: Practice Management Information Corp; 1994. 17. Ruoff GR. Management of pain in patients with multiple health problems: a guide for the practicing physician. Am J Med. 1998;105;53S60S. 18. Alchol use. In: Summary of Findings from the 2000 National Household Survey on Drug Abuse. Rockville, Md: Substance Abuse and Mental Health Services Administration; 2001. Available at: www.samhsa.gov/ oas/NHSDA/2KNHSDA/Chapter3htm. Accessed October 7, 2003. 19. Aronson MD. Nonsteroidal anti-inflammatory drugs, traditional opioids, and tramadol: contrasting therapies for the treatment of chronic pain. Clin Ther. 1997;19:420-32. 20. Quallich LG, Brown W, Shehab TM, Fontana RJ. Management of acetaminophen hepatotoxicity: a survey of practicing physicians. J Clin Outcomes Manage. 2001;8:25-32. 21. Hawton K, Ware C, Mistry H, et al. Paracetamol self-poisoning: characteristics, prevention and harm reduction. Br J Psychiatry. 1996;168:438.
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22. Cranney M, Cranney J, Stubbs H. Limitation of over the counter sales of paracetamol: packaging policy is unlikely to achieve its aim of reducing suicide [letter]. BMJ. 1998;317:1657. 23. Ganley J. Issue: unintentional acetaminophen hepatotoxicity. Presented at: Nonprescription Drugs Advisory Committee meeting; Bethesda, Md. September 19, 2002. Available at: www.fda.gov/ohrms/ dockets/ac/02/slides/3882s1_01_Ganley.pdf. Accessed: October 7, 2003. 24. Strom BL, Carson JL. Use of automated databases for pharmacoepidemiology research. Epidemiol Rev. 1990;12:87-107. 25. Bright RA, Avorn J, Everitt DE. Medicaid data as a resource for epidemiologic studies: strengths and limitations. J Clin Epidemiol. 1989;42:937-45.
Appendix 1. ICD-9 Codes Used in Defining Disease Contraindications Code
Description
303
Alcohol dependence syndrome
304
Drug dependence
305
Nondependent abuse of drugs
292
Drug withdrawal
291
Alcoholic psychoses
570
Acute and subacute necrosis of liver
571
Chronic liver disease and cirrhosis
572
Liver abscess and sequelae of chronic liver disease
573
Other disorders of liver
070.0–070.9 Viral hepatitis 277.3
Amyloid or lardaceous degeneration of liver
751.62
Congenital cystic disease of liver
271.0
Glycogen infiltration of liver
789.1
Hepatomegaly not otherwise specified
452
Portal vein obstruction
095.3
Hepatitis in late syphilis
091.62
Hepatitis in secondary syphilis
130.5
Hepatitis in toxoplasmosis
V02.6
Viral hepatitis
V02.60
Viral hepatitis carrier, unspecified
V02.61
Hepatitis B carrier
V02.62
Hepatitis C carrier
V02.69
Other viral hepatitis carrier
ICD = International Classification of Diseases. Source Reference 18.
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Acetaminophen Overuse in the Ohio Medicaid Population Pamela C. Heaton, Robert J. Cluxton Jr., and Charles J. Moomaw
Objective: To examine patterns of use of acetaminophen in patients with and without risk factors for hepatotoxicity in the Ohio Medicaid population. Design: Retrospective, cross-sectional analysis of claims data. Setting: Ohio. Patients: Ohio Medicaid patients (n = 22,496) who received at least 6 prescriptions for acetaminophen from November 1998 through April 1999. Main Outcome
Measure: Overuse of acetaminophen, defined as an average daily dose (ADD) greater than or equal to 4 grams/day or an ADD of greater than or equal to 3 grams/day along with diagnosis codes suggesting underlying liver dysfunction. Results: We identified 687 patients (3.05%) who received either greater than or equal to 4 grams/day or greater than or equal to 3 grams/day and had diagnosis codes suggesting underlying liver dysfunction (n = 128). Conclusion: Although the number is relatively small, some Ohio Medicaid patients are receiving acetaminophen doses that exceed safety recommendations. Because acetaminophen overuse is the leading cause of liver failure, health care professionals should be alert to the possibility of acetaminophen overuse.
