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Tips from Other Journals
Approval of Tizanidine for Treatment of Spasticity
According to consultants for The Medical Letter on Drugs and Therapeutics, tizanidine was recently approved by the U.S. Food and Drug Administration for oral treatment of increased muscle tone associated with spasticity. It has been available in other countries for 12 years as a short-term muscle relaxant.
Tizanidine is a short-acting, centrally active alpha-adrenergic receptor agonist similar to clonidine. However, it lacks the antihypertensive efficacy of clonidine. Therefore, during initial titration of tizanidine, the patient's blood pressure must be monitored. Another agent, baclofen, has been available for many years to reduce the painful muscle spasms associated with multiple sclerosis and other disorders affecting the spinal cord, but it has been ineffective as extended therapy in some patients. Diazepam and dantrolene sodium have also been used to treat spasticity, but these agents are less effective than baclofen.
In its oral form, tizanidine is rapidly and completely absorbed, especially when taken with food. It is excreted in the urine and feces. Since absorption is increased when it is taken with food, taking the drug regularly with meals can increase the consistency of both therapeutic and adverse effects.
The typical initial dosage is one 4-mg tablet taken at night, which can be increased by one-half tablet (2 mg) every three days until a dosing schedule of three times daily can be achieved. Most patients eventually take about 24 mg daily. However, even when given three times a day, tizanidine does not remain effective for a full 24 hours. Peak clinical effects occur one to two hours after each dose and disappear after six hours.
Randomized double-blind studies in patients with multiple sclerosis or spinal cord injuries showed that tizanidine was more effective than placebo in decreasing overall spasticity, and the frequency of daytime muscle spasms and night awakenings caused by spasm. When used together, carefully titrated doses of tizanidine and baclofen may have additive effects.
Dry mouth, dizziness, sedation, hypotension and bradycardia are common side effects but are usually mild to moderate in severity and can be minimized by increasing the dosage gradually. Visual hallucinations or delusions are rare. Increased aminotransferase activity occurred in 5 percent of the patients in the study group, and three patients died as a result of hepatic failure. The safety of tizanidine in children or in pregnant and lactating women has not been determined. In addition, this drug should be used with caution in elderly patients, those with renal or hepatic impairment, and those taking antihypertensives, especially clonidine.
Concurrent use of diazepam or alcohol may potentiate the sedative effects of tizanidine. Because oral contraceptives decrease the clearance of tizanidine by 50 percent, the starting dosage of tizanidine should be reduced in women taking these agents. Tizanidine also increases serum concentrations of phenytoin.
According to the 1997 edition of Redbook, the wholesale cost to pharmacies is $135 for 150 tablets of tizanidine (4 mg). Medical Letter consultants suggest that oral tizanidine can decrease spasticity caused by multiple sclerosis or spinal cord injury.
BARBARA APGAR, M.D., M.S.
Tizanidine for spasticity. Med Lett Drugs Ther 1997;39 (1004):62-3.
Rates of Mortality and Use of Postmenopausal HRT
Hormone replacement therapy confers many benefits, including a decreased risk of osteoporosis and cardiovascular disease, but it is also associated with risks, such as an increased incidence of breast and endometrial cancers. Extrapolation of data from available studies to the general population of women may be problematic, since women who receive hormone replacement therapy are often healthier initially than the general population of women of the same age and those who continue to take hormones are generally disease-free. Thus, decreased rates of mortality among women who receive hormone replacement therapy may be misattributed to the use of hormones. Grodstein and colleagues investigated the association between mortality and hormone use among participants in the Nurses' Health Study.
Women in this longitudinal study were between 30 and 55 years of age when they entered the study in 1976. Biennial questionnaires have been used to follow study subjects. A total of 3,637 postmenopausal women in this study died between 1976 and 1994, and data on these participants were used in the authors' analysis. Of the 3,637 women who died, 461 (12.8 percent) died of coronary heart disease, 167 (4.6 percent) died of stroke and 1,985 (54.6 percent) died of cancer. Of women who died of cancer, 425 died of breast cancer and 58 of endometrial cancer.
Among the women who died, 15.8 percent reported current hormone use on the last questionnaire they completed before they died, 27.8 reported past use, and 56.4 percent had never used hormones. Each woman who died was matched with 10 control subjects who were alive at the time of the case subject's death. The authors determined the status of hormone use on the basis of information on the last questionnaire completed before death or before the diagnosis of the disease that led to death. This approach reduced the bias that would be caused by discontinuation of hormone use between the diagnosis of a potentially fatal disease and death.
