Clinical Inquiries

Evidence summary

FOBT is the only CRC screening tool with evidence of efficacy from randomized controlled trials.¹ A meta-analysis of 4 trials showed that 1173 patients would need to be screened for 10 years on a biennial basis to prevent 1 death from CRC. The upper age limits of patients were 75,² 64,³ 74,⁴ and 80 years.⁵ In the one study that included subjects to age 80, only 13% were older than 70 years. One case control study of FOBT showed a significant reduction in risk of mortality from CRC for individuals younger than 75 years, but not for patients older than 75; however, confidence intervals were wide.⁶

Evidence for screening with flexible sigmoidoscopy and colonoscopy comes primarily from case-control studies, and little information about appropriate upperage limits is available.^7-9 However, average time from onset of polyp to carcinoma is 10 to 15 years.¹⁰ Furthermore, cancers, large polyps (>1 cm), or dysplastic polyps were not found in any patient examined a mean of 3.4 years after normal flexible sigmoidoscopy,¹¹ and subsequent cancer is a rare early event after endoscopy, even in patients who have had polyps removed.¹² This suggests the cessation of endoscopic screening would miss few cancers in the very old.

While CRC incidence approximately doubles with each decade from age 40 to 80,¹³ the average life expectancy is 11.2 years at age 75 and 8.5 years at age 80.¹⁴ Given the slow progression from polyp to carcinoma, such patients may not live long enough to achieve any screening benefits. Similar reasoning suggests that even high-risk patients (eg, those with a family history of CRC) with repeatedly normal endoscopic examination results may be able to discontinue screening between ages 75 and 80, unless they are unusually healthy.

Risks of screening include discomfort from endoscopic examinations and complications relating to the many false-positive results of FOBT (98% in Minnesota study).⁵ A meta-analysis found that patients experience 1 perforation or hemorrhage for every 2.5 to 4.7 lives saved.¹ The risk of death is only about 1 in 50,000 for colonoscopy at the Mayo Clinic.¹⁵ Other complications include worry, perforation, and complications of treatment.

Recommendations from others

The USPSTF, AAFP, American Gastroenterology Association, and the American Cancer Society recommend screening adults 50 years of age and older for colon cancer; none sets an upper limit.^16-20 The USPSTF specifically states, “the appropriate age to discontinue screening has not been determined.”¹⁶ The American Geriatrics Society recommends that patients with short life expectancy or patients who could not undergo colonoscopy or barium enema plus sigmoidoscopy should not be screened.²¹

Evidence summary

FOBT is the only CRC screening tool with evidence of efficacy from randomized controlled trials.¹ A meta-analysis of 4 trials showed that 1173 patients would need to be screened for 10 years on a biennial basis to prevent 1 death from CRC. The upper age limits of patients were 75,² 64,³ 74,⁴ and 80 years.⁵ In the one study that included subjects to age 80, only 13% were older than 70 years. One case control study of FOBT showed a significant reduction in risk of mortality from CRC for individuals younger than 75 years, but not for patients older than 75; however, confidence intervals were wide.⁶

Evidence for screening with flexible sigmoidoscopy and colonoscopy comes primarily from case-control studies, and little information about appropriate upperage limits is available.^7-9 However, average time from onset of polyp to carcinoma is 10 to 15 years.¹⁰ Furthermore, cancers, large polyps (>1 cm), or dysplastic polyps were not found in any patient examined a mean of 3.4 years after normal flexible sigmoidoscopy,¹¹ and subsequent cancer is a rare early event after endoscopy, even in patients who have had polyps removed.¹² This suggests the cessation of endoscopic screening would miss few cancers in the very old.

While CRC incidence approximately doubles with each decade from age 40 to 80,¹³ the average life expectancy is 11.2 years at age 75 and 8.5 years at age 80.¹⁴ Given the slow progression from polyp to carcinoma, such patients may not live long enough to achieve any screening benefits. Similar reasoning suggests that even high-risk patients (eg, those with a family history of CRC) with repeatedly normal endoscopic examination results may be able to discontinue screening between ages 75 and 80, unless they are unusually healthy.

Risks of screening include discomfort from endoscopic examinations and complications relating to the many false-positive results of FOBT (98% in Minnesota study).⁵ A meta-analysis found that patients experience 1 perforation or hemorrhage for every 2.5 to 4.7 lives saved.¹ The risk of death is only about 1 in 50,000 for colonoscopy at the Mayo Clinic.¹⁵ Other complications include worry, perforation, and complications of treatment.

Recommendations from others

The USPSTF, AAFP, American Gastroenterology Association, and the American Cancer Society recommend screening adults 50 years of age and older for colon cancer; none sets an upper limit.^16-20 The USPSTF specifically states, “the appropriate age to discontinue screening has not been determined.”¹⁶ The American Geriatrics Society recommends that patients with short life expectancy or patients who could not undergo colonoscopy or barium enema plus sigmoidoscopy should not be screened.²¹

Evidence summary

FOBT is the only CRC screening tool with evidence of efficacy from randomized controlled trials.¹ A meta-analysis of 4 trials showed that 1173 patients would need to be screened for 10 years on a biennial basis to prevent 1 death from CRC. The upper age limits of patients were 75,² 64,³ 74,⁴ and 80 years.⁵ In the one study that included subjects to age 80, only 13% were older than 70 years. One case control study of FOBT showed a significant reduction in risk of mortality from CRC for individuals younger than 75 years, but not for patients older than 75; however, confidence intervals were wide.⁶

Evidence for screening with flexible sigmoidoscopy and colonoscopy comes primarily from case-control studies, and little information about appropriate upperage limits is available.^7-9 However, average time from onset of polyp to carcinoma is 10 to 15 years.¹⁰ Furthermore, cancers, large polyps (>1 cm), or dysplastic polyps were not found in any patient examined a mean of 3.4 years after normal flexible sigmoidoscopy,¹¹ and subsequent cancer is a rare early event after endoscopy, even in patients who have had polyps removed.¹² This suggests the cessation of endoscopic screening would miss few cancers in the very old.

While CRC incidence approximately doubles with each decade from age 40 to 80,¹³ the average life expectancy is 11.2 years at age 75 and 8.5 years at age 80.¹⁴ Given the slow progression from polyp to carcinoma, such patients may not live long enough to achieve any screening benefits. Similar reasoning suggests that even high-risk patients (eg, those with a family history of CRC) with repeatedly normal endoscopic examination results may be able to discontinue screening between ages 75 and 80, unless they are unusually healthy.

Risks of screening include discomfort from endoscopic examinations and complications relating to the many false-positive results of FOBT (98% in Minnesota study).⁵ A meta-analysis found that patients experience 1 perforation or hemorrhage for every 2.5 to 4.7 lives saved.¹ The risk of death is only about 1 in 50,000 for colonoscopy at the Mayo Clinic.¹⁵ Other complications include worry, perforation, and complications of treatment.

Recommendations from others

The USPSTF, AAFP, American Gastroenterology Association, and the American Cancer Society recommend screening adults 50 years of age and older for colon cancer; none sets an upper limit.^16-20 The USPSTF specifically states, “the appropriate age to discontinue screening has not been determined.”¹⁶ The American Geriatrics Society recommends that patients with short life expectancy or patients who could not undergo colonoscopy or barium enema plus sigmoidoscopy should not be screened.²¹

Recommendations from others

According to the Canadian Association of Gastroenterology Practice guidelines, an elevation in AP is associated with cholestatic liver disease, pregnancy, bone disease, and occasionally with inflammatory bowel disease. For an elevation in AP greater than 1.5 times the upper limits of normal (ULN) on 2 occasions at least 6 months apart, a workup for liver and bone disease is recommended followed by a referral to a specialist in hepatobiliary disease.³

Evidence summary

Liver, bone, and placental isoenzymes of AP are the most common sources of elevations reported in standard textbooks. Studies of men, women, and children have identified factors associated with normal elevations in AP. Hospital and laboratory-based studies report a variety of diseases associated with elevated AP. Within-day biologic variation is estimated at 4%, and day-to-day variation is estimated at 8% to 10%.² The Table 1 shows the causes of normal or physiologic elevations and pathologic elevations.

In a case series of hospitalized Department of Veterans Affairs patients (95% men; average age=62), 87 charts were reviewed.⁴ Those patients had elevated AP with normal aspartate aminotransferase (serum glutamate oxaloacetate transaminase) and calcium values. Seventy-eight percent of the diagnoses could be made through a careful history, physical examination, routine laboratory tests (lactate dehydrogenase, bilirubin, phosphorus, creatinine, protein, and albumin), and admitting chest X-ray. In this cohort, 32% of elevated AP values resolved in 3 months, another 20% resolved in 12 months, and 20% persisted. In the remaining 28%, an explanation was not sought because of the presence of an obvious terminal illness or severe dementia. Persistence was associated with an AP value greater than 1.5 times the ULN. In 19 (22%), the AP elevation was unexplained. In a case series of patients referred for bone scan secondary to an elevated AP not due to hepatic causes, 21% had normal findings, and of these, 92% had AP values less than 3 times the ULN.⁵ In this group, patients were subsequently found to have uncontrolled diabetes mellitus, ethanol abuse, drug toxicity, renal abnormalities, and chronic active hepatitis.

