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Objective: Our objective was to evaluate ethnic differences in response to morphine and to determine whether any detectable differences were pharmacokinetically based., Methods: This cohort study was carried out in a teaching hospital. Sixty-six young, healthy male subjects from 3 ethnic groups (Caucasians, native Indians, and Latinos; n = 22 in each group) consented to participate. All subjects received an intravenous morphine bolus of 0.08 mg/kg followed by 0.002 mg/kg. min infused for 30 minutes. Respiratory response was evaluated with the carbon dioxide rebreathing method before and at 25, 95, 180, and 360 minutes after morphine administration. Vital signs and opioid side effects were recorded, and serial blood samples were analyzed for morphine, morphine-3-glucuronide, and morphine-6-glucuronide (M6G)., Results: All 3 groups had suppression of the ventilatory response to hypercapnia, but the degree of blunting of the ventilatory response differed among groups. Compared with Caucasians, native Indians had an additional 18% reduction in ventilatory response after morphine administration (95% confidence interval, -35% to -2%). The incidence of side effects was similar in all groups (P =.18). Caucasians had higher plasma levels of M6G than did native Indians or Latinos. M6G areas under 6-hour concentration-versus-time curve were as follows: Caucasians, 12,065 +/- 4354; native Indians, 8464 +/- 4809; and Latinos, 9156 +/- 3764 ng. min/mL (P =.03)., Conclusions: Ethnicity influences the response to morphine. Native Indians are more susceptible to morphine depression of the ventilatory response than Caucasians, despite the higher serum M6G levels in Caucasians.

This paper overviews the use of claims data in pharmacoepidemiology, examines problems related to claims data use, and focuses on the uncertain validity of diagnosis data. Two contrasting studies are provided of drug-induced neutropenia and Stevens-Johnson Syndrome; both studies were launched at the same time with similar designs. Neutropenia is a laboratory-driven diagnosis, easy to make and confirm. The neutropenia study yielded many useful results, ranging from incidence rates to results with specific drug classes and individual drugs. However, the medical records revealed major unexpected issues from chronic and cyclic neutropenia. In contrast, Stevens-Johnson Syndrome is harder to diagnose, and is represented poorly in the ICD-9-CM coding system. The result was a study productive of much less clinical information. These studies show the important implications of variable data validity to study interpretation. Uniquely problematic situations exist: the illness does not reliably come to medical attention; inpatient drug exposures; an outcome is poorly defined by the diagnostic coding system; descriptive studies; drug effects are delayed and patients lose eligibility; and there are important unknown confounders such as cigarette smoking, occupation, menarche, menopause, etc., about which information cannot be obtained without accessing the patient.

Cohort studies require the use of large samples when the risk of the event is very low. Databases that are large and population-based, such as Medicaid files, are frequently used for cohort studies, since they provide access to the large samples required for adequate statistical power at a relatively affordable cost. Epidemiologic studies using these databases typically require verification of reported diagnoses, however, because of the potential for errors in disease reporting. When exposure prevalence is also low, as in many pharmacoepidemiologic investigations of drug toxicity, there are few exposed cases compared to the number of unexposed cases. Verification of all unexposed presumptive cases through medical records is costly. We investigate the statistical efficiency of a design in which all exposed cases but only a subsample of the unexposed cases are verified. We show that good efficiency can usually be achieved with a small subsample of unexposed cases. Published in 1999 by John Wiley & Sons, Ltd.