The data revealed that current hormone users had a lower risk of death (relative risk of 0.63) than women who had never received hormone replacement therapy. Survival benefit decreased with long-term hormone use of 10 or more years (relative risk of death: 0.80), primarily because of a 43 percent increase in mortality resulting from breast cancer.
Women with cardiovascular risk factors derived the most benefit from hormone replacement therapy. Women with at least one major cardiovascular risk factor had the largest reduction in mortality. Among this group, there was a 49 percent decrease in deaths from all causes for current hormone users, compared with those who had never used hormones. Substantially less benefit was found in women with a low risk of cardiovascular disease. The cardiovascular benefits disappeared within five years after discontinuing hormone replacement therapy.
The authors conclude that their population had a similar number of deaths caused by heart disease and breast cancer. They note that in the general population, heart disease is more prevalent. While the data indicate that survival benefits from hormone replacement therapy appear to outweigh the risks, the risks and benefits vary and depend on the presence of risk factors and the duration of hormone replacement therapy.
KATHRYN M. ANDOLSEK, M.D., M.P.H.
Grodstein F, et al. Postmenopausal hormone therapy and mortality. N Engl J Med 1997;336:1769-75.
Contraindications to Metformin Therapy
In 1995, biguanide metformin was approved by the U.S. Food and Drug Administration for use in the treatment of type 2 diabetes. Use of biguanide phenformin in the 1970s led to its subsequent withdrawal from the market in many countries because of a high incidence of lactic acidosis in patients with renal impairment, hepatic dysfunction or cardiac disease. Sulkin and associates studied the prevalence of conditions currently regarded as contraindications or cautions to the use of metformin in patients receiving this agent.
The authors identified the following potential contraindications or cautions to metformin therapy: (1) renal impairment, defined as a plasma creatinine level greater than 1.4 mg per dL (120 µmol per L) or dipstick-positive proteinuria, (2) cardiac failure, (3) chronic hepatic dysfunction, (4) significant chronic pulmonary disease, (5) coronary artery disease, (6) peripheral vascular disease, and (7) miscellaneous conditions (intercurrent illnesses, acute trauma or major surgical procedures, and metastatic malignancy).
The authors reviewed the medical records of 89 patients receiving metformin to identify the prevalence of potential contraindications to the use of the drug. These patients were seen at a university hospital diabetes clinic in the United Kingdom. The authors found that over one half of the patients had conditions regarded as cautions or contraindications to the use of metformin, eight of the patients had two conditions, five patients had three conditions and one patient had four conditions. The most common conditions were peripheral vascular disease (22 patients), ischemic heart disease (20 patients) and proteinuria (14 patients). Two of the patients had a significant degree of renal impairment.
The authors conclude that metformin should be used with caution in such high-risk patients until data from large clinical trials provide further information on the risks and benefits of metformin therapy.
JAMES NUOVO, M.D.
Sulkin TV, et al. Contraindications to metformin therapy in patients with NIDDM. Diabetes Care 1997;20:925-8.
EDITOR'S NOTE: While the clinical characteristics of type 2 diabetes may vary between the patients in this study and those seen by family physicians in the United States, it is important for clinicians to recognize potential contraindications to the use of metformin and prevent drug-related morbidity. We should remain vigilant and exercise caution before prescribing metformin.
--J.N.
Long-Distance Medicine by Way of Telecommunications
For the 15 to 25 percent of Americans who live in nonurban or medically underserved communities, electronic communication may be a way to increase access to health care. Telemedicine may take one of several forms, from relatively simple systems such as telephone or facsimile communication to high-tech computer systems that allow transmission of images (such as radiographs) and other data. Balas and associates studied the efficacy of "distance medicine" technology by reviewing data from 80 clinical trials of various methods of telecommunications.
