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Does neonatal circumcision decrease morbidity?
Evidence suggests that neonatal circumcision decreases the incidence of childhood urinary tract infections, phimosis, paraphimosis, balanitis and other genital dermatoses, invasive penile cancer, and the sexually transmitted diseases human papilloma virus (HPV) and HIV (strength of recommendation [SOR]: B, based on case control and cohort studies). The benefits of decreased incidence of HPV and HIV infections go beyond the index patient and have public health implications on the transmission of these diseases (SOR: B). Further, a decrease in HPV incidence and transmission may lead to a lower incidence of cervical cancer (SOR: B).
While there appears to be some evidence for reduced morbidity with routine circumcision, decisions regarding routine neonatal circumcision requires balancing risks and benefits of the procedure with the alternatives in the context of social, familial, and religious beliefs.
Evidence summary
Observational studies have shown at least a 10- to 12-fold increase in urinary tract infections (UTIs) in uncircumcised male infants compared with their circumcised counterparts.1 The number of male infants that need to be circumcised to prevent 1 UTI is estimated to be between 44 and 100.2,3 The only randomized controlled trial of circumcision for UTI prevention was not during the neonatal period (average age was 30 months) and focused on secondary prevention.4 It demonstrated a statistically significant decrease in the rate of bacteriuria. The long-term effect on UTI incidence, renal scarring, and subsequent complications such as hypertension and end-stage renal disease is unknown.
Evidence from case series supports the protective effect of circumcision on the rates of penile cancer. A review of 592 cases of penile cancer revealed that none of those affected had been circumcised in infancy.5 In another series of 89 men with penile cancer, only 2 had been circumcised in infancy, while 87 were uncircumcised.6 Since HPV is thought to be a major etiologic agent in both penile cancer and cervical cancer, investigators studied the link between circumcision status and cervical cancer. In a meta-analysis of 7 case-control studies, penile HPV was detected 2.7 times more often in uncircumcised men after controlling for confounders.7 In this same meta-analysis, monogamous female partners of high-risk circumcised men (men with more than 6 lifetime partners) had a lower risk of cervical cancer than women whose high-risk partner was uncircumcised (adjusted odds ratio=0.42; 95% confidence interval [CI], 0.23–0.79).7
The evidence that circumcision prevents most sexually transmitted diseases is not very strong, with the exception of HIV and genital ulcer disease. Most of these studies are from sub-Saharan Africa, where rates of HIV infection are extremely high. A meta-analysis of 15 observational studies in Africa, with adjustment for potential confounding factors, found that circumcision decreased the risk of acquiring HIV by more than half (relative risk [RR]=0.42; 95% CI, 0.34–0.54).8 A more recent prospective study from India showed a strong protective effect of circumcision against HIV infection (RR=0.15; 95% CI, 0.04–0.62).9 This study found no protective effect of circumcision against herpes, syphilis, or gonorrhea, suggesting a biological rather than a behavioral explanation for the protective effect of circumcision against HIV.
A conservative estimate of the post-neonatal childhood circumcision rate for purely medical reasons is 2% to 5%; estimates go as high as 7% to 10%.10 The most common medical indication for circumcision is phimosis, followed by recurrent balanitis and paraphimosis. Circumcision may also be protective against genital dermatoses; a case-control study found an age-adjusted odds ratio of 3.2 (95% CI, 2.3–4.6) for penile skin diseases in uncircumcised men compared with circumcised men.11
Recommendations from others
Circumcision rates vary widely worldwide, with strong cultural and religious preferences. Most major organizations have cautiously neutral opinions on circumcision, stating that medical benefits are not large enough to justify routine neonatal circumcision. The American Academy of Pediatrics Task Force on Circumcision recommends parents “should be given accurate and unbiased information” and that “parents should determine what is in the best interest of the child.”12 The American Medical Association, American College of Obstetrics and Gynecology, and the American Academy of Family Physicians all use similar statements.13-15
Explain risks and benefits of circumcision to parents so they make informed decisions
A dilemma exists in the practice of recommending circumcision to parents of newborn males. Although the evidence shows that morbidity is decreased in circumcised males, the occurrence of complications (such as UTI or balanitis) is believed to be preventable through good hygiene, and the incidence of the preventable disease (such as penile cancer) is so low in the general population as to not justify the procedure. The challenge is there because the procedure is not without pain or risk of complications.
This is the basis for the American Academy of Pediatrics not recommending routine neonatal circumcision. The consensus was that the evidence was not sufficient to support it. Since then, many studies have been published on HPV and HIV transmission, the incidence of phimosis and paraphimosis, UTI, and balanitis, and how circumcision reduces the incidence of these diseases. Again, these are believed to be preventable through hygiene and condom use. In practice, it is difficult to persuade parents because these complications usually occur much later in life. Most patients made their decisions on circumcision based on religious or cultural experiences.
1. Wiswell TE. The prepuce, urinary tract infections, and the consequences. Pediatrics 2000;105:860-862.
2. Sethi N, Schwierling K, Kim J, et al. Newborn circumcision and urinary tract infections. Pediatrics 2001;107:212.-
3. Christakis DA, Harvey E, Zerr DM, Feudtner C, Wright JA, Connell FA. A trade off analysis of routine newborn circumcision. Pediatrics 2000;105:246-249.
4. Nayir A. Circumcision for the prevention of significant bacteriuria in boys. Pediatr Nephrol 2001;16:1129-1134.Erratum in: Pediatr Nephrol. 2002; 17: 307.
5. Lerman SE, Liao JC. Neonatal circumcision. Pediatr Clin North Am 2001;48:1539-557.
6. Mallon E, Hawkins D, Dinneen M, et al. Circumcision and genital dermatoses. Arch Dermatol 2000;136:350-354.
7. Schoen EJ. The relationship between circumcision and cancer of the penis. CA Cancer J Clin 1991;41:306-309.
8. Schoen EJ, Oehrli M, Colby C, Machin G. The highly protective effect of newborn circumcision against invasive penile cancer. Pediatrics 2000;105:E36.-
9. Castellsague X, Bosch FX, Munoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med 2002;346:1105-1112.
10. Weiss HA, Quigley MA, Hayes RJ. Male circumcision and risk of HIV infection in sub-Saharan Africa: a systematic review and meta-analysis. AIDS 2000;14:2361-2370.
11. Reynolds SJ, Shepherd ME, Risbud AR, et al. Male circumcision and risk of HIV-1 and other sexually transmitted infections in India. Lancet 2004;363:1039-1040.
12. American Academy of Pediatrics. Task Force on Circumcision. Circumcision policy statement. Pediatrics 1999;103:686-693.
13. American Medical Association. Report 10 of the Council on Scientific Affairs (I-99) Neonatal Circumcision. Available at: www.ama-assn.org/ama/pub/category/ 13585.html. Accessed on December 8, 2004.
14. American College of Obstetricians and Gynecologists. ACOG Committee Opinion Number 260: Circumcision. Obstet Gynecol 2001;98:707-708.
15. American Academy of Family Physicians. Position Paper on Neonatal Circumcision. Available at: www.aafp.org/ x1462.xml. Accessed on December 8, 2004.
Evidence suggests that neonatal circumcision decreases the incidence of childhood urinary tract infections, phimosis, paraphimosis, balanitis and other genital dermatoses, invasive penile cancer, and the sexually transmitted diseases human papilloma virus (HPV) and HIV (strength of recommendation [SOR]: B, based on case control and cohort studies). The benefits of decreased incidence of HPV and HIV infections go beyond the index patient and have public health implications on the transmission of these diseases (SOR: B). Further, a decrease in HPV incidence and transmission may lead to a lower incidence of cervical cancer (SOR: B).
While there appears to be some evidence for reduced morbidity with routine circumcision, decisions regarding routine neonatal circumcision requires balancing risks and benefits of the procedure with the alternatives in the context of social, familial, and religious beliefs.
Evidence summary
Observational studies have shown at least a 10- to 12-fold increase in urinary tract infections (UTIs) in uncircumcised male infants compared with their circumcised counterparts.1 The number of male infants that need to be circumcised to prevent 1 UTI is estimated to be between 44 and 100.2,3 The only randomized controlled trial of circumcision for UTI prevention was not during the neonatal period (average age was 30 months) and focused on secondary prevention.4 It demonstrated a statistically significant decrease in the rate of bacteriuria. The long-term effect on UTI incidence, renal scarring, and subsequent complications such as hypertension and end-stage renal disease is unknown.
Evidence from case series supports the protective effect of circumcision on the rates of penile cancer. A review of 592 cases of penile cancer revealed that none of those affected had been circumcised in infancy.5 In another series of 89 men with penile cancer, only 2 had been circumcised in infancy, while 87 were uncircumcised.6 Since HPV is thought to be a major etiologic agent in both penile cancer and cervical cancer, investigators studied the link between circumcision status and cervical cancer. In a meta-analysis of 7 case-control studies, penile HPV was detected 2.7 times more often in uncircumcised men after controlling for confounders.7 In this same meta-analysis, monogamous female partners of high-risk circumcised men (men with more than 6 lifetime partners) had a lower risk of cervical cancer than women whose high-risk partner was uncircumcised (adjusted odds ratio=0.42; 95% confidence interval [CI], 0.23–0.79).7
The evidence that circumcision prevents most sexually transmitted diseases is not very strong, with the exception of HIV and genital ulcer disease. Most of these studies are from sub-Saharan Africa, where rates of HIV infection are extremely high. A meta-analysis of 15 observational studies in Africa, with adjustment for potential confounding factors, found that circumcision decreased the risk of acquiring HIV by more than half (relative risk [RR]=0.42; 95% CI, 0.34–0.54).8 A more recent prospective study from India showed a strong protective effect of circumcision against HIV infection (RR=0.15; 95% CI, 0.04–0.62).9 This study found no protective effect of circumcision against herpes, syphilis, or gonorrhea, suggesting a biological rather than a behavioral explanation for the protective effect of circumcision against HIV.
A conservative estimate of the post-neonatal childhood circumcision rate for purely medical reasons is 2% to 5%; estimates go as high as 7% to 10%.10 The most common medical indication for circumcision is phimosis, followed by recurrent balanitis and paraphimosis. Circumcision may also be protective against genital dermatoses; a case-control study found an age-adjusted odds ratio of 3.2 (95% CI, 2.3–4.6) for penile skin diseases in uncircumcised men compared with circumcised men.11
Recommendations from others
Circumcision rates vary widely worldwide, with strong cultural and religious preferences. Most major organizations have cautiously neutral opinions on circumcision, stating that medical benefits are not large enough to justify routine neonatal circumcision. The American Academy of Pediatrics Task Force on Circumcision recommends parents “should be given accurate and unbiased information” and that “parents should determine what is in the best interest of the child.”12 The American Medical Association, American College of Obstetrics and Gynecology, and the American Academy of Family Physicians all use similar statements.13-15
Explain risks and benefits of circumcision to parents so they make informed decisions
A dilemma exists in the practice of recommending circumcision to parents of newborn males. Although the evidence shows that morbidity is decreased in circumcised males, the occurrence of complications (such as UTI or balanitis) is believed to be preventable through good hygiene, and the incidence of the preventable disease (such as penile cancer) is so low in the general population as to not justify the procedure. The challenge is there because the procedure is not without pain or risk of complications.
This is the basis for the American Academy of Pediatrics not recommending routine neonatal circumcision. The consensus was that the evidence was not sufficient to support it. Since then, many studies have been published on HPV and HIV transmission, the incidence of phimosis and paraphimosis, UTI, and balanitis, and how circumcision reduces the incidence of these diseases. Again, these are believed to be preventable through hygiene and condom use. In practice, it is difficult to persuade parents because these complications usually occur much later in life. Most patients made their decisions on circumcision based on religious or cultural experiences.
Evidence suggests that neonatal circumcision decreases the incidence of childhood urinary tract infections, phimosis, paraphimosis, balanitis and other genital dermatoses, invasive penile cancer, and the sexually transmitted diseases human papilloma virus (HPV) and HIV (strength of recommendation [SOR]: B, based on case control and cohort studies). The benefits of decreased incidence of HPV and HIV infections go beyond the index patient and have public health implications on the transmission of these diseases (SOR: B). Further, a decrease in HPV incidence and transmission may lead to a lower incidence of cervical cancer (SOR: B).
While there appears to be some evidence for reduced morbidity with routine circumcision, decisions regarding routine neonatal circumcision requires balancing risks and benefits of the procedure with the alternatives in the context of social, familial, and religious beliefs.
Evidence summary
Observational studies have shown at least a 10- to 12-fold increase in urinary tract infections (UTIs) in uncircumcised male infants compared with their circumcised counterparts.1 The number of male infants that need to be circumcised to prevent 1 UTI is estimated to be between 44 and 100.2,3 The only randomized controlled trial of circumcision for UTI prevention was not during the neonatal period (average age was 30 months) and focused on secondary prevention.4 It demonstrated a statistically significant decrease in the rate of bacteriuria. The long-term effect on UTI incidence, renal scarring, and subsequent complications such as hypertension and end-stage renal disease is unknown.
Evidence from case series supports the protective effect of circumcision on the rates of penile cancer. A review of 592 cases of penile cancer revealed that none of those affected had been circumcised in infancy.5 In another series of 89 men with penile cancer, only 2 had been circumcised in infancy, while 87 were uncircumcised.6 Since HPV is thought to be a major etiologic agent in both penile cancer and cervical cancer, investigators studied the link between circumcision status and cervical cancer. In a meta-analysis of 7 case-control studies, penile HPV was detected 2.7 times more often in uncircumcised men after controlling for confounders.7 In this same meta-analysis, monogamous female partners of high-risk circumcised men (men with more than 6 lifetime partners) had a lower risk of cervical cancer than women whose high-risk partner was uncircumcised (adjusted odds ratio=0.42; 95% confidence interval [CI], 0.23–0.79).7
The evidence that circumcision prevents most sexually transmitted diseases is not very strong, with the exception of HIV and genital ulcer disease. Most of these studies are from sub-Saharan Africa, where rates of HIV infection are extremely high. A meta-analysis of 15 observational studies in Africa, with adjustment for potential confounding factors, found that circumcision decreased the risk of acquiring HIV by more than half (relative risk [RR]=0.42; 95% CI, 0.34–0.54).8 A more recent prospective study from India showed a strong protective effect of circumcision against HIV infection (RR=0.15; 95% CI, 0.04–0.62).9 This study found no protective effect of circumcision against herpes, syphilis, or gonorrhea, suggesting a biological rather than a behavioral explanation for the protective effect of circumcision against HIV.
A conservative estimate of the post-neonatal childhood circumcision rate for purely medical reasons is 2% to 5%; estimates go as high as 7% to 10%.10 The most common medical indication for circumcision is phimosis, followed by recurrent balanitis and paraphimosis. Circumcision may also be protective against genital dermatoses; a case-control study found an age-adjusted odds ratio of 3.2 (95% CI, 2.3–4.6) for penile skin diseases in uncircumcised men compared with circumcised men.11
Recommendations from others
Circumcision rates vary widely worldwide, with strong cultural and religious preferences. Most major organizations have cautiously neutral opinions on circumcision, stating that medical benefits are not large enough to justify routine neonatal circumcision. The American Academy of Pediatrics Task Force on Circumcision recommends parents “should be given accurate and unbiased information” and that “parents should determine what is in the best interest of the child.”12 The American Medical Association, American College of Obstetrics and Gynecology, and the American Academy of Family Physicians all use similar statements.13-15
Explain risks and benefits of circumcision to parents so they make informed decisions
A dilemma exists in the practice of recommending circumcision to parents of newborn males. Although the evidence shows that morbidity is decreased in circumcised males, the occurrence of complications (such as UTI or balanitis) is believed to be preventable through good hygiene, and the incidence of the preventable disease (such as penile cancer) is so low in the general population as to not justify the procedure. The challenge is there because the procedure is not without pain or risk of complications.
This is the basis for the American Academy of Pediatrics not recommending routine neonatal circumcision. The consensus was that the evidence was not sufficient to support it. Since then, many studies have been published on HPV and HIV transmission, the incidence of phimosis and paraphimosis, UTI, and balanitis, and how circumcision reduces the incidence of these diseases. Again, these are believed to be preventable through hygiene and condom use. In practice, it is difficult to persuade parents because these complications usually occur much later in life. Most patients made their decisions on circumcision based on religious or cultural experiences.
1. Wiswell TE. The prepuce, urinary tract infections, and the consequences. Pediatrics 2000;105:860-862.
2. Sethi N, Schwierling K, Kim J, et al. Newborn circumcision and urinary tract infections. Pediatrics 2001;107:212.-
3. Christakis DA, Harvey E, Zerr DM, Feudtner C, Wright JA, Connell FA. A trade off analysis of routine newborn circumcision. Pediatrics 2000;105:246-249.
4. Nayir A. Circumcision for the prevention of significant bacteriuria in boys. Pediatr Nephrol 2001;16:1129-1134.Erratum in: Pediatr Nephrol. 2002; 17: 307.
