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Objective: This study was designed to describe and compare individuals in rural Appalachia prescribed, abusing or diverting OxyContin® a region with high rates of prescription medication abuse and misuse.Setting and Participants: Fifty subjects treated for OxyContin®abuse, 34 subjects prescribed OxyContin®for pain and 50 subjects incarcerated due to OxyContin®-related charges from rural Appalachia.Interventions: The Addiction Severity Index, DSM-IV Checklist, and an investigator developed questionnaire were administered to all three groups.Results: All three groups included individuals prescribed OxyContin® for pain and demographic variables and psychiatric/medical histories failed to discriminate between the pain and substance abuse (SA) subjects. SA and criminal justice subjects were significantly more likely to have a current DSM-IV diagnosis of psychoactive abuse/dependence and more likely to be younger and unmarried.Conclusion: This study found that these groups are not distinct and in depth evaluations, including a detailed SA history, are needed to identify the pain patient at risk for abuse and/or diversion of prescribed opioids.

Tramadol has been marketed in the US since 1995. The US Food and Drug Administration agreed to release tramadol as a non-scheduled drug if proactive post-marketing surveillance studies would be conducted. This study was one of two phase IV protocols that were part of the overall surveillance program. It focused on impaired health professionals who are a high risk/high access population for drug abuse. All active participants in four state monitoring programs between November 1, 1995 and August 15, 1998 ( n =1601) were recruited for the study. With the exceptions of implementing a standardized intake interview and urine testing for tramadol metabolites, all states operated their programs in the usual fashion. The programs were alerted to persistent non-prescribed tramadol use so that appropriate interventions could be employed. Despite availability of tramadol and the conditions that might lead to its abuse, the incidence rate for tramadol use in the study population was only 69 per thousand persons per year and the incidence rate for tramadol abuse or dependence was 6.9 per thousand persons per year.

In in vitro testing, no pharmacologic synergism has been found for the combination of cisplatin and etoposide in P388 leukemia in contrast to the demonstration of therapeutic synergism in the same model. No pharmacologic synergism has been found for the same combination in the treatment of four small-cell lung-cancer cell lines, although clinical results obtained using this combination in small-cell lung cancer and other cancers suggest a therapeutic advantage. The popular concept of synergy, implying a therapeutic advantage, is different from the pharmacologic meaning, which generally implies that less drug is required in a combination for an equal effect. Therapeutic advantage may be obtained regardless of whether drugs are synergistic in the pharmacologic sense in the treatment of a tumor. To gain a more comprehensive insight into concepts of drug interaction, it is important to recognize that the type of drug interaction seen is dependent on the drug doses used and may vary with the treatment of different cell lines. All of these factors complicate the use of the word synergism, or any associated term, in a categorical manner to describe the effects of combinations of antineoplastic drugs.

Physostigmine (PHY) has the advantage over pyridostigmine of minimizing OP-induced incapacitation because it penetrates into the CNS. However, physostigmine is behaviorally toxic at relatively low concentrations. It is anticipated that this could be offset by a cholinolytic to prevent behavioral deficit due to the carbamate pretreatment alone. The therapeutic efficacy of physostigmine/azaprophen pretreatment therapy was evaluated in soman-challenged guinea pigs. Response surface methodology was employed to describe the relationship of the pretreatment combination with duration of incapacitation. The significance of the combination relative to PHY alone was evaluated in addition to dose combinations that yield optimal time to recovery. Analysis of the fitted response surface indicated that combination pretreatment with these compounds significantly reduces the time to recovery after soman challenge versus pretreatment with PHY alone.

The Prescription Opioid Misuse Index (POMI) was developed and used in a larger study designed to assess correlates of OxyContin abuse in pain patients prescribed OxyContin, patients treated for OxyContin addiction, and individuals incarcerated for OxyContin-related charges. The POMI was administered to 40 subjects with addiction problems and 34 pain patients who had received OxyContin for pain. Receiver operating characteristic curve analysis indicated that endorsing two or more of six items reliably classified a person as at risk for misuse of their medication. When comparing drug abuse/dependence in subjects classified as misusers or users, significantly more misusers received a diagnosis for alcohol (p < .01), illicit drugs (p < .05), and other prescription medications (p < .05) and reported greater lifetime use of alcohol (p < .002) and illicit drugs (p < .01). No between-group differences were found regarding psychiatric problems. The POMI appears to be a sensitive and specific instrument for identifying patients who misuse opioid medications.