Studies were included in the analysis if they were prospective controlled trials that randomly assigned patients to the intervention in question and if the consequence of the electronic intervention was evaluated. Information about the intervention, the clinician involved and the patient population was abstracted, as was information about the difference in outcome between the intervention and nonintervention groups. The interventions were classified into six categories:
(1) computerized communications between physician and patient, (2) telephone follow-up care, (3) telephone reminders, (4) interactive telephone systems that used regular telephone lines to deliver messages, (5) patients' telephone access to the physician and (6) telephone screening. The authors summarized the data from studies that fit into one of the six categories.Data from four studies of the use of telecommunications in the management of diabetes were evaluated. Three studies revealed significant decreases in glucose levels among patients who had their blood glucose levels transmitted to the physician by modem. The control group used traditional written records and did not show similar decreases in blood glucose levels. Members of the group using the modem also had better motivation for glucose management. In the fourth study, a computerized diet education program improved knowledge, habits and metabolic balance in patients with diabetes, compared with patients who did not have access to the computer-assisted diet education program.
Four studies of telephone follow-up after emergency department visits demonstrated greater compliance with treatment of urinary tract infection, pediatric emergencies and other acute and chronic illnesses. A greater degree of patient satisfaction and fewer missed appointments were also noted when telephone follow-up was used. There was also less inappropriate follow-up care.
Four studies of telephone programs for patients with myocardial infarction or cardiac surgery showed that telephone counseling was associated with improvement in rates of smoking cessation and in low-density lipoprotein cholesterol levels. The patients counseled by telephone also returned to normal activity more quickly than those who did not receive telephone follow-up.
Three studies of the impact of telephone follow-up on patients undergoing mammography showed that telephone counseling motivated women to obtain a mammogram. A study of the effect of telephone counseling in women who were recommended to undergo colposcopic examinations demonstrated significantly greater adherence to the recommendation in women who received telephone follow-up, compared with women who did not have this intervention. Compliance with colposcopy occurred in 67 percent of the women who were counseled by telephone, compared with 43 percent of the women who did not receive telephone counseling.
Other studies of telephone follow-up and counseling showed improvements in the areas of arthritis pain, adherence to antituberculosis drug therapy, tobacco use prevention and dental screening. Seventeen studies of telephone follow-up conducted in various clinical situations failed to show significant and beneficial differences between intervention and control groups.
Studies of the effects of telephone reminders showed increased compliance with influenza vaccination and childhood immunization in patients who received reminders. In one study, telephone reminders increased compliance with diabetic foot care instructions. Other successful applications of telephone reminders included reminders about medications and appointments.
Three trials of interactive telephone systems demonstrated beneficial effects among elderly patients with respect to drug compliance, influenza vaccination and knowledge of Alzheimer's disease. In another study, pre-recorded recall messages were associated with a higher number of visits to the health department in the month after the call. The volume of visits was not increased in the nonintervention group.
The authors conclude that distance medicine can have many benefits, especially in preventive care and in the management of chronic conditions such as diabetes mellitus. Vaccination rates among children and the elderly could be improved by use of various electronic forms of communication. Continuity of care between physician and patient may be enhanced by the use of such technologies.
GRACE BROOKE HUFFMAN, M.D.
Balas EA, et al. Electronic communication with patients: evaluation of distance medicine technology. JAMA 1997;278:152-9.
Intervention to Reduce Use of Restraints in Nursing Homes
Use of physical restraints in nursing homes is often rationalized as necessary to prevent falls, to prevent resistance to treatment and to manage uncontrollable behavior. However, research clearly shows that prolonged use of restraints is associated with adverse events, such as fall-related injuries and decreased physical and psychologic function. Evans and colleagues prospectively studied whether an educational and interventional program in nursing homes would have an effect on the use of physical restraints.
Three nursing homes were included in the study. Staff in one nursing home received no intervention, staff in the second nursing home received restraint education and staff in the third nursing home received restraint education and were provided with interventional consultation that was customized for patients who were particularly problematic.
The six-month, 10-session restraint education program was taught by a gerontologic nurse specialist. The 30- to 40-minute sessions focused on the effects of physical restraints, the behavior of residents, ways to minimize the risk of falls and ways to cope with problem behaviors such as wandering and agitation. Interventional consultation was provided for 12 hours each week. The consultations focused on residents who posed a challenge because of their behavior.
The greatest reduction in restraint use occurred in the nursing home in which the staff received education and consultation. The average absolute decline in restraint use at this nursing home was 18 percent, and this reduction was maintained during the follow-up period. Use of vest restraints decreased by 41 percent in the nursing home that provided education sessions and by 77 percent in the nursing home that provided education and consultation. Geriatric chair use was not signficantly affected by any of the interventions.