A retrospective cohort study was performed to determine the incidence of hypoprothrombinaemia and bleeding in patients receiving cefoperazone, a third-generation cephalosporin that contains an NMTT side chain. 374 patients receiving cefoperazone from February 1983 to March 1986 at a teaching hospital in Philadelphia were compared with 497 patients receiving either ceftizoxime or cefotaxime during the same period, and with 476 patients receiving ceftazidime from April 1985 to December 1987. Adverse events (any bleeding episodes, decrease in haemoglobin, prolongation of prothrombin time (PT), and prolongation of partial thromboplastin times (PTT)) were evaluated, if occurring during the period from the start of cephalosporin therapy, or the start of therapy with one of the two control drugs, for 14 days after the last date of the first course of therapy were recorded. An increased risk of hypoprothrombinaemia was associated with the use of cefoperazone: the prothrombin time was prolonged by 5 s or more in 12.3% of patients receiving cefoperazone vs. 5.8% of patients receiving ceftizoxime or cefotaxime, and vs. 5.8% receiving ceftazidime; the adjusted odds ratios (95% CIs) were 3.6 (1.7-7.4) and 3.8 (1.8-7.8), respectively, and these increased at higher doses of cephalosporin. No protection was apparent from the administration of vitamin K prior to or during the course of cephalosporin. No overall increased risks were observed for bleeding (adjusted odds ratios (95% CIs) were 1.1 (0.8-1.4) vs. ceftizoxime or cefotaxime, and 0.9 (0.6-1.2) vs. ceftazidime), decrease in haemoglobin, or increased partial thromboplastin time. In subgroup analyses, increased risks of bleeding were observed with high dose cefoperazone use [2.8 (1.5-5.5) vs. ceftizoxime or cefotaxime, and 2.3 (1.1-4.6) vs. ceftazidime]. Patients receiving NMTT side chain antibiotics should be monitored for hypoprothrombinaemia, but any increase in bleeding is likely to be small, and prophylactic vitamin K is probably not warranted., (Copyright 1999 John Wiley & Sons, Ltd.)

Poor compliance with prescribed medications limits the effectiveness of many pharmacologic therapies and enhances their potential toxicities. Traditional methods of measuring drug-taking behavior, including direct observation, patient self-report, pill counts, and therapeutic drug level monitoring, all have well-described limitations in validity and interpretability. Electronic medication event monitoring has been used to assess compliance with therapies for hypertension, glaucoma, anemia, and epilepsy, overcoming many problems of traditional approaches. However, no published reports describe the use of electronic monitoring with immunosuppressive agents, despite their increasing use for non-life-threatening conditions and their many dose-dependent toxicities. Transplant recipients are thought to be at particular risk from noncompliance. Therefore, we undertook this study to assess the feasibility of electronically monitoring compliance with immunosuppressive drugs among renal allograft recipients. Twenty-five kidney transplant patients receiving immunosuppressive medications from a single pharmacy were enrolled. Each subject received electronic monitors with their immunosuppressive serum drug refills for cyclosporine and azathioprine. Each subject returned their monitors after the first month of this 2-month study for downloading data. The frequency distribution of interdose intervals were described. Two measures of average non-compliance were calculated for both drugs: the proportion of monitored days that had missed doses, and the proportion of missed doses. Once daily and twice daily regimens of cyclosporine were compared. Concordance in drug compliance between the two drugs was calculated for each subject and averaged over the study population. Twenty-two of 25 subjects missed one or more doses of cyclosporine or azathioprine. Seventeen (68%) subjects never missed four or more consecutive doses. Subjects were non-compliant with cyclosporine on 8.7% of monitored days, and non-compliance with azathioprine on 9.8% of monitored days. Subjects were non-compliant with 6.8% of their cyclosporine doses and 9.8% of their azathioprine doses. Patients were compliant with both drugs on 86.6% of days and were non-compliant with both drugs on 5.1% of days. Subjects were non-compliant with cyclosporine during 5% and 13.2% of monitored days for once and twice daily dosing regimens, respectively. Concordance analysis demonstrated that for 91.7% of days of monitoring, compliance information was identical for both drugs. This study demonstrated the feasibility of electronic medication event monitoring among kidney transplant patients. This methodology represents an important tool for monitoring compliance of immunosuppressive agents essential to their safe and effective use, and should be considered for use in future studies of these drugs and others with substantial dose-dependent toxicity., (Copyright 1999 John Wiley & Sons, Ltd.)