5. Lerman SE, Liao JC. Neonatal circumcision. Pediatr Clin North Am 2001;48:1539-557.
6. Mallon E, Hawkins D, Dinneen M, et al. Circumcision and genital dermatoses. Arch Dermatol 2000;136:350-354.
7. Schoen EJ. The relationship between circumcision and cancer of the penis. CA Cancer J Clin 1991;41:306-309.
8. Schoen EJ, Oehrli M, Colby C, Machin G. The highly protective effect of newborn circumcision against invasive penile cancer. Pediatrics 2000;105:E36.-
9. Castellsague X, Bosch FX, Munoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med 2002;346:1105-1112.
10. Weiss HA, Quigley MA, Hayes RJ. Male circumcision and risk of HIV infection in sub-Saharan Africa: a systematic review and meta-analysis. AIDS 2000;14:2361-2370.
11. Reynolds SJ, Shepherd ME, Risbud AR, et al. Male circumcision and risk of HIV-1 and other sexually transmitted infections in India. Lancet 2004;363:1039-1040.
12. American Academy of Pediatrics. Task Force on Circumcision. Circumcision policy statement. Pediatrics 1999;103:686-693.
13. American Medical Association. Report 10 of the Council on Scientific Affairs (I-99) Neonatal Circumcision. Available at: www.ama-assn.org/ama/pub/category/ 13585.html. Accessed on December 8, 2004.
14. American College of Obstetricians and Gynecologists. ACOG Committee Opinion Number 260: Circumcision. Obstet Gynecol 2001;98:707-708.
15. American Academy of Family Physicians. Position Paper on Neonatal Circumcision. Available at: www.aafp.org/ x1462.xml. Accessed on December 8, 2004.
1. Wiswell TE. The prepuce, urinary tract infections, and the consequences. Pediatrics 2000;105:860-862.
2. Sethi N, Schwierling K, Kim J, et al. Newborn circumcision and urinary tract infections. Pediatrics 2001;107:212.-
3. Christakis DA, Harvey E, Zerr DM, Feudtner C, Wright JA, Connell FA. A trade off analysis of routine newborn circumcision. Pediatrics 2000;105:246-249.
4. Nayir A. Circumcision for the prevention of significant bacteriuria in boys. Pediatr Nephrol 2001;16:1129-1134.Erratum in: Pediatr Nephrol. 2002; 17: 307.
5. Lerman SE, Liao JC. Neonatal circumcision. Pediatr Clin North Am 2001;48:1539-557.
6. Mallon E, Hawkins D, Dinneen M, et al. Circumcision and genital dermatoses. Arch Dermatol 2000;136:350-354.
7. Schoen EJ. The relationship between circumcision and cancer of the penis. CA Cancer J Clin 1991;41:306-309.
8. Schoen EJ, Oehrli M, Colby C, Machin G. The highly protective effect of newborn circumcision against invasive penile cancer. Pediatrics 2000;105:E36.-
9. Castellsague X, Bosch FX, Munoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med 2002;346:1105-1112.
10. Weiss HA, Quigley MA, Hayes RJ. Male circumcision and risk of HIV infection in sub-Saharan Africa: a systematic review and meta-analysis. AIDS 2000;14:2361-2370.
11. Reynolds SJ, Shepherd ME, Risbud AR, et al. Male circumcision and risk of HIV-1 and other sexually transmitted infections in India. Lancet 2004;363:1039-1040.
12. American Academy of Pediatrics. Task Force on Circumcision. Circumcision policy statement. Pediatrics 1999;103:686-693.
13. American Medical Association. Report 10 of the Council on Scientific Affairs (I-99) Neonatal Circumcision. Available at: www.ama-assn.org/ama/pub/category/ 13585.html. Accessed on December 8, 2004.
14. American College of Obstetricians and Gynecologists. ACOG Committee Opinion Number 260: Circumcision. Obstet Gynecol 2001;98:707-708.
15. American Academy of Family Physicians. Position Paper on Neonatal Circumcision. Available at: www.aafp.org/ x1462.xml. Accessed on December 8, 2004.
Evidence-based answers from the Family Physicians Inquiries Network
Can type 2 diabetes be prevented through diet and exercise?
Diets that result in long-term weight loss of 5% to 7%, along with moderate-intensity exercise for more than 150 minutes per week, reduce the incidence of type 2 diabetes for patients with impaired glucose tolerance (IGT) (strength of recommendation [SOR]: A, based on multiple randomized controlled trials [RCTs]). Each of the trials demonstrating this finding included fairly intensive counseling as part of the successful intervention. Diet and exercise reduce the incidence of diabetes in both lean (body mass index [BMI] <25) and overweight patients with IGT (SOR: B, based on a single, large RCT).
Evidence summary
Three large prospective RCTs evaluated the effect of dietary and exercise interventions in populations at risk for developing diabetes.
The Diabetes Prevention Program Research Group1 randomized 3234 patients age >24 years without diabetes but with IGT and a BMI >24 to 1 of 3 groups: intensive lifestyle modification, metformin, or control; they then compared the incidence of diabetes over 3 years. Patients were men and women from primary care populations and represented diverse ethnic backgrounds. Investigators defined IGT as plasma glucose of 140 to 200 mg/dL 2 hours after a 75-g glucose bolus when the fasting glucose was <140 mg/dL. Intensive lifestyle intervention comprised individual training sessions on a low-calorie, low-fat diet, aerobic exercise (such as brisk walking), and behavior modification. Case managers met with each participant for at least 16 sessions during the first 24 weeks and at least monthly thereafter. The control group received lifestyle change recommendations without individualized attention.
After 24 weeks, 50% of the lifestyle group met the 7% weight loss goal and 74% were exercising at least 150 minutes per week. At the final visit, 38% maintained their target weight and 58% met their exercise goal. Lifestyle intervention produced greater weight reduction and increased activity compared with the metformin and control groups, with a corresponding decreased incidence of diabetes (TABLE). Subgroup analysis found that lifestyle intervention produced the greatest reduction in diabetes (71%) for patients aged >60 years.
The Finnish Diabetes Prevention Study2 similarly randomized 522 patients, aged 40 to 65 years, with IGT and obesity (mean BMI=31) to either intensive lifestyle intervention or control and followed them for 3.2 years. The lifestyle intervention included moderate exercise for at least 150 minutes per week and weight loss of at least 5%. Patients were offered an individualized exercise plan with supervised aerobic exercise plus circuit-type resistance sessions 3 times a week. Nutritionists met with patients 7 times in the first year and every 3 months after that. Patients were counseled to increase fiber intake, reduce total fat below 30% of total calories, and reduce saturated fat below 10%. The control group was given general information on diet and exercise without individualized programs. Most patients (86%) in the intervention group met their exercise goal, and 25% met the fiber requirement.
Compared with the control group, the intervention group had greater success rate for each category. Intensive lifestyle intervention reduced the incidence of diabetes by 58% (number needed to treat=5 for 5 years; (see TABLE).
The Da Qing IGT and Diabetes Study3 divided 577 patients with IGT into 1 control and 3 intervention groups: diet, aerobic exercise, and combined diet plus aerobic exercise. Patients in this study had the lowest average BMI (25.8) of the 3 studies. The intervention group received individual and group counseling sessions at weekly intervals for 1 month, then monthly for 3 months, and then every 3 months. The control group received generalized information on IGT and diabetes but individual or group instruction was not included.
At the 6-year follow-up, the quantity of exercise was significantly higher in the exercise intervention groups, but no significant difference in caloric intake was seen among all 4 groups. The incidence of diabetes in the exercise intervention group was approximately half that in the control group overall (TABLE 1). Exercise was more effective in reducing diabetes in lean patients (BMI <25), but both lean and overweight patients benefited. The combination of diet plus exercise and diet changes also significantly reduced diabetes, although to a lesser degree.
TABLE
Incidence of diabetes among patients with impaired glucose tolerance participating in diet and exercise programs
| Study population | Mean BMI | Intervention | Diabetes incidence* | RRR | NNT |
|---|---|---|---|---|---|
| Diabetes Prevention Program1(3234 primary care patients, men and women, mixed ethnic backgrounds, various ages) | 34 | Control | 11.0 | Baseline | Baseline |
| Metformin | 7.8 | 31% | 14 (over 7 years) | ||
| Intensive lifestyle modification | 4.8 | 58% | 7 (over 7 years) | ||
| Finnish Diabetes PreventionStudy2 (522 patients) | 31 | Control | 23 | Baseline | Baseline |
| Intensive lifestyle modification | 11 | 58% | 5 (over 5 years) | ||
| Da Qing IGTand Diabetes Study3 (577 primary care patients, men and women aged >25 years) | 25.8 | Control | 15 | Baseline | Baseline (all over 6 years) |
| Diet | 10 | 31% | 17 | ||
| Exercise | 8 | 46% | 14 | ||
| Diet and exercise | 9.5 | 42% | 16 | ||
| *Incidence of diabetes per 100 person-years. | |||||
| IGT, intensive glucose control; BMI, body mass index; RRR, relative risk reduction; NNT, number needed to treat. | |||||
Recommendations from others
The American Diabetes Association recommends structured programs that emphasize lifestyle changes, including education, reduced fat and energy intake, regular physical activity, and regular participant contact. These changes can produce long-term weight loss of 5% to 7% of starting weight and reduce the risk for developing diabetes.4 They also stress the importance of promoting exercise as a vital component of the prevention as well as management of type 2 diabetes. The benefit of exercise in improving the metabolic abnormalities of type 2 diabetes is probably greatest when it is used early in its progression from insulin resistance to impaired glucose tolerance to overt hyperglycemia.5 The Exercise was more effective in reducing diabetes in lean patients, but overweight patients also benefited World Health Organization states that increased physical activity and maintaining a healthy weight play critical roles in the prevention and treatment of diabetes.6
Encourage patients to exercise and eat well, and see a dietician if they are willing
Julia Fashner, MD
St. Joseph Family Medicine Residency, South Bend, Ind
Diet and exercise are important components in the management of patients at risk for diabetes; the challenge revolves around the time and money commitment necessary for these interventions. A physician in a typical office setting has limited time to implement the interventions used in these trials. Referral to other health professionals (dietician, exercise physiatrist, etc) for counseling or individual guidance may be prohibitively costly, as these services are often not covered by insurance, and patients may not be willing to pay.
Bottom line—at every office visit, encourage patients to increase their exercise and watch what they eat as part of prevention. If they are willing to see a dietician, by all means send them.
1. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.
2. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-1350.
3. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIIDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:537-544.
4. American Diabetes Association. Evidence based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care 2002;25(Suppl 1):S50-S60.
5. American Diabetes Association. Diabetes mellitus and exercise. Diabetes Care 2002;25(Suppl 1):S64-S68.
6. World Health Organization. Diet, nutrition and the prevention of chronic diseases: report of the joint WHO/FAO expert consultation. WHO Technical Report Series No. 916 (TRS 916), 2002.
Diets that result in long-term weight loss of 5% to 7%, along with moderate-intensity exercise for more than 150 minutes per week, reduce the incidence of type 2 diabetes for patients with impaired glucose tolerance (IGT) (strength of recommendation [SOR]: A, based on multiple randomized controlled trials [RCTs]). Each of the trials demonstrating this finding included fairly intensive counseling as part of the successful intervention. Diet and exercise reduce the incidence of diabetes in both lean (body mass index [BMI] <25) and overweight patients with IGT (SOR: B, based on a single, large RCT).
Evidence summary
Three large prospective RCTs evaluated the effect of dietary and exercise interventions in populations at risk for developing diabetes.
The Diabetes Prevention Program Research Group1 randomized 3234 patients age >24 years without diabetes but with IGT and a BMI >24 to 1 of 3 groups: intensive lifestyle modification, metformin, or control; they then compared the incidence of diabetes over 3 years. Patients were men and women from primary care populations and represented diverse ethnic backgrounds. Investigators defined IGT as plasma glucose of 140 to 200 mg/dL 2 hours after a 75-g glucose bolus when the fasting glucose was <140 mg/dL. Intensive lifestyle intervention comprised individual training sessions on a low-calorie, low-fat diet, aerobic exercise (such as brisk walking), and behavior modification. Case managers met with each participant for at least 16 sessions during the first 24 weeks and at least monthly thereafter. The control group received lifestyle change recommendations without individualized attention.
After 24 weeks, 50% of the lifestyle group met the 7% weight loss goal and 74% were exercising at least 150 minutes per week. At the final visit, 38% maintained their target weight and 58% met their exercise goal. Lifestyle intervention produced greater weight reduction and increased activity compared with the metformin and control groups, with a corresponding decreased incidence of diabetes (TABLE). Subgroup analysis found that lifestyle intervention produced the greatest reduction in diabetes (71%) for patients aged >60 years.
The Finnish Diabetes Prevention Study2 similarly randomized 522 patients, aged 40 to 65 years, with IGT and obesity (mean BMI=31) to either intensive lifestyle intervention or control and followed them for 3.2 years. The lifestyle intervention included moderate exercise for at least 150 minutes per week and weight loss of at least 5%. Patients were offered an individualized exercise plan with supervised aerobic exercise plus circuit-type resistance sessions 3 times a week. Nutritionists met with patients 7 times in the first year and every 3 months after that. Patients were counseled to increase fiber intake, reduce total fat below 30% of total calories, and reduce saturated fat below 10%. The control group was given general information on diet and exercise without individualized programs. Most patients (86%) in the intervention group met their exercise goal, and 25% met the fiber requirement.
Compared with the control group, the intervention group had greater success rate for each category. Intensive lifestyle intervention reduced the incidence of diabetes by 58% (number needed to treat=5 for 5 years; (see TABLE).
The Da Qing IGT and Diabetes Study3 divided 577 patients with IGT into 1 control and 3 intervention groups: diet, aerobic exercise, and combined diet plus aerobic exercise. Patients in this study had the lowest average BMI (25.8) of the 3 studies. The intervention group received individual and group counseling sessions at weekly intervals for 1 month, then monthly for 3 months, and then every 3 months. The control group received generalized information on IGT and diabetes but individual or group instruction was not included.
At the 6-year follow-up, the quantity of exercise was significantly higher in the exercise intervention groups, but no significant difference in caloric intake was seen among all 4 groups. The incidence of diabetes in the exercise intervention group was approximately half that in the control group overall (TABLE 1). Exercise was more effective in reducing diabetes in lean patients (BMI <25), but both lean and overweight patients benefited. The combination of diet plus exercise and diet changes also significantly reduced diabetes, although to a lesser degree.
TABLE
Incidence of diabetes among patients with impaired glucose tolerance participating in diet and exercise programs
| Study population | Mean BMI | Intervention | Diabetes incidence* | RRR | NNT |
|---|---|---|---|---|---|
| Diabetes Prevention Program1(3234 primary care patients, men and women, mixed ethnic backgrounds, various ages) | 34 | Control | 11.0 | Baseline | Baseline |
| Metformin | 7.8 | 31% | 14 (over 7 years) | ||
| Intensive lifestyle modification | 4.8 | 58% | 7 (over 7 years) | ||
| Finnish Diabetes PreventionStudy2 (522 patients) | 31 | Control | 23 | Baseline | Baseline |
| Intensive lifestyle modification | 11 | 58% | 5 (over 5 years) | ||
| Da Qing IGTand Diabetes Study3 (577 primary care patients, men and women aged >25 years) | 25.8 | Control | 15 | Baseline | Baseline (all over 6 years) |
| Diet | 10 | 31% | 17 | ||
| Exercise | 8 | 46% | 14 | ||
| Diet and exercise | 9.5 | 42% | 16 | ||
| *Incidence of diabetes per 100 person-years. | |||||
| IGT, intensive glucose control; BMI, body mass index; RRR, relative risk reduction; NNT, number needed to treat. | |||||
Recommendations from others
The American Diabetes Association recommends structured programs that emphasize lifestyle changes, including education, reduced fat and energy intake, regular physical activity, and regular participant contact. These changes can produce long-term weight loss of 5% to 7% of starting weight and reduce the risk for developing diabetes.4 They also stress the importance of promoting exercise as a vital component of the prevention as well as management of type 2 diabetes. The benefit of exercise in improving the metabolic abnormalities of type 2 diabetes is probably greatest when it is used early in its progression from insulin resistance to impaired glucose tolerance to overt hyperglycemia.5 The Exercise was more effective in reducing diabetes in lean patients, but overweight patients also benefited World Health Organization states that increased physical activity and maintaining a healthy weight play critical roles in the prevention and treatment of diabetes.6
Encourage patients to exercise and eat well, and see a dietician if they are willing
Julia Fashner, MD
St. Joseph Family Medicine Residency, South Bend, Ind
Diet and exercise are important components in the management of patients at risk for diabetes; the challenge revolves around the time and money commitment necessary for these interventions. A physician in a typical office setting has limited time to implement the interventions used in these trials. Referral to other health professionals (dietician, exercise physiatrist, etc) for counseling or individual guidance may be prohibitively costly, as these services are often not covered by insurance, and patients may not be willing to pay.
Bottom line—at every office visit, encourage patients to increase their exercise and watch what they eat as part of prevention. If they are willing to see a dietician, by all means send them.
Diets that result in long-term weight loss of 5% to 7%, along with moderate-intensity exercise for more than 150 minutes per week, reduce the incidence of type 2 diabetes for patients with impaired glucose tolerance (IGT) (strength of recommendation [SOR]: A, based on multiple randomized controlled trials [RCTs]). Each of the trials demonstrating this finding included fairly intensive counseling as part of the successful intervention. Diet and exercise reduce the incidence of diabetes in both lean (body mass index [BMI] <25) and overweight patients with IGT (SOR: B, based on a single, large RCT).