No change occurred in the number of staff hours per resident, and no increase was seen in psychoactive drug use in the two nursing homes that underwent intervention. The baseline rate of falls was lowest in the control nursing home but, after the interventions, this nursing home had a higher rate of falls than the other two nursing homes. The rate of falls in the control nursing home was 53.3 percent in the three to six months after the intervention period, compared with rates of 32.2 percent in the nursing home that provided restraint education and 37.8 percent in the nursing home that provided restraint education and consultation.
The authors conclude that a combination of staff education and consultation leads to a decrease in the use of physical restraints in nursing homes, without a concomitant increase in staff time, use of psychoactive drugs or injuries related to falls. In an accompanying editorial, Williams and Finch discuss the effects of "restraint stress": functional decline, psychologic distress, agitation, impaired circulation, incontinence, immobility and serious accidents. Evidence also suggests that restraint stress can heighten memory impairment. They emphasize that the fairly widespread goal of "restraint reduction" or "restraint alternatives" will not, in fact, come near to achieving what should be the true goal: a restraint-free facility. They state that restraint-free care is most likely to be achieved if the director of nursing and the facility administrator are committed to it. The medical director and attending physicians must support the leaders of the nursing home in this endeavor.
GRACE BROOKE HUFFMAN, M.D.
Evans LK, et al. A clinical trial to reduce restraints in nursing homes. J Am Geriatr Soc 1997;45:675-8l, and Williams CC, Finch CE. Physical restraints: not fit for women, man or beast [Editorial]. J Am Geriatr Soc 1997;45:773-5.
Effect of Physical Activity on Breast Cancer in Women
Vigorous and even moderate exercise may affect the menstrual cycle, perhaps by suppressing gonadotropin-releasing hormone and lowering a woman's cumulative exposure to estrogen and progesterone. Energy balance and caloric restriction might also inhibit carcinogenesis. Thune and colleagues conducted a survey to investigate the relationship between everyday exercise and the risk of breast cancer in women.
Norwegian women from 35 to 49 years of age and a random sample of 10 percent of women from 20 to 34 years of age in three counties were invited to participate in the study. A total of 25,624 women were surveyed from 1974 to 1978 and from 1977 to 1983. All of these women were asked to complete a questionnaire and bring it with them when they attended a screening clinical examination. Participants were also asked to complete a food frequency questionnaire that was used to calculate energy and fat intake.
The women were asked to self-report their physical activity during leisure and work hours using a scale of 1 to 4. A grade of 1 was assigned to those whose leisure time was spent reading, watching television or in other sedentary activities and to those whose work was described as sedentary. A grade of 2 was given to women who spent at least four hours per week walking, bicycling or engaging in other types of physical activity or had jobs that involved a great deal of walking. A grade of 3 was given to women who spent at least four hours a week exercising to keep fit and participating in recreational activities, and whose jobs involved both walking and lifting. A grade of 4 was given to women who engaged in regular, vigorous training or participated in competitive sports several times a week or whose jobs required heavy manual labor.
Women were followed for a mean of 14 years. Women who developed cancer or who died within the first year of the study were excluded from the analyses. Breast cancer was diagnosed in 351 women. Two thirds of women reported participating in moderate activity during leisure time. Fifteen percent exercised regularly. Only 14 percent reported being sedentary at work. Energy intake was positively correlated with physical activity. The association was more pronounced with work activity than with leisure time activity.
After adjustment for the factors of age, body mass index, height, parity and county, greater activity during leisure time was associated with a reduced risk of breast cancer. In women who exercised regularly, the risk reduction was greater in premenopausal women and in women younger than 45 years of age. Women who exercised at least four hours a week during their leisure time had a 37 percent reduction in the risk of breast cancer. The risk of breast cancer was lowest in lean women (body mass index less than 22.8) who exercised at least four hours per week. Risk was also reduced in women with higher levels of activity at work, again with a more pronounced effect among premenopausal than postmenopausal women.
The authors conclude that physical activity during both leisure time and work reduced the overall risk of breast cancer in women, particularly among premenopausal and younger postmenopausal women.
KATHRYN M. ANDOLSEK, M.D.