Background: Gallbladder cancer has an unusual geographic and demographic distribution, suggesting many possible etiologies., Methods: A case-control study was undertaken at four hospitals in La Paz, Bolivia, and at one hospital in Mexico City, Mexico. Eighty-four patients with newly diagnosed, histologically confirmed gallbladder cancer were compared with 126 control subjects without stones and with 264 control subjects with cholelithiasis or choledocholithiasis without cancer. All study subjects underwent abdominal surgery. Study subjects were interviewed regarding demographic characteristics, medical history, family history, diet, and exposure to agents presumed to be risk factors for biliary cancer., Results: Virtually all subjects in Mexico were judged to be mestizos (i.e., persons of mixed ancestry) In contrast, race was a very strong risk factor for gallbladder cancer in Bolivia. Relative to mestizos who spoke neither language, the odds ratio (95% confidence interval [CI]) for cases versus control subjects without stones for those who spoke Aymara well was 15.9 (CI, 1.9-179), whereas it was 1.4 (CI, 0.2-8.2) for those who spoke Quechua well. An increased risk was also noted for elevated maximum body mass index (P = 0.03), family history of gallstones (odds ratio [OR] = 3.6 [CI, 1.3-11.4]), and physician-diagnosed typhoid (OR = 12.7 [CI, 1.5-598]). An increased risk was also seen with elevated maximum body mass index; compared with those with a body mass index less than 24 kg/m2, those with an index of 24-25 kg/m2, 26-28 kg/m2, and greater than 28 kg/m2 had odds ratios of 1.6 (CI, 0.4-7.6), 1.3 (CI, 0.3-5.6), and 2.6 (CI, 0.5-18.6), respectively (asymptotic test for trend, P = 0.03). Finally, a number of associations were noted with certain dietary and cooking habits., Conclusions: Patients with gallbladder cancer differed from control subjects in race, body mass, physician-diagnosed typhoid, and certain dietary patterns. These findings may provide useful clues to the pathogenesis of gallbladder cancer, but given the number of analyses performed, additional cases need to be studied.

To determine the feasibility of the use of Medicaid data to study drug-induced acute liver disease, we reviewed the medical records of 414 patients receiving Medicaid, age 20 or older, with an ICD-9-CM inpatient billing code consistent with acute hepatitis. Of the patients whose records were reviewed, 15.9% were alcoholics, 31.9% had acute hepatitis A or B, 13.5% were intravenous drug users, 8.2% had acute cholecystitis or choledocholithiasis, and 4.1% had received a blood transfusion within the previous 6 months. No diagnosis of liver disease was found in 10.6% of the patients, and 5.7% had chronic liver disease. Of the 169 patients with idiopathic acute liver disease identified, many had very mild liver disease and were hospitalized for reasons other than liver disease. We conclude that Medicaid billing data has high reliability and validity for the diagnosis of acute liver disease. However, primary medical records are essential for the study of drug-induced hepatitis, to be able to exclude other causes of liver disease, and to obtain information not included in the computer data.

Because of case reports suggesting that use of transdermal scopolamine might be associated with the subsequent development of seizures, a retrospective cohort study was performed with computerized Medicaid claims data. Patients receiving transdermal scopolamine were compared with patients receiving diphenhydramine, meclizine, prochlorperazine, and promethazine. A four-fold increased risk of seizures after transdermal scopolamine use was observed in the claims data. However, this was not supported by the primary medical records. All patients who had seizures after using transdermal scopolamine either had seizures before receiving the drug as well or did not really suffer from seizures. The original finding appeared to be the result of the use of transdermal scopolamine for "dizziness, rule out seizures"; the ICD-9-CM coding system does not include "rule out" diagnoses. Thus these data do not confirm the existence of an association between seizures and the use of transdermal scopolamine. In addition, this study demonstrates the usefulness of pharmacoepidemiology studies in documenting drug safety and the importance of obtaining primary medical records when performing pharmacoepidemiologic studies with claims data.