Evidence summary
Three large prospective RCTs evaluated the effect of dietary and exercise interventions in populations at risk for developing diabetes.
The Diabetes Prevention Program Research Group1 randomized 3234 patients age >24 years without diabetes but with IGT and a BMI >24 to 1 of 3 groups: intensive lifestyle modification, metformin, or control; they then compared the incidence of diabetes over 3 years. Patients were men and women from primary care populations and represented diverse ethnic backgrounds. Investigators defined IGT as plasma glucose of 140 to 200 mg/dL 2 hours after a 75-g glucose bolus when the fasting glucose was <140 mg/dL. Intensive lifestyle intervention comprised individual training sessions on a low-calorie, low-fat diet, aerobic exercise (such as brisk walking), and behavior modification. Case managers met with each participant for at least 16 sessions during the first 24 weeks and at least monthly thereafter. The control group received lifestyle change recommendations without individualized attention.
After 24 weeks, 50% of the lifestyle group met the 7% weight loss goal and 74% were exercising at least 150 minutes per week. At the final visit, 38% maintained their target weight and 58% met their exercise goal. Lifestyle intervention produced greater weight reduction and increased activity compared with the metformin and control groups, with a corresponding decreased incidence of diabetes (TABLE). Subgroup analysis found that lifestyle intervention produced the greatest reduction in diabetes (71%) for patients aged >60 years.
The Finnish Diabetes Prevention Study2 similarly randomized 522 patients, aged 40 to 65 years, with IGT and obesity (mean BMI=31) to either intensive lifestyle intervention or control and followed them for 3.2 years. The lifestyle intervention included moderate exercise for at least 150 minutes per week and weight loss of at least 5%. Patients were offered an individualized exercise plan with supervised aerobic exercise plus circuit-type resistance sessions 3 times a week. Nutritionists met with patients 7 times in the first year and every 3 months after that. Patients were counseled to increase fiber intake, reduce total fat below 30% of total calories, and reduce saturated fat below 10%. The control group was given general information on diet and exercise without individualized programs. Most patients (86%) in the intervention group met their exercise goal, and 25% met the fiber requirement.
Compared with the control group, the intervention group had greater success rate for each category. Intensive lifestyle intervention reduced the incidence of diabetes by 58% (number needed to treat=5 for 5 years; (see TABLE).
The Da Qing IGT and Diabetes Study3 divided 577 patients with IGT into 1 control and 3 intervention groups: diet, aerobic exercise, and combined diet plus aerobic exercise. Patients in this study had the lowest average BMI (25.8) of the 3 studies. The intervention group received individual and group counseling sessions at weekly intervals for 1 month, then monthly for 3 months, and then every 3 months. The control group received generalized information on IGT and diabetes but individual or group instruction was not included.
At the 6-year follow-up, the quantity of exercise was significantly higher in the exercise intervention groups, but no significant difference in caloric intake was seen among all 4 groups. The incidence of diabetes in the exercise intervention group was approximately half that in the control group overall (TABLE 1). Exercise was more effective in reducing diabetes in lean patients (BMI <25), but both lean and overweight patients benefited. The combination of diet plus exercise and diet changes also significantly reduced diabetes, although to a lesser degree.
TABLE
Incidence of diabetes among patients with impaired glucose tolerance participating in diet and exercise programs
| Study population | Mean BMI | Intervention | Diabetes incidence* | RRR | NNT |
|---|---|---|---|---|---|
| Diabetes Prevention Program1(3234 primary care patients, men and women, mixed ethnic backgrounds, various ages) | 34 | Control | 11.0 | Baseline | Baseline |
| Metformin | 7.8 | 31% | 14 (over 7 years) | ||
| Intensive lifestyle modification | 4.8 | 58% | 7 (over 7 years) | ||
| Finnish Diabetes PreventionStudy2 (522 patients) | 31 | Control | 23 | Baseline | Baseline |
| Intensive lifestyle modification | 11 | 58% | 5 (over 5 years) | ||
| Da Qing IGTand Diabetes Study3 (577 primary care patients, men and women aged >25 years) | 25.8 | Control | 15 | Baseline | Baseline (all over 6 years) |
| Diet | 10 | 31% | 17 | ||
| Exercise | 8 | 46% | 14 | ||
| Diet and exercise | 9.5 | 42% | 16 | ||
| *Incidence of diabetes per 100 person-years. | |||||
| IGT, intensive glucose control; BMI, body mass index; RRR, relative risk reduction; NNT, number needed to treat. | |||||
Recommendations from others
The American Diabetes Association recommends structured programs that emphasize lifestyle changes, including education, reduced fat and energy intake, regular physical activity, and regular participant contact. These changes can produce long-term weight loss of 5% to 7% of starting weight and reduce the risk for developing diabetes.4 They also stress the importance of promoting exercise as a vital component of the prevention as well as management of type 2 diabetes. The benefit of exercise in improving the metabolic abnormalities of type 2 diabetes is probably greatest when it is used early in its progression from insulin resistance to impaired glucose tolerance to overt hyperglycemia.5 The Exercise was more effective in reducing diabetes in lean patients, but overweight patients also benefited World Health Organization states that increased physical activity and maintaining a healthy weight play critical roles in the prevention and treatment of diabetes.6
Encourage patients to exercise and eat well, and see a dietician if they are willing
Julia Fashner, MD
St. Joseph Family Medicine Residency, South Bend, Ind
Diet and exercise are important components in the management of patients at risk for diabetes; the challenge revolves around the time and money commitment necessary for these interventions. A physician in a typical office setting has limited time to implement the interventions used in these trials. Referral to other health professionals (dietician, exercise physiatrist, etc) for counseling or individual guidance may be prohibitively costly, as these services are often not covered by insurance, and patients may not be willing to pay.
Bottom line—at every office visit, encourage patients to increase their exercise and watch what they eat as part of prevention. If they are willing to see a dietician, by all means send them.
1. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.
2. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-1350.
3. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIIDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:537-544.
4. American Diabetes Association. Evidence based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care 2002;25(Suppl 1):S50-S60.
5. American Diabetes Association. Diabetes mellitus and exercise. Diabetes Care 2002;25(Suppl 1):S64-S68.
6. World Health Organization. Diet, nutrition and the prevention of chronic diseases: report of the joint WHO/FAO expert consultation. WHO Technical Report Series No. 916 (TRS 916), 2002.
1. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.
2. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-1350.
3. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIIDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:537-544.
4. American Diabetes Association. Evidence based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care 2002;25(Suppl 1):S50-S60.
5. American Diabetes Association. Diabetes mellitus and exercise. Diabetes Care 2002;25(Suppl 1):S64-S68.
6. World Health Organization. Diet, nutrition and the prevention of chronic diseases: report of the joint WHO/FAO expert consultation. WHO Technical Report Series No. 916 (TRS 916), 2002.
Evidence-based answers from the Family Physicians Inquiries Network
Does quinine reduce leg cramps for young athletes?
Very little evidence exists regarding the use of quinine for cramps in young adult athletes. Quinine may be an effective treatment for heat cramps in athletes (strength of recommendation [SOR]: C, 1 case series involving 2 patients). Quinine is better established as an effective treatment for nocturnal leg cramps in the general adult population (SOR: A, 1 meta-analysis and 2 randomized controlled trials).
Evidence summary
Leg cramps (heat cramps) in athletes are defined as painful involuntary muscle contractions, usually in the large muscle groups of the legs, which occur during or in the hours following exercise. Oral quinine is sometimes used to treat nocturnal leg cramps in the general adult and elderly populations. However, its use is controversial secondary to concerns regarding efficacy and safety.
Efficacy of quinine in young athletes has not been well studied. A case series reported on 2 athletes: 1 college basketball player and 1 professional football player.1 The basketball player experienced heat cramps during games that were resistant to hydration and dietary treatment. A regimen of 60 mg oral quinine sulfate taken 1 hour before game time and again at halftime eliminated cramps during the first game and the subsequent 15 games. The football player’s heat cramps were only partially improved with oral electrolyte repletion and oral hydration. However, he suffered no further cramps after initiating a regimen of 120 mg oral quinine sulfate before games and 60 mg oral quinine during games for an undisclosed period of time. Both players had normal blood chemistries before starting quinine. No side effects were mentioned.
Several trials involving the general adult population exist. A meta-analysis of 4 published and 3 unpublished reports of randomized, double-blind controlled crossover trials (n=409) showed that adult patients had significantly fewer nocturnal cramps when taking quinine compared with placebo.2 The absolute reduction in number of leg cramps was 3.6 (95% confidence interval [CI], 2.15–5.05) over a 4-week period, and the relative risk reduction was 0.21 (95% CI, 0.12–0.30).
Two randomized controlled trials were not included in the meta-analysis discussed above. One double-blind, randomized, controlled parallel group trial of 98 adult patients with a mean age of 50 years demonstrated that a regimen of daily quinine sulfate therapy of 200 mg with the evening meal and 200 mg at bedtime significantly reduced the number of nocturnal muscle cramps compared with placebo.3 Over a 2-week treatment period the quinine group experienced a median of 8 fewer cramps (95% CI, 7–10), while the placebo group experienced a median of 6 fewer cramps (95% CI, 3–7). However, patient evaluation of global efficacy of treatment was not statistically significant between the quinine and placebo groups.
A second double-blind, randomized, controlled parallel group trial of 102 adult patients, mean age approximately 50 years, showed that a 2-week treatment period of hydroquinine (not available in the US) also produced a significant reduction in day- and nighttime muscle cramps compared with placebo.4 This study used a regimen of two 100-mg hydroquinine or placebo tablets with the evening meal and one 100-mg tablet or placebo at bedtime. The median difference in the number of cramps between the treatment and control groups was 5 (95% CI, 2–8).
It should be noted that during the 2 weeks immediately following the treatment period, numbers of cramps were still low compared with the pretreatment period and no significant difference was seen in number of cramps between groups. This raises suspicion that the improvement in both groups was due to the self-limited nature of cramps and represented the regression-to-the-mean phenomenon rather than a true treatment effect of hydroquinine. In addition, extrapolating results from studies of nocturnal cramps to heat cramps is problematic, as it is unknown whether these differ in physiology or cause.
Use of quinine for common cramps in nonathletes has been controversial. In 1994 the Food and Drug Administration (FDA) issued a statement banning over-the-counter sale of quinine for nocturnal leg cramps, citing lack of adequate data to establish efficacy and concern for potential toxicity.5 Between 1969 and 1990 the FDA received 26 adverse reaction reports in which quinine was concluded to be the causative agent. The 3 studies discussed above consistently mention only tinnitus as likely related to quinine use. However, the descriptions and inference testing of side effects were inadequate in each study.
Of note, quinine is a category X drug and should not be used during pregnancy.6
Recommendations from others
No specific recommendations exist regarding the use of quinine in athletes. The American Medical Society of Sports Medicine recommends rest, stretching, and oral hydration for simple heat cramps, and intravenous fluids for very severe cases.7 Several texts also recommend rehydration with an oral electrolyte solution, as well as rest, stretching, and massage.8-10
Hydration and salt intake best approach for cramping in athletes
Sourav Poddar, MD
Team Physician, University of Colorado Buffaloes, University of Colorado Health Sciences Center, Denver
The use of quinine for the treatment or prevention of leg cramps in young adult athletes is not well studied. Safety and efficacy issues make it an unappealing option in the treatment of cramps and consequently it is not recommended for use in athletes. Hydration before, during, and after activity remains the cornerstone to approaching cramping in athletes. Appropriate salt intake for those who lose high concentrations of salt in their sweat may also be useful in prophylaxis. Once cramps occur, rehydration, stretching, massage, and rest work best.
1. Brubaker DA, Whitesel J, Barth BI. Quinine sulfate: A treatment for recurrent muscle spasms. Athletic Training (Greenville, NC) 1985;20:121-122.
2. Man-Son-Hing M, Wells G, Lau A. Quinine for nocturnal leg cramps. A meta-analysis including unpublished data. J Gen Intern Med 1998;13:600-606.
3. Diener HC, Dethlefsen U, Dethlefsen-Gruber S, Verbeek P. Effectiveness of quinine in treating muscle cramps: a double-blind, placebo-controlled, parallel-group, multicentre trial. Int J Clin Pract 2002;56:243-246.
4. Jansen PH, Veenhuizen KC, Wesseling AI, de Boo T, Verbeek AL. Randomised controlled trial of hydroquinine in muscle cramps. Lancet 1997;349:528-532.
5. Drug products for the treatment and/or prevention of nocturnal leg muscle cramps for over-the-counter human use; final rule. Federal Registrar 1994;59:43234-43252.Available at www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfcfr/CFRSearch.cfm?fr=310.546. Accessed on December 9, 2004.
6. Drug Facts and Comparisons. [book on CD-ROM]. St. Louis, Mo: Wolters Kluwer Health; 2004.
7. Joy E. Heat Illness. Sports Medicine Tip Sheet. American Medical Society for Sports Medicine. Last modified November 8, 2002. Available at www.amssm.org/Handouts/ Heatillness.pdf. Accessed on December 9, 2004.
8. Watts K, Mulder G. Heat illness. In: Richmond JC, Shahady EJ, eds: Sports Medicine for Primary Care. Ann Arbor, Mich: Braun-Brumfield, 1966;525-540.
9. Eicher ER. Chronic fatigue and staleness. In: Strauss RH, ed: Sports Medicine, 2nd ed. Philadelphia: W.B. Saunders, 1991;207-220.
10. Lisle D, Kernan M. The athlete and the outdoors: Environmental influences on sports. In: Birrer RB and O’Connor FG, eds: Sports Medicine for the Primary Care Physician, 3rd ed. Boca Raton, Fla: CRC Press, 2004;99-112.
Very little evidence exists regarding the use of quinine for cramps in young adult athletes. Quinine may be an effective treatment for heat cramps in athletes (strength of recommendation [SOR]: C, 1 case series involving 2 patients). Quinine is better established as an effective treatment for nocturnal leg cramps in the general adult population (SOR: A, 1 meta-analysis and 2 randomized controlled trials).
Evidence summary
Leg cramps (heat cramps) in athletes are defined as painful involuntary muscle contractions, usually in the large muscle groups of the legs, which occur during or in the hours following exercise. Oral quinine is sometimes used to treat nocturnal leg cramps in the general adult and elderly populations. However, its use is controversial secondary to concerns regarding efficacy and safety.
Efficacy of quinine in young athletes has not been well studied. A case series reported on 2 athletes: 1 college basketball player and 1 professional football player.1 The basketball player experienced heat cramps during games that were resistant to hydration and dietary treatment. A regimen of 60 mg oral quinine sulfate taken 1 hour before game time and again at halftime eliminated cramps during the first game and the subsequent 15 games. The football player’s heat cramps were only partially improved with oral electrolyte repletion and oral hydration. However, he suffered no further cramps after initiating a regimen of 120 mg oral quinine sulfate before games and 60 mg oral quinine during games for an undisclosed period of time. Both players had normal blood chemistries before starting quinine. No side effects were mentioned.
Several trials involving the general adult population exist. A meta-analysis of 4 published and 3 unpublished reports of randomized, double-blind controlled crossover trials (n=409) showed that adult patients had significantly fewer nocturnal cramps when taking quinine compared with placebo.2 The absolute reduction in number of leg cramps was 3.6 (95% confidence interval [CI], 2.15–5.05) over a 4-week period, and the relative risk reduction was 0.21 (95% CI, 0.12–0.30).
Two randomized controlled trials were not included in the meta-analysis discussed above. One double-blind, randomized, controlled parallel group trial of 98 adult patients with a mean age of 50 years demonstrated that a regimen of daily quinine sulfate therapy of 200 mg with the evening meal and 200 mg at bedtime significantly reduced the number of nocturnal muscle cramps compared with placebo.3 Over a 2-week treatment period the quinine group experienced a median of 8 fewer cramps (95% CI, 7–10), while the placebo group experienced a median of 6 fewer cramps (95% CI, 3–7). However, patient evaluation of global efficacy of treatment was not statistically significant between the quinine and placebo groups.
A second double-blind, randomized, controlled parallel group trial of 102 adult patients, mean age approximately 50 years, showed that a 2-week treatment period of hydroquinine (not available in the US) also produced a significant reduction in day- and nighttime muscle cramps compared with placebo.4 This study used a regimen of two 100-mg hydroquinine or placebo tablets with the evening meal and one 100-mg tablet or placebo at bedtime. The median difference in the number of cramps between the treatment and control groups was 5 (95% CI, 2–8).
It should be noted that during the 2 weeks immediately following the treatment period, numbers of cramps were still low compared with the pretreatment period and no significant difference was seen in number of cramps between groups. This raises suspicion that the improvement in both groups was due to the self-limited nature of cramps and represented the regression-to-the-mean phenomenon rather than a true treatment effect of hydroquinine. In addition, extrapolating results from studies of nocturnal cramps to heat cramps is problematic, as it is unknown whether these differ in physiology or cause.
Use of quinine for common cramps in nonathletes has been controversial. In 1994 the Food and Drug Administration (FDA) issued a statement banning over-the-counter sale of quinine for nocturnal leg cramps, citing lack of adequate data to establish efficacy and concern for potential toxicity.5 Between 1969 and 1990 the FDA received 26 adverse reaction reports in which quinine was concluded to be the causative agent. The 3 studies discussed above consistently mention only tinnitus as likely related to quinine use. However, the descriptions and inference testing of side effects were inadequate in each study.
