Sumatriptan treatment for migraine in a health maintenance organization: economic, humanistic, and clinical outcomes.

This study was undertaken to assess the impact of 12 months of sumatriptan therapy (6 mg subcutaneously) for migraine on health care use, health-related quality of life, productivity, patient satisfaction with the medication, and clinical efficacy in a health maintenance organization (HMO). One hundred forty-eight patients received open-label sumatriptan for 12 months for the treatment of migraine. Medical records were reviewed to obtain information on the frequency of migraine-related health care use during the 12 months before and during sumatriptan treatment. Patients completed questionnaires on their productivity at work, health-related quality of life, and satisfaction with medication at baseline and after 3, 6, and 12 months of sumatriptan treatment. For each migraine, patients recorded pain severity scores before and after taking sumatriptan and the time between dosing and onset of meaningful relief. Sumatriptan was associated with significant reductions in migraine-related use of general outpatient services, telephone calls, urgent care services, and emergency department visits (P < 0.05); a significant increase in the use of pharmacy services (P < 0.05); and significant and sustained improvements in health-related quality-of-life scores compared with baseline (P < 0.001). Patients lost significantly less time from work and were significantly more satisfied with sumatriptan compared with their usual therapy (P < 0.05). Two hours after dosing, 81% of patients experienced reduction of moderate or severe pain to mild or no pain, and 90% of all patients experienced meaningful relief of pain. The use of sumatriptan for 12 months in an HMO was associated with reductions in health care use and improved health-related quality of life, productivity, and patient satisfaction with medication.

Sumatriptan injection reduces productivity loss during a migraine attack: results of a double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the impact of sumatriptan succinate injection compared with placebo on productivity loss during a migraine attack in the workplace. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group clinical trial. SETTING: Fifteen clinical centers in the United States. PATIENTS: One hundred thirty-five patients 18 years and older diagnosed as having migraine according to International Headache Society criteria. INTERVENTIONS: Patients self-administered sumatriptan injection (6 mg) or matching placebo to treat a moderate or severe migraine occurring within the first 4 hours of a minimum 8-hour work shift. MAIN OUTCOME MEASURES: Mean productivity loss 2 hours after dosing and across the work shift; percentages of patients returning to normal work performance within 2 hours after dosing and across the work shift; percentages of patients experiencing headache relief (reduction of moderate or severe predose pain to mild or no pain) 1 and 2 hours after dosing. RESULTS: Mean productivity loss was significantly (P< or =.002) lower in the sumatriptan group compared with the placebo group both during the 2-hour postdose period (sumatriptan, 39 minutes; placebo, 54 minutes) and across the work shift (sumatriptan, 86 minutes; placebo, 168 minutes). Significantly (P<.001) greater percentages of patients in the sumatriptan group compared with the placebo group returned to normal work performance by 2 hours after dosing (sumatriptan, 52%; placebo, 9%) and across the work shift (sumatriptan, 66%; placebo, 18%). Significantly (P< or =.001) greater percentages of patients in the sumatriptan group compared with the placebo group experienced headache relief 1 hour after dosing (sumatriptan, 69%; placebo, 18%) and 2 hours after dosing (sumatriptan, 79%; placebo, 32%). CONCLUSION: Sumatriptan reduced migraine-associated productivity loss during a minimum 8-hour work shift by approximately 50% compared with placebo and alleviated headache in more than three fourths of patients.

Use of animal studies in risk assessment for immunotoxicology.

We have previously reported on the design and content of a screening battery involving a 'tier' approach for detecting potential immunosuppressive compounds in mice. This battery has been used to examine a variety of compounds, and the database generated from these studies, which consists of over 50 compounds, has been collected and analyzed in an attempt to improve the accuracy and efficiency of screening chemicals for immunosuppression and to identify better those tests that predict experimentally-induced, immune-mediated diseases. Specifically, these analyses attempted to develop an improved testing configuration for the accurate prediction of immunotoxic agents and to provide insight into the qualitative and quantitative relationships between a number of immune and host resistance assays commonly employed to examine potential immunotoxic chemicals in experimental animals. While a number of limitations existed in the analyses, several conclusions were drawn from the results which will be discussed.

The use of animal tests in risk assessment for immunotoxicology.

The design and content of a screening battery using a 'tier' approach for detecting potential immunotoxic compounds in mice has been described (M. I. Luster et al., Fundamental and Applied Toxicology 1988, 10, 2-19). The database generated from these studies, which consists of over 50 selected compounds, has been analysed in an attempt to improve future testing strategies and provide information to aid in developing future quantitative risk assessment for immunotoxicity. In a recent study it was shown that as few as two or three immune parameters were needed to predict immunotoxicants in mice (M. I. Luster et al., Fundamental and Applied Toxicology 1992, 18, 200-210). The analyses described here focus on the use of this database to develop statistical models that examine the qualitative and quantitative relationship(s) between the immune function and host resistance tests. The conclusions derived from these analyses are as follows: (1) A good correlation exists between changes in the immune tests and altered host resistance, in that there were no instances where host resistance was altered without affecting one or more immune test(s). However, in some instances immune changes occurred without corresponding changes in host resistance. (2) No single immune test could be identified that was fully predictive for altered host resistance, although most assays were relatively good indicators (i.e. 70%). Several others, such as proliferative response to lipopolysaccharide and leucocyte counts, were found to be relatively poor indicators for host resistance changes. (3) The ability to resist infectious agent challenge is dependent on the degrees of immunosuppression and the quantity of infectious agent administered. (4) Logistic and standard regression modelling using one extensive chemical data set from the immunosuppressive agent, cyclophosphamide, indicated that most immune function-host resistance relationships followed linear rather than linear-quadratic (threshold-like) models. For most of the relationships this could not be confirmed using a large chemical data set and, thus, a more mechanistically based approach for modelling will need to be developed.