Thune I, et al. Physical activity and the risk of breast cancer. N Engl J Med 1997;336:1269-75.
Fluoxetine for Depression in Alcohol-Dependent Patients
Few studies have been performed in patients with a dual diagnosis of depression and alcohol dependence. Most data have been gathered at detoxification centers, where rates of depression would be expected to be lower than those in patients of psychiatric hospitals. Patients with alcohol dependence and depression have been noted to have symptoms associated with a low serotonergic state, including suicidal tendency and impulsivity, and low cerebrospinal fluid levels of 5-hydroxyindoleacetic acid, the major metabolite of serotonin. Cornelius and associates studied the ability of fluoxetine, a selective serotonin reuptake inhibitor, to reduce depressive symptoms and alcohol consumption in alcoholic patients with depression.
The 51 patients included in the study met the criteria for both major depressive disorder and alcohol dependence. Patients were randomly assigned to receive fluoxetine, 20 mg daily initially, or placebo. The daily fluoxetine dosage was increased to 40 mg after two weeks if substantial depressive symptoms persisted. Compliance was monitored by weekly pill counts and plasma drug levels obtained at weeks 2, 4 and 12. Patients were seen weekly for routine psychiatric care, which included psychotherapy sessions with the same psychiatrist. In addition, weekly ratings of depression and alcohol use were obtained throughout the 12-week study.
No significant differences were apparent between the two groups in age, sex, race, and marital and employment status. The percentage of patients who had made a suicide attempt during the current depressive episode did not differ in the two groups.
At the end of 12 weeks, the fluoxetine group showed a significant decrease in depression based on the Hamilton Rating Scale for Depression (HAM-D) and the Global Assessment Scale (GAS). Improvement in the GAS was three times greater in the fluoxetine group than in the placebo group.
Total alcohol consumption was three times greater in the placebo group than in the fluoxetine group. Both the cumulative number of drinking days and the number of drinks per day were significantly higher in the placebo group. Also, no significant correlation was noted in the fluoxetine group between the level of drinking and the level of depression at baseline, six weeks and 12 weeks.
The authors conclude that fluoxetine is effective in treating depressive symptoms as well as reducing alcohol consumption in patients with these comorbid illnesses. Moreover, the findings suggest that the antidrinking effect of fluoxetine is not entirely due to its antidepressant effect. However, the pharmacology of fluoxetine's antidrinking effect remains to be determined. Larger trials of selective serotonergic agents in depressed alcoholic patients are recommended.
JEFFREY T. KIRCHNER, D.O.
Cornelius JR, et al. Fluoxetine in depressed alcoholics. Arch Gen Psych 1997;54:700-5.
Effect of Dermatologic Drugs on Pregnancy and Lactation
Physicians are often reluctant to prescribe dermatologic drugs to pregnant and lactating women, since this type of treatment is often considered elective rather than life-saving. Despite opinions and advisories disseminated by various organizations, scientists and manufacturers, no one database provides definitive guidelines on the exact risks associated with drug use during pregnancy and lactation. Data from birth defect registries are inconclusive as a result of the small numbers of reported cases, the low frequencies of exposure to certain drugs and the concern that findings may not be extrapolated to all populations. Reed evaluated dermatologic drugs with a low known risk in pregnant and lactating women.
TABLE 1
Topical Drugs With Minimal Risk During PregnancyTopical drug
FDA pregnancy
category
Drug class
Amphotericin B
Azelaic acid
Bacitracin
Benzoyl peroxide
Cicloprox
Clindamycin
Erythromycin
Haloprogin
Hydroquinone agent
Masoprocol
Antiproliferative
Meclocycline
Metronidazole gel or cream
Mupirocin
Naftifine hydrochloride
Nystatin
Oxiconazole nitrate
Permethrin
TerbinafineB
B
OTC
C, OTC
B
B
B, C
B
B
B
B
B
B
B
A
B
B
BAntifungal
Antiacne
Antibiotic
Antiacne
Antifungal
Antibiotic
Antibiotic, antiacne
Antifungal
Bleaching
Antiacne
Antiacne
Antibiotic
Antifungal
Antifungal*
Antifungal
Antiscabetic
Antifungal
FDA=U.S. Food and Drug Administration;
OTC=over the counter.*--Topical administration of intravaginal yeast medications is not advised close to term because there is a risk of contamination if membranes have ruptured.