Of note, quinine is a category X drug and should not be used during pregnancy.6
Recommendations from others
No specific recommendations exist regarding the use of quinine in athletes. The American Medical Society of Sports Medicine recommends rest, stretching, and oral hydration for simple heat cramps, and intravenous fluids for very severe cases.7 Several texts also recommend rehydration with an oral electrolyte solution, as well as rest, stretching, and massage.8-10
Hydration and salt intake best approach for cramping in athletes
Sourav Poddar, MD
Team Physician, University of Colorado Buffaloes, University of Colorado Health Sciences Center, Denver
The use of quinine for the treatment or prevention of leg cramps in young adult athletes is not well studied. Safety and efficacy issues make it an unappealing option in the treatment of cramps and consequently it is not recommended for use in athletes. Hydration before, during, and after activity remains the cornerstone to approaching cramping in athletes. Appropriate salt intake for those who lose high concentrations of salt in their sweat may also be useful in prophylaxis. Once cramps occur, rehydration, stretching, massage, and rest work best.
Very little evidence exists regarding the use of quinine for cramps in young adult athletes. Quinine may be an effective treatment for heat cramps in athletes (strength of recommendation [SOR]: C, 1 case series involving 2 patients). Quinine is better established as an effective treatment for nocturnal leg cramps in the general adult population (SOR: A, 1 meta-analysis and 2 randomized controlled trials).
Evidence summary
Leg cramps (heat cramps) in athletes are defined as painful involuntary muscle contractions, usually in the large muscle groups of the legs, which occur during or in the hours following exercise. Oral quinine is sometimes used to treat nocturnal leg cramps in the general adult and elderly populations. However, its use is controversial secondary to concerns regarding efficacy and safety.
Efficacy of quinine in young athletes has not been well studied. A case series reported on 2 athletes: 1 college basketball player and 1 professional football player.1 The basketball player experienced heat cramps during games that were resistant to hydration and dietary treatment. A regimen of 60 mg oral quinine sulfate taken 1 hour before game time and again at halftime eliminated cramps during the first game and the subsequent 15 games. The football player’s heat cramps were only partially improved with oral electrolyte repletion and oral hydration. However, he suffered no further cramps after initiating a regimen of 120 mg oral quinine sulfate before games and 60 mg oral quinine during games for an undisclosed period of time. Both players had normal blood chemistries before starting quinine. No side effects were mentioned.
Several trials involving the general adult population exist. A meta-analysis of 4 published and 3 unpublished reports of randomized, double-blind controlled crossover trials (n=409) showed that adult patients had significantly fewer nocturnal cramps when taking quinine compared with placebo.2 The absolute reduction in number of leg cramps was 3.6 (95% confidence interval [CI], 2.15–5.05) over a 4-week period, and the relative risk reduction was 0.21 (95% CI, 0.12–0.30).
Two randomized controlled trials were not included in the meta-analysis discussed above. One double-blind, randomized, controlled parallel group trial of 98 adult patients with a mean age of 50 years demonstrated that a regimen of daily quinine sulfate therapy of 200 mg with the evening meal and 200 mg at bedtime significantly reduced the number of nocturnal muscle cramps compared with placebo.3 Over a 2-week treatment period the quinine group experienced a median of 8 fewer cramps (95% CI, 7–10), while the placebo group experienced a median of 6 fewer cramps (95% CI, 3–7). However, patient evaluation of global efficacy of treatment was not statistically significant between the quinine and placebo groups.
A second double-blind, randomized, controlled parallel group trial of 102 adult patients, mean age approximately 50 years, showed that a 2-week treatment period of hydroquinine (not available in the US) also produced a significant reduction in day- and nighttime muscle cramps compared with placebo.4 This study used a regimen of two 100-mg hydroquinine or placebo tablets with the evening meal and one 100-mg tablet or placebo at bedtime. The median difference in the number of cramps between the treatment and control groups was 5 (95% CI, 2–8).
It should be noted that during the 2 weeks immediately following the treatment period, numbers of cramps were still low compared with the pretreatment period and no significant difference was seen in number of cramps between groups. This raises suspicion that the improvement in both groups was due to the self-limited nature of cramps and represented the regression-to-the-mean phenomenon rather than a true treatment effect of hydroquinine. In addition, extrapolating results from studies of nocturnal cramps to heat cramps is problematic, as it is unknown whether these differ in physiology or cause.
Use of quinine for common cramps in nonathletes has been controversial. In 1994 the Food and Drug Administration (FDA) issued a statement banning over-the-counter sale of quinine for nocturnal leg cramps, citing lack of adequate data to establish efficacy and concern for potential toxicity.5 Between 1969 and 1990 the FDA received 26 adverse reaction reports in which quinine was concluded to be the causative agent. The 3 studies discussed above consistently mention only tinnitus as likely related to quinine use. However, the descriptions and inference testing of side effects were inadequate in each study.
Of note, quinine is a category X drug and should not be used during pregnancy.6
Recommendations from others
No specific recommendations exist regarding the use of quinine in athletes. The American Medical Society of Sports Medicine recommends rest, stretching, and oral hydration for simple heat cramps, and intravenous fluids for very severe cases.7 Several texts also recommend rehydration with an oral electrolyte solution, as well as rest, stretching, and massage.8-10
Hydration and salt intake best approach for cramping in athletes
Sourav Poddar, MD
Team Physician, University of Colorado Buffaloes, University of Colorado Health Sciences Center, Denver
The use of quinine for the treatment or prevention of leg cramps in young adult athletes is not well studied. Safety and efficacy issues make it an unappealing option in the treatment of cramps and consequently it is not recommended for use in athletes. Hydration before, during, and after activity remains the cornerstone to approaching cramping in athletes. Appropriate salt intake for those who lose high concentrations of salt in their sweat may also be useful in prophylaxis. Once cramps occur, rehydration, stretching, massage, and rest work best.
1. Brubaker DA, Whitesel J, Barth BI. Quinine sulfate: A treatment for recurrent muscle spasms. Athletic Training (Greenville, NC) 1985;20:121-122.
2. Man-Son-Hing M, Wells G, Lau A. Quinine for nocturnal leg cramps. A meta-analysis including unpublished data. J Gen Intern Med 1998;13:600-606.
3. Diener HC, Dethlefsen U, Dethlefsen-Gruber S, Verbeek P. Effectiveness of quinine in treating muscle cramps: a double-blind, placebo-controlled, parallel-group, multicentre trial. Int J Clin Pract 2002;56:243-246.
4. Jansen PH, Veenhuizen KC, Wesseling AI, de Boo T, Verbeek AL. Randomised controlled trial of hydroquinine in muscle cramps. Lancet 1997;349:528-532.
5. Drug products for the treatment and/or prevention of nocturnal leg muscle cramps for over-the-counter human use; final rule. Federal Registrar 1994;59:43234-43252.Available at www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfcfr/CFRSearch.cfm?fr=310.546. Accessed on December 9, 2004.
6. Drug Facts and Comparisons. [book on CD-ROM]. St. Louis, Mo: Wolters Kluwer Health; 2004.
7. Joy E. Heat Illness. Sports Medicine Tip Sheet. American Medical Society for Sports Medicine. Last modified November 8, 2002. Available at www.amssm.org/Handouts/ Heatillness.pdf. Accessed on December 9, 2004.
8. Watts K, Mulder G. Heat illness. In: Richmond JC, Shahady EJ, eds: Sports Medicine for Primary Care. Ann Arbor, Mich: Braun-Brumfield, 1966;525-540.
9. Eicher ER. Chronic fatigue and staleness. In: Strauss RH, ed: Sports Medicine, 2nd ed. Philadelphia: W.B. Saunders, 1991;207-220.
10. Lisle D, Kernan M. The athlete and the outdoors: Environmental influences on sports. In: Birrer RB and O’Connor FG, eds: Sports Medicine for the Primary Care Physician, 3rd ed. Boca Raton, Fla: CRC Press, 2004;99-112.
1. Brubaker DA, Whitesel J, Barth BI. Quinine sulfate: A treatment for recurrent muscle spasms. Athletic Training (Greenville, NC) 1985;20:121-122.
2. Man-Son-Hing M, Wells G, Lau A. Quinine for nocturnal leg cramps. A meta-analysis including unpublished data. J Gen Intern Med 1998;13:600-606.
3. Diener HC, Dethlefsen U, Dethlefsen-Gruber S, Verbeek P. Effectiveness of quinine in treating muscle cramps: a double-blind, placebo-controlled, parallel-group, multicentre trial. Int J Clin Pract 2002;56:243-246.
4. Jansen PH, Veenhuizen KC, Wesseling AI, de Boo T, Verbeek AL. Randomised controlled trial of hydroquinine in muscle cramps. Lancet 1997;349:528-532.
5. Drug products for the treatment and/or prevention of nocturnal leg muscle cramps for over-the-counter human use; final rule. Federal Registrar 1994;59:43234-43252.Available at www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfcfr/CFRSearch.cfm?fr=310.546. Accessed on December 9, 2004.
6. Drug Facts and Comparisons. [book on CD-ROM]. St. Louis, Mo: Wolters Kluwer Health; 2004.
7. Joy E. Heat Illness. Sports Medicine Tip Sheet. American Medical Society for Sports Medicine. Last modified November 8, 2002. Available at www.amssm.org/Handouts/ Heatillness.pdf. Accessed on December 9, 2004.
8. Watts K, Mulder G. Heat illness. In: Richmond JC, Shahady EJ, eds: Sports Medicine for Primary Care. Ann Arbor, Mich: Braun-Brumfield, 1966;525-540.
9. Eicher ER. Chronic fatigue and staleness. In: Strauss RH, ed: Sports Medicine, 2nd ed. Philadelphia: W.B. Saunders, 1991;207-220.
10. Lisle D, Kernan M. The athlete and the outdoors: Environmental influences on sports. In: Birrer RB and O’Connor FG, eds: Sports Medicine for the Primary Care Physician, 3rd ed. Boca Raton, Fla: CRC Press, 2004;99-112.
Evidence-based answers from the Family Physicians Inquiries Network
What are the indications for evaluating a patient with cough for pertussis?
Pertussis should be considered in infants with apnea or severe coughing illnesses of any duration, and in older children or adults with prolonged cough (eg, longer than 2 weeks), especially if accompanied by inspiratory whoop or household exposure to a prolonged cough illness (strength of recommendation [SOR]: B, based on consecutive cohort studies with poor reference standards). Coughing paroxysms, posttussive vomiting, and absence of fever, while typical of pertussis, are of little help in distinguishing it from other causes of prolonged coughing illnesses (SOR: B, based on consecutive cohort studies with poor reference standards).
Evidence summary
Pertussis is an important cause of cough in all age groups. Ten prevalence studies of adolescents and adults seeking medical attention for a prolonged cough (defined variously as >1–4 weeks) found acute pertussis in 12% to 32%.1
While cough longer than 2 weeks, inspiratory whoop, posttussive vomiting, coughing paroxysms, and absence of fever are commonly associated with pertussis, relatively few studies have assessed the sensitivities and specificities of these symptoms. The TABLE summarizes results from 5 cohort series of children and adults with laboratory-confirmed pertussis. Comparison groups were variously defined by negative pertussis cultures, negative pertussis serology, or serologic confirmation of other respiratory infections. Likelihood ratios (LR) were calculated from the data presented in each paper.
The magnitude and variability of these likelihood ratios suggest that individual symptoms may be of limited help in distinguishing pertussis from other causes of prolonged cough. Combinations of symptoms may be slightly more helpful. In a study comparing 10 patients with culture-confirmed pertussis with 10 patients with serologically confirmed mycoplasma pneumonia, the combination of cough >14 days and whoop had a sensitivity of 80%, a positive LR (LR+) of 8 and a negative LR (LR–) of 0.22.2 A cohort series of children aged <5 years with suspected pertussis compared 33 with positive cultures to 55 with negative cultures. The constellation of spasmodic cough and lymphocytosis (>10,000) had a sensitivity of 83%, a LR+ of 2.5, and a LR– of 0.25. Cough >14 days with whoop and vomiting had a sensitivity of 67%, a LR+ of 3.2, and LR– of 0.42.3
Infants aged <6 months with pertussis are at particular risk for atypical presentations and serious complications. In a US series of 18,500 infants with pertussis, apnea was seen in 64% of infants under 1 month and in 44% between 6 and 11 months. Forty percent of the 6- to 11-month-olds had received at least 3 doses of pertussis vaccine.4 A British study of 126 infants aged <5 months admitted to the pediatric intensive care unit with apnea, bradycardia, or respiratory failure found that 20% had pertussis. Apnea as a predictor of pertussis had a sensitivity of 68% and a specificity of 60%.5
Pertussis should be considered early in the evaluation of young infants with cough. In a case-control study comparing 15 fatal cases of pertussis with 32 who survived (infants aged <6 months), the mean number of days from symptom onset to hospital admission were 5.3 (fatal) and 8.6 (survivors). Rates of apnea on admission were 40% and 52%.6 A case series of 9 infants aged <7 weeks requiring admission to an intensive care unit for pertussis found that 8 had been sick for less than 4 days at the time of admission. All 9 presented with poor feeding and cough, and 5 had experienced apnea.7
TABLE
Clinical features of pertussis
| History | Sensitivity | Specificity | LR+ | LR– |
|---|---|---|---|---|
| Cough >2 weeks3,12 | 84%–100% | 35%–36% | 1.3–1.5 | 0–0.44 |
| Cough >3 weeks3,12 | 75%–97% | 51%–59% | 1.8–2.0 | 0.06–0.42 |
| Whoop3,10-12 | 37%–90% | 49%–96% | 1.6–9.2 | 0.18–0.66 |
| Posttussivevomiting3,10,11,13 | 28%–84% | 45%–84% | 0.9–2.2 | 0.36–1.0 |
| Paroxysms3,12,13 | 68%–94% | 15%–45% | 1.1–1.4 | 0.29–0.71 |
| Householdexposure11,13 | 20%–50% | 73%–91% | 1.9–2.2 | 0.68–0.88 |
| Afebrile(temp <38°C)11-13 | 62%–96% | 12%–54% | 0.8–1.1 | 0–1.7 |
| Lymphocytosis3 | 88% | 57% | 2.0 | 0.21 |
| LR+ = positive likelihood ratio: sensitivity/(1–specificity); † LR– = negative likelihood ratio: (1–sensitivity)/specificity. | ||||
Recommendations from others
The Centers for Disease Control and Prevention and the World Health Organization describe the clinical case definition for pertussis as a cough illness lasting at least 2 weeks with at least 1 of the following: paroxysms of coughing, inspiratory whoop, or posttussive vomiting, without other apparent cause. Laboratory criteria for diagnosis include a positive Bordetella pertussis. culture or a positive polymerase chain reaction (PCR) for B pertussis.8,9
Infants may have complications; evaluate if there is apnea or significant cough
Michael Ohl, MD
University of Missouri–Columbia
Immunity to pertussis wanes following vaccination, leaving many adolescents and adults susceptible to infection. In older children and adults, there is often little in the clinical presentation that distinguishes chronic cough due to pertussis from that associated with other causes. Clinicians should consider evaluating for pertussis in older children and adults with chronic cough (>2 weeks) if there is reason to suspect they have been exposed, if the cough is associated with inspiratory whoop, or if the individual has household or frequent contact with infants.
Infants may suffer severe complications from pertussis, and should receive evaluation when presenting with apnea or significant cough of any duration. In current practice, evaluation usually includes obtaining a nasopharyngeal swab for culture and PCR, though these tests may be insensitive, especially in later phases of illness. The usefulness of single, quantitative immunoglobulin G titers with comparison to popimpact the epidemiology of pertussis in the US.
1. von König CHW, Halperin S, Riffelman M, Guiso N. Pertussis of adults and infants. Lancet Infect Dis 2002;2:744-750.
2. Davis SF, Sutter RW, Strebel PM, Orton C, Alexander V, Sanden GN, et al. Concurrent outbreaks of pertussis and Mycoplasma pneumoniae infection: clinical and epidemiological characteristics of illnesses manifested by cough. Clin Infect Dis 1995;20:621-628.
3. Strebel PM, Cochi SL, Farizo KM, Payne BJ, Hanauer SD, Baughman AL. Pertussis in Missouri: evaluation of nasopharyngeal culture, direct fluorescent antibody testing, and clinical case definitions in the diagnosis of pertussis. Clin Infect Dis 1993;16:276-285.
4. Tanaka M, Vitck CR, Pascual FB, Bisgard KM, Tate JE, Murphy TV. Trends in pertussis among infants in the United States, 1980–1999. JAMA 2003;290:2968-2975.
5. Crowcroft NS, Booy R, Harrison T, Spicer L, Britto J, Mok Q, et al. Severe and unrecognised: pertussis in UK infants. Arch Dis Child 2003;88:802-806.
6. Mikelova LK, Halperin SA, Scheifele D, et al. Predictors of death in infants hospitalized with pertussis: a case-control study of 16 pertussis deaths in Canada. J Pediatr 2003;143:575-581.
7. Smith C, Vyas H. Early infantile pertussis; increasingly prevalent and potentially fatal. Eur J Pediatr 2000;159:898-900.