Keywords: Acetaminophen, adverse effects, hepatotoxicity, liver failure, Medicaid utilization, retrospective studies, database research. J Am Pharm Assoc. 2003;43:680–4.
Acetaminophen is one of the most commonly used drugs in the United States. In 1999 it was mentioned 36.3 million times in physicians’ offices, making it the most frequently mentioned generic medication, and it was prescribed 11.3 million times, ranking it eighth among the most often prescribed medications.1 It is a relatively safe drug, low in cost and widely available. However, each year intentional and unintentional acetaminophen overdoses do occur. Using data compiled from 1990 through 1999, the U.S. Food and Drug Administration (FDA) estimated that acetaminophen overuse results in an average of 458 deaths, 26,256 hospitalizations, and 56,680 emergency department (ED) visits each year. For this same period, FDA estimated that a yearly average of 100 deaths, 2,189 hospitalizations, and 13,036 ED visits occur because of unintentional acetaminophen overdoses.2 Produced by numerous manufacturers, acetaminophen is availReceived December 13, 2002, and in revised form May 30, 2003. Accepted for publication August 4, 2003. Pamela C. Heaton, RPh, PhD, is assistant professor; Robert J. Cluxton Jr., PharmD, is associate professor, Division of Pharmacy Practice, College of Pharmacy, University of Cincinnati, Cincinnati, Ohio. Charles J. Moomaw, PhD, is research associate, Institute for Health Policy and Health Services Research, University of Cincinnati Medical Center, Cincinnati, Ohio. Correspondence: Pamela C. Heaton, RPh, PhD, College of Pharmacy, University of Cincinnati, 3223 Eden Avenue, Cincinnati, OH 45267-0004. Fax: 513-558-0731. E-mail: [email protected].
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able in both over-the-counter (OTC) and prescription products. It comes in a wide range of doses and in various dosage forms. It is in part because of this wide availability that overdoses have occurred, either because patients took too much of a single product or combined multiple products containing acetaminophen. Multiplicity is a particular problem given the variety of OTC cough and cold products that contain acetaminophen. Acetaminophen is the most common drug to cause hepatotoxicity. In a study of 308 acute liver failure cases at 17 tertiary care centers participating in the United States Acute Liver Failure Study Group, 39% were linked to acetaminophen, whereas 13% were linked to all other medications.3 Although there have been case reports of patients with no risk factors taking chronic therapeutic doses who developed hepatotoxicity,4 the majority of cases have involved patients taking chronic high doses,5 alcoholic patients,6,7 patients with underlying liver disease,8 or patients taking medications that induce cytochrome P450 2E1 enzymes. Also, evidence exists that patients who are fasting or have a low nutritional status may also be at risk for developing hepatotoxicity.9 Alcoholic, fasting, and low nutritional status patients are at risk because they have low levels of stored glutathione. Recently, FDA recommended strengthening the warning concerning hepatotoxicity on the labels of OTC acetaminophen-containing products.10 Long-term use of acetaminophen may also lead to chronic renal disease.11,12 Recommended maximum daily doses for acetaminophen vary. Drug Facts and Comparisons states the maximum daily dose is
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4 grams.13 The Textbook of Adverse Drug Reactions recommends giving less than 2 grams a day to patients who drink more than 60 grams/day of ethanol.14 Since 1998 OTC labeling on acetaminophen products has warned that patients who have three or more alcoholic drinks daily should not take acetaminophen at all.
Objective No population-based studies have been conducted on the overuse of acetaminophen. Our objective was to examine patterns of acetaminophen use in patients with and without risk factors for hepatotoxicity in the Ohio Medicaid population.