Expert opinion as reflected in standard textbooks and opinion pieces suggests values of 1.5 to 3 times the ULN are consistent with hepatocellular (viral infection, drug toxicity, alcohol) etiology, while values greater than 3 times the ULN are usually associated with biliary involvement. Bone involvement can be found at any value. Extremely high values (>7 times the ULN) are associated with the familial and transient isolated hyperphosphatasemia of infancy. Further workup should evaluate the presence of liver or bone disease, familial patterns, and rarely preclinical cancers.

Recommendations from others

According to the Canadian Association of Gastroenterology Practice guidelines, an elevation in AP is associated with cholestatic liver disease, pregnancy, bone disease, and occasionally with inflammatory bowel disease. For an elevation in AP greater than 1.5 times the upper limits of normal (ULN) on 2 occasions at least 6 months apart, a workup for liver and bone disease is recommended followed by a referral to a specialist in hepatobiliary disease.³

Evidence summary

Liver, bone, and placental isoenzymes of AP are the most common sources of elevations reported in standard textbooks. Studies of men, women, and children have identified factors associated with normal elevations in AP. Hospital and laboratory-based studies report a variety of diseases associated with elevated AP. Within-day biologic variation is estimated at 4%, and day-to-day variation is estimated at 8% to 10%.² The Table 1 shows the causes of normal or physiologic elevations and pathologic elevations.

In a case series of hospitalized Department of Veterans Affairs patients (95% men; average age=62), 87 charts were reviewed.⁴ Those patients had elevated AP with normal aspartate aminotransferase (serum glutamate oxaloacetate transaminase) and calcium values. Seventy-eight percent of the diagnoses could be made through a careful history, physical examination, routine laboratory tests (lactate dehydrogenase, bilirubin, phosphorus, creatinine, protein, and albumin), and admitting chest X-ray. In this cohort, 32% of elevated AP values resolved in 3 months, another 20% resolved in 12 months, and 20% persisted. In the remaining 28%, an explanation was not sought because of the presence of an obvious terminal illness or severe dementia. Persistence was associated with an AP value greater than 1.5 times the ULN. In 19 (22%), the AP elevation was unexplained. In a case series of patients referred for bone scan secondary to an elevated AP not due to hepatic causes, 21% had normal findings, and of these, 92% had AP values less than 3 times the ULN.⁵ In this group, patients were subsequently found to have uncontrolled diabetes mellitus, ethanol abuse, drug toxicity, renal abnormalities, and chronic active hepatitis.

Expert opinion as reflected in standard textbooks and opinion pieces suggests values of 1.5 to 3 times the ULN are consistent with hepatocellular (viral infection, drug toxicity, alcohol) etiology, while values greater than 3 times the ULN are usually associated with biliary involvement. Bone involvement can be found at any value. Extremely high values (>7 times the ULN) are associated with the familial and transient isolated hyperphosphatasemia of infancy. Further workup should evaluate the presence of liver or bone disease, familial patterns, and rarely preclinical cancers.

Recommendations from others

According to the Canadian Association of Gastroenterology Practice guidelines, an elevation in AP is associated with cholestatic liver disease, pregnancy, bone disease, and occasionally with inflammatory bowel disease. For an elevation in AP greater than 1.5 times the upper limits of normal (ULN) on 2 occasions at least 6 months apart, a workup for liver and bone disease is recommended followed by a referral to a specialist in hepatobiliary disease.³

Evidence summary

Liver, bone, and placental isoenzymes of AP are the most common sources of elevations reported in standard textbooks. Studies of men, women, and children have identified factors associated with normal elevations in AP. Hospital and laboratory-based studies report a variety of diseases associated with elevated AP. Within-day biologic variation is estimated at 4%, and day-to-day variation is estimated at 8% to 10%.² The Table 1 shows the causes of normal or physiologic elevations and pathologic elevations.

In a case series of hospitalized Department of Veterans Affairs patients (95% men; average age=62), 87 charts were reviewed.⁴ Those patients had elevated AP with normal aspartate aminotransferase (serum glutamate oxaloacetate transaminase) and calcium values. Seventy-eight percent of the diagnoses could be made through a careful history, physical examination, routine laboratory tests (lactate dehydrogenase, bilirubin, phosphorus, creatinine, protein, and albumin), and admitting chest X-ray. In this cohort, 32% of elevated AP values resolved in 3 months, another 20% resolved in 12 months, and 20% persisted. In the remaining 28%, an explanation was not sought because of the presence of an obvious terminal illness or severe dementia. Persistence was associated with an AP value greater than 1.5 times the ULN. In 19 (22%), the AP elevation was unexplained. In a case series of patients referred for bone scan secondary to an elevated AP not due to hepatic causes, 21% had normal findings, and of these, 92% had AP values less than 3 times the ULN.⁵ In this group, patients were subsequently found to have uncontrolled diabetes mellitus, ethanol abuse, drug toxicity, renal abnormalities, and chronic active hepatitis.

Expert opinion as reflected in standard textbooks and opinion pieces suggests values of 1.5 to 3 times the ULN are consistent with hepatocellular (viral infection, drug toxicity, alcohol) etiology, while values greater than 3 times the ULN are usually associated with biliary involvement. Bone involvement can be found at any value. Extremely high values (>7 times the ULN) are associated with the familial and transient isolated hyperphosphatasemia of infancy. Further workup should evaluate the presence of liver or bone disease, familial patterns, and rarely preclinical cancers.

Recommendations from others

The United States Centers for Disease Control and Prevention (CDC) state that travelers with nausea, vomiting, cramps, fever, or blood in stools may benefit from treatment for travelers’ diarrhea with ciprofloxacin (500 mg twice daily) or trimethoprim-sulfamethoxazole (double-strength tablet twice daily) for 3 days. The CDC also advises use of World Health Organization oral rehydration solution for replacement of lost fluids and salts.¹ The American College of Gastroenterology Practice Parameters Guidelines Committee recommends that travelers bring loperamide and an antimicrobial with them to use in self-therapy of TD.² However, neither the CDC nor the American College of Gastroenterology recommend antibiotic prophylaxis for otherwise healthy travelers.^1,2 Dosage and cost information is shown in the Table 1.

Evidence Summary

Many studies have documented the efficacy of treating TD with antibiotics. Recent studies have emphasized the use of the 4-fluoroquinolones because of the emergence of bacterial resistance against doxycycline and trimethoprim that was found in previous studies of the prophylactic use of antibiotics for TD. Other quinolones besides ciprofloxacin can be expected to be effective; ofloxacin 300 mg twice daily and norfloxacin 400 mg twice daily have been effective in clinical trials.¹ Illness duration can be shortened by 1 to 2.5 days with antibiotic treatment.³ A review of antibiotic use for TD in The Cochrane Library concluded that antibiotic treatment is associated with a shorter duration of illness at the cost of side effects. Antibiotics increased the proportion of those without diarrhea 72 hours after beginning treatment and also reduced the severity of illness.⁴

Antibiotics should be considered only part of the treatment of TD. Fluid and electrolyte therapy is the first and most important step in treatment and can usually be accomplished through oral rehydration therapy.⁵ Nonspecific agents such as bismuth subsalicylate can reduce stool frequency and shorten illness duration as shown in placebo-controlled trials. Antimotility agents such as loperamide (Imodium) and diphenoxylate with atropine (Lomotil) act to slow intraluminal flow of intestinal contents by increasing segmenting contractions in the intestine. Studies show reduced stool frequency and shortened duration of illness. Antimotility drugs should not be used in the setting of febrile dysentery with bloody stools, because such use may prolong or worsen the illness.²

Recommendations from others

The United States Centers for Disease Control and Prevention (CDC) state that travelers with nausea, vomiting, cramps, fever, or blood in stools may benefit from treatment for travelers’ diarrhea with ciprofloxacin (500 mg twice daily) or trimethoprim-sulfamethoxazole (double-strength tablet twice daily) for 3 days. The CDC also advises use of World Health Organization oral rehydration solution for replacement of lost fluids and salts.¹ The American College of Gastroenterology Practice Parameters Guidelines Committee recommends that travelers bring loperamide and an antimicrobial with them to use in self-therapy of TD.² However, neither the CDC nor the American College of Gastroenterology recommend antibiotic prophylaxis for otherwise healthy travelers.^1,2 Dosage and cost information is shown in the Table 1.