8. Pertussis (Bordetella pertussis) (Whooping cough). Epidemiology Program Office, Centers for Disease Control and Prevention. Last updated April 7, 2004. Available at: www.cdc.gov/epo/dphsi/casedef/pertussis_current.htm. Accessed on December 8, 2004.
9. VaccinesImmunizations and Biologicals: Pertussis. Geneva, Switzerland: World Health Organization; 2003. Available at: www.who.int/vaccines-surveillance/deseasedesc/ RSS_pertus.htm. Accessed on December 8, 2004.
10. Wirsing von Konig CH, Rott H, Bogaerts H, Schmitt HJ. A serologic study of organisms possibly associated with pertussis-like coughing. Pediatr Infect Dis J 1998;17:645-649.
11. Granström G, Wretlind B, Granström M. Diagnostic value of clinical and bacteriological findings in pertussis. J Infect 1991;22:17-26.
12. Heininger U, Cherry JD, Eckhardt T, Lorenz C, Christenson P, Stehr K. Clinical and laboratory diagnosis of pertussis in the regions of a large vaccine efficacy trial in Germany. Pediatr Infect Dis J 1993;12:504-509.
13. Wright SW, Edwards KM, Decker MD, Zeldin MH. Pertussis infection in adults with persistent cough. JAMA 1995;273:1044-1046.
Pertussis should be considered in infants with apnea or severe coughing illnesses of any duration, and in older children or adults with prolonged cough (eg, longer than 2 weeks), especially if accompanied by inspiratory whoop or household exposure to a prolonged cough illness (strength of recommendation [SOR]: B, based on consecutive cohort studies with poor reference standards). Coughing paroxysms, posttussive vomiting, and absence of fever, while typical of pertussis, are of little help in distinguishing it from other causes of prolonged coughing illnesses (SOR: B, based on consecutive cohort studies with poor reference standards).
Evidence summary
Pertussis is an important cause of cough in all age groups. Ten prevalence studies of adolescents and adults seeking medical attention for a prolonged cough (defined variously as >1–4 weeks) found acute pertussis in 12% to 32%.1
While cough longer than 2 weeks, inspiratory whoop, posttussive vomiting, coughing paroxysms, and absence of fever are commonly associated with pertussis, relatively few studies have assessed the sensitivities and specificities of these symptoms. The TABLE summarizes results from 5 cohort series of children and adults with laboratory-confirmed pertussis. Comparison groups were variously defined by negative pertussis cultures, negative pertussis serology, or serologic confirmation of other respiratory infections. Likelihood ratios (LR) were calculated from the data presented in each paper.
The magnitude and variability of these likelihood ratios suggest that individual symptoms may be of limited help in distinguishing pertussis from other causes of prolonged cough. Combinations of symptoms may be slightly more helpful. In a study comparing 10 patients with culture-confirmed pertussis with 10 patients with serologically confirmed mycoplasma pneumonia, the combination of cough >14 days and whoop had a sensitivity of 80%, a positive LR (LR+) of 8 and a negative LR (LR–) of 0.22.2 A cohort series of children aged <5 years with suspected pertussis compared 33 with positive cultures to 55 with negative cultures. The constellation of spasmodic cough and lymphocytosis (>10,000) had a sensitivity of 83%, a LR+ of 2.5, and a LR– of 0.25. Cough >14 days with whoop and vomiting had a sensitivity of 67%, a LR+ of 3.2, and LR– of 0.42.3
Infants aged <6 months with pertussis are at particular risk for atypical presentations and serious complications. In a US series of 18,500 infants with pertussis, apnea was seen in 64% of infants under 1 month and in 44% between 6 and 11 months. Forty percent of the 6- to 11-month-olds had received at least 3 doses of pertussis vaccine.4 A British study of 126 infants aged <5 months admitted to the pediatric intensive care unit with apnea, bradycardia, or respiratory failure found that 20% had pertussis. Apnea as a predictor of pertussis had a sensitivity of 68% and a specificity of 60%.5
Pertussis should be considered early in the evaluation of young infants with cough. In a case-control study comparing 15 fatal cases of pertussis with 32 who survived (infants aged <6 months), the mean number of days from symptom onset to hospital admission were 5.3 (fatal) and 8.6 (survivors). Rates of apnea on admission were 40% and 52%.6 A case series of 9 infants aged <7 weeks requiring admission to an intensive care unit for pertussis found that 8 had been sick for less than 4 days at the time of admission. All 9 presented with poor feeding and cough, and 5 had experienced apnea.7
TABLE
Clinical features of pertussis
| History | Sensitivity | Specificity | LR+ | LR– |
|---|---|---|---|---|
| Cough >2 weeks3,12 | 84%–100% | 35%–36% | 1.3–1.5 | 0–0.44 |
| Cough >3 weeks3,12 | 75%–97% | 51%–59% | 1.8–2.0 | 0.06–0.42 |
| Whoop3,10-12 | 37%–90% | 49%–96% | 1.6–9.2 | 0.18–0.66 |
| Posttussivevomiting3,10,11,13 | 28%–84% | 45%–84% | 0.9–2.2 | 0.36–1.0 |
| Paroxysms3,12,13 | 68%–94% | 15%–45% | 1.1–1.4 | 0.29–0.71 |
| Householdexposure11,13 | 20%–50% | 73%–91% | 1.9–2.2 | 0.68–0.88 |
| Afebrile(temp <38°C)11-13 | 62%–96% | 12%–54% | 0.8–1.1 | 0–1.7 |
| Lymphocytosis3 | 88% | 57% | 2.0 | 0.21 |
| LR+ = positive likelihood ratio: sensitivity/(1–specificity); † LR– = negative likelihood ratio: (1–sensitivity)/specificity. | ||||
Recommendations from others
The Centers for Disease Control and Prevention and the World Health Organization describe the clinical case definition for pertussis as a cough illness lasting at least 2 weeks with at least 1 of the following: paroxysms of coughing, inspiratory whoop, or posttussive vomiting, without other apparent cause. Laboratory criteria for diagnosis include a positive Bordetella pertussis. culture or a positive polymerase chain reaction (PCR) for B pertussis.8,9
Infants may have complications; evaluate if there is apnea or significant cough
Michael Ohl, MD
University of Missouri–Columbia
Immunity to pertussis wanes following vaccination, leaving many adolescents and adults susceptible to infection. In older children and adults, there is often little in the clinical presentation that distinguishes chronic cough due to pertussis from that associated with other causes. Clinicians should consider evaluating for pertussis in older children and adults with chronic cough (>2 weeks) if there is reason to suspect they have been exposed, if the cough is associated with inspiratory whoop, or if the individual has household or frequent contact with infants.
Infants may suffer severe complications from pertussis, and should receive evaluation when presenting with apnea or significant cough of any duration. In current practice, evaluation usually includes obtaining a nasopharyngeal swab for culture and PCR, though these tests may be insensitive, especially in later phases of illness. The usefulness of single, quantitative immunoglobulin G titers with comparison to popimpact the epidemiology of pertussis in the US.
Pertussis should be considered in infants with apnea or severe coughing illnesses of any duration, and in older children or adults with prolonged cough (eg, longer than 2 weeks), especially if accompanied by inspiratory whoop or household exposure to a prolonged cough illness (strength of recommendation [SOR]: B, based on consecutive cohort studies with poor reference standards). Coughing paroxysms, posttussive vomiting, and absence of fever, while typical of pertussis, are of little help in distinguishing it from other causes of prolonged coughing illnesses (SOR: B, based on consecutive cohort studies with poor reference standards).
Evidence summary
Pertussis is an important cause of cough in all age groups. Ten prevalence studies of adolescents and adults seeking medical attention for a prolonged cough (defined variously as >1–4 weeks) found acute pertussis in 12% to 32%.1
While cough longer than 2 weeks, inspiratory whoop, posttussive vomiting, coughing paroxysms, and absence of fever are commonly associated with pertussis, relatively few studies have assessed the sensitivities and specificities of these symptoms. The TABLE summarizes results from 5 cohort series of children and adults with laboratory-confirmed pertussis. Comparison groups were variously defined by negative pertussis cultures, negative pertussis serology, or serologic confirmation of other respiratory infections. Likelihood ratios (LR) were calculated from the data presented in each paper.
The magnitude and variability of these likelihood ratios suggest that individual symptoms may be of limited help in distinguishing pertussis from other causes of prolonged cough. Combinations of symptoms may be slightly more helpful. In a study comparing 10 patients with culture-confirmed pertussis with 10 patients with serologically confirmed mycoplasma pneumonia, the combination of cough >14 days and whoop had a sensitivity of 80%, a positive LR (LR+) of 8 and a negative LR (LR–) of 0.22.2 A cohort series of children aged <5 years with suspected pertussis compared 33 with positive cultures to 55 with negative cultures. The constellation of spasmodic cough and lymphocytosis (>10,000) had a sensitivity of 83%, a LR+ of 2.5, and a LR– of 0.25. Cough >14 days with whoop and vomiting had a sensitivity of 67%, a LR+ of 3.2, and LR– of 0.42.3
Infants aged <6 months with pertussis are at particular risk for atypical presentations and serious complications. In a US series of 18,500 infants with pertussis, apnea was seen in 64% of infants under 1 month and in 44% between 6 and 11 months. Forty percent of the 6- to 11-month-olds had received at least 3 doses of pertussis vaccine.4 A British study of 126 infants aged <5 months admitted to the pediatric intensive care unit with apnea, bradycardia, or respiratory failure found that 20% had pertussis. Apnea as a predictor of pertussis had a sensitivity of 68% and a specificity of 60%.5
Pertussis should be considered early in the evaluation of young infants with cough. In a case-control study comparing 15 fatal cases of pertussis with 32 who survived (infants aged <6 months), the mean number of days from symptom onset to hospital admission were 5.3 (fatal) and 8.6 (survivors). Rates of apnea on admission were 40% and 52%.6 A case series of 9 infants aged <7 weeks requiring admission to an intensive care unit for pertussis found that 8 had been sick for less than 4 days at the time of admission. All 9 presented with poor feeding and cough, and 5 had experienced apnea.7
TABLE
Clinical features of pertussis
| History | Sensitivity | Specificity | LR+ | LR– |
|---|---|---|---|---|
| Cough >2 weeks3,12 | 84%–100% | 35%–36% | 1.3–1.5 | 0–0.44 |
| Cough >3 weeks3,12 | 75%–97% | 51%–59% | 1.8–2.0 | 0.06–0.42 |
| Whoop3,10-12 | 37%–90% | 49%–96% | 1.6–9.2 | 0.18–0.66 |
| Posttussivevomiting3,10,11,13 | 28%–84% | 45%–84% | 0.9–2.2 | 0.36–1.0 |
| Paroxysms3,12,13 | 68%–94% | 15%–45% | 1.1–1.4 | 0.29–0.71 |
| Householdexposure11,13 | 20%–50% | 73%–91% | 1.9–2.2 | 0.68–0.88 |
| Afebrile(temp <38°C)11-13 | 62%–96% | 12%–54% | 0.8–1.1 | 0–1.7 |
| Lymphocytosis3 | 88% | 57% | 2.0 | 0.21 |
| LR+ = positive likelihood ratio: sensitivity/(1–specificity); † LR– = negative likelihood ratio: (1–sensitivity)/specificity. | ||||
Recommendations from others
The Centers for Disease Control and Prevention and the World Health Organization describe the clinical case definition for pertussis as a cough illness lasting at least 2 weeks with at least 1 of the following: paroxysms of coughing, inspiratory whoop, or posttussive vomiting, without other apparent cause. Laboratory criteria for diagnosis include a positive Bordetella pertussis. culture or a positive polymerase chain reaction (PCR) for B pertussis.8,9
Infants may have complications; evaluate if there is apnea or significant cough
Michael Ohl, MD
University of Missouri–Columbia
Immunity to pertussis wanes following vaccination, leaving many adolescents and adults susceptible to infection. In older children and adults, there is often little in the clinical presentation that distinguishes chronic cough due to pertussis from that associated with other causes. Clinicians should consider evaluating for pertussis in older children and adults with chronic cough (>2 weeks) if there is reason to suspect they have been exposed, if the cough is associated with inspiratory whoop, or if the individual has household or frequent contact with infants.
Infants may suffer severe complications from pertussis, and should receive evaluation when presenting with apnea or significant cough of any duration. In current practice, evaluation usually includes obtaining a nasopharyngeal swab for culture and PCR, though these tests may be insensitive, especially in later phases of illness. The usefulness of single, quantitative immunoglobulin G titers with comparison to popimpact the epidemiology of pertussis in the US.
1. von König CHW, Halperin S, Riffelman M, Guiso N. Pertussis of adults and infants. Lancet Infect Dis 2002;2:744-750.
2. Davis SF, Sutter RW, Strebel PM, Orton C, Alexander V, Sanden GN, et al. Concurrent outbreaks of pertussis and Mycoplasma pneumoniae infection: clinical and epidemiological characteristics of illnesses manifested by cough. Clin Infect Dis 1995;20:621-628.
3. Strebel PM, Cochi SL, Farizo KM, Payne BJ, Hanauer SD, Baughman AL. Pertussis in Missouri: evaluation of nasopharyngeal culture, direct fluorescent antibody testing, and clinical case definitions in the diagnosis of pertussis. Clin Infect Dis 1993;16:276-285.
4. Tanaka M, Vitck CR, Pascual FB, Bisgard KM, Tate JE, Murphy TV. Trends in pertussis among infants in the United States, 1980–1999. JAMA 2003;290:2968-2975.
5. Crowcroft NS, Booy R, Harrison T, Spicer L, Britto J, Mok Q, et al. Severe and unrecognised: pertussis in UK infants. Arch Dis Child 2003;88:802-806.
6. Mikelova LK, Halperin SA, Scheifele D, et al. Predictors of death in infants hospitalized with pertussis: a case-control study of 16 pertussis deaths in Canada. J Pediatr 2003;143:575-581.
7. Smith C, Vyas H. Early infantile pertussis; increasingly prevalent and potentially fatal. Eur J Pediatr 2000;159:898-900.
8. Pertussis (Bordetella pertussis) (Whooping cough). Epidemiology Program Office, Centers for Disease Control and Prevention. Last updated April 7, 2004. Available at: www.cdc.gov/epo/dphsi/casedef/pertussis_current.htm. Accessed on December 8, 2004.
9. VaccinesImmunizations and Biologicals: Pertussis. Geneva, Switzerland: World Health Organization; 2003. Available at: www.who.int/vaccines-surveillance/deseasedesc/ RSS_pertus.htm. Accessed on December 8, 2004.
10. Wirsing von Konig CH, Rott H, Bogaerts H, Schmitt HJ. A serologic study of organisms possibly associated with pertussis-like coughing. Pediatr Infect Dis J 1998;17:645-649.
11. Granström G, Wretlind B, Granström M. Diagnostic value of clinical and bacteriological findings in pertussis. J Infect 1991;22:17-26.
12. Heininger U, Cherry JD, Eckhardt T, Lorenz C, Christenson P, Stehr K. Clinical and laboratory diagnosis of pertussis in the regions of a large vaccine efficacy trial in Germany. Pediatr Infect Dis J 1993;12:504-509.
13. Wright SW, Edwards KM, Decker MD, Zeldin MH. Pertussis infection in adults with persistent cough. JAMA 1995;273:1044-1046.
1. von König CHW, Halperin S, Riffelman M, Guiso N. Pertussis of adults and infants. Lancet Infect Dis 2002;2:744-750.
2. Davis SF, Sutter RW, Strebel PM, Orton C, Alexander V, Sanden GN, et al. Concurrent outbreaks of pertussis and Mycoplasma pneumoniae infection: clinical and epidemiological characteristics of illnesses manifested by cough. Clin Infect Dis 1995;20:621-628.
3. Strebel PM, Cochi SL, Farizo KM, Payne BJ, Hanauer SD, Baughman AL. Pertussis in Missouri: evaluation of nasopharyngeal culture, direct fluorescent antibody testing, and clinical case definitions in the diagnosis of pertussis. Clin Infect Dis 1993;16:276-285.
4. Tanaka M, Vitck CR, Pascual FB, Bisgard KM, Tate JE, Murphy TV. Trends in pertussis among infants in the United States, 1980–1999. JAMA 2003;290:2968-2975.
5. Crowcroft NS, Booy R, Harrison T, Spicer L, Britto J, Mok Q, et al. Severe and unrecognised: pertussis in UK infants. Arch Dis Child 2003;88:802-806.
6. Mikelova LK, Halperin SA, Scheifele D, et al. Predictors of death in infants hospitalized with pertussis: a case-control study of 16 pertussis deaths in Canada. J Pediatr 2003;143:575-581.
7. Smith C, Vyas H. Early infantile pertussis; increasingly prevalent and potentially fatal. Eur J Pediatr 2000;159:898-900.
8. Pertussis (Bordetella pertussis) (Whooping cough). Epidemiology Program Office, Centers for Disease Control and Prevention. Last updated April 7, 2004. Available at: www.cdc.gov/epo/dphsi/casedef/pertussis_current.htm. Accessed on December 8, 2004.
9. VaccinesImmunizations and Biologicals: Pertussis. Geneva, Switzerland: World Health Organization; 2003. Available at: www.who.int/vaccines-surveillance/deseasedesc/ RSS_pertus.htm. Accessed on December 8, 2004.