Nine hundred and sixty-nine impaired physicians (125 women and 844 men) enrolled in one of four state physician health programs were evaluated with comprehensive psychosocial, psychiatric and substance abuse/dependence profiles. When compared to male impaired physicians at time of entry to physician health programs, the 125 female impaired physicians were younger (39.9 vs. 43.7 years; p.0001), reported more medical (48.7% vs. 34.4%; OR = 1.81) and psychiatric (76.5% vs. 63.9%; OR = 1.84) problems at intake. They were more likely to report past (51.8% vs. 29.9%; OR = 2.51) or current (11.4% vs. 4.8%; OR = 2.54) suicidal ideation, and more likely to have made a suicide attempt under the influence (20.0% vs. 5.1%; OR = 4.64) or not under the influence (14.0% vs. 1.7%; OR = 9.67) of a substance. Although alcohol was the primary drug of abuse for all physicians studied, women physicians were more likely to abuse sedative hypnotics than men (11.4 vs. 6.4; OR = 1.87). There were no gender differences in employment problems (65.3% vs. 67.5%; ns) or legal problems (15% vs. 21%; OR = .66) due to addiction. These findings suggest different characteristics between male and female impaired physicians which may have implications for identification and treatment of this population.

A dual-exposure drug treatment of cell lines in tissue culture provides a possible method for determining schedule dependency. This is suggested by results of treatment of human small cell lung carcinoma NIH H209 and murine L1210 leukemia cell lines with cisplatin, a non-schedule-dependent drug, and etoposide, a schedule-dependent drug. Nonlinear least squares was used to estimate the dose-response surface. The estimated regression coefficients for the effect of the first dose compared to that of the second dose support the premise that cisplatin is not schedule dependent. Unlike cisplatin, the second dose of etoposide was shown to be more effective than the first dose in the human small cell carcinoma line. This agrees with known clinical results where multiple etoposide dosing has been shown to be more effective and confirms schedule dependency. This methodology, or a refinement, may offer another tool for studying schedule dependency of drugs using tissue culture methods.

The delta method is utilized to construct an asymptotic 100(1 - alpha)% confidence interval for the response at the stationary point of a quadratic response surface. The end-points of the interval can be found directly, compared to other more, computationally intense procedures that result in a conservative interval. The coverage probability associated with intervals constructed in this manner from studies with relatively small numbers of observations is investigated via a simulation study. Finally, the methodology is illustrated with an example involving the evaluation of a combination of cytotoxic agents in the treatment of murine L1210 leukemia.

The interaction of 5-fluorouracil and cyclophosphamide in the treatment of L1210 and P388 leukemias was studied using response surface methodology. Single dose treatment of each drug was administered simultaneously or with a 24-hr interval between 5-fluorouracil and cyclophosphamide to the advanced tumors or at various times after L1210 inoculation. While at low doses the action of the combination of the two drugs was greater than expected, there was no therapeutic synergism if the drugs were given together (optimum doses cyclophosphamide 366 mg/kg and 364 mg/kg, respectively, in advanced L1210 and P388 leukemias) or in the early tumor when cyclophosphamide was given 24 hours after 5-fluorouracil. In the advanced tumor, using the regimen employing a 24-hr interval between drugs, therapeutic synergism could be demonstrated (optimum doses 5-fluorouracil 130 mg/kg followed by cyclophosphamide 248 mg/kg in advanced L1210 leukemia and 5-fluorouracil 110 mg/kg followed by cyclophosphamide 263 mg/kg in advanced P388 leukemia). The evidence generated suggested that improved therapy could be found in two separate regions of the treatment space, raising the possibility of more than one mechanism of drug interaction. The location of the optimal treatment depended on the tumor burden at the time treatment was initiated. A shift from one region to the other occurred after 4-6 days of tumor growth when the original inoculum was 10(5) i.p. L1210 cells. Another more obvious conclusion that can be drawn is that treatment was less effective as the tumor became more advanced. The notion that different tumor stages may require different ratios of drugs in a clinically useful combination should receive attention.

Response-surface methodology (RSM) techniques provide a useful statistical approach for the design and analysis of experiments involving multiple variables. Although it has been used for some time in the areas of chemical engineering and agriculture, RSM has only recently been applied to the solution of biological problems. Here we have utilized RSM to investigate the interaction of two direct-acting, monofunctional alkylating agents [ethyl methanesulfonate (EMS) and ethylnitrosourea (ENU)] in Chinese hamster V79 cells with respect to the in vitro induction of sister chromatid exchanges (SCEs). A factorial design was employed in which the cells were exposed to the agents singly and in simultaneous combinations for 4 h. The cells were collected for SCE determination 30 h after treatment. The analysis revealed concentration-dependent increases in SCEs for both of the agents, with ENU being the more effective on an equimolar basis. In addition, single- and multiple-agent interactions were detected. The most important finding was that over the treatment range studied, a significant negative interaction occurs between EMS and ENU with regard to SCE induction. It is suggested that RSM not only may be useful in determining the statistical relevance of experimental variables but also may generate hypotheses the evaluation of which could provide additional insights into the underlying mechanisms involved.