Reprinted with permission from Reed BR. Dermatologic drugs, pregnancy, and lactation. A conservative guide. Arch Dermatol 1997;133:894-8.
More than 30 years ago, the U.S. Food and Drug Administration (FDA) devised regulations for drug use during pregnancy. These regulations became known as the Pregnancy and Lactation Categories. These categories are graded, balancing fetal risk against potential benefits to the mother. Drugs in FDA categories A and B pose either no risk or minimal risk, respectively. Category C drugs are those in which risk to humans cannot be ruled out. Topical nystatin was the only category A drug found. Since category B drugs are not without risk, informed consent should be obtained before prescribing these drugs during pregnancy. Another source of information, the Teratogen Information Service (TERIS), rates drugs according to exposure risk to the fetus or infant (none, minimal, moderate and high).
Patients who need or desire elective treatment of dermatologic problems during pregnancy often use topical agents. Most benign topical agents are FDA category B drugs. The accompanying table on topical drugs with minimal risk (Table 1) shows only those category B drugs not contraindicated by the manufacturer for use during pregnancy. Some topical agents, such as erythromycin and benzoyl peroxide, are designated as category C drugs. Use of small amounts of topical steroids during pregnancy is not believed to be associated with significant risk to the fetus.
Life-threatening dermatologic conditions may require the use of systemic antibiotics during pregnancy. The accompanying table on drugs that may be used when medically necessary (Table 2) lists the FDA and TERIS risk categories of these drugs. Most of these drugs are either category B or C, but much of the data regarding risk have been compiled from less than optimal sources. Ibuprofen, ketoprofen and naproxen are category B drugs that should not be used during the latter part of pregnancy. The use of lidocaine with or without epinephrine for routine dermatologic excisions during pregnancy has not been contraindicated. TERIS ratings indicate that oral corticosteroids are unlikely to cause harm, but the data sources are listed as fair to poor.
Few topical or systemic dermatologic drugs are contraindicated during lactation, although some, including topical antifungal agents, have manufacturer's prohibitions. Drugs with no specific contraindications during lactation are also listed. The American Academy of Pediatrics regards prednisolone and prednisone as usually compatible with lactation.
The author presents a list of dermatologic drugs that may be used during pregnancy and lactation. Potential problems can be minimized by increasing awareness of potential fetal risks and obtaining informed consent from patients. Safety must always be weighed against the need to use the specific drug for a documented condition.
BARBARA APGAR, M.D., M.S.
Reed BR. Dermatologic drugs, pregnancy, and lactation. A conservative guide. Arch Dermatol 1997;133:894-8.
TABLE 2
Systemic Antibiotics, Antiviral Agents, Antihistamines and Antifungal Agents for Use When Medically Necessary During PregnancyFDA pregnancy TERIS category
Drug category Risk Data
Antibiotics
Amoxicillin
Azithromycin
Cephalosporins
Dicloxacillin
Erythromycin
Penicillin
Antiviral agents
Acyclovir
Famciclovir
Valacyclovir
Antihistamines
Brompheniramine maleate
Chlorpheniramine
Cyproheptadine hydrochloride
Diphenhydramine
Antifungal agent
Nystatin
B
B
B
B
B*
B
C
B
B
B
B
B
B
B
None
N/A
None/minimal
None/minimal
None
None
Unlikely
N/A
N/A
None
None/minimal
Undetermined
None/minimal
None
Good
N/A
Poor/fair
Poor/fair
Fair/good
Good
Fair/good
N/A
N/A
Fair
Fair/good
Poor
Fair/good
Fair/good
FDA=U.S. Food and Drug Administration; TERIS=Teratogen Information Service; N/A=not available.
*--Except estolates and clarithromycin.
Reprinted with permission from Reed BR. Dermatologic drugs, pregnancy, and lactation. A conservative guide. Arch Dermatol 1997;133:894-8.
Relationship Between Oral Potassium and Blood Pressure
It is known that potassium levels and blood pressure are inversely related. Whelton and colleagues conducted a meta-analysis to determine the effects of supplementation with oral potassium on blood pressure.
Studies were included in the analysis if they were based on human experimentation, had randomly assigned study participants to groups, had a control group that was not substantively different from the treatment group and reported mean changes in blood pressure. In the 33 trials analyzed, the median length of treatment was five weeks. The median amount of daily potassium supplementation was 75 mmol. Pretreatment blood pressures averaged 147/95 mm Hg.