10. Wirsing von Konig CH, Rott H, Bogaerts H, Schmitt HJ. A serologic study of organisms possibly associated with pertussis-like coughing. Pediatr Infect Dis J 1998;17:645-649.
11. Granström G, Wretlind B, Granström M. Diagnostic value of clinical and bacteriological findings in pertussis. J Infect 1991;22:17-26.
12. Heininger U, Cherry JD, Eckhardt T, Lorenz C, Christenson P, Stehr K. Clinical and laboratory diagnosis of pertussis in the regions of a large vaccine efficacy trial in Germany. Pediatr Infect Dis J 1993;12:504-509.
13. Wright SW, Edwards KM, Decker MD, Zeldin MH. Pertussis infection in adults with persistent cough. JAMA 1995;273:1044-1046.
Evidence-based answers from the Family Physicians Inquiries Network
What is the addiction risk associated with tramadol?
Tramadol (Ultram, generic and with acetaminophen in Ultracet) carries a risk of substance abuse (strength of recommendation [SOR]: B, based on case report surveillance programs). While it appears that tramadol’s risk of substance abuse is low (SOR: B, based on case report surveillance programs), tramadol is associated with a withdrawal syndrome usually typical of opioid withdrawal (SOR: B, based on case report surveillance programs, and a prospective descriptive study).
Evidence summary
Tramadol is a novel, central-acting synthetic opioid with weak mu-opioid activity, and is approved for treatment of moderate to moderately severe pain in adults. Anecdotally, some clinicians have assumed this popular analgesic’s nonscheduled status under the Controlled Substance Act (CSA) means tramadol has no substance abuse potential. (The term “abuse” herein denotes substance abuse or dependence.)
Evidence of tramadol abuse in the US comes primarily from federally operated programs collecting adverse drug event (ADE) data. The MedWatch program of the Food and Drug Administration (FDA) provides a central depository for receiving and compiling postmarketing voluntary case reports. While passive reporting systems can significantly underestimate serious ADE numbers, these reports are often the first evidence of an ADE after a new drug’s release into the market.1 MedWatch has received 766 case reports of abuse associated with tramadol, as well as 482 cases of withdrawal associated with tramadol from the drug’s initial US marketing in 1995 through September 2004.2,3
The Drug Abuse Warning Network (DAWN) is a federally operated, national surveillance system that monitors trends in drug-related emergency department visits. Over the period from 1995 to 2002, DAWN reported drug-related emergency department visits mentioning tramadol in more than 12,000 cases. Tramadol case numbers significantly increased 165% during this time. For perspective, during the same period, DAWN found nalbuphine (Nubain, also not CSA scheduled) in 118 cases, propoxyphene drug combinations (CSA Class IV) in more than 45,000 cases, codeine drug combinations (CSA Classes III & V) in about 50,000 cases, and hydrocodone drug combinations (CSA Class III) in around 128,000 cases.4
Using data from observational postmarketing studies, investigators have extrapolated a tramadol abuse rate for the general tramadolexposed population.5,6 Ortho-McNeil, Ultram’s manufacturer, funded a surveillance program that compiled tramadol abuse and withdrawal case reports from 2 sources: (1) periodic surveys for tramadol abuse case reports from a group of 255 substance abuse experts studying and caring for addiction communities, and (2) voluntary ADE case reports from health care professionals and consumers received by Ortho-McNeil. Over 3 years of surveillance, the program received 454 case reports classified as tramadol abuse. Over 5 years of surveillance, 422 cases of substance withdrawal, with primarily opioid withdrawal symptoms, were reported. There are significant threats to the validity and generalizability of the investigators’ estimated abuse rate of 1 to 3 cases per 100,000 tramadol-exposed patients. The abuse cases were collected in nonrepresentative samples of the tramadol-exposed population. Tramadol exposure is likely suppressed in addiction communities with access to preferred, more potent or euphoriant opioids than tramadol. Voluntary case reports of tramadol abuse significantly underestimate the actual number of abuse cases in the tramadol-exposed population. In addition, the low survey return rate (49%) further decreases the accuracy of any estimation of tramadol abuse rates.
Prospective studies among patients with known abuse, or at high risk of abuse, reported a tramadol abuse rate, as well as subjective experiences of tramadol withdrawal. A 3-year post-marketing cohort study measured tramadol’s nonmedical misuse rates using urine drug testing for tramadol among 1601 participants in 4 US state monitoring programs for impaired healthcare professionals.7 Tramadol exposure occurred in 140 (8.7%) participants. Thirty-nine (28%) were classified as extensive experimentation or abuse of tramadol. Overall, the rate of extensive experimentation or abuse was 18 cases per thousand personyears. The Hawthorne effect, where awareness of being monitored alters a subject’s behavior, may threaten these measured frequency rates’ generalizability. Another prospective study assessed the subjective tramadol withdrawal experience in 219 patients with a diagnosis of “Tramadol misuse” who were attending 6 drug detoxification centers in China.8 Validated drug dependence symptom scales found that while the degree of physical dependence reported was uniformly mild, the majority of patients reported the psychic dependence symptom of tramadol craving.
The FDA’s Drug Abuse Advisory Committee performed a formal review of the tramadol abuse evidence in 1998, including the data from OrthoMcNeil’s surveillance studies and federal case reporting/surveillance programs. The FDA did not recommend changing tramadol’s unscheduled status.9 The FDA’s considered decision to not schedule tramadol as a controlled substance implies its abuse risk to the general population is low. in comparison to its novel analgesic benefit.
Recommendations from others
Ortho-McNeil’s revised 2001 product package insert for Ultram states, “Tramadol may induce psychic and physical dependence of the morphine type (mu-opioid). Dependence and abuse, including drug-seeking behavior and taking illicit actions to obtain the drug are not limited to those patients with prior history of opioid dependence.” (italics in original, emphasizing 2001 addition). The risk for patients with a history of substance abuse has been observed to be higher.10
Though it may not have high abuse potential, prescribe tramadol cautiously
David M. Schneider, MD
Sutter Medical Center Family Practice Residency Program, Santa Rosa, Calif
Although tramadol appears to have a low potential for abuse, the literature does reveal evidence of abuse, addiction, and withdrawal, even in patients without a history of such problems. We do not know if tramadol is less addictive than other narcotics in high-risk patients. For patients at risk for dependence, tramadol is a reasonable alternative to other opioids, but abuse appears more likely in these patients. Tramadol may be most appropriate for treatment of acute painful conditions, but it can be administered chronically under a watchful eye. Providers should prescribe it cautiously, particularly in patients with a history of abuse or addiction, at least until more definitive evidence surfaces.
1. Brewer T, Colditz GA. Postmarketing surveillance and adverse drug reactions: current perspectives and future needs. JAMA 1999;281:824-829.
2. Brinker A, Bonnel RA, Beitz J. Abuse, dependence, or withdrawal associated with tramadol. Am J Psychiatry 2002;159:881-882.
3. Adverse Event Reporting System. Freedom of Information Report. Rockville, Md: Office of Drug Safety, Food and Drug Administration: search November 1997 to September 2004.
4. Drug Abuse Warning Network. Emergency Department Trends From DAWN: Final Estimates 1995 to 2002. Available at: dawninfo.samhsa.gov. Accessed on August 25, 2004.
5. Cicero TJ, Adams EH, Geller A, et al. A postmarketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States. Drug Alcohol Depend 1999;57:7-22.
6. Senay EC, Adams EH, Geller A, et al. Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur. Drug Alcohol Depend 2003;69:233-241.
7. Knisely JS, Campbell ED, Dawson KS, Schnoll SH. Tramadol post-marketing surveillance in health care professionals. Drug Alcohol Depend 2002;68:15-22.
8. Liu ZM, Zhou WH, Lian Z, et al. Drug dependence and abuse potential of tramadol. Zhongguo Yao Li Xue Bao 1999;20:52-54.
9. FDA Drug Abuse Advisory Committee. The Scientific Evidence for Initiating a Scheduling Action for Ultrammadol hydrochloride). 1998. Available at: www.fda.gov.
10. Murray L, ed. Physicians’ Desk Reference. 58th ed. Montvale, NJ: Thomson PDR; 2004;2496.-
Tramadol (Ultram, generic and with acetaminophen in Ultracet) carries a risk of substance abuse (strength of recommendation [SOR]: B, based on case report surveillance programs). While it appears that tramadol’s risk of substance abuse is low (SOR: B, based on case report surveillance programs), tramadol is associated with a withdrawal syndrome usually typical of opioid withdrawal (SOR: B, based on case report surveillance programs, and a prospective descriptive study).
Evidence summary
Tramadol is a novel, central-acting synthetic opioid with weak mu-opioid activity, and is approved for treatment of moderate to moderately severe pain in adults. Anecdotally, some clinicians have assumed this popular analgesic’s nonscheduled status under the Controlled Substance Act (CSA) means tramadol has no substance abuse potential. (The term “abuse” herein denotes substance abuse or dependence.)
Evidence of tramadol abuse in the US comes primarily from federally operated programs collecting adverse drug event (ADE) data. The MedWatch program of the Food and Drug Administration (FDA) provides a central depository for receiving and compiling postmarketing voluntary case reports. While passive reporting systems can significantly underestimate serious ADE numbers, these reports are often the first evidence of an ADE after a new drug’s release into the market.1 MedWatch has received 766 case reports of abuse associated with tramadol, as well as 482 cases of withdrawal associated with tramadol from the drug’s initial US marketing in 1995 through September 2004.2,3
The Drug Abuse Warning Network (DAWN) is a federally operated, national surveillance system that monitors trends in drug-related emergency department visits. Over the period from 1995 to 2002, DAWN reported drug-related emergency department visits mentioning tramadol in more than 12,000 cases. Tramadol case numbers significantly increased 165% during this time. For perspective, during the same period, DAWN found nalbuphine (Nubain, also not CSA scheduled) in 118 cases, propoxyphene drug combinations (CSA Class IV) in more than 45,000 cases, codeine drug combinations (CSA Classes III & V) in about 50,000 cases, and hydrocodone drug combinations (CSA Class III) in around 128,000 cases.4
Using data from observational postmarketing studies, investigators have extrapolated a tramadol abuse rate for the general tramadolexposed population.5,6 Ortho-McNeil, Ultram’s manufacturer, funded a surveillance program that compiled tramadol abuse and withdrawal case reports from 2 sources: (1) periodic surveys for tramadol abuse case reports from a group of 255 substance abuse experts studying and caring for addiction communities, and (2) voluntary ADE case reports from health care professionals and consumers received by Ortho-McNeil. Over 3 years of surveillance, the program received 454 case reports classified as tramadol abuse. Over 5 years of surveillance, 422 cases of substance withdrawal, with primarily opioid withdrawal symptoms, were reported. There are significant threats to the validity and generalizability of the investigators’ estimated abuse rate of 1 to 3 cases per 100,000 tramadol-exposed patients. The abuse cases were collected in nonrepresentative samples of the tramadol-exposed population. Tramadol exposure is likely suppressed in addiction communities with access to preferred, more potent or euphoriant opioids than tramadol. Voluntary case reports of tramadol abuse significantly underestimate the actual number of abuse cases in the tramadol-exposed population. In addition, the low survey return rate (49%) further decreases the accuracy of any estimation of tramadol abuse rates.
Prospective studies among patients with known abuse, or at high risk of abuse, reported a tramadol abuse rate, as well as subjective experiences of tramadol withdrawal. A 3-year post-marketing cohort study measured tramadol’s nonmedical misuse rates using urine drug testing for tramadol among 1601 participants in 4 US state monitoring programs for impaired healthcare professionals.7 Tramadol exposure occurred in 140 (8.7%) participants. Thirty-nine (28%) were classified as extensive experimentation or abuse of tramadol. Overall, the rate of extensive experimentation or abuse was 18 cases per thousand personyears. The Hawthorne effect, where awareness of being monitored alters a subject’s behavior, may threaten these measured frequency rates’ generalizability. Another prospective study assessed the subjective tramadol withdrawal experience in 219 patients with a diagnosis of “Tramadol misuse” who were attending 6 drug detoxification centers in China.8 Validated drug dependence symptom scales found that while the degree of physical dependence reported was uniformly mild, the majority of patients reported the psychic dependence symptom of tramadol craving.
The FDA’s Drug Abuse Advisory Committee performed a formal review of the tramadol abuse evidence in 1998, including the data from OrthoMcNeil’s surveillance studies and federal case reporting/surveillance programs. The FDA did not recommend changing tramadol’s unscheduled status.9 The FDA’s considered decision to not schedule tramadol as a controlled substance implies its abuse risk to the general population is low. in comparison to its novel analgesic benefit.
Recommendations from others
Ortho-McNeil’s revised 2001 product package insert for Ultram states, “Tramadol may induce psychic and physical dependence of the morphine type (mu-opioid). Dependence and abuse, including drug-seeking behavior and taking illicit actions to obtain the drug are not limited to those patients with prior history of opioid dependence.” (italics in original, emphasizing 2001 addition). The risk for patients with a history of substance abuse has been observed to be higher.10
Though it may not have high abuse potential, prescribe tramadol cautiously
David M. Schneider, MD
Sutter Medical Center Family Practice Residency Program, Santa Rosa, Calif
Although tramadol appears to have a low potential for abuse, the literature does reveal evidence of abuse, addiction, and withdrawal, even in patients without a history of such problems. We do not know if tramadol is less addictive than other narcotics in high-risk patients. For patients at risk for dependence, tramadol is a reasonable alternative to other opioids, but abuse appears more likely in these patients. Tramadol may be most appropriate for treatment of acute painful conditions, but it can be administered chronically under a watchful eye. Providers should prescribe it cautiously, particularly in patients with a history of abuse or addiction, at least until more definitive evidence surfaces.
Tramadol (Ultram, generic and with acetaminophen in Ultracet) carries a risk of substance abuse (strength of recommendation [SOR]: B, based on case report surveillance programs). While it appears that tramadol’s risk of substance abuse is low (SOR: B, based on case report surveillance programs), tramadol is associated with a withdrawal syndrome usually typical of opioid withdrawal (SOR: B, based on case report surveillance programs, and a prospective descriptive study).
Evidence summary
Tramadol is a novel, central-acting synthetic opioid with weak mu-opioid activity, and is approved for treatment of moderate to moderately severe pain in adults. Anecdotally, some clinicians have assumed this popular analgesic’s nonscheduled status under the Controlled Substance Act (CSA) means tramadol has no substance abuse potential. (The term “abuse” herein denotes substance abuse or dependence.)
Evidence of tramadol abuse in the US comes primarily from federally operated programs collecting adverse drug event (ADE) data. The MedWatch program of the Food and Drug Administration (FDA) provides a central depository for receiving and compiling postmarketing voluntary case reports. While passive reporting systems can significantly underestimate serious ADE numbers, these reports are often the first evidence of an ADE after a new drug’s release into the market.1 MedWatch has received 766 case reports of abuse associated with tramadol, as well as 482 cases of withdrawal associated with tramadol from the drug’s initial US marketing in 1995 through September 2004.2,3
The Drug Abuse Warning Network (DAWN) is a federally operated, national surveillance system that monitors trends in drug-related emergency department visits. Over the period from 1995 to 2002, DAWN reported drug-related emergency department visits mentioning tramadol in more than 12,000 cases. Tramadol case numbers significantly increased 165% during this time. For perspective, during the same period, DAWN found nalbuphine (Nubain, also not CSA scheduled) in 118 cases, propoxyphene drug combinations (CSA Class IV) in more than 45,000 cases, codeine drug combinations (CSA Classes III & V) in about 50,000 cases, and hydrocodone drug combinations (CSA Class III) in around 128,000 cases.4
Using data from observational postmarketing studies, investigators have extrapolated a tramadol abuse rate for the general tramadolexposed population.5,6 Ortho-McNeil, Ultram’s manufacturer, funded a surveillance program that compiled tramadol abuse and withdrawal case reports from 2 sources: (1) periodic surveys for tramadol abuse case reports from a group of 255 substance abuse experts studying and caring for addiction communities, and (2) voluntary ADE case reports from health care professionals and consumers received by Ortho-McNeil. Over 3 years of surveillance, the program received 454 case reports classified as tramadol abuse. Over 5 years of surveillance, 422 cases of substance withdrawal, with primarily opioid withdrawal symptoms, were reported. There are significant threats to the validity and generalizability of the investigators’ estimated abuse rate of 1 to 3 cases per 100,000 tramadol-exposed patients. The abuse cases were collected in nonrepresentative samples of the tramadol-exposed population. Tramadol exposure is likely suppressed in addiction communities with access to preferred, more potent or euphoriant opioids than tramadol. Voluntary case reports of tramadol abuse significantly underestimate the actual number of abuse cases in the tramadol-exposed population. In addition, the low survey return rate (49%) further decreases the accuracy of any estimation of tramadol abuse rates.