Methods Design, Setting, and Patients This study was a retrospective cross-sectional analysis of Medicaid claims data obtained from the Ohio Department of Jobs and Family Services. The sample included all fee-for-service (FFS) Medicaid beneficiaries who received at least six acetaminophen-containing prescriptions between November 1, 1998 and April 30, 1999. At least one of these prescriptions must have been filled during the last 2 months of the study period. The reason for this restriction was that this information was ultimately to be used as data for a drug utilization review (DUR) for the Ohio DUR Committee, which was looking for “current” problems, not patients who had problems several months before. In fiscal year 1999, 1,387,581 Ohio residents were enrolled in Medicaid (i.e., determined eligible and issued a Medicaid card) and 1,230,510 individuals received services.15 Eligible persons can be grouped into two general categories: Covered Families and Children (CFC) and people who are Aged, Blind, or Disabled (ABD). CFC beneficiaries can opt to be in a capitated (health maintenance organization [HMO]) or fee-for-service (FFS) program. In 1999, of all eligible beneficiaries, 32% opted for an HMO and 68%, comprising both ABD (31%) and CFC (37%) beneficiaries, chose the FFS program. Capitated recipients cannot be included in the study sample because their claim records do not include billing details such as National Drug Code codes or International Classification of Diseases 9 (ICD.9.CM) codes. Acetam inophen U se Patterns For patients who met the selection criteria, we identified their most recent acetaminophen-containing prescription, counted back 180 days from the date of that prescription, and found within that 180-day window their oldest prescription. We then calculated average daily dose (ADD) as mg/day by dividing the total milligrams of acetaminophen dispensed during the 180-day window (excluding the amount dispensed at the most recent fill) by the number of days between the oldest and most recent prescriptions.
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We identified patients who had an ADD of at least 4 grams per day; we also identified patients who had an ADD of as low as 3 grams per day if they also had a diagnosis suggesting possible liver dysfunction. Such patients were identified by screening institutional and medical claims for specific ICD.9.CM16 diagnosis codes (see Appendix 1). We did not go as low as 2 grams per day because we were concerned that level would generate too many false positives. All acetaminophen-containing products covered by the state of Ohio were included in the review. The majority of these products are prescription pain medications and prescription cough and cold medications. Medicaid covers some OTC cough and cold products that contain acetaminophen, such as Tylenol Severe Allergy (McNeil). However, OTC acetaminophen-only products, either in liquid, drops, or solid oral forms, are not covered. The only nonprescription acetaminophen-only products that are covered are rectal suppositories.
Analysis We used descriptive statistics to summarize the data. Frequency tables were generated for sex, ethnicity, and age groups. Means, standard deviations (SDs), medians, and ranges were calculated for the number of different pharmacy providers, number of different prescribing physicians, and number of ED visits.
Results We identified 22,496 patients who met the study inclusion criteria. These patients received 236,772 acetaminophen prescriptions during the 6-month period, visited a mean ± SD of 2.47 ± 1.95 (range 1-30; median = 2) different pharmacies; saw 4.07 ± 3.04 (range 1-38; median = 3) different physicians; and had a mean of 3.25 ± 3.96 (range 1-56; median = 2) ED visits. Among the 22,496 patients, 687 patients (3%), receiving a mean of 20.15 ± 10.92 (range, 6-84; median = 17) acetaminophen prescriptions over the 6-month period, met one or both of the criteria for acetaminophen overuse. About 5% of these prescriptions contained only acetaminophen; the remaining prescriptions were for combination products. Table 1 shows the distribution of acetaminophen-containing products. Almost 50% of these prescriptions contained propoxyphene. Demographically, 68% of the overusers were women; 85% were white, and 14% were African American. The overusers were significantly more likely to be men, white, and between the ages of 40 and 59, and less likely to have reached the age of 80. Table 2 shows the demographics of the sample. Of the 687 overusers, 606 patients, receiving a mean of 20.57 ± 10.97 (range, 6-84; median = 17.5) prescriptions, used acetaminophen at a rate exceeding 4 grams/day; among them, 47 patients also had an underlying liver problem. Another 81 patients with liver problems used acetaminophen at a rate of 3 grams/day
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to 4 grams/day over the 6-month study period. Thus, a total of 128 patients, receiving a mean of 18.35 ± 9.98 (range, 6-51; median = 16) prescriptions, had diagnoses suggesting liver problems. The distribution of grams per day average daily dose is detailed in Table 3. Table 4 delineates the type of disease contraindication and the distributions of ADD. Only the diseases associated with highutilizing patients are listed.
