WASHINGTON, DC—Data collected from nearly 20 years of research on medication compliance have shown that despite the increased risk of seizures, patients with epilepsy are just as likely to skip prescribed doses as are patients with other chronic disorders. Now insight gained from some of these same studies is yielding effective, office-based interventions for increasing antiepileptic drug compliance and reducing the incidence of seizures that result from poor or partial compliance.

Researchers have learned that patients with epilepsy take, on average, approximately 75% of their medication as it is prescribed—a percentage comparable to what has been observed for patients with other diseases, said Joyce A. Cramer. Poor compliance in terms of the number and timing of doses and poor persistence with respect to long-term compliance often result in breakthrough seizures, she noted. Ms. Cramer is Associate Research Scientist in the Department of Psychiatry at the Yale University School of Medicine in West Haven, Connecticut.

ENCOURAGING COMPLIANCE

There are several steps that neurologists can take to help break this cycle, Ms. Cramer asserted at the 2005 Joint Annual Meeting of the American Epilepsy Society and the American Clinical Neurophysiology Society. After explaining why the medication is needed, clinicians should focus on specific use of the drug on a daily basis and why patients need to continue it on a long-term basis. Clinicians should help their patients develop cues for remembering when to take doses, while also encouraging them to use "reminder boxes"—plastic pill containers that have compartments for each day of the week.

Attention to compliance is needed at every visit, especially when adverse effects or seizures have occurred. Neurologists should not just ask how many seizures patients have had and what drugs they are taking, but they should also inquire how patients are taking the medicines and then determine if better compliance can be facilitated with help from the doctor’s office or the clinic. Because every patient is potentially poorly compliant or poorly persistent, clinicians must give clear instructions on dose timing and what to do if a dose is missed or an adverse effect is experienced, said Ms. Cramer.

Although she admitted that there is no "magic answer" for ensuring high rates of compliance, Ms. Cramer has developed a simple, office-based intervention that has worked for many patients, even those with schizophrenia. "It does not require any high-tech equipment," she said. "First of all, we teach people to think about the appropriate interval between doses, and to consider a specific schedule of dose times. Teaching patients how to take their medicine probably is more important than explaining mechanisms of action."

Typically, Ms. Cramer will encourage patients to pick the times of day to take doses that will work best for them. While she has used electronic medication monitoring (see sidebar), she recommends the plastic reminder boxes. "Plastic pill boxes are very useful reminders for people," she said. "If you see tablets left at the end of the day or at the end of the week, then you didn’t take them. This is a clear indication that you have to improve your memory and your skills in taking the medicine."

Ms. Cramer observed, "When I’ve used this method in research, even with schizophrenia patients, I’ve gotten a statistically significant improvement in compliance rates over time—even when the patients had had excellent medical education in the past," she said. "Before the intervention [they were] highly erratic patients.... After the intervention [we saw] much, much better compliance rates and much more consistency." In addition to providing feedback at every visit, clinicians should be checking patients’ prescription refills, she noted.

THE PROBLEM OF PARTIAL COMPLIANCE

Ms. Cramer has been conducting research on medication compliance since the mid-1980s. From her work in clinical trials, she has come to the realization that drugs cannot be accurately tested if the patients are not compliant. "‘Drugs don’t work in patients who don’t take them,’" she said, quoting former Surgeon General C. Everett Koop, MD. "It’s a very obvious thing, but it’s a stunning realization for some people."

Besides day-to-day and long-term compliance, the other key component to the issue is outcome. "The goal is not taking 100% of tablets ever prescribed," Ms. Cramer emphasized. "The goal is good outcome. But you can’t get good outcome unless the patient works with the dose that you presumed would be adequate for the patient."

Although some patients can be categorized as "noncompliant," indicating that they are simply not taking their medication, most patients with compliance problems fall into the category of "partial compliance." Based on various sources of evidence, Ms. Cramer has found that in general, more than half of patients take enough of their medication to achieve adequate management, and the remainder have partial compliance, with inadequate management. Reasons for inadequate compliance include lack of belief in the diagnosis or in the need for treatment, lack of commitment or organization, and unwillingness to change one’s lifestyle.

ORGANIZATION IS THE KEY

One thing years of research has not accomplished is enabling clinicians to predict compliance. Asking how many members of the audience thought they could look at a patient in the office and know whether he or she would be poorly compliant, Ms. Cramer maintained that their accuracy would be less than if they flipped a coin. She cited a study in which she and her colleagues conducted formal neuropsychological testing on a series of patients. The investigators predicted that poor compliance would be associated with such aspects as low IQ, poor memory, personality disorder, older age, and less education. It turned out that there were no statistically significant correlations with any of these factors.

"What does this come down to?" Ms. Cramer asked. "It’s usually a sense of organization, which has nothing to do with education [or] with memory function."

This finding has led to what she calls her "clean closet/clean desk" theory. "There’s no neuropsychological test for it, but if you could go home and check your patients’ closet or desk, you’d see if they’re organized," she explained. "If they are, my guess is they’ll be good compliers because they have a sense of timing for things. Those of you whose desks are piled high with things are more likely to be forgetful of your dose, your car keys, appointments, and everything else."

KEEP IT SIMPLE

Putting together the various data gathered over the years, Ms. Cramer highlighted a couple of findings that have emerged as clear and consistent. One has to do with precision, which involves taking doses within the appropriate time frame. Compliance in dose taking, it turns out, is inversely related to the number of doses prescribed per day.

Ms. Cramer pointed to a seminal 1989 study published in JAMA in which she and her coauthors used continuous electronic monitoring to measure compliance. Once-a-day dosing was found to result in a mean compliance rate of 87%; twice a day, 81%; three times a day, 77%; and four times a day, 39%. The results convey several different messages, according to Ms. Cramer.

"Once-a-day dosing is not the cure-all," she said. "It’s nowhere near 100% compliance. It also demonstrates, to those who think that using the [electronic] pill bottle in a clinical trial is in itself an incentive, that it’s not an incentive, because patients knew they were being monitored, and they still didn’t [always] take it once a day.

"Two and three times a day are manageable for people with complex disorders—but four times a day? Don’t even think about prescribing four doses a day," she said.

Obtaining compliance with respect to timing of doses is even trickier than doing so with daily dose taking. "You may prescribe drugs based on pharmacokinetic principles, but people don’t live by those principles, and their schedules don’t work that way," Ms. Cramer told her audience. "So think again about simple dosing regimens and the need to combine everything—including all the other medications they’re taking—into a couple of convenient times a day."

NR

—Fred Balzac

Suggested Reading
Cramer JA. Obtaining optimal compliance with drug therapy. Manag Care. 2003;12(10 suppl):9-11.
Cramer JA, Glassman M, Rienzi V. The relationship between poor medication compliance and seizures. Epilepsy Behav. 2002;3:338-342.
Cramer JA, Mattson RH, Prevey ML, et al. How often is medication taken as prescribed? A novel assessment technique. JAMA. 1989;261:3273-3277.
Cramer JA, Scheyer RD, Mattson RH. Compliance declines between clinic visits. Arch Int Med. 1990;150:1377-1378.

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