Evidence Summary

Many studies have documented the efficacy of treating TD with antibiotics. Recent studies have emphasized the use of the 4-fluoroquinolones because of the emergence of bacterial resistance against doxycycline and trimethoprim that was found in previous studies of the prophylactic use of antibiotics for TD. Other quinolones besides ciprofloxacin can be expected to be effective; ofloxacin 300 mg twice daily and norfloxacin 400 mg twice daily have been effective in clinical trials.¹ Illness duration can be shortened by 1 to 2.5 days with antibiotic treatment.³ A review of antibiotic use for TD in The Cochrane Library concluded that antibiotic treatment is associated with a shorter duration of illness at the cost of side effects. Antibiotics increased the proportion of those without diarrhea 72 hours after beginning treatment and also reduced the severity of illness.⁴

Antibiotics should be considered only part of the treatment of TD. Fluid and electrolyte therapy is the first and most important step in treatment and can usually be accomplished through oral rehydration therapy.⁵ Nonspecific agents such as bismuth subsalicylate can reduce stool frequency and shorten illness duration as shown in placebo-controlled trials. Antimotility agents such as loperamide (Imodium) and diphenoxylate with atropine (Lomotil) act to slow intraluminal flow of intestinal contents by increasing segmenting contractions in the intestine. Studies show reduced stool frequency and shortened duration of illness. Antimotility drugs should not be used in the setting of febrile dysentery with bloody stools, because such use may prolong or worsen the illness.²

Recommendations from others

The United States Centers for Disease Control and Prevention (CDC) state that travelers with nausea, vomiting, cramps, fever, or blood in stools may benefit from treatment for travelers’ diarrhea with ciprofloxacin (500 mg twice daily) or trimethoprim-sulfamethoxazole (double-strength tablet twice daily) for 3 days. The CDC also advises use of World Health Organization oral rehydration solution for replacement of lost fluids and salts.¹ The American College of Gastroenterology Practice Parameters Guidelines Committee recommends that travelers bring loperamide and an antimicrobial with them to use in self-therapy of TD.² However, neither the CDC nor the American College of Gastroenterology recommend antibiotic prophylaxis for otherwise healthy travelers.^1,2 Dosage and cost information is shown in the Table 1.

Evidence Summary

Many studies have documented the efficacy of treating TD with antibiotics. Recent studies have emphasized the use of the 4-fluoroquinolones because of the emergence of bacterial resistance against doxycycline and trimethoprim that was found in previous studies of the prophylactic use of antibiotics for TD. Other quinolones besides ciprofloxacin can be expected to be effective; ofloxacin 300 mg twice daily and norfloxacin 400 mg twice daily have been effective in clinical trials.¹ Illness duration can be shortened by 1 to 2.5 days with antibiotic treatment.³ A review of antibiotic use for TD in The Cochrane Library concluded that antibiotic treatment is associated with a shorter duration of illness at the cost of side effects. Antibiotics increased the proportion of those without diarrhea 72 hours after beginning treatment and also reduced the severity of illness.⁴

Antibiotics should be considered only part of the treatment of TD. Fluid and electrolyte therapy is the first and most important step in treatment and can usually be accomplished through oral rehydration therapy.⁵ Nonspecific agents such as bismuth subsalicylate can reduce stool frequency and shorten illness duration as shown in placebo-controlled trials. Antimotility agents such as loperamide (Imodium) and diphenoxylate with atropine (Lomotil) act to slow intraluminal flow of intestinal contents by increasing segmenting contractions in the intestine. Studies show reduced stool frequency and shortened duration of illness. Antimotility drugs should not be used in the setting of febrile dysentery with bloody stools, because such use may prolong or worsen the illness.²

Evidence Summary

For this question I excluded conventional medical therapy for fibromyalgia (prescription antidepressants, muscle relaxants, cognitive-behavioral therapy, and exercise). In general, the literature on CAM therapy for fibromyalgia is characterized by small poor-quality studies that use many different outcome measures. A recent systematic review of fibromyalgia therapy found that nonpharmacologic interventions were at least as effective as pharmacologic interventions.¹ The Table shows a summary, based on this article and my review of the literature, of the strength of evidence and benefit of the more common CAM therapies.

A nonsystematic review article identified 7 studies of acupuncture for fibromyalgia.² All but one of these studies were small and poorly designed. The exception was a study of 70 fibromyalgia patients who were randomly assigned to electroacupuncture using the tai chi meridians or sham electroacupuncture.³ The patients and evaluating physicians were blinded to the treatment assignment, although the acupuncturist was not. Patients in the treatment group improved significantly more than the control group in 5 of 8 outcome measures.

Biofeedback was found to be effective in a randomized controlled trial of 24 patients with questionable blinding.⁴ Another study randomized 119 patients to biofeedback/relaxation training, exercise, a combination of the 2, or an education-only control group. All 3 of the active treatment groups had better outcomes than the control group, but this was primarily because of worsening outcomes in the control group.⁵

SAMe has been evaluated in several double-blind randomized controlled trials.^6-8 Although fairly well designed, all were small and had mixed results. Only one used the oral form of the drug. While the drug appears to be relatively safe, it is expensive, and interactions with antidepressants and other drugs have been reported.

Although not studied in well-designed clinical trials, fibromyalgia patients may wish to try spa treatments,⁹ massage,¹⁰ hypnotherapy,¹¹ and meditation.¹² These are generally safe and relatively inexpensive interventions, and the limited studies to date suggest a benefit. It is important that conventional therapies for fibromyalgia be given an opportunity to help the patient. Where evidence is lacking, the cost and potential harm of an alternative therapy must be balanced against uncertain efficacy.*

Recommendations From Others

Conn’s Current Therapy, 52nd edition states: “Nonpharmacologic modalities, including meditation, relaxation techniques, and biofeedback, may be useful in lessening tension.” Koopman’s Arthritis and Allied Conditions recommends SAMe, biofeedback, and hypnotherapy as possibly helpful but requiring further study.

Evidence Summary

For this question I excluded conventional medical therapy for fibromyalgia (prescription antidepressants, muscle relaxants, cognitive-behavioral therapy, and exercise). In general, the literature on CAM therapy for fibromyalgia is characterized by small poor-quality studies that use many different outcome measures. A recent systematic review of fibromyalgia therapy found that nonpharmacologic interventions were at least as effective as pharmacologic interventions.¹ The Table shows a summary, based on this article and my review of the literature, of the strength of evidence and benefit of the more common CAM therapies.

A nonsystematic review article identified 7 studies of acupuncture for fibromyalgia.² All but one of these studies were small and poorly designed. The exception was a study of 70 fibromyalgia patients who were randomly assigned to electroacupuncture using the tai chi meridians or sham electroacupuncture.³ The patients and evaluating physicians were blinded to the treatment assignment, although the acupuncturist was not. Patients in the treatment group improved significantly more than the control group in 5 of 8 outcome measures.

Biofeedback was found to be effective in a randomized controlled trial of 24 patients with questionable blinding.⁴ Another study randomized 119 patients to biofeedback/relaxation training, exercise, a combination of the 2, or an education-only control group. All 3 of the active treatment groups had better outcomes than the control group, but this was primarily because of worsening outcomes in the control group.⁵

SAMe has been evaluated in several double-blind randomized controlled trials.^6-8 Although fairly well designed, all were small and had mixed results. Only one used the oral form of the drug. While the drug appears to be relatively safe, it is expensive, and interactions with antidepressants and other drugs have been reported.

Although not studied in well-designed clinical trials, fibromyalgia patients may wish to try spa treatments,⁹ massage,¹⁰ hypnotherapy,¹¹ and meditation.¹² These are generally safe and relatively inexpensive interventions, and the limited studies to date suggest a benefit. It is important that conventional therapies for fibromyalgia be given an opportunity to help the patient. Where evidence is lacking, the cost and potential harm of an alternative therapy must be balanced against uncertain efficacy.*

Recommendations From Others

Conn’s Current Therapy, 52nd edition states: “Nonpharmacologic modalities, including meditation, relaxation techniques, and biofeedback, may be useful in lessening tension.” Koopman’s Arthritis and Allied Conditions recommends SAMe, biofeedback, and hypnotherapy as possibly helpful but requiring further study.

Evidence Summary

For this question I excluded conventional medical therapy for fibromyalgia (prescription antidepressants, muscle relaxants, cognitive-behavioral therapy, and exercise). In general, the literature on CAM therapy for fibromyalgia is characterized by small poor-quality studies that use many different outcome measures. A recent systematic review of fibromyalgia therapy found that nonpharmacologic interventions were at least as effective as pharmacologic interventions.¹ The Table shows a summary, based on this article and my review of the literature, of the strength of evidence and benefit of the more common CAM therapies.

A nonsystematic review article identified 7 studies of acupuncture for fibromyalgia.² All but one of these studies were small and poorly designed. The exception was a study of 70 fibromyalgia patients who were randomly assigned to electroacupuncture using the tai chi meridians or sham electroacupuncture.³ The patients and evaluating physicians were blinded to the treatment assignment, although the acupuncturist was not. Patients in the treatment group improved significantly more than the control group in 5 of 8 outcome measures.

Biofeedback was found to be effective in a randomized controlled trial of 24 patients with questionable blinding.⁴ Another study randomized 119 patients to biofeedback/relaxation training, exercise, a combination of the 2, or an education-only control group. All 3 of the active treatment groups had better outcomes than the control group, but this was primarily because of worsening outcomes in the control group.⁵

SAMe has been evaluated in several double-blind randomized controlled trials.^6-8 Although fairly well designed, all were small and had mixed results. Only one used the oral form of the drug. While the drug appears to be relatively safe, it is expensive, and interactions with antidepressants and other drugs have been reported.