The groups treated with potassium had an average change in systolic blood pressure from a decrease of 41.0 to an increase of 2.8 mm Hg and changes in diastolic blood pressure from a decrease of 17.0 to an increase of 4.8 mm Hg. In one third of the trials, the change in blood pressure was statistically significant. There were no significant adverse effects. The size of the effect of potassium on blood pressure was small (a decrease of 3.1 mm Hg for systolic blood pressure and a decrease of 1.97 mm Hg for diastolic blood pressure).
The authors conclude that this and previous studies support the idea that potassium supplementation has a role in the treatment of hypertension. However, further studies are clearly needed.
GRACE BROOKE HUFFMAN, M.D.
Whelton PK, et al. Effects of oral potassium on blood pressure: meta-analysis of randomized controlled clinical trials. JAMA 1997;277:1624-32.
Side Effects of Medications in Children with ADHD
Children with attention-deficit hyperactivity disorder (ADHD) may be successfully treated with stimulant medications. The medications most commonly used are methylphenidate and dexamphetamine. Unfortunately, it is sometimes difficult to determine whether the behaviors seen in children with ADHD are a result of the disorder or the treatment. Efron and colleagues conducted a blinded crossover trial to compare the side effects of methylphenidate and dexamphetamine in children with ADHD.
Children between five and 15 years of age were included in the study if they met Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for ADHD and had no other neurologic abnormality. Patients were randomized to receive either methylphenidate (0.3 mg per kg) or dexamphetamine (0.15 mg per kg) twice daily for two weeks. After a 24-hour washout period, each child began receiving the other study medication. Standardized teacher and parent rating scales were completed, as was a "behavior questionnaire" designed to collect information about side effects and medication effects.
Most of the patients (81.8 percent) were classified as having ADHD-mixed type, 17.6 percent as ADHD-predominantly inattentive and 1.6 percent as ADHD-predominantly hyperactive/impulsive. Patients in the dexamphetamine group were rated as improved by their parents 68.8 percent of the time, and patients in the methylphenidate group were rated as improved 72.0 percent of the time. Certain behaviors were reportedly more frequent before the trial of medication: nightmares, stomachaches and anxiousness decreased in the children taking methylphenidate. Only insomnia increased in children taking dexamphetamine, and only poor appetite increased in children taking either drug. Only 3.2 percent of patients had to discontinue the study medication because of side effects.
The authors conclude that the behaviors often attributed to medication side effects may simply be features of the ADHD itself. The other possibility is that parents who were motivated to have their child diagnosed with ADHD may have overreported symptoms at the beginning of the trial. At any rate, a careful review of symptoms, including those most often associated with use of methylphenidate or dexamphetamine, should be undertaken before prescribing these medications in children with ADHD.
GRACE BROOKE HUFFMAN, M.D.
Efron D, et al. Side effects of methylphenidate and dexamphetamine in children with attention deficit hyperactivity disorder: a double-blind, crossover trial. Pediatrics 1997;100:662-6.
EDITOR'S NOTE: Although there is certainly some controversy about overdiagnosis of ADHD and overprescription of methylphenidate and dexamphetamine in children, this study provides reassurance for those who treat patients with these medications.--g.b.h.
Copayments and Emergency Care for Myocardial Infarction
Copayment by the patient has been shown to reduce the number of visits to the emergency department by 20 to 40 percent. It is not known, however, whether copayment delays care for truly urgent conditions, such as acute myocardial infarction. Magid and colleagues evaluated the interval between the onset of symptoms of myocardial infarction and arrival at the hospital to determine whether copayment for emergency services is associated with a delay in seeking care.
The Group Health Cooperative of Puget Sound is a prepaid health plan with more than 500,000 enrollees. From 1989 through 1994, a total of 1,523 patients with myocardial infarction were admitted to one of 19 hospitals participating in the Myocardial Infarction Triage and Intervention Project. Copayment status was known for 1,450 of these patients. The time from the onset of symptoms until hospital arrival was known for 1,331 (91.8 percent) of the 1,450 patients. These patients were enrolled in the study.