Table 1. Distribution of Acetaminophen-Containing Products DEA Schedule
Drug
Frequency
%
Codeine and dihydrocodeine oral
5
14
0.10
Pentazocine
4
142
1.03
Codeine and dihydrocodeine oral
3
550
3.97
NA
735
5.31
Acetaminophen only Oxycodone oral
2
1,637
11.83
Hydrocodone oral
3
4,286
30.97
Propoxyphene oral
4
6,477
46.79
DEA = Drug Enforcement Administration; NA = not applicable.
Discussion A relatively small number of patients were taking more than 4 grams of acetaminophen per day. It is striking, however, that these overusers received an average of 20 prescriptions containing acetaminophen over a 6-month period. Most of these prescriptions were combination products containing narcotics. One possible explanation could be that particular patients were “drug shopping” and intended to sell medications they received; however, this is a sizeable number of prescriptions to obtain without a physician or pharmacist becoming aware of a problem. The total amount of acetaminophen these patients were receiving is probably underestimated. It is also conceivable that patients were taking OTC acetaminophen concomitantly with their prescription products. For example, patients taking chronic doses for osteoarthritis might be unaware that cough and cold products they take for their cold symptoms also contain acetaminophen. This problem is of particular concern for elderly patients.17 Only 128 patients appeared to have an underlying liver problem. This number, too, is most likely an underestimate. Only patients whose physicians had documented a problem with a diagnosis code could be identified. The federal Substance Abuse and Mental Health Services Administration estimates that 104 million people (46.6%), almost half of all Americans age 12 or older, currently drink alcohol. The agency also reports that 46 million people (26.6%) participated in binge drinking at least once in the 30 days
Table 2. Patient Demographics % All Patients (n = 22,496)
% Acetaminophen Overusers (n = 687)
% Acetaminophen Nonoverusers (n = 21,809)
Men
26.75
32.02
26.59
.0019 b
Ethnicity White African American Other
80.30 18.59 1.12
85.15 13.83 1.02
80.15 18.74 1.12
.0009 b .0010 b 1.0
Age, years < 40 40–59 60–79 80
19.99 42.71 24.66 12.64
19.21 52.55 23.00 5.24
20.01 42.40 24.71 12.88
.6283 < .0001 b 0.3,228 < .0001 b
Characteristic
Pa
a Two-sided Fisher exact test. b Significant at P < .01.
Table 3. Overuse of Acetaminophen
No. of Recipients
No. of Acetaminophen Prescriptions
4–5.99
510
9,823
19.26 ± 9.47 (16.5)
6–7.99
78
2,067
26.50 ± 13.42 (25.0)
8–9.99
12
295
24.58 ± 16.13 (23.0)
10–11.99
1
65
>12
5
215
43.00 ± 23.18 (35.0)
606
12,465
20.57 ± 10.97 (17.5)
Use in 180-Day Period (grams/day)
Total
Acetaminophen Prescriptions Mean ± SD (Median) per Recipient
65.00 ± 0
SD = standard deviation.
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Table 4. Type of Disease Contraindication Versus Acetaminophen Use 3–3.99 Grams/Day
4–5.99 Grams/Day
6–7.99 Grams/Day
8–9.99 Grams/Day
10–11.99 Grams/Day
> 12 Grams/Day
Other disorders of liver (573)
26
13
1
—
—
—
40
Alcohol dependence syndrome (303)
26
12
1
—
—
1
40
Chronic liver disease and cirrhosis (571)
25
10
2
1
—
—
38
Viral hepatitis (070)
Disease (ICD-9 Code)
Total
25
10
2
—
—
—
37
Hepatomegaly not otherwise specified (789.1)
3
6
1
—
—
—
10
Alcoholic psychoses (291)
2
2
—
—
—
—
4
Liver abscess and sequelae of chronic liver disease (572)
2
1
1
—
—
—
4
Acute and subacute necrosis of liver (570)
1
—
—
—
—
—
1
81
38
7
1
0
1
128
Total (per unique recipient)a
ICD = International Classification of Diseases. a Thirty-five recipients appear in multiple disease categories.