Although not studied in well-designed clinical trials, fibromyalgia patients may wish to try spa treatments,⁹ massage,¹⁰ hypnotherapy,¹¹ and meditation.¹² These are generally safe and relatively inexpensive interventions, and the limited studies to date suggest a benefit. It is important that conventional therapies for fibromyalgia be given an opportunity to help the patient. Where evidence is lacking, the cost and potential harm of an alternative therapy must be balanced against uncertain efficacy.*

Recommendations From Others

Conn’s Current Therapy, 52nd edition states: “Nonpharmacologic modalities, including meditation, relaxation techniques, and biofeedback, may be useful in lessening tension.” Koopman’s Arthritis and Allied Conditions recommends SAMe, biofeedback, and hypnotherapy as possibly helpful but requiring further study.

Evidence summary

One systematic review calculated cure rates from 5 randomized controlled trials comparing oral metronidazole, clindamycin 2% vaginal cream, and metronidazole 0.75% vaginal gel.² Cumulative cure rates at 5 to 10 days and 4 weeks post-treatment were essentially equal for all treatments Table 1. The most common side effects were vaginal Candida infections (for both treatments) and gastrointestional symptoms (for metronidazole tablets and gels).

Metronidazole 0.75% gel used once daily for 5 days had equal efficacy compared with twice-daily dosing (cure rate = 77% vs 80%).³ One study found a cure rate of 94% with oral clindamycin 300 mg twice daily for 7 days and 96% with metronidazole 500 mg twice daily for 7 days.

A meta-analysis of 10 clinical trials compared different dosing regimens of oral metronidazole.⁴ The results showed comparable cure rates (85% to 87%) among groups treated with either a single 2-g dose or 500 mg twice daily for 7 days. A systematic review showed a significantly lower cure rate with a single 2-g dose compared with the 7-day regimen (54% vs 88%).⁵

Metronidazole (400 mg or 500 mg twice daily) achieved significantly higher cure rates compared with ofloxacin (200 mg or 300 mg twice daily) 1 to 7 days post-treatment.^6,7 One review reports that ampicillin and erythromycin are ineffective and ampicillin sulbactam and ciprofloxacin are less effective than oral metronidazole.⁸ A systematic review of 4 studies on treatments to restore depleted Lactobacilli concluded that “these trials do not constitute enough evidence to recommend using yogurt or Lactobacillus to cure vaginal infections.”⁹ One systematic review of 6 randomized controlled trials found no benefit from treating male partners of women with bacterial vaginosis.¹⁰

Recommendations from others

The Clinical Effectiveness Group and the American College of Obstetricians and Gynecologists recommend: (1) 2% clindamycin cream 5 g at bedtime for 7 days or 300 mg orally twice daily for 7 days; or (2) metronidazole gel, 0.75% 5 g twice daily for 5 days or 500 mg orally twice daily for 7 days.^11,12

Evidence summary

One systematic review calculated cure rates from 5 randomized controlled trials comparing oral metronidazole, clindamycin 2% vaginal cream, and metronidazole 0.75% vaginal gel.² Cumulative cure rates at 5 to 10 days and 4 weeks post-treatment were essentially equal for all treatments Table 1. The most common side effects were vaginal Candida infections (for both treatments) and gastrointestional symptoms (for metronidazole tablets and gels).

Metronidazole 0.75% gel used once daily for 5 days had equal efficacy compared with twice-daily dosing (cure rate = 77% vs 80%).³ One study found a cure rate of 94% with oral clindamycin 300 mg twice daily for 7 days and 96% with metronidazole 500 mg twice daily for 7 days.

A meta-analysis of 10 clinical trials compared different dosing regimens of oral metronidazole.⁴ The results showed comparable cure rates (85% to 87%) among groups treated with either a single 2-g dose or 500 mg twice daily for 7 days. A systematic review showed a significantly lower cure rate with a single 2-g dose compared with the 7-day regimen (54% vs 88%).⁵

Metronidazole (400 mg or 500 mg twice daily) achieved significantly higher cure rates compared with ofloxacin (200 mg or 300 mg twice daily) 1 to 7 days post-treatment.^6,7 One review reports that ampicillin and erythromycin are ineffective and ampicillin sulbactam and ciprofloxacin are less effective than oral metronidazole.⁸ A systematic review of 4 studies on treatments to restore depleted Lactobacilli concluded that “these trials do not constitute enough evidence to recommend using yogurt or Lactobacillus to cure vaginal infections.”⁹ One systematic review of 6 randomized controlled trials found no benefit from treating male partners of women with bacterial vaginosis.¹⁰

Recommendations from others

The Clinical Effectiveness Group and the American College of Obstetricians and Gynecologists recommend: (1) 2% clindamycin cream 5 g at bedtime for 7 days or 300 mg orally twice daily for 7 days; or (2) metronidazole gel, 0.75% 5 g twice daily for 5 days or 500 mg orally twice daily for 7 days.^11,12

Evidence summary

One systematic review calculated cure rates from 5 randomized controlled trials comparing oral metronidazole, clindamycin 2% vaginal cream, and metronidazole 0.75% vaginal gel.² Cumulative cure rates at 5 to 10 days and 4 weeks post-treatment were essentially equal for all treatments Table 1. The most common side effects were vaginal Candida infections (for both treatments) and gastrointestional symptoms (for metronidazole tablets and gels).

Metronidazole 0.75% gel used once daily for 5 days had equal efficacy compared with twice-daily dosing (cure rate = 77% vs 80%).³ One study found a cure rate of 94% with oral clindamycin 300 mg twice daily for 7 days and 96% with metronidazole 500 mg twice daily for 7 days.

A meta-analysis of 10 clinical trials compared different dosing regimens of oral metronidazole.⁴ The results showed comparable cure rates (85% to 87%) among groups treated with either a single 2-g dose or 500 mg twice daily for 7 days. A systematic review showed a significantly lower cure rate with a single 2-g dose compared with the 7-day regimen (54% vs 88%).⁵

Metronidazole (400 mg or 500 mg twice daily) achieved significantly higher cure rates compared with ofloxacin (200 mg or 300 mg twice daily) 1 to 7 days post-treatment.^6,7 One review reports that ampicillin and erythromycin are ineffective and ampicillin sulbactam and ciprofloxacin are less effective than oral metronidazole.⁸ A systematic review of 4 studies on treatments to restore depleted Lactobacilli concluded that “these trials do not constitute enough evidence to recommend using yogurt or Lactobacillus to cure vaginal infections.”⁹ One systematic review of 6 randomized controlled trials found no benefit from treating male partners of women with bacterial vaginosis.¹⁰

Recommendations from others

The Clinical Effectiveness Group and the American College of Obstetricians and Gynecologists recommend: (1) 2% clindamycin cream 5 g at bedtime for 7 days or 300 mg orally twice daily for 7 days; or (2) metronidazole gel, 0.75% 5 g twice daily for 5 days or 500 mg orally twice daily for 7 days.^11,12

Recommendations from others

Standard texts suggest that antacids¹ or histamine (H2) blockers² be used as first-line agents for reflux. Burrow and Duffyz³ recommend a stratified approach with antacids followed by H2-blockers, reserving the use of proton pump inhibitors for the more severe cases.

Evidence summary

Heartburn affects 30% to 50% of pregnancies and occurs primarily in the second and third trimesters.⁴ Lifestyle changes and dietary modification are recommended as initial measures for relief of symptoms.

Antacids

Each of the 3 identified placebo-controlled trials of antacid therapy had significant methodologic limitations. Aluminum phosphate more frequently produced complete relief of moderate to severe heartburn at 60 minutes compared with placebo (P <.001; number needed to treat [NNT] = 2.1 for mild heartburn and 20 for severe).⁵ Patients who received a combination of magnesium and aluminum hydroxide for 7 days had no more relief of symptoms than the placebo group.⁶ Atlay and colleagues⁷ found that sodium bicarbonate significantly reduced reflux symptoms compared with placebo (P=.021; NNT=6.0).

There are limited data regarding the safety of antacids during pregnancy. A single case-control study found a higher rate of congenital anomalies in children of women who took antacids in the first trimester (unadjusted odds ratio calculated from data=2.36; P <.05).⁸ This association was not detected when studied over the entire pregnancy. The rate of malformations was not different for magnesium, aluminum, and bicarbonate. The association could well be due to recall bias or other systematic biases inherent in case-control methodology.

H2-Blockers

The only identified studies of H2-blockers evaluated ranitidine. A 4-week double-blind randomized control trial found that ranitidine 150 mg twice daily reduced patient symptoms by 44% over placebo (P <.05).⁹ This study was limited by its short duration (<1 month) and small sample size (N=30). A 2-week study that compared antacids plus ranitidine to antacids alone found a 52% decrease in symptoms in the ranitidine group and a 44% reduction in the antacid-alone group.¹⁰ Ranitidine, cimetidine, and famotidine are US Food and Drug Administration (FDA) pregnancy category B (no demonstrated risk).