Prospective studies among patients with known abuse, or at high risk of abuse, reported a tramadol abuse rate, as well as subjective experiences of tramadol withdrawal. A 3-year post-marketing cohort study measured tramadol’s nonmedical misuse rates using urine drug testing for tramadol among 1601 participants in 4 US state monitoring programs for impaired healthcare professionals.7 Tramadol exposure occurred in 140 (8.7%) participants. Thirty-nine (28%) were classified as extensive experimentation or abuse of tramadol. Overall, the rate of extensive experimentation or abuse was 18 cases per thousand personyears. The Hawthorne effect, where awareness of being monitored alters a subject’s behavior, may threaten these measured frequency rates’ generalizability. Another prospective study assessed the subjective tramadol withdrawal experience in 219 patients with a diagnosis of “Tramadol misuse” who were attending 6 drug detoxification centers in China.8 Validated drug dependence symptom scales found that while the degree of physical dependence reported was uniformly mild, the majority of patients reported the psychic dependence symptom of tramadol craving.
The FDA’s Drug Abuse Advisory Committee performed a formal review of the tramadol abuse evidence in 1998, including the data from OrthoMcNeil’s surveillance studies and federal case reporting/surveillance programs. The FDA did not recommend changing tramadol’s unscheduled status.9 The FDA’s considered decision to not schedule tramadol as a controlled substance implies its abuse risk to the general population is low. in comparison to its novel analgesic benefit.
Recommendations from others
Ortho-McNeil’s revised 2001 product package insert for Ultram states, “Tramadol may induce psychic and physical dependence of the morphine type (mu-opioid). Dependence and abuse, including drug-seeking behavior and taking illicit actions to obtain the drug are not limited to those patients with prior history of opioid dependence.” (italics in original, emphasizing 2001 addition). The risk for patients with a history of substance abuse has been observed to be higher.10
Though it may not have high abuse potential, prescribe tramadol cautiously
David M. Schneider, MD
Sutter Medical Center Family Practice Residency Program, Santa Rosa, Calif
Although tramadol appears to have a low potential for abuse, the literature does reveal evidence of abuse, addiction, and withdrawal, even in patients without a history of such problems. We do not know if tramadol is less addictive than other narcotics in high-risk patients. For patients at risk for dependence, tramadol is a reasonable alternative to other opioids, but abuse appears more likely in these patients. Tramadol may be most appropriate for treatment of acute painful conditions, but it can be administered chronically under a watchful eye. Providers should prescribe it cautiously, particularly in patients with a history of abuse or addiction, at least until more definitive evidence surfaces.
1. Brewer T, Colditz GA. Postmarketing surveillance and adverse drug reactions: current perspectives and future needs. JAMA 1999;281:824-829.
2. Brinker A, Bonnel RA, Beitz J. Abuse, dependence, or withdrawal associated with tramadol. Am J Psychiatry 2002;159:881-882.
3. Adverse Event Reporting System. Freedom of Information Report. Rockville, Md: Office of Drug Safety, Food and Drug Administration: search November 1997 to September 2004.
4. Drug Abuse Warning Network. Emergency Department Trends From DAWN: Final Estimates 1995 to 2002. Available at: dawninfo.samhsa.gov. Accessed on August 25, 2004.
5. Cicero TJ, Adams EH, Geller A, et al. A postmarketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States. Drug Alcohol Depend 1999;57:7-22.
6. Senay EC, Adams EH, Geller A, et al. Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur. Drug Alcohol Depend 2003;69:233-241.
7. Knisely JS, Campbell ED, Dawson KS, Schnoll SH. Tramadol post-marketing surveillance in health care professionals. Drug Alcohol Depend 2002;68:15-22.
8. Liu ZM, Zhou WH, Lian Z, et al. Drug dependence and abuse potential of tramadol. Zhongguo Yao Li Xue Bao 1999;20:52-54.
9. FDA Drug Abuse Advisory Committee. The Scientific Evidence for Initiating a Scheduling Action for Ultrammadol hydrochloride). 1998. Available at: www.fda.gov.
10. Murray L, ed. Physicians’ Desk Reference. 58th ed. Montvale, NJ: Thomson PDR; 2004;2496.-
1. Brewer T, Colditz GA. Postmarketing surveillance and adverse drug reactions: current perspectives and future needs. JAMA 1999;281:824-829.
2. Brinker A, Bonnel RA, Beitz J. Abuse, dependence, or withdrawal associated with tramadol. Am J Psychiatry 2002;159:881-882.
3. Adverse Event Reporting System. Freedom of Information Report. Rockville, Md: Office of Drug Safety, Food and Drug Administration: search November 1997 to September 2004.
4. Drug Abuse Warning Network. Emergency Department Trends From DAWN: Final Estimates 1995 to 2002. Available at: dawninfo.samhsa.gov. Accessed on August 25, 2004.
5. Cicero TJ, Adams EH, Geller A, et al. A postmarketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States. Drug Alcohol Depend 1999;57:7-22.
6. Senay EC, Adams EH, Geller A, et al. Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur. Drug Alcohol Depend 2003;69:233-241.
7. Knisely JS, Campbell ED, Dawson KS, Schnoll SH. Tramadol post-marketing surveillance in health care professionals. Drug Alcohol Depend 2002;68:15-22.
8. Liu ZM, Zhou WH, Lian Z, et al. Drug dependence and abuse potential of tramadol. Zhongguo Yao Li Xue Bao 1999;20:52-54.
9. FDA Drug Abuse Advisory Committee. The Scientific Evidence for Initiating a Scheduling Action for Ultrammadol hydrochloride). 1998. Available at: www.fda.gov.
10. Murray L, ed. Physicians’ Desk Reference. 58th ed. Montvale, NJ: Thomson PDR; 2004;2496.-
Evidence-based answers from the Family Physicians Inquiries Network
How should a DEXA scan be used to evaluate bisphosphonate therapy for osteoporosis?
If bone density is evaluated after initiating bisphosphonate drug therapy, it should be tested no earlier than 2 years (strength of recommendation [SOR]: B, based on case series of dual energy X-ray absorptiometry [DEXA] scanning precision and bisphosphonate efficacy). Currently no prospective, randomized trials investigate the impact of bone density follow-up testing on osteoporotic patients receiving bisphosphonate therapy.
Evidence summary
Testing the effectiveness of therapy for osteoporosis by measuring changes in bone mineral density (BMD) is difficult because changes are often small and occur slowly, and a decrease in BMD does not necessarily mean treatment failure. Testing patients after starting bisphosphonate therapy has been part of many drug trials to assess the effectiveness of therapy. Follow-up testing in clinical practice has not been the focus of a prospective trial and therefore remains controversial.1
DEXA is considered the gold standard because it is the most extensively validated test for predicting fracture outcomes.2 Understanding the rate of bone density response to therapy, and the precision error of DEXA, helps to determine monitoring intervals. The larger the responses in BMD to therapy and the more precise the DEXA scan result, the shorter the period between testing in which clinically relevant differences can be found. Precision error rates are estimated at <1% for the anterior-posterior spine and 1% to 2% for the hip.3 The BMD change after the initiation of treatment must escape the precision error of the testing device or exceed the least significant change (LSC) value.4 The LSC—roughly analogous to a 95% confidence interval—is 2.8 times the precision error of the test on a specific machine and site of measurement. If the precision error for DEXA of the femoral neck BMD is 2%, then the LSC is 5.6%.5 Changes in BMD of <2%–4% in the vertebrae and 3% to 6% at the hip could be due to inherent measurement error.6
A clinician must also understand the anticipated response to the prescribed therapy. It is not clinically useful to retest BMD before a therapy would have time to affect bone turnover. Alendronate and risedronate increase lumbar spine BMD by 5% to 7% and hip BMD by 3% to 6% when used for approximately 3 years.7,8 These increases in BMD are associated with 30% to 50% reductions in vertebral and hip fractures.6 Alendronate continues to increase BMD: following 10 years of treatment, it increased BMD by 13.7% in the lumbar spine, 6.7% in the total hip, and 5.4 % in the femoral neck.9
Frequent testing, as seen in bisphosphonate clinical trials, demonstrates the phenomenon of regression to the mean. One analysis of the FIT trial, which compared alendronate with placebo in postmenopausal women with low BMD and at least 1 vertebral fracture, focused on the early evaluation of BMD. The study found a high degree of variability in BMD when tested after 1 year of treatment. This wide variety of response in the first year normalized in the second year.10 A second analysis showed that when women were divided into 8 groups, the group with the greatest increase in BMD in the first year (10.4%) also had the greatest decrease (1.0%) in year 2. In addition, the group with the greatest decrease in year 1 (6.6%) had the greatest increase in year 2 (4.8%). The variability in response among the 8 groups was approximately 17% (+10.4% and –6.6%) in year 1 and narrowed to a 6% difference in year 2 This regression to the mean leads to a normalization of bone density results.11,12 This patient variability in BMD response to the prescribed therapy should be considered when deciding to retest.
In summary, limitations in DEXA precision mean any changes in BMD of less than 5.6% at the femoral neck may be due to measurement error, and BMD response to bisphosphonates vacillates in the first few years of use but can be expected to increase femoral neck BMD 3% to 6% over 3 years. Therefore, if serial DEXA scanning is preformed on patients prescribed bisphosphonate therapy, it should be considered no earlier than 2 to 3 years after therapy begins. When monitoring osteoporosis therapy, a BMD change within the LSC should be interpreted as “no change” and should not lead to changes in patient management. If the BMD has decreased beyond the LSC there is cause for concern and reevaluation of diagnosis and treatment are warranted.4
Recommendations from others
Guidelines on monitoring the clinical response to osteoporosis therapy with DEXA are available from numerous groups ( TABLE ). In clinical practice, it is common for a BMD difference of 3% to 5% at the spine or 4% to 6 % at the hip to be considered clinically significant.13
TABLE
Recommendations on monitoring the clinical response to DEXA in osteoporosis therapy
| Organization | Method used to formulate responses recommendation | Recommendations for monitoring treatment to anti-resorptive therapy |
|---|---|---|
| AHRQ Evidence Report (Osteoporosis in Postmenopausal Women)14 | Systematic review | Advises against repeating bone density tests within the first year of treatment. Insufficient evidence to determine whether repeating tests 2 years after starting therapy is useful |
| American Association of Clinical Endocrinologists13 | Rating scheme (Statement not rated) | Yearly for 2 years and if bone mass has stabilized, follow-up measurements are recommended every 2 years |
| Canadian Panel of Clinical Densitometry15 | Not stated | Repeat scan should be considered after 1 to 3 years if concerned about progressive bone loss or with new intervention |
| Institute for Clinical Systems Improvement1 | Not stated | Controversy exists as to whether follow-up testing is necessary in all patients, but if performed, it should be done after 1 to 2 years of therapy |
| National Institute of Health16 change | Expert consensus | Monitoring has not been shown to improve compliance. Physicians should not stop or therapies because of modest bone density loss |
| National Osteoporosis Foundation6 | Expert consensus | Recommended 1 to 2 years following initiation of therapy |
| North American Menopause Society17 | Expert consensus | Monitoring before 2 years of treatment would not be useful |
| Osteoporosis Society of Canada18 | Not stated | Suggests at least 1 follow-up measurement is necessary. Central bone densitometry 1 to 2 years following initiation of bisphosphonate therapy. For patients receiving hormone therapy, repeat BMD is recommended at 2 to 4 years |
| University of Michigan19 | Evidence rating scheme | For most persons an interval of >2 years between DEXAs provides the most meaningful information |
If follow-up is needed, rescan in 2 to 3 years
Ann B. Gotschall, MD
Baylor College of Medicine, Houston, Tex
Rates of vertebral and hip fractures are significantly reduced by alendronate and risedronate, making them important in the prevention and treatment of osteoporosis. Despite controversies over the timing and necessity of monitoring bisphosphonate therapy with DEXA scans, they may be useful clinically if their limitations are recognized. It is necessary to wait 2 to 3 years to repeat the DEXA after initiating therapy to account for the slow rate of change of bone density and compensate for the regression-to-the-mean phenomenon seen in clinical trials.
If after 2 or 3 years the bone density remains stable or has increased, reassurance can be given that fracture risk has decreased. If bone density has decreased more than the LSC, consider the following questions. Is the medicine is being taken first thing in the morning on an empty stomach? Is weight-bearing exercise performed routinely, tobacco avoided, and caffeine limited? Is the patient continuing adequate calcium and vitamin D supplements? The physician should also consider secondary causes of osteoporosis, such as hyperthyroidism and hyperparathyroidism.
1. Institute for Clinical Systems Improvement (ICSI). Diagnosis and Treatment of Osteoporosis. Bloomington, Minn: ICSI; 2002:1-67. Last updated July 31, 2002. Available at: www.icsi.org/knowledge/detail.asp?catID=29&itemID=547. Accessed on December 8, 2004.
2. Nelson HD, Helfand M, Woolf SH, Allan JD. Screening for postmenopausal osteoporosis: a review of the evidence for the U.S. Preventive Services task force. Ann Intern Med 2002;137:529-541.
3. Mazees R, Chestnut CH 3rd, McClung M, Genant H. Enhanced precision with dual-energy X-rat absorptiometry. Calcif Tissue Int 1992;51:14-17.
4. Lenchik L, Kiebzak GM, Blunt BA. International Society for Clinical Densitometry Position Development Panel and Scientific Advisory Committee. What is the role of serial bone mineral density measurements in patient management? J Clin Densitom 2002;5 Suppl:S29-S38.
5. Cummings SR, Bates D, Black DM. Clinical use of bone densitometry scientific review. JAMA 2002;288:1889-1897.Erratum in: JAMA 2002; 288:2825.
6. National steoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation, 2003. Available at: www.nof.org. Accessed on December 8, 2004.
7. Cranney A, Wells G, Willan A, et al. Meta-analysis of therapies for postmenopausal osteoporosis. II. Meta-analysis of alendronate for the treatment of postmenopausal women. Endocr Rev 2002;23:508-516.
8. Cranney A, Tugwell P, Adachi J, et al. Meta-analysis of therapies for postmenopausal osteoporosis. III. Meta-analysis of risedronate for the treatment of postmenopausal osteoporosis. Endocr Rev 2002;23:517-523.
9. Bone HG, Hosking D, Devogelaer JP, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004;350:1189-1199.
10. Bonnick SL. Monitoring osteoporosis therapy with bone densitometry: a vital tool or regression toward mediocrity. J Clin Endocrinol Metabl 2000;85:3493-3495.
11. Cummings SR, Palermo L, Browner W, et al. Monitoring osteoporosis therapy with bone densitometry: misleading changes and regression to the mean. Fracture Intervention Trial Research Group. JAMA 2000;283:1318-1321.
12. Hochberg MC, Ross PD, Black D, et al. Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Fracture Intervention Trial Research Group. Arthritis Rheum 1999;42:1246-1254.
13. Hodgson SF, Watts NB, Bilezikian JP, et al. American Association of Clinical Endocrinologists 2001 Medical Guidelines for Clinical Practice for the Prevention and Management of Postmenopausal Osteoporosis. Endocr Pract 2000;7:293-312.
14. Nelson HD, Morris CD, Kraemer DF, et al. Osteoporosis in Postmenopausal Women: Diagnosis and Monitoring. Evidence Report/Technology Assessment No. 28 (Prepared by the Oregon Health & Science University Evidence-based Practice Center under Contract No. 290-97-0018). AHRQ Publication No. 01-E032. Rockville, Md: Agency for Healthcare Research and Quality. January 2001. Available at: www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.Show Section&rid=hstat1.chapter.39885. Accessed on December 8, 2004.
15. Khan AA, Brown J, Faulkner K, et al. Standards and guidelines for performing central dual X-ray densitometry from the Canadian Panel of International Society for Clinical Densitometry. J Clin Densitom 2002;5:435-445.
16. Osteoporosis Prevention Diagnosis and Therapy. NIH Consensus Statement 2000; 17:1-36. Available at: consen-sus.nih.gov/cons/111/111_statement.htm. Accessed on December 8, 2004.
17. North American Menopause Society. Management of postmenopausal osteoporosis: position statement of the North American Menopause Society. Menopause 2002;9:84-101.
18. Sturtridge W, Lentle B, Hanley DA. Prevention and management of osteoporosis: consensus statements from the Scientific Advisory Board of the Osteoporosis Society of Canada. 2. The use of bone density measurement in the diagnosis and management of osteoporosis. CMAJ 1996;155:924-929.
19. University of Michigan Health System. Osteoporosis: Prevention and Treatment. Ann Arbor: University of Michigan Health System; 2002:1-12. Available at: cme.med.umich.edu/pdf/guideline/osteoporosis.pdf. Accessed on December 8, 2004.
If bone density is evaluated after initiating bisphosphonate drug therapy, it should be tested no earlier than 2 years (strength of recommendation [SOR]: B, based on case series of dual energy X-ray absorptiometry [DEXA] scanning precision and bisphosphonate efficacy). Currently no prospective, randomized trials investigate the impact of bone density follow-up testing on osteoporotic patients receiving bisphosphonate therapy.
