Controlled Clinical Trials

The method used to determine medication efficacy is called the controlled clinical trial. The key components of clinical trials include the following: control groups; random assignments of eligible subjects to medication or to control groups; use of placebos (identically appearing but inactive medications) for the control group—unless a standard effective medication is available to serve as the comparison; assurance that neither the patients receiving the drug nor the physicians administering/ prescribing know whether they are getting the active medication or the placebo (called doubleblind); methods that validly and reproducibly measure the response to the medication; methods to monitor whether subjects take the medication; and procedures to follow all the patients who entered the study for the duration of the clinical trial. After the data are collected, they must be analyzed by using the appropriate statistical tests.

Randomizing. It is important to randomize eligible patients to the treatment and placebo groups, because this assures that the two groups are comparable except for the medications being prescribed. If some method other than randomization is used to assign patients to treatments, it is likely that the groups will differ in important characteristics such as severity of illness. If one of the groups is in general more severely ill than the other, the sicker group is less likely to do well regardless of the treatment. If the more severely ill group receives the active medication, the difference between the medication group and the placebo group after treatment does not appear as great because the placebo (control) group was less ill at the beginning. Thus, it may appear that the medication was not effective.

Double-blinding. "Blinding" of both the patients and the physicians is necessary because of their expectations and beliefs. Patients usually seek treatment in the expectation that the physician will prescribe or recommend something that will cure or improve their condition. Hence, patients who receive placebos often feel better. Therefore, if a placebo control is not used, one might conclude that a new treatment works when one is only observing the placebo kind of response. (Conversely, patients often report side effects when they take placebos. So not all side effects are necessarily due to an active medication.) Physicians often believe very strongly that the new drug will be the effective treatment they are searching for, and their objectivity is diminished by this bias. To remove this influence on their perception of the outcome of treatment, the physicians treating the patients are ''blinded'' as well as the patients, hence a double-blinding is effected.

Accurate Assessment. If the methods used to assess the response to treatment do not accurately measure the response to the medication, erroneous conclusions may be drawn (Fuller, Lee, & Gordis, 1988). Patients' self-reports about their response to treatment should not be used without corroborating data in controlled clinical trials unless no other means for obtaining information is available. Such reports may be inaccurate for a variety of reasons, including inaccurate memory and the tendency to give socially desirable answers.

It is also important to know whether the patients actually took the medications. Often, patients do not take their medications or take them erratically, particularly if they are being treated for an asymptomatic condition for a long period of time and/or if the medication has a high incidence of unacceptable side effects (Haynes, Taylor & Sackett, 1979).

Patients who drop out of treatment frequently are atypical of all patients in treatment. In alcoholism treatment, the dropouts are usually drinking and having problems because of their drinking. So, if a study bases its conclusions only on those who stay in treatment, the results of the therapy are likely to be exaggerated. Therefore, it is important to locate and assess treatment response in all or almost all who initially began treatment. For an excellent description of clinical trials, their methods and issues, see Byar et al. (1976).

If control groups were used, methods other than randomization were used to assign patients to the disulfiram group or the control group. Hence, the groups were not comparable, and placebo groups were rarely used. ''Blinding'' was not done. No attempts were made in most of the studies to determine whether patients took the medication. The alcoholic's report on abstention from alcohol was the only information obtained to judge whether disulfiram was effective. In some studies, only about half the patients were available for follow-up.

Multi-Site Trial. During the past decade, more rigorously designed clinical trials of disulfiram have been done, and these give more precise information about the efficacy of disulfiram. The largest of these was a multi-site clinical trial done in nine Veterans Administration clinics (Fuller et al., 1986). In this study, 605 men were randomly assigned to three groups:

1) a 250-milligram disulfiram group (the usual dose);

2) a 1-milligram disulfiram group; and

3) a no-disulfiram group.

The 1-milligram group was equivalent to a placebo, because this dose is not sufficient to cause a disulfiram—ethanol reaction (DER) but controls for the expectation that one will get sick if one drinks alcohol while taking disulfiram. The no-disulfiram group was told they were not receiving Antabuse®; it was a control for the standard counseling that alcoholics receive in treatment. The patients in the two disulfiram conditions were ''blinded'' as to whether they were receiving the 250-milligram or the 1-milligram dose. The data to judge the effect of treatment were collected by research personnel who had no involvement in the treatment of the patients and were ''blinded'' to group assignment. The research staff members interviewed the patients, cohabiting relatives, and friends (collaterals) every two months during the year of follow-up. Urine specimens were collected every time the patients returned to the clinic and were analyzed for the presence of alcohol. A vitamin, riboflavin, was incorporated into the 250-mil-ligram and 1-milligram tablets. The nodisulfiram patients received a tablet identical in appearance to the disulfiram tablets but containing only ribofla-vin. The urine specimens were also analyzed for riboflavin. This allowed the investigators to tell whether the patients were taking their medications regularly.

In contrast to most of the previous studies, this tightly designed study did not find that more of the patients who received disulfiram stayed sober for the year than those who received the placebo or counseling only. Nor was disulfiram associated with better employment or social stability; however, in about 50 percent of the men who relapsed, drinking frequency was significantly less for those who received disulfiram than for those who received either the placebo or no disulfiram. This subset of men who relapsed by drinking less frequently if assigned to disulfiram were slightly older and had more social stability (as indicated by longer residence at their current address) than the other men who relapsed. These results indicate that disulfiram is not more effective than routine treatment for most male alcoholics—female alcoholics were not included in the study—but may have some benefit for socially stable male alcoholics.

In the multi-site study, only 20 percent of the patients took the medication regularly; however, abstinence for the year was highly associated with compliance with the disulfiram regimen. This suggests that if ways were found to get patients to take disulfiram regularly, the effectiveness of the drug would be greatly improved. This conclusion has to be tempered by the finding that those who regularly took the 1-milligram placebo or the vitamin without disulfiram, as well as those who took di-sulfiram, were much more likely to remain sober than those who were less adherent to their regimens. Nevertheless, alcoholism treatment researchers have studied various methods for improving compliance with disulfiram, and preliminary results suggest that these may be beneficial. These treatment strategies have included having the spouse or a treatment facility staff member observe the patient ingesting the medication, establishing a contract with the patient about taking it, and/or building in positive (rewards) or negative (loss of privileges) incentives to take it. A recent controlled study of disulfiram taken in the presence of a relative, friend, or member of the clinic staff found that this method of administration resulted in significantly less alcohol being consumed during a six-month period (Chick et al., 1992). More well-designed studies of these measures to improve compliance with the disulfiram regimen are needed before it is known if they will improve the effectiveness of disulfiram as a treatment for alcohol dependence.

On the basis of the large well-designed studies done to date, it seems prudent to recommend that disulfiram should not be used initially in the treatment for alcoholism. However, if the patient relapses and has indicators of social stability, a discussion with the patient about the possible benefits and the possible risks of disulfiram is warranted, and if the patient is willing to take disulfiram, a trial course is warranted. During the first six months of treatment, it is important that liver tests be monitored closely. The effectiveness of the drug may be enhanced if the patient agrees to take it under supervision.

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