Proton Pump Inhibitors

In nonpregnant adults, proton pump inhibitors are more effective than antacids and H2-blockers for gastroesophageal reflux disease (GERD). No cohort or control studies have been performed on their efficacy in pregnancy. On the basis of animal studies, omeprazole is a category C drug (potential benefit of use should outweigh potential risks). A cohort study of 113 women found no associated anomalies (relative risk=1.94; 95% confidence interval, 0.36-10.36).¹¹ Pantoprazole, lansoprazole and rabeprazole are category B medications.

Other Agents

Metoclopramide and sucralfate have been used in nonpregnant adults with GERD. Although both are category B, there are no data about their effectiveness for heartburn during pregnancy.

Recommendations from others

Standard texts suggest that antacids¹ or histamine (H2) blockers² be used as first-line agents for reflux. Burrow and Duffyz³ recommend a stratified approach with antacids followed by H2-blockers, reserving the use of proton pump inhibitors for the more severe cases.

Evidence summary

Heartburn affects 30% to 50% of pregnancies and occurs primarily in the second and third trimesters.⁴ Lifestyle changes and dietary modification are recommended as initial measures for relief of symptoms.

Antacids

Each of the 3 identified placebo-controlled trials of antacid therapy had significant methodologic limitations. Aluminum phosphate more frequently produced complete relief of moderate to severe heartburn at 60 minutes compared with placebo (P <.001; number needed to treat [NNT] = 2.1 for mild heartburn and 20 for severe).⁵ Patients who received a combination of magnesium and aluminum hydroxide for 7 days had no more relief of symptoms than the placebo group.⁶ Atlay and colleagues⁷ found that sodium bicarbonate significantly reduced reflux symptoms compared with placebo (P=.021; NNT=6.0).

There are limited data regarding the safety of antacids during pregnancy. A single case-control study found a higher rate of congenital anomalies in children of women who took antacids in the first trimester (unadjusted odds ratio calculated from data=2.36; P <.05).⁸ This association was not detected when studied over the entire pregnancy. The rate of malformations was not different for magnesium, aluminum, and bicarbonate. The association could well be due to recall bias or other systematic biases inherent in case-control methodology.

H2-Blockers

The only identified studies of H2-blockers evaluated ranitidine. A 4-week double-blind randomized control trial found that ranitidine 150 mg twice daily reduced patient symptoms by 44% over placebo (P <.05).⁹ This study was limited by its short duration (<1 month) and small sample size (N=30). A 2-week study that compared antacids plus ranitidine to antacids alone found a 52% decrease in symptoms in the ranitidine group and a 44% reduction in the antacid-alone group.¹⁰ Ranitidine, cimetidine, and famotidine are US Food and Drug Administration (FDA) pregnancy category B (no demonstrated risk).

Proton Pump Inhibitors

In nonpregnant adults, proton pump inhibitors are more effective than antacids and H2-blockers for gastroesophageal reflux disease (GERD). No cohort or control studies have been performed on their efficacy in pregnancy. On the basis of animal studies, omeprazole is a category C drug (potential benefit of use should outweigh potential risks). A cohort study of 113 women found no associated anomalies (relative risk=1.94; 95% confidence interval, 0.36-10.36).¹¹ Pantoprazole, lansoprazole and rabeprazole are category B medications.

Other Agents

Metoclopramide and sucralfate have been used in nonpregnant adults with GERD. Although both are category B, there are no data about their effectiveness for heartburn during pregnancy.

Recommendations from others

Standard texts suggest that antacids¹ or histamine (H2) blockers² be used as first-line agents for reflux. Burrow and Duffyz³ recommend a stratified approach with antacids followed by H2-blockers, reserving the use of proton pump inhibitors for the more severe cases.

Evidence summary

Heartburn affects 30% to 50% of pregnancies and occurs primarily in the second and third trimesters.⁴ Lifestyle changes and dietary modification are recommended as initial measures for relief of symptoms.

Antacids

Each of the 3 identified placebo-controlled trials of antacid therapy had significant methodologic limitations. Aluminum phosphate more frequently produced complete relief of moderate to severe heartburn at 60 minutes compared with placebo (P <.001; number needed to treat [NNT] = 2.1 for mild heartburn and 20 for severe).⁵ Patients who received a combination of magnesium and aluminum hydroxide for 7 days had no more relief of symptoms than the placebo group.⁶ Atlay and colleagues⁷ found that sodium bicarbonate significantly reduced reflux symptoms compared with placebo (P=.021; NNT=6.0).

There are limited data regarding the safety of antacids during pregnancy. A single case-control study found a higher rate of congenital anomalies in children of women who took antacids in the first trimester (unadjusted odds ratio calculated from data=2.36; P <.05).⁸ This association was not detected when studied over the entire pregnancy. The rate of malformations was not different for magnesium, aluminum, and bicarbonate. The association could well be due to recall bias or other systematic biases inherent in case-control methodology.

H2-Blockers

The only identified studies of H2-blockers evaluated ranitidine. A 4-week double-blind randomized control trial found that ranitidine 150 mg twice daily reduced patient symptoms by 44% over placebo (P <.05).⁹ This study was limited by its short duration (<1 month) and small sample size (N=30). A 2-week study that compared antacids plus ranitidine to antacids alone found a 52% decrease in symptoms in the ranitidine group and a 44% reduction in the antacid-alone group.¹⁰ Ranitidine, cimetidine, and famotidine are US Food and Drug Administration (FDA) pregnancy category B (no demonstrated risk).

Proton Pump Inhibitors

In nonpregnant adults, proton pump inhibitors are more effective than antacids and H2-blockers for gastroesophageal reflux disease (GERD). No cohort or control studies have been performed on their efficacy in pregnancy. On the basis of animal studies, omeprazole is a category C drug (potential benefit of use should outweigh potential risks). A cohort study of 113 women found no associated anomalies (relative risk=1.94; 95% confidence interval, 0.36-10.36).¹¹ Pantoprazole, lansoprazole and rabeprazole are category B medications.

Other Agents

Metoclopramide and sucralfate have been used in nonpregnant adults with GERD. Although both are category B, there are no data about their effectiveness for heartburn during pregnancy.

Recommendations from others

Three primary care textbooks recommend providing patients with simple written instructions to enhance compliance with medications.^1-3 Another text⁴ also advocates simple written instructions and recommends follow-up reminders, addressing compliance issues at patient visits, and maintaining compliance interventions throughout the duration of treatment.

Evidence summary

Medication adherence is defined as the extent to which patients follow instructions for prescribed treatments.⁵ Estimates of medication adherence range from 0% to 100% and are typically approximately 50%.⁵ The Cochrane Database of Systematic Reviews evaluated the published, unbiased, randomized controlled trials of interventions to improve medication adherence that measured both adherence and treatment outcome. Eighty percent follow-up was required, as well as a 6-month follow-up period for long-term treatments with initial positive outcomes. A total of 4762 citations were evaluated; only 19 met their criteria for full consideration. We did not find any more recent or additional trials that met the Cochrane criteria for consideration.

The interventions studied included combinations of patient and family counseling (verbal, written, telephone, and automated); patient involvement in self-monitoring of outcomes (eg, blood pressure); simplified medication regimens; reminders of appointments, refills, and pill schedules; and care provided at the workplace. All interventions were for single clinical conditions including hypertension (7 studies), schizophrenia and psychosis (6), asthma (2), acute infection (2), hyperlipidemia (1), and epilepsy (1). Both of the studies concerning simplifying medication regimens showed a positive effect on medication adherence. Nine of 16 studies on varying strategies of interventions reported statistically significant increases in medication adherence. Most of the studies that used multidimensional interventions did not assess the individual components of the interventions; therefore, it is impossible to determine if one part of a complex intervention was more important than another. Also, only small improvements in adherence or treatment outcomes were observed in these studies.

This review was designed to specifically address interventions to improve patient compliance with prescribed medication. Other areas of potential significance to patient compliance are health care access, continuity of care, and medication side effects. In addition to simplifying dosing regimens, it would stand to reason that maximizing the provision of care and minimizing adverse medication side effects would have a positive effect on patient compliance.

Recommendations from others

Three primary care textbooks recommend providing patients with simple written instructions to enhance compliance with medications.^1-3 Another text⁴ also advocates simple written instructions and recommends follow-up reminders, addressing compliance issues at patient visits, and maintaining compliance interventions throughout the duration of treatment.

Evidence summary

Medication adherence is defined as the extent to which patients follow instructions for prescribed treatments.⁵ Estimates of medication adherence range from 0% to 100% and are typically approximately 50%.⁵ The Cochrane Database of Systematic Reviews evaluated the published, unbiased, randomized controlled trials of interventions to improve medication adherence that measured both adherence and treatment outcome. Eighty percent follow-up was required, as well as a 6-month follow-up period for long-term treatments with initial positive outcomes. A total of 4762 citations were evaluated; only 19 met their criteria for full consideration. We did not find any more recent or additional trials that met the Cochrane criteria for consideration.