In order to explore a priori hypotheses about drug-induced Stevens-Johnson Syndrome (SJS), a case-control study was initiated using data from COMPASS, a computerized data base consisting of Medicaid claims data. The records of 3.8 million patients in five U.S. states were searched to identify patients with an inpatient diagnosis of ICD-9-CM code 695.1 (erythema multiforme-EM). Out of the total of 367 cases that were identified, primary medical records for 249 were sought and 128 (51.4 per cent) of these were obtained. The remainder could not be obtained because: in 36 (29.8 per cent) the hospital refused to provide medical records; in 33 (27.3 per cent) there were transcription errors; in 20 (16.5 per cent) the state could not translate the identification number, primarily because the patients lost Medicaid eligibility too long before our request; in 27 (22.3 per cent) the hospital could not locate the patient's record; and in 5 (4.1 per cent) there were other reasons. Of those with a medical record, 121 (94.5 per cent) had a skin diagnosis and 109 (85.2 per cent) had a diagnosis compatible with ICD-9-CM code 695.1 specified on their discharge summary. However, in 35 (27.3 per cent) an expert reviewer felt that the discharge diagnosis was incorrect. In 50 (39 per cent) the computer diagnosis was incorrect. Only 19 (14.8 per cent) were judged by the expert reviewer to truly have Stevens-Johnson Syndrome, and an additional 37 (28.9 per cent) were judged to have erythema multiforme minor. Thus, the computerized diagnosis agreed very well with the diagnoses specified on the discharge summary. However, EM is frequently misdiagnosed, ICD-9-CM code 695.1 contains multiple other diagnoses which are not EM, and much of hospitalized EM is EM minor. Thus, studies of SJS cannot be performed except in patients whose medical records are available.

Suprofen, a new nonsteroidal anti-inflammatory drug, was marketed in early 1986 as an analgesic agent. Until physicians began reporting an unusual acute flank pain syndrome to the spontaneous reporting system, 700,000 persons used the drug in the United States. Through August 1986, a total of 163 cases of this syndrome were reported. To elucidate the epidemiology of the syndrome, a case-control study was performed, comparing 62 of the case patients who had been reported to the spontaneous reporting system to 185 suprofen-exposed control subjects who did not have the syndrome. Case patients were more likely to be men (odds ratio, 3.8; 95% confidence interval, 1.2-12.1), suffer from hay fever and asthma (odds ratio, 3.4; 95% confidence interval, 1.0-11.9); to participate in regular exercise (odds ratio, 5.9; 95% confidence interval, 1.1-30.7), especially in the use of Nautilus equipment (p = 0.02); and to use alcohol (odds ratio, 4.4; 95% confidence interval, 1.1-17.5). Possible risk factors included young age, concurrent use of other analgesic agents (especially ibuprofen), preexisting renal disease, a history of kidney stones, a history of gout, a recent increase in activity, a recent increase in sun exposure, and residence in the Sunbelt. These were findings that were suggestive but did not reach conventional statistical significance. These findings are consistent with the postulated mechanism for this unusual syndrome: acute diffuse crystallization of uric acid in renal tubules.

Prior studies of the association between oral contraceptives (OCs) and gallbladder disease (GBD) have yielded conflicting results. To clarify this association, a retrospective (historical) cohort study was performed on a very large data base including 1980 and 1981 Medicaid billing data from the states of Michigan and Minnesota in which 138,943 users of OCs were compared with 341,478 nonusers. The crude relative risk (RR) and 95% confidence interval (CI) for symptomatic GBD resulting in medical care was 1.14 (CI 1.09 to 1.20), with a clear dose-response (P less than 0.001). Age markedly modified the effect of OCs on GBD. The RR (CI) decreased from 3.1 (2.7 to 3.6) in women 15 to 19 years old to 1.2 (0.9 to 1.5) in women 40 to 44 years old, providing an explanation for previously conflicting reports. The effects of a number of other risk factors on GBD, some which have been controversial, were also confirmed. Adjustment for these did not change the results. In conclusion, OCs are risk factors for GBD, although the risk is of sufficient magnitude to be of potential clinical importance only in young women.