before they took the survey. Of all Americans age 12 or older, 12.6 million (5.6%) are heavy drinkers. The estimates for 2000 were almost identical to the 1999 estimates.18 Despite the risk of hepatotoxicity with high doses of acetaminophen, annual toxicity deaths from nonsteroidal antiinflammatory drugs exceed those caused by acetaminophen.19 Our results show only a small number of patients receiving high chronic doses of acetaminophen, with most (84%) of these high users receiving between 4 grams and 6 grams per day, which is less likely to be toxic than higher doses. Risk of acetaminophen-related toxicity may be minimized because primary care physicians’ overall knowledge of acetaminophen toxicity is excellent20 and pharmacists are well trained to provide patients with the necessary information to improve health outcomes and reduce potential problems. Action from governmental drug agencies may also help control toxicity risk. In the United Kingdom, for example, acetaminophen must be packaged in blister packs, which limits the total number of tablets that can be dispensed.21,22 In the United States, as recently as September 2002, FDA suggested that increased education of consumers is warranted to lessen the risk for unintentional hepatotoxicity from acetaminophen.23
cific codes, changing codes, or outcomes poorly defined by ICD9 codes. Despite these potential biases, observational studies clearly depict actual utilization patterns, which reflect patient as well as prescriber behavior. Medicaid pharmacy claims are perhaps the most reliable and valid data source for Medicaid patients; in one validation study, the correspondence between medical records and Medicaid pharmacy claims was 94%.25 Another limitation is that the study design rested on the assumption that a prescription filled is a prescription consumed. Thus, we were possibly overestimating an already small number of acetaminophen overusers.
Limitations
The authors declare no conflicts of interest or financial interest in any product or service mentioned in the article, including grants, employment, gifts, stock holdings, or honoraria.
This study is limited by the classic concerns that arise from large claims database analysis, such as selection bias and misclassification bias.24 Selection bias may occur because patients whose information is in retrospective, observational databases cannot be randomized to receive or not receive certain interventions or medications. Misclassification bias may occur through the use of nonspe-
This project was funded by a grant through an interagency agreement between the Ohio Department of Jobs and Family Services (ODJFS) and the Ohio Board of Regents (OBR) through the Medicaid Technical Assistance and Policy Program (MEDTAPP), Grant #A-98-07-001. The conclusions and opinions expressed do not necessarily represent the official views or opinions of ODJFS, OBR, or MEDTAPP.
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Conclusion Acetaminophen is a relatively safe drug that is prescribed extensively. Acetaminophen overuse, however, is the leading cause of liver failure. In the Ohio Medicaid population, only about 3% of patients who filled at least 6 acetaminophen-containing prescriptions in a 6-month period received greater than 4 grams per day. Despite these small numbers, health care professionals should be alert to the possibility of acetaminophen overuse leading to avoidable hepatotoxicity.
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References 1. Fast Stats A to Z. Therapeutic Drug Use. 1999. National Center for Health Statistics Web site. Avalable at: www.cdc.gov/nchs/ fastats/drugs.htm. Accessed October 1, 2003. 2. Parivash N, Ahmad SR, Karwoski CB. Safety analysis of acetaminophen (APAP)-associated hepatotoxicity. Presented at: Nonprescription Drugs Advisory Committee meeting; Bethesda, Md. September 19, 2002. Available at: www.fda.gov/ohrms/dockets/ac/02/slides/3882S1_05_ Nourjah-Ahmad-Karwoski.pdf. Accessed October 1, 2003. 3. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med. 2002;137:947-54. 4. Kwan D, Bartle WR, Walker SE. Abnormal serum transaminases following therapeutic doses of acetaminophen in the absence of known risk factors. Dig Dis Sci. 1995;40:1951-5. 