The interventions studied included combinations of patient and family counseling (verbal, written, telephone, and automated); patient involvement in self-monitoring of outcomes (eg, blood pressure); simplified medication regimens; reminders of appointments, refills, and pill schedules; and care provided at the workplace. All interventions were for single clinical conditions including hypertension (7 studies), schizophrenia and psychosis (6), asthma (2), acute infection (2), hyperlipidemia (1), and epilepsy (1). Both of the studies concerning simplifying medication regimens showed a positive effect on medication adherence. Nine of 16 studies on varying strategies of interventions reported statistically significant increases in medication adherence. Most of the studies that used multidimensional interventions did not assess the individual components of the interventions; therefore, it is impossible to determine if one part of a complex intervention was more important than another. Also, only small improvements in adherence or treatment outcomes were observed in these studies.

This review was designed to specifically address interventions to improve patient compliance with prescribed medication. Other areas of potential significance to patient compliance are health care access, continuity of care, and medication side effects. In addition to simplifying dosing regimens, it would stand to reason that maximizing the provision of care and minimizing adverse medication side effects would have a positive effect on patient compliance.

Recommendations from others

Three primary care textbooks recommend providing patients with simple written instructions to enhance compliance with medications.^1-3 Another text⁴ also advocates simple written instructions and recommends follow-up reminders, addressing compliance issues at patient visits, and maintaining compliance interventions throughout the duration of treatment.

Evidence summary

Medication adherence is defined as the extent to which patients follow instructions for prescribed treatments.⁵ Estimates of medication adherence range from 0% to 100% and are typically approximately 50%.⁵ The Cochrane Database of Systematic Reviews evaluated the published, unbiased, randomized controlled trials of interventions to improve medication adherence that measured both adherence and treatment outcome. Eighty percent follow-up was required, as well as a 6-month follow-up period for long-term treatments with initial positive outcomes. A total of 4762 citations were evaluated; only 19 met their criteria for full consideration. We did not find any more recent or additional trials that met the Cochrane criteria for consideration.

The interventions studied included combinations of patient and family counseling (verbal, written, telephone, and automated); patient involvement in self-monitoring of outcomes (eg, blood pressure); simplified medication regimens; reminders of appointments, refills, and pill schedules; and care provided at the workplace. All interventions were for single clinical conditions including hypertension (7 studies), schizophrenia and psychosis (6), asthma (2), acute infection (2), hyperlipidemia (1), and epilepsy (1). Both of the studies concerning simplifying medication regimens showed a positive effect on medication adherence. Nine of 16 studies on varying strategies of interventions reported statistically significant increases in medication adherence. Most of the studies that used multidimensional interventions did not assess the individual components of the interventions; therefore, it is impossible to determine if one part of a complex intervention was more important than another. Also, only small improvements in adherence or treatment outcomes were observed in these studies.

This review was designed to specifically address interventions to improve patient compliance with prescribed medication. Other areas of potential significance to patient compliance are health care access, continuity of care, and medication side effects. In addition to simplifying dosing regimens, it would stand to reason that maximizing the provision of care and minimizing adverse medication side effects would have a positive effect on patient compliance.

Recommendations from others

The National Council on Potassium in Clinical Practice issued a set of guidelines for potassium replacement in September 2000.1 The authors recommend using thiazide diuretics at a low dose only (eg, 12.5-25 mg of hydrochlorothiazide daily) and adding a potassium-sparing diuretic drug when higher diuretic doses are needed. For patients with asymptomatic hypertension they recommend trying to maintain a serum potassium level of at least 4.0 mmol/L. The University of Iowa Family Practice Handbook2 states: “Maximal decrease in serum K+ concentration is usually seen after 7 days of treatment. Serum K+ concentration should be measured before initiation of a diuretic and 1 week after initiation of increase in dose of the diuretic.”

Evidence summary

Hypokalemia is defined as a serum potassium level less than 3.5 mmol/L (3.5 mEq/L); hypokalemia at levels between 3.1 and 3.4 mmol/L is considered mild. The incidence of hypokalemia reported for patients on diuretic therapy is broad (7.2% to 56%),^3-6 and the time period required to develop hypokalemia varies (1 week6 to >1 year⁷). Factors including the type of diuretic used, dosage, duration of use, dietary potassium, and so forth, make predicting an individual patient’s progression nearly impossible. Widmer and coworkers5 found that the risk of hypokalemia was greatest with concomitant glucocorticoid use, polypharmacy (greater than 12 medications administered), and female sex. The latter risk factor may be related to a higher dose-to-weight relationship.

Lemieux and colleagues8 followed 50 patients receiving a variety of diuretic regimens (hydrochlorothiazide 50 to 100 mg daily or every other day with or without reserpine 0.25 mg daily). Only 3 patients in this group had potassium levels below 3.5 mmol/L, and all decreases were only transient. Peters and coworkers6 documented potassium levels below 3.5 mEq/L in 6 of 19 patients taking hydrochlorothiazide 25 or 50 mg for 20 weeks. Three of these patients normalized without therapy. One of these transiently hypokalemic patients was also taking triamterene, a potassium-sparing diuretic.

Potassium-sparing diuretics may not free the clinician from checking a potassium level, however. Penhall and coworkers⁹ found hypokalemia in 24 of 54 patients receiving a fixed-combination diuretic (hydrochlorothiazide 50 mg and potassium-sparing amiloride 5 mg). Note that the dose of hydrochlorothiazide was higher in this study than is generally used today. Most recent studies have found that hydrochlorothiazide in doses above 12.5 to 25 mg do not result in significantly lower blood pressure and only lead to more electrolyte abnormalities.¹⁰

Morgan and Davidson¹¹ performed an analysis of the published data available in 1980. They found that the average fall in potassium is less for patients taking furosemide (0.3mmol/L) than on thiazide diuretics (0.6mmol/L) and that this fall was only slightly influenced by dose or duration of treatment.

Recommendations from others

The National Council on Potassium in Clinical Practice issued a set of guidelines for potassium replacement in September 2000.1 The authors recommend using thiazide diuretics at a low dose only (eg, 12.5-25 mg of hydrochlorothiazide daily) and adding a potassium-sparing diuretic drug when higher diuretic doses are needed. For patients with asymptomatic hypertension they recommend trying to maintain a serum potassium level of at least 4.0 mmol/L. The University of Iowa Family Practice Handbook2 states: “Maximal decrease in serum K+ concentration is usually seen after 7 days of treatment. Serum K+ concentration should be measured before initiation of a diuretic and 1 week after initiation of increase in dose of the diuretic.”

Evidence summary

Hypokalemia is defined as a serum potassium level less than 3.5 mmol/L (3.5 mEq/L); hypokalemia at levels between 3.1 and 3.4 mmol/L is considered mild. The incidence of hypokalemia reported for patients on diuretic therapy is broad (7.2% to 56%),^3-6 and the time period required to develop hypokalemia varies (1 week6 to >1 year⁷). Factors including the type of diuretic used, dosage, duration of use, dietary potassium, and so forth, make predicting an individual patient’s progression nearly impossible. Widmer and coworkers5 found that the risk of hypokalemia was greatest with concomitant glucocorticoid use, polypharmacy (greater than 12 medications administered), and female sex. The latter risk factor may be related to a higher dose-to-weight relationship.

Lemieux and colleagues8 followed 50 patients receiving a variety of diuretic regimens (hydrochlorothiazide 50 to 100 mg daily or every other day with or without reserpine 0.25 mg daily). Only 3 patients in this group had potassium levels below 3.5 mmol/L, and all decreases were only transient. Peters and coworkers6 documented potassium levels below 3.5 mEq/L in 6 of 19 patients taking hydrochlorothiazide 25 or 50 mg for 20 weeks. Three of these patients normalized without therapy. One of these transiently hypokalemic patients was also taking triamterene, a potassium-sparing diuretic.

Potassium-sparing diuretics may not free the clinician from checking a potassium level, however. Penhall and coworkers⁹ found hypokalemia in 24 of 54 patients receiving a fixed-combination diuretic (hydrochlorothiazide 50 mg and potassium-sparing amiloride 5 mg). Note that the dose of hydrochlorothiazide was higher in this study than is generally used today. Most recent studies have found that hydrochlorothiazide in doses above 12.5 to 25 mg do not result in significantly lower blood pressure and only lead to more electrolyte abnormalities.¹⁰

Morgan and Davidson¹¹ performed an analysis of the published data available in 1980. They found that the average fall in potassium is less for patients taking furosemide (0.3mmol/L) than on thiazide diuretics (0.6mmol/L) and that this fall was only slightly influenced by dose or duration of treatment.

Recommendations from others

The National Council on Potassium in Clinical Practice issued a set of guidelines for potassium replacement in September 2000.1 The authors recommend using thiazide diuretics at a low dose only (eg, 12.5-25 mg of hydrochlorothiazide daily) and adding a potassium-sparing diuretic drug when higher diuretic doses are needed. For patients with asymptomatic hypertension they recommend trying to maintain a serum potassium level of at least 4.0 mmol/L. The University of Iowa Family Practice Handbook2 states: “Maximal decrease in serum K+ concentration is usually seen after 7 days of treatment. Serum K+ concentration should be measured before initiation of a diuretic and 1 week after initiation of increase in dose of the diuretic.”