Current statistical procedures used in the construction of isobolograms do not use recent advances in mathematical statistics. The variability in the experimental data is either ignored or incompletely accounted for in the analyses. The decision procedures currently used to characterize the type of interaction between two agents do not permit the determination of the level of statistical significance associated with a given conclusion. Furthermore, the often formidable sample size is not exploited in the current isobologram methodology. Statistical techniques exist that may be used to construct isobolograms and decision procedures with a reliable level of significance. An isobologram is a contour of constant response of the underlying dose-response surface. Consequently, response surface methods (RSM) are useful in the estimation and analysis of isobolograms. The interaction between ethanol and chloral hydrate in female ICR mice was evaluated using the RSM approach by fitting the logistic model to quantal data. The loss of righting reflex was quantitated in mice 30 min after coadministration of the two drugs, injected IP on a body weight basis (mg/kg). The study consisted of 39 groups with 6 animals per group. Analysis of our data supports the conclusion of synergy between the drugs as reported by others; however, our results were obtained with a significantly smaller number of animals. These studies also demonstrate that response surface modeling can be used for determining additivity, synergism, and antagonism at a given preselected level of significance.

When viewed in light of the simplicity of the solution in a single variable, it is not surprising that the estimation of the ED10op in combinations has received little attention in the statistical literature. As a result of the increasing interest in the effects of combinations of agents either as the result of treatment or environmental exposure, however, consideration of the estimation of the ED1oop in combinations is warranted. [Skarin, Canellos, Rosenthal, Case, Maclntyre, Pinkus, Moloney, and Frei (1983) reported on the use of a combination of six drugs in the treatment of lymphoma, and Lang, Kurzepa, Cole, and Loper (1980) indicated that several known or suspected carcinogens were identified among the many compounds present in drinking water.] Confidence bands on the logistic response curve were considered by Hauck (1983) and Brand, Pinnock, and Jackson (1973). One of the advantages claimed by Hauck is that his method is not restricted to a single explanatory variable, as is the approach taken by Brand et al. In their paper, however, Brand et al. discussed placing confidence bands about points on the inverse response curve, for example, the ED1oop, a topic not discussed by Hauck. It is the purpose of this article to develop and illustrate a method for estimating a large sample confidence region about the ED1oOP from the logistic curve in the case of multiple explanatory variables. 2. BACKGROUND

The therapeutic efficacy of atropine sulfate/pralidoxime chloride (ATR/2-PAM) treatment therapy and physostigmine (PHY) pretreatment therapy was evaluated in soman-challenged guinea pigs. Response surface analysis (RSM) of treatment efficacy indicated that the optimal ATR/2-PAM dose combination varied as a function of both the soman (GD) challenge level and the PHY pretreatment dose. Efficacy was, therefore, evaluated for varying PHY pretreatment doses in combination with the appropriate optimal ATR/2-PAM treatment (as determined by RSM for each soman challenge dose and PHY dose evaluated). The response surfaces depicting the effects (i.e., probability of survival) of ATR/2-PAM combinations at fixed levels of PHY and GD are presented, and confidence regions and point estimates for optimal ATR/2-PAM treatment combination are included. It was estimated that with optimal therapy a protective ratio (PR) of 6 can be observed. Comparisons were made between the use of PHY/ATR/2-PAM as presented here and the use of PYR/ATR/2-PAM, as discussed by Jones et al.(1) Both studies showed a strong positive (r ≥ 0.98) relationship between dose and the PR. However, the estimated slope parameter for PHY was significantly larger ( P < 0.001) than the slope parameter for pyridostigmine (PYR). This difference in slopes may indicate different mechanisms of action for PYR and PHY.

SUMMARY A method of calculating a confidence interval about the response at the stationary point of a response surface is presented. We show that the technique can also be used to calculate a confidence region about the location of the stationary point. The procedure is applied, via Cox's proportional-hazards model, to the analysis of survival data from a preclinical cancer chemotherapy experiment involving the combination of two drugs. It is seen that the results can be useful in determining the existence of a therapeutic synergism.