Risk assessment in immunotoxicology. II. Relationships between immune and host resistance tests.

We have reported on the design and content of a screening battery using a "tier" approach for detecting potential immunotoxic compounds in mice (Luster et al., Fundam. Appl. Toxicol., 10, 2-19, 1988). The data base generated from these studies, which consists of over 50 selected compounds, has been collected and analyzed in an attempt to improve future testing strategies and provide information to aid in developing future quantitative risk assessment for immunotoxicity. In a recent study it was shown that as few as two or three immune parameters were needed to predict immunotoxicants in mice (Luster et al., Fundam. Appl. Toxicol., 18, 200-210, 1992). In particular, enumeration of lymphocyte populations and quantitation of the T-dependent antibody response were particularly beneficial. Furthermore, commonly employed apical measures (e.g., leukocyte counts, lymphoid organ weights) were fairly insensitive. The present analyses focus on the use of this data base to develop statistical models that examine the qualitative and quantitative relationship(s) between the immune function and host resistance tests. The conclusion derived from these analyses are: (1) A good correlation exists between changes in the immune tests and altered host resistance in that there were no instances where host resistance was altered without affecting an immune test(s). However, in some instances immune changes occurred without corresponding changes in host resistance. (2) No single immune test could be identified which was fully predictive for altered host resistance, although most assays were relatively good indicators (i.e., > 70%). Several others, such as proliferative response to lipopolysaccharide and leukocyte counts, were found to be relatively poor indicators for host resistance changes. (3) The ability to resist infectious agent challenge is dependent upon the degrees of immunosuppression and the quantity of infectious agent administered. (4) Logistic and standard regression modeling using one extensive chemical data set from the immunosuppressive agent, cyclophosphamide, indicated that most immune function-host resistance relationships followed linear rather than linear-quadratic (threshold-like) models. For most of the relationships this could not be confirmed using a large chemical data set and, thus, a more mechanistically based approach for modeling will need to be developed. (5) Using this limited data set, methods were developed for modeling the precise quantitative relationships between changes in selected immune tests and host resistance tests.

Qualitative and quantitative experimental models to aid in risk assessment for immunotoxicology.

We have previously reported on the design and content of a screening battery using a "tier" approach for detecting potential immunosuppressive compounds in mice [1]. This battery was composed of various immune function, immunopathology and host resistance tests, the results of which could help establish the potential of chemical and biological agents to cause immunosuppression. The data from these studies, which now encompass over 50 compounds, have been analyzed in an attempt to improve future testing strategies and provide information to aid in the risk assessment process. Specifically, the following two issues will be addressed; what are the likelihood(s) for each of the individual tests and testing configurations to accurately identify immunotoxic compounds? and what are the quantitative and qualitative relationships between the immune tests and host resistance assays?

Risk assessment in immunotoxicology. I. Sensitivity and predictability of immune tests.

We have previously reported on the design and content of a screening battery involving a "tier" approach for detecting potential immunotoxic compounds in mice (Luster et al., 1988, Fundam. Appl. Toxicol. 10, 2-19). This battery has now been utilized to examine a variety of compounds by the NIEHS Immunotoxicology Laboratory, the National Toxicology Program-sponsored laboratories, and by the Cell Biology Department at the Chemical Industry Institute of Toxicology. The database generated from these studies, which consists of over 50 selected compounds, has been collected and analyzed in an attempt to improve future testing strategies and provide information to aid in quantitative risk assessment for immunotoxicity. Studies presented here have established the ability of each of the tests or test combinations in the screening battery to detect immunotoxic compounds. Efforts are currently underway using this database to determine the relationships between these immune tests and susceptibility to challenge with infectious agents or transplantable tumor cells. The present analyses indicated that the performance of only two or three immune tests are sufficient to predict immunotoxic compounds in rodents (greater than 90% concordance). The tests that showed the highest association with immunotoxicity were the splenic antibody plaque forming cell response (78%) and cell surface marker analysis (83%). The relationship between immunotoxicity and carcinogenicity, as well as genotoxicity, was also determined. These analyses suggested that potential immunotoxic compounds are likely to be rodent carcinogens (p = 0.019) although for compounds that are not immunotoxic the carcinogenic status is unclear. There was no relationship observed between immunotoxicity and mutagenicity as determined using in vitro genotoxicity tests. The significance of these observations is discussed in terms of the relationship between immunotoxicity tests and biological/toxicological processes concerned with human health (e.g., infectious disease).