Evidence summary

Hypokalemia is defined as a serum potassium level less than 3.5 mmol/L (3.5 mEq/L); hypokalemia at levels between 3.1 and 3.4 mmol/L is considered mild. The incidence of hypokalemia reported for patients on diuretic therapy is broad (7.2% to 56%),^3-6 and the time period required to develop hypokalemia varies (1 week6 to >1 year⁷). Factors including the type of diuretic used, dosage, duration of use, dietary potassium, and so forth, make predicting an individual patient’s progression nearly impossible. Widmer and coworkers5 found that the risk of hypokalemia was greatest with concomitant glucocorticoid use, polypharmacy (greater than 12 medications administered), and female sex. The latter risk factor may be related to a higher dose-to-weight relationship.

Lemieux and colleagues8 followed 50 patients receiving a variety of diuretic regimens (hydrochlorothiazide 50 to 100 mg daily or every other day with or without reserpine 0.25 mg daily). Only 3 patients in this group had potassium levels below 3.5 mmol/L, and all decreases were only transient. Peters and coworkers6 documented potassium levels below 3.5 mEq/L in 6 of 19 patients taking hydrochlorothiazide 25 or 50 mg for 20 weeks. Three of these patients normalized without therapy. One of these transiently hypokalemic patients was also taking triamterene, a potassium-sparing diuretic.

Potassium-sparing diuretics may not free the clinician from checking a potassium level, however. Penhall and coworkers⁹ found hypokalemia in 24 of 54 patients receiving a fixed-combination diuretic (hydrochlorothiazide 50 mg and potassium-sparing amiloride 5 mg). Note that the dose of hydrochlorothiazide was higher in this study than is generally used today. Most recent studies have found that hydrochlorothiazide in doses above 12.5 to 25 mg do not result in significantly lower blood pressure and only lead to more electrolyte abnormalities.¹⁰

Morgan and Davidson¹¹ performed an analysis of the published data available in 1980. They found that the average fall in potassium is less for patients taking furosemide (0.3mmol/L) than on thiazide diuretics (0.6mmol/L) and that this fall was only slightly influenced by dose or duration of treatment.

Recommendations From Others

Major pediatric and infectious disease textbooks continue to recommend griseofulvin as first-line therapy for tinea capitis but recognize that other safe and effective treatments exist.^1-4 A recent practice guideline from the British Association of Dermatologists did not recommend any oral antifungal agent as clearly superior.⁵

Evidence Summary

Tinea capitis is one of the most common dermatophyte infections in the pediatric population, affecting up to 4% of all children. The peak age is 4 to 6 years; infection is rare after puberty. Systemic therapy is generally required.6 The exact efficacy of any agent is difficult to determine, because most studies were small, used different doses and definitions of cure, and were conducted in different populations. With the exception of ketoconazole, all agents seem to have roughly similar efficacy and cure rates of approximately 70% to 80%. None of these agents require laboratory monitoring at the recommended lengths of treatment for tinea capitis Table.⁷

Griseofulvin’s safety and long history of use in children are its best assets. Recommended dosages and treatment duration have been increased because of fears of developing resistance.⁸ Tablets are approximately one third the cost of the liquid preparations.

Ketoconazole was one of the first “-azoles” studied for the treatment of tinea in children. It is not as efficacious or as safe as other available treatments, making it unsuitable for the treatment of tinea capitis in children.⁵

Itraconazole has been associated with several abnormalities of bone and soft tissue at doses exceeding normal human exposure. Additionally, at more normal doses a component of the liquid formulation causes pancreatic adenocarcinoma in rats.⁶ It has had mixed efficacy in clinical trials, with cure rates ranging from 40% to 89%.^9-11

Fluconazole is another broad-spectrum antifungal in the triazole class. It has been approved by the Food and Drug Administration (FDA) for use in children with systemic fungal infections. The safety profile is very good; it has no known significant carcinogenic potential. Fluconazole is available in both tablet and liquid formulations that make dosing in young children convenient. There are very few clinical studies comparing fluconazole with other antifungal drugs, and no head-to-head prospective randomized controlled trials with griseofulvin have been published to date.⁵

Terbinafine is an allyamine antifungal drug that has a very good safety profile. Unfortunately, there is no liquid formulation of terbinafine, but tablets may be hidden in food.¹² Although terbinafine is efficacious against Trichophyton tonsurans and Trichophyton violaceum, it does not work as well against Microsporum canis, which accounts for approximately 3% of the infections.^12-15 Terbinafine is the most attractively priced treatment for tinea capitis, particularly if a short course is used.

Recommendations From Others

Major pediatric and infectious disease textbooks continue to recommend griseofulvin as first-line therapy for tinea capitis but recognize that other safe and effective treatments exist.^1-4 A recent practice guideline from the British Association of Dermatologists did not recommend any oral antifungal agent as clearly superior.⁵

Evidence Summary

Tinea capitis is one of the most common dermatophyte infections in the pediatric population, affecting up to 4% of all children. The peak age is 4 to 6 years; infection is rare after puberty. Systemic therapy is generally required.6 The exact efficacy of any agent is difficult to determine, because most studies were small, used different doses and definitions of cure, and were conducted in different populations. With the exception of ketoconazole, all agents seem to have roughly similar efficacy and cure rates of approximately 70% to 80%. None of these agents require laboratory monitoring at the recommended lengths of treatment for tinea capitis Table.⁷

Griseofulvin’s safety and long history of use in children are its best assets. Recommended dosages and treatment duration have been increased because of fears of developing resistance.⁸ Tablets are approximately one third the cost of the liquid preparations.

Ketoconazole was one of the first “-azoles” studied for the treatment of tinea in children. It is not as efficacious or as safe as other available treatments, making it unsuitable for the treatment of tinea capitis in children.⁵

Itraconazole has been associated with several abnormalities of bone and soft tissue at doses exceeding normal human exposure. Additionally, at more normal doses a component of the liquid formulation causes pancreatic adenocarcinoma in rats.⁶ It has had mixed efficacy in clinical trials, with cure rates ranging from 40% to 89%.^9-11

Fluconazole is another broad-spectrum antifungal in the triazole class. It has been approved by the Food and Drug Administration (FDA) for use in children with systemic fungal infections. The safety profile is very good; it has no known significant carcinogenic potential. Fluconazole is available in both tablet and liquid formulations that make dosing in young children convenient. There are very few clinical studies comparing fluconazole with other antifungal drugs, and no head-to-head prospective randomized controlled trials with griseofulvin have been published to date.⁵

Terbinafine is an allyamine antifungal drug that has a very good safety profile. Unfortunately, there is no liquid formulation of terbinafine, but tablets may be hidden in food.¹² Although terbinafine is efficacious against Trichophyton tonsurans and Trichophyton violaceum, it does not work as well against Microsporum canis, which accounts for approximately 3% of the infections.^12-15 Terbinafine is the most attractively priced treatment for tinea capitis, particularly if a short course is used.

Recommendations From Others

Major pediatric and infectious disease textbooks continue to recommend griseofulvin as first-line therapy for tinea capitis but recognize that other safe and effective treatments exist.^1-4 A recent practice guideline from the British Association of Dermatologists did not recommend any oral antifungal agent as clearly superior.⁵

Evidence Summary

Tinea capitis is one of the most common dermatophyte infections in the pediatric population, affecting up to 4% of all children. The peak age is 4 to 6 years; infection is rare after puberty. Systemic therapy is generally required.6 The exact efficacy of any agent is difficult to determine, because most studies were small, used different doses and definitions of cure, and were conducted in different populations. With the exception of ketoconazole, all agents seem to have roughly similar efficacy and cure rates of approximately 70% to 80%. None of these agents require laboratory monitoring at the recommended lengths of treatment for tinea capitis Table.⁷

Griseofulvin’s safety and long history of use in children are its best assets. Recommended dosages and treatment duration have been increased because of fears of developing resistance.⁸ Tablets are approximately one third the cost of the liquid preparations.

Ketoconazole was one of the first “-azoles” studied for the treatment of tinea in children. It is not as efficacious or as safe as other available treatments, making it unsuitable for the treatment of tinea capitis in children.⁵

Itraconazole has been associated with several abnormalities of bone and soft tissue at doses exceeding normal human exposure. Additionally, at more normal doses a component of the liquid formulation causes pancreatic adenocarcinoma in rats.⁶ It has had mixed efficacy in clinical trials, with cure rates ranging from 40% to 89%.^9-11

Fluconazole is another broad-spectrum antifungal in the triazole class. It has been approved by the Food and Drug Administration (FDA) for use in children with systemic fungal infections. The safety profile is very good; it has no known significant carcinogenic potential. Fluconazole is available in both tablet and liquid formulations that make dosing in young children convenient. There are very few clinical studies comparing fluconazole with other antifungal drugs, and no head-to-head prospective randomized controlled trials with griseofulvin have been published to date.⁵

Terbinafine is an allyamine antifungal drug that has a very good safety profile. Unfortunately, there is no liquid formulation of terbinafine, but tablets may be hidden in food.¹² Although terbinafine is efficacious against Trichophyton tonsurans and Trichophyton violaceum, it does not work as well against Microsporum canis, which accounts for approximately 3% of the infections.^12-15 Terbinafine is the most attractively priced treatment for tinea capitis, particularly if a short course is used.