A total of 602 patients (45.2 percent) were enrolled in health care plans that required copayment for emergency services, and 729 patients (54.8 percent) were in plans that did not require copayment. Of the patients enrolled in plans that required copayment, 308 (51.2 percent) paid $25 for an emergency department visit, 289 (48.0 percent) paid $50 and five (0.8 percent) paid $100 for an emergency department visit.
Most of the patients younger than 65 years of age were enrolled in plans that required copayment. Fewer plans in which older patients were enrolled required copayment for emergency services.
The age-adjusted median time until arrival at the hospital was 136 minutes for patients with no copayment requirement, compared with 135 minutes for those with a $25 copayment and 138 minutes for those with a copayment of $50 or more. In the subgroup of 449 patients who had a cardiac arrest, no association between copayment status and the occurrence of cardiac arrest was demonstrated. The proportion of patients with plans that required copayment was similar in the group with cardiac arrest and in the group without cardiac arrest (48.3 percent and 49.5 percent, respectively). No statistically significant differences were noted in in-hospital case fatality rates or in long-term survival during the follow-up period (mean: 2.1 years).
The authors conclude that copayments for emergency services were not associated with a delay in seeking emergency treatment of myocardial infarction in the population they studied. Although no significant association was noted between income and the effect of copayment, the authors note that this lack of an association should be viewed with caution for two reasons: they used census-block data as a proxy for family income, and few indigent people are enrolled in the Group Health Cooperative of Puget Sound.
KATHRYN M. ANDOLSEK, M.D., M.P.H.
Magid DJ, et al. Absence of association between insurance copayments and delays in seeking emergency care among patients with myocardial infarction. N Engl J Med 1997;336:1722-9.
Improper Dosing of OTC Medications by Caregivers
Patients often do not tell their physicians about over-the-counter (OTC) medications they or their children are taking, and in many cases patients are not aware of the potential side effects of these drugs. One study suggested that at least 50 percent of three-year-olds in the United States have received some type of OTC medication. Simon and Weinkle evaluated the ability of caregivers to accurately measure and administer acetaminophen to children.
A questionnaire was administered to 100 caregivers of children under 12 years of age seen in an emergency department for nonemergent concerns. Mothers represented almost 90 percent of the caregivers. The mean age of the caregivers was 29.0 years, and the mean age of the children was 2.8 years. Eighty-seven percent of the caregivers had graduated from high school.
The caregivers were asked for information about OTC use in the previous two months. They were then given a mock scenario in which they had to determine the correct dose of acetaminophen for their child with a febrile illness. Package labeling was available to the caregivers, as was the child's weight. A dose of 9.0 to 16.5 mg per kg was considered correct. The caregivers were asked to measure the correct dose in a device of their choice, such as a dropper, syringe, teaspoon or measuring cup. The amount was considered to be accurate if it was within 20 percent of the dose that the caregivers stated they intended to give.
Seventy-seven percent of the caregivers stated that they had given OTC medications to their children, most commonly acetaminophen, cough and cold preparations, vitamins and ibuprofen, during the two-month period before the emergency visit. Only 28 percent of the caregivers were aware that OTCs could have adverse effects. Only two caregivers said they would consult their physicians before giving an OTC medication to their children.
During the mock scenario, only 40 percent of the caregivers calculated the correct dose of acetaminophen for their child, although 67 percent accurately measured the dose they stated they intended to give. The actual measured doses ranged from 8 to 210 percent of the stated intended dose. Forty-three percent of the caregivers measured a correct amount of acetaminophen for their child, but one third of these did so strictly by accident because they had calculated an incorrect dose. An underdosage was measured by 48 percent of the caregivers and an overdosage by 9 percent. When the data for calculating and measuring the dose were combined, only 30 percent of the caregivers both determined and measured the correct amount of acetaminophen for their child.
The authors conclude that a significant number of caregivers inaccurately administer OTC products to children. Since 50 percent of emergency room visits are for fever-related concerns, improper use of acetaminophen may contribute to a lack of clinical response and an overuse of emergency room services. The authors also state that primary care physicians need to teach their patients about proper dosing and administration of OTCs and the potential for adverse side effects.
JEFFREY T. KIRCHNER, D.O.
Simon HK, Weinkle DA. Over-the counter medications: do parents give what they intend to give? Arch Pediatr Adolesc Med 1997;151:654-6. *
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Copyright © 1998 by the American Academy of Family Physicians.
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