5. Barker JD, DeCarle DJ, Anuras S. Chronic excessive acetaminophen use and liver damage. Ann Intern Med. 1977;87:299-301. 6. Leist MH, Gluskin LE, Payne JA. Enhanced toxicity of acetaminophen in alcoholics: report of three cases. J Clin Gastroenterol. 1986;7:55-9. 7. McClain CJ, Kromhout JP, Peterson FJ, Holtzman JL. Potentiation of acetaminophen hepatotoxicity by alcohol. JAMA. 1980;244:251-3. 8. McClain CJ, Holtzman J, Allen J, et al. Clinical features of acetaminophen toxicity. J Clin Gastroenterol. 1988;10:76-80. 9. Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA. 1994;272;1845-50. 10. Fored CM, Ejerblad E, Linbblad P, Fryzek JP. Acetaminophen, aspirin and chronic renal failure. N Engl J Med. 2001;345:1801-8. 11. Acetaminophen safety. Med Lett Drugs Ther. October 28, 2002:91. 12. Perneger TV, Whelton PK, Klag MJ. Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs. N Engl J Med. 1994;331:1675-9. 13. Drug Facts and Comparisons. St. Louis, Mo: Facts and Comparisons; 2001:827. 14. Davies DM, Ferner RE, de Glanville H, eds. Textbook of Adverse Drug Reactions. 5th ed. New York, NY: Chapman & Hall Medical; 1998:282. 15. Ohio Medicaid Report. 3rd edition. Columbus, Ohio: Ohio Department of Job and Family Services; 2001. Available at: www.state.oh.us/odjfs/ ohp/bhpp/reports/omr1999/omr1.pdf. Accessed October 1, 2003. 16. International Classification of Diseases, Ninth Revision, Clinical Modification. 4th ed. Los Angeles, Calif: Practice Management Information Corp; 1994. 17. Ruoff GR. Management of pain in patients with multiple health problems: a guide for the practicing physician. Am J Med. 1998;105;53S60S. 18. Alchol use. In: Summary of Findings from the 2000 National Household Survey on Drug Abuse. Rockville, Md: Substance Abuse and Mental Health Services Administration; 2001. Available at: www.samhsa.gov/ oas/NHSDA/2KNHSDA/Chapter3htm. Accessed October 7, 2003. 19. Aronson MD. Nonsteroidal anti-inflammatory drugs, traditional opioids, and tramadol: contrasting therapies for the treatment of chronic pain. Clin Ther. 1997;19:420-32. 20. Quallich LG, Brown W, Shehab TM, Fontana RJ. Management of acetaminophen hepatotoxicity: a survey of practicing physicians. J Clin Outcomes Manage. 2001;8:25-32. 21. Hawton K, Ware C, Mistry H, et al. Paracetamol self-poisoning: characteristics, prevention and harm reduction. Br J Psychiatry. 1996;168:438.
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22. Cranney M, Cranney J, Stubbs H. Limitation of over the counter sales of paracetamol: packaging policy is unlikely to achieve its aim of reducing suicide [letter]. BMJ. 1998;317:1657. 23. Ganley J. Issue: unintentional acetaminophen hepatotoxicity. Presented at: Nonprescription Drugs Advisory Committee meeting; Bethesda, Md. September 19, 2002. Available at: www.fda.gov/ohrms/ dockets/ac/02/slides/3882s1_01_Ganley.pdf. Accessed: October 7, 2003. 24. Strom BL, Carson JL. Use of automated databases for pharmacoepidemiology research. Epidemiol Rev. 1990;12:87-107. 25. Bright RA, Avorn J, Everitt DE. Medicaid data as a resource for epidemiologic studies: strengths and limitations. J Clin Epidemiol. 1989;42:937-45.
Appendix 1. ICD-9 Codes Used in Defining Disease Contraindications Code
Description
303
Alcohol dependence syndrome
304
Drug dependence
305
Nondependent abuse of drugs
292
Drug withdrawal
291
Alcoholic psychoses
570
Acute and subacute necrosis of liver
571
Chronic liver disease and cirrhosis
572
Liver abscess and sequelae of chronic liver disease
573
Other disorders of liver
070.0–070.9 Viral hepatitis 277.3
Amyloid or lardaceous degeneration of liver
751.62
Congenital cystic disease of liver
271.0
Glycogen infiltration of liver
789.1
Hepatomegaly not otherwise specified
452
Portal vein obstruction
095.3
Hepatitis in late syphilis
091.62
Hepatitis in secondary syphilis
130.5
Hepatitis in toxoplasmosis
V02.6
Viral hepatitis
V02.60
Viral hepatitis carrier, unspecified
V02.61
Hepatitis B carrier
V02.62
Hepatitis C carrier
V02.69
Other viral hepatitis carrier
ICD = International Classification of Diseases. Source Reference 18.
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