Recommendations from others

Evidence summary

Vaginal cuff screening is common. Of women with a hysterectomy attending teaching hospital clinics in San Francisco,⁵ 51% had a Pap test in the previous 3 years. In a Wisconsin survey,⁶ 55% of women with a hysterectomy had a Pap test in the previous 3 years. The annual risk of vaginal cancer is low (0.7 cases per 100,000 women). It is estimated that approximately 250 women will die of vaginal cancer annually in the United States.⁷ As with cervical disease, the rationale for vaginal cuff tests is to detect precancerous changes before cancer develops. Vaginal intraepithelial neoplasia (VAIN) is graded from VAIN 1 for a low-grade lesion to VAIN 3, which includes carcinoma-in-situ and highly dysplastic lesions. The natural history of VAIN is not well delineated. Although VAIN may be a common precursor to vaginal cancer, it will also resolve without treatment. In one study,8 23 women with VAIN were followed from 3 to 15 years. While the diseases of 2 women progressed (9%), the overall regression rate was 78%.

The accuracy of the Pap test for detecting VAIN has not been well documented. The estimated sensitivity of the Pap test is 50%9 to 83%.¹⁰ Fetters and colleagues⁷ estimated that the positive predictive value of an abnormal vaginal Pap test result was 0.05%; only 1 in 2000 women with abnormal test results would have cancer.

In the largest cohort study,¹¹ 9610 vaginal cuff Pap tests from 5682 women who had had a hysterectomy for benign disease were reviewed. The authors found 104 test results (from 79 women) were abnormal. Of these, 52 showed atypical squamous cells of undetermined significance, 44 were low-grade squamous intraepithelial lesions, 6 were high-grade squamous intraepithelial lesions, and 2 were read as carcinoma. Of the 79 women 27 were referred for colposcopy. Colposcopy results showed that 19 had normal mucosa, and 8 had VAIN 1 or 2. Six of these cases resolved without further treatment. Two were lost to follow-up, and no cancers were diagnosed. One of the women with a Pap-based diagnosis of cancer was lost to follow-up; the other had VAIN 1. No confirmed cases of carcinoma were found. The positive predictive value (the probability that an abnormal test result meant the patient had cancer) was 0% (95% confidence interval, 0.0%-33.0%).

There are multiple suggested treatments for VAIN, all based on case series. No randomized controlled trials were found comparing any of these treatments either to each other or to watchful waiting.

In summary, the overall risk of mortality and morbidity due to primary vaginal cancer is low. The natural history of the purported precursor lesion (VAIN) is not well understood, and it can regress without treatment. There are no trials showing that treatments of VAIN are more effective than placebo. The Pap test of the vaginal cuff is almost certain to miss some abnormalities. In addition, the extremely low prevalence means that almost all abnormal test results will be false positives. Given these data, it is unlikely that Pap test screening for vaginal cancer is clinically effective, and it is almost certain to be cost-prohibitive.

Recommendations from others

Evidence summary

Vaginal cuff screening is common. Of women with a hysterectomy attending teaching hospital clinics in San Francisco,⁵ 51% had a Pap test in the previous 3 years. In a Wisconsin survey,⁶ 55% of women with a hysterectomy had a Pap test in the previous 3 years. The annual risk of vaginal cancer is low (0.7 cases per 100,000 women). It is estimated that approximately 250 women will die of vaginal cancer annually in the United States.⁷ As with cervical disease, the rationale for vaginal cuff tests is to detect precancerous changes before cancer develops. Vaginal intraepithelial neoplasia (VAIN) is graded from VAIN 1 for a low-grade lesion to VAIN 3, which includes carcinoma-in-situ and highly dysplastic lesions. The natural history of VAIN is not well delineated. Although VAIN may be a common precursor to vaginal cancer, it will also resolve without treatment. In one study,8 23 women with VAIN were followed from 3 to 15 years. While the diseases of 2 women progressed (9%), the overall regression rate was 78%.

The accuracy of the Pap test for detecting VAIN has not been well documented. The estimated sensitivity of the Pap test is 50%9 to 83%.¹⁰ Fetters and colleagues⁷ estimated that the positive predictive value of an abnormal vaginal Pap test result was 0.05%; only 1 in 2000 women with abnormal test results would have cancer.

In the largest cohort study,¹¹ 9610 vaginal cuff Pap tests from 5682 women who had had a hysterectomy for benign disease were reviewed. The authors found 104 test results (from 79 women) were abnormal. Of these, 52 showed atypical squamous cells of undetermined significance, 44 were low-grade squamous intraepithelial lesions, 6 were high-grade squamous intraepithelial lesions, and 2 were read as carcinoma. Of the 79 women 27 were referred for colposcopy. Colposcopy results showed that 19 had normal mucosa, and 8 had VAIN 1 or 2. Six of these cases resolved without further treatment. Two were lost to follow-up, and no cancers were diagnosed. One of the women with a Pap-based diagnosis of cancer was lost to follow-up; the other had VAIN 1. No confirmed cases of carcinoma were found. The positive predictive value (the probability that an abnormal test result meant the patient had cancer) was 0% (95% confidence interval, 0.0%-33.0%).

There are multiple suggested treatments for VAIN, all based on case series. No randomized controlled trials were found comparing any of these treatments either to each other or to watchful waiting.

In summary, the overall risk of mortality and morbidity due to primary vaginal cancer is low. The natural history of the purported precursor lesion (VAIN) is not well understood, and it can regress without treatment. There are no trials showing that treatments of VAIN are more effective than placebo. The Pap test of the vaginal cuff is almost certain to miss some abnormalities. In addition, the extremely low prevalence means that almost all abnormal test results will be false positives. Given these data, it is unlikely that Pap test screening for vaginal cancer is clinically effective, and it is almost certain to be cost-prohibitive.

Recommendations from others

Evidence summary

Vaginal cuff screening is common. Of women with a hysterectomy attending teaching hospital clinics in San Francisco,⁵ 51% had a Pap test in the previous 3 years. In a Wisconsin survey,⁶ 55% of women with a hysterectomy had a Pap test in the previous 3 years. The annual risk of vaginal cancer is low (0.7 cases per 100,000 women). It is estimated that approximately 250 women will die of vaginal cancer annually in the United States.⁷ As with cervical disease, the rationale for vaginal cuff tests is to detect precancerous changes before cancer develops. Vaginal intraepithelial neoplasia (VAIN) is graded from VAIN 1 for a low-grade lesion to VAIN 3, which includes carcinoma-in-situ and highly dysplastic lesions. The natural history of VAIN is not well delineated. Although VAIN may be a common precursor to vaginal cancer, it will also resolve without treatment. In one study,8 23 women with VAIN were followed from 3 to 15 years. While the diseases of 2 women progressed (9%), the overall regression rate was 78%.

The accuracy of the Pap test for detecting VAIN has not been well documented. The estimated sensitivity of the Pap test is 50%9 to 83%.¹⁰ Fetters and colleagues⁷ estimated that the positive predictive value of an abnormal vaginal Pap test result was 0.05%; only 1 in 2000 women with abnormal test results would have cancer.

In the largest cohort study,¹¹ 9610 vaginal cuff Pap tests from 5682 women who had had a hysterectomy for benign disease were reviewed. The authors found 104 test results (from 79 women) were abnormal. Of these, 52 showed atypical squamous cells of undetermined significance, 44 were low-grade squamous intraepithelial lesions, 6 were high-grade squamous intraepithelial lesions, and 2 were read as carcinoma. Of the 79 women 27 were referred for colposcopy. Colposcopy results showed that 19 had normal mucosa, and 8 had VAIN 1 or 2. Six of these cases resolved without further treatment. Two were lost to follow-up, and no cancers were diagnosed. One of the women with a Pap-based diagnosis of cancer was lost to follow-up; the other had VAIN 1. No confirmed cases of carcinoma were found. The positive predictive value (the probability that an abnormal test result meant the patient had cancer) was 0% (95% confidence interval, 0.0%-33.0%).

There are multiple suggested treatments for VAIN, all based on case series. No randomized controlled trials were found comparing any of these treatments either to each other or to watchful waiting.

In summary, the overall risk of mortality and morbidity due to primary vaginal cancer is low. The natural history of the purported precursor lesion (VAIN) is not well understood, and it can regress without treatment. There are no trials showing that treatments of VAIN are more effective than placebo. The Pap test of the vaginal cuff is almost certain to miss some abnormalities. In addition, the extremely low prevalence means that almost all abnormal test results will be false positives. Given these data, it is unlikely that Pap test screening for vaginal cancer is clinically effective, and it is almost certain to be cost-prohibitive.