Evidence summary
Testing the effectiveness of therapy for osteoporosis by measuring changes in bone mineral density (BMD) is difficult because changes are often small and occur slowly, and a decrease in BMD does not necessarily mean treatment failure. Testing patients after starting bisphosphonate therapy has been part of many drug trials to assess the effectiveness of therapy. Follow-up testing in clinical practice has not been the focus of a prospective trial and therefore remains controversial.1
DEXA is considered the gold standard because it is the most extensively validated test for predicting fracture outcomes.2 Understanding the rate of bone density response to therapy, and the precision error of DEXA, helps to determine monitoring intervals. The larger the responses in BMD to therapy and the more precise the DEXA scan result, the shorter the period between testing in which clinically relevant differences can be found. Precision error rates are estimated at <1% for the anterior-posterior spine and 1% to 2% for the hip.3 The BMD change after the initiation of treatment must escape the precision error of the testing device or exceed the least significant change (LSC) value.4 The LSC—roughly analogous to a 95% confidence interval—is 2.8 times the precision error of the test on a specific machine and site of measurement. If the precision error for DEXA of the femoral neck BMD is 2%, then the LSC is 5.6%.5 Changes in BMD of <2%–4% in the vertebrae and 3% to 6% at the hip could be due to inherent measurement error.6
A clinician must also understand the anticipated response to the prescribed therapy. It is not clinically useful to retest BMD before a therapy would have time to affect bone turnover. Alendronate and risedronate increase lumbar spine BMD by 5% to 7% and hip BMD by 3% to 6% when used for approximately 3 years.7,8 These increases in BMD are associated with 30% to 50% reductions in vertebral and hip fractures.6 Alendronate continues to increase BMD: following 10 years of treatment, it increased BMD by 13.7% in the lumbar spine, 6.7% in the total hip, and 5.4 % in the femoral neck.9
Frequent testing, as seen in bisphosphonate clinical trials, demonstrates the phenomenon of regression to the mean. One analysis of the FIT trial, which compared alendronate with placebo in postmenopausal women with low BMD and at least 1 vertebral fracture, focused on the early evaluation of BMD. The study found a high degree of variability in BMD when tested after 1 year of treatment. This wide variety of response in the first year normalized in the second year.10 A second analysis showed that when women were divided into 8 groups, the group with the greatest increase in BMD in the first year (10.4%) also had the greatest decrease (1.0%) in year 2. In addition, the group with the greatest decrease in year 1 (6.6%) had the greatest increase in year 2 (4.8%). The variability in response among the 8 groups was approximately 17% (+10.4% and –6.6%) in year 1 and narrowed to a 6% difference in year 2 This regression to the mean leads to a normalization of bone density results.11,12 This patient variability in BMD response to the prescribed therapy should be considered when deciding to retest.
In summary, limitations in DEXA precision mean any changes in BMD of less than 5.6% at the femoral neck may be due to measurement error, and BMD response to bisphosphonates vacillates in the first few years of use but can be expected to increase femoral neck BMD 3% to 6% over 3 years. Therefore, if serial DEXA scanning is preformed on patients prescribed bisphosphonate therapy, it should be considered no earlier than 2 to 3 years after therapy begins. When monitoring osteoporosis therapy, a BMD change within the LSC should be interpreted as “no change” and should not lead to changes in patient management. If the BMD has decreased beyond the LSC there is cause for concern and reevaluation of diagnosis and treatment are warranted.4
Recommendations from others
Guidelines on monitoring the clinical response to osteoporosis therapy with DEXA are available from numerous groups ( TABLE ). In clinical practice, it is common for a BMD difference of 3% to 5% at the spine or 4% to 6 % at the hip to be considered clinically significant.13
TABLE
Recommendations on monitoring the clinical response to DEXA in osteoporosis therapy
| Organization | Method used to formulate responses recommendation | Recommendations for monitoring treatment to anti-resorptive therapy |
|---|---|---|
| AHRQ Evidence Report (Osteoporosis in Postmenopausal Women)14 | Systematic review | Advises against repeating bone density tests within the first year of treatment. Insufficient evidence to determine whether repeating tests 2 years after starting therapy is useful |
| American Association of Clinical Endocrinologists13 | Rating scheme (Statement not rated) | Yearly for 2 years and if bone mass has stabilized, follow-up measurements are recommended every 2 years |
| Canadian Panel of Clinical Densitometry15 | Not stated | Repeat scan should be considered after 1 to 3 years if concerned about progressive bone loss or with new intervention |
| Institute for Clinical Systems Improvement1 | Not stated | Controversy exists as to whether follow-up testing is necessary in all patients, but if performed, it should be done after 1 to 2 years of therapy |
| National Institute of Health16 change | Expert consensus | Monitoring has not been shown to improve compliance. Physicians should not stop or therapies because of modest bone density loss |
| National Osteoporosis Foundation6 | Expert consensus | Recommended 1 to 2 years following initiation of therapy |
| North American Menopause Society17 | Expert consensus | Monitoring before 2 years of treatment would not be useful |
| Osteoporosis Society of Canada18 | Not stated | Suggests at least 1 follow-up measurement is necessary. Central bone densitometry 1 to 2 years following initiation of bisphosphonate therapy. For patients receiving hormone therapy, repeat BMD is recommended at 2 to 4 years |
| University of Michigan19 | Evidence rating scheme | For most persons an interval of >2 years between DEXAs provides the most meaningful information |
If follow-up is needed, rescan in 2 to 3 years
Ann B. Gotschall, MD
Baylor College of Medicine, Houston, Tex
Rates of vertebral and hip fractures are significantly reduced by alendronate and risedronate, making them important in the prevention and treatment of osteoporosis. Despite controversies over the timing and necessity of monitoring bisphosphonate therapy with DEXA scans, they may be useful clinically if their limitations are recognized. It is necessary to wait 2 to 3 years to repeat the DEXA after initiating therapy to account for the slow rate of change of bone density and compensate for the regression-to-the-mean phenomenon seen in clinical trials.
If after 2 or 3 years the bone density remains stable or has increased, reassurance can be given that fracture risk has decreased. If bone density has decreased more than the LSC, consider the following questions. Is the medicine is being taken first thing in the morning on an empty stomach? Is weight-bearing exercise performed routinely, tobacco avoided, and caffeine limited? Is the patient continuing adequate calcium and vitamin D supplements? The physician should also consider secondary causes of osteoporosis, such as hyperthyroidism and hyperparathyroidism.
If bone density is evaluated after initiating bisphosphonate drug therapy, it should be tested no earlier than 2 years (strength of recommendation [SOR]: B, based on case series of dual energy X-ray absorptiometry [DEXA] scanning precision and bisphosphonate efficacy). Currently no prospective, randomized trials investigate the impact of bone density follow-up testing on osteoporotic patients receiving bisphosphonate therapy.
Evidence summary
Testing the effectiveness of therapy for osteoporosis by measuring changes in bone mineral density (BMD) is difficult because changes are often small and occur slowly, and a decrease in BMD does not necessarily mean treatment failure. Testing patients after starting bisphosphonate therapy has been part of many drug trials to assess the effectiveness of therapy. Follow-up testing in clinical practice has not been the focus of a prospective trial and therefore remains controversial.1
DEXA is considered the gold standard because it is the most extensively validated test for predicting fracture outcomes.2 Understanding the rate of bone density response to therapy, and the precision error of DEXA, helps to determine monitoring intervals. The larger the responses in BMD to therapy and the more precise the DEXA scan result, the shorter the period between testing in which clinically relevant differences can be found. Precision error rates are estimated at <1% for the anterior-posterior spine and 1% to 2% for the hip.3 The BMD change after the initiation of treatment must escape the precision error of the testing device or exceed the least significant change (LSC) value.4 The LSC—roughly analogous to a 95% confidence interval—is 2.8 times the precision error of the test on a specific machine and site of measurement. If the precision error for DEXA of the femoral neck BMD is 2%, then the LSC is 5.6%.5 Changes in BMD of <2%–4% in the vertebrae and 3% to 6% at the hip could be due to inherent measurement error.6
A clinician must also understand the anticipated response to the prescribed therapy. It is not clinically useful to retest BMD before a therapy would have time to affect bone turnover. Alendronate and risedronate increase lumbar spine BMD by 5% to 7% and hip BMD by 3% to 6% when used for approximately 3 years.7,8 These increases in BMD are associated with 30% to 50% reductions in vertebral and hip fractures.6 Alendronate continues to increase BMD: following 10 years of treatment, it increased BMD by 13.7% in the lumbar spine, 6.7% in the total hip, and 5.4 % in the femoral neck.9
Frequent testing, as seen in bisphosphonate clinical trials, demonstrates the phenomenon of regression to the mean. One analysis of the FIT trial, which compared alendronate with placebo in postmenopausal women with low BMD and at least 1 vertebral fracture, focused on the early evaluation of BMD. The study found a high degree of variability in BMD when tested after 1 year of treatment. This wide variety of response in the first year normalized in the second year.10 A second analysis showed that when women were divided into 8 groups, the group with the greatest increase in BMD in the first year (10.4%) also had the greatest decrease (1.0%) in year 2. In addition, the group with the greatest decrease in year 1 (6.6%) had the greatest increase in year 2 (4.8%). The variability in response among the 8 groups was approximately 17% (+10.4% and –6.6%) in year 1 and narrowed to a 6% difference in year 2 This regression to the mean leads to a normalization of bone density results.11,12 This patient variability in BMD response to the prescribed therapy should be considered when deciding to retest.
In summary, limitations in DEXA precision mean any changes in BMD of less than 5.6% at the femoral neck may be due to measurement error, and BMD response to bisphosphonates vacillates in the first few years of use but can be expected to increase femoral neck BMD 3% to 6% over 3 years. Therefore, if serial DEXA scanning is preformed on patients prescribed bisphosphonate therapy, it should be considered no earlier than 2 to 3 years after therapy begins. When monitoring osteoporosis therapy, a BMD change within the LSC should be interpreted as “no change” and should not lead to changes in patient management. If the BMD has decreased beyond the LSC there is cause for concern and reevaluation of diagnosis and treatment are warranted.4
Recommendations from others
Guidelines on monitoring the clinical response to osteoporosis therapy with DEXA are available from numerous groups ( TABLE ). In clinical practice, it is common for a BMD difference of 3% to 5% at the spine or 4% to 6 % at the hip to be considered clinically significant.13
TABLE
Recommendations on monitoring the clinical response to DEXA in osteoporosis therapy
| Organization | Method used to formulate responses recommendation | Recommendations for monitoring treatment to anti-resorptive therapy |
|---|---|---|
| AHRQ Evidence Report (Osteoporosis in Postmenopausal Women)14 | Systematic review | Advises against repeating bone density tests within the first year of treatment. Insufficient evidence to determine whether repeating tests 2 years after starting therapy is useful |
| American Association of Clinical Endocrinologists13 | Rating scheme (Statement not rated) | Yearly for 2 years and if bone mass has stabilized, follow-up measurements are recommended every 2 years |
| Canadian Panel of Clinical Densitometry15 | Not stated | Repeat scan should be considered after 1 to 3 years if concerned about progressive bone loss or with new intervention |
| Institute for Clinical Systems Improvement1 | Not stated | Controversy exists as to whether follow-up testing is necessary in all patients, but if performed, it should be done after 1 to 2 years of therapy |
| National Institute of Health16 change | Expert consensus | Monitoring has not been shown to improve compliance. Physicians should not stop or therapies because of modest bone density loss |
| National Osteoporosis Foundation6 | Expert consensus | Recommended 1 to 2 years following initiation of therapy |
| North American Menopause Society17 | Expert consensus | Monitoring before 2 years of treatment would not be useful |
| Osteoporosis Society of Canada18 | Not stated | Suggests at least 1 follow-up measurement is necessary. Central bone densitometry 1 to 2 years following initiation of bisphosphonate therapy. For patients receiving hormone therapy, repeat BMD is recommended at 2 to 4 years |
| University of Michigan19 | Evidence rating scheme | For most persons an interval of >2 years between DEXAs provides the most meaningful information |
If follow-up is needed, rescan in 2 to 3 years
Ann B. Gotschall, MD
Baylor College of Medicine, Houston, Tex
Rates of vertebral and hip fractures are significantly reduced by alendronate and risedronate, making them important in the prevention and treatment of osteoporosis. Despite controversies over the timing and necessity of monitoring bisphosphonate therapy with DEXA scans, they may be useful clinically if their limitations are recognized. It is necessary to wait 2 to 3 years to repeat the DEXA after initiating therapy to account for the slow rate of change of bone density and compensate for the regression-to-the-mean phenomenon seen in clinical trials.
If after 2 or 3 years the bone density remains stable or has increased, reassurance can be given that fracture risk has decreased. If bone density has decreased more than the LSC, consider the following questions. Is the medicine is being taken first thing in the morning on an empty stomach? Is weight-bearing exercise performed routinely, tobacco avoided, and caffeine limited? Is the patient continuing adequate calcium and vitamin D supplements? The physician should also consider secondary causes of osteoporosis, such as hyperthyroidism and hyperparathyroidism.
1. Institute for Clinical Systems Improvement (ICSI). Diagnosis and Treatment of Osteoporosis. Bloomington, Minn: ICSI; 2002:1-67. Last updated July 31, 2002. Available at: www.icsi.org/knowledge/detail.asp?catID=29&itemID=547. Accessed on December 8, 2004.
2. Nelson HD, Helfand M, Woolf SH, Allan JD. Screening for postmenopausal osteoporosis: a review of the evidence for the U.S. Preventive Services task force. Ann Intern Med 2002;137:529-541.
3. Mazees R, Chestnut CH 3rd, McClung M, Genant H. Enhanced precision with dual-energy X-rat absorptiometry. Calcif Tissue Int 1992;51:14-17.
4. Lenchik L, Kiebzak GM, Blunt BA. International Society for Clinical Densitometry Position Development Panel and Scientific Advisory Committee. What is the role of serial bone mineral density measurements in patient management? J Clin Densitom 2002;5 Suppl:S29-S38.
5. Cummings SR, Bates D, Black DM. Clinical use of bone densitometry scientific review. JAMA 2002;288:1889-1897.Erratum in: JAMA 2002; 288:2825.
6. National steoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation, 2003. Available at: www.nof.org. Accessed on December 8, 2004.
7. Cranney A, Wells G, Willan A, et al. Meta-analysis of therapies for postmenopausal osteoporosis. II. Meta-analysis of alendronate for the treatment of postmenopausal women. Endocr Rev 2002;23:508-516.
8. Cranney A, Tugwell P, Adachi J, et al. Meta-analysis of therapies for postmenopausal osteoporosis. III. Meta-analysis of risedronate for the treatment of postmenopausal osteoporosis. Endocr Rev 2002;23:517-523.
9. Bone HG, Hosking D, Devogelaer JP, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004;350:1189-1199.
10. Bonnick SL. Monitoring osteoporosis therapy with bone densitometry: a vital tool or regression toward mediocrity. J Clin Endocrinol Metabl 2000;85:3493-3495.
11. Cummings SR, Palermo L, Browner W, et al. Monitoring osteoporosis therapy with bone densitometry: misleading changes and regression to the mean. Fracture Intervention Trial Research Group. JAMA 2000;283:1318-1321.
12. Hochberg MC, Ross PD, Black D, et al. Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Fracture Intervention Trial Research Group. Arthritis Rheum 1999;42:1246-1254.
13. Hodgson SF, Watts NB, Bilezikian JP, et al. American Association of Clinical Endocrinologists 2001 Medical Guidelines for Clinical Practice for the Prevention and Management of Postmenopausal Osteoporosis. Endocr Pract 2000;7:293-312.
14. Nelson HD, Morris CD, Kraemer DF, et al. Osteoporosis in Postmenopausal Women: Diagnosis and Monitoring. Evidence Report/Technology Assessment No. 28 (Prepared by the Oregon Health & Science University Evidence-based Practice Center under Contract No. 290-97-0018). AHRQ Publication No. 01-E032. Rockville, Md: Agency for Healthcare Research and Quality. January 2001. Available at: www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.Show Section&rid=hstat1.chapter.39885. Accessed on December 8, 2004.
15. Khan AA, Brown J, Faulkner K, et al. Standards and guidelines for performing central dual X-ray densitometry from the Canadian Panel of International Society for Clinical Densitometry. J Clin Densitom 2002;5:435-445.
16. Osteoporosis Prevention Diagnosis and Therapy. NIH Consensus Statement 2000; 17:1-36. Available at: consen-sus.nih.gov/cons/111/111_statement.htm. Accessed on December 8, 2004.
17. North American Menopause Society. Management of postmenopausal osteoporosis: position statement of the North American Menopause Society. Menopause 2002;9:84-101.
18. Sturtridge W, Lentle B, Hanley DA. Prevention and management of osteoporosis: consensus statements from the Scientific Advisory Board of the Osteoporosis Society of Canada. 2. The use of bone density measurement in the diagnosis and management of osteoporosis. CMAJ 1996;155:924-929.
19. University of Michigan Health System. Osteoporosis: Prevention and Treatment. Ann Arbor: University of Michigan Health System; 2002:1-12. Available at: cme.med.umich.edu/pdf/guideline/osteoporosis.pdf. Accessed on December 8, 2004.
1. Institute for Clinical Systems Improvement (ICSI). Diagnosis and Treatment of Osteoporosis. Bloomington, Minn: ICSI; 2002:1-67. Last updated July 31, 2002. Available at: www.icsi.org/knowledge/detail.asp?catID=29&itemID=547. Accessed on December 8, 2004.
2. Nelson HD, Helfand M, Woolf SH, Allan JD. Screening for postmenopausal osteoporosis: a review of the evidence for the U.S. Preventive Services task force. Ann Intern Med 2002;137:529-541.
3. Mazees R, Chestnut CH 3rd, McClung M, Genant H. Enhanced precision with dual-energy X-rat absorptiometry. Calcif Tissue Int 1992;51:14-17.
4. Lenchik L, Kiebzak GM, Blunt BA. International Society for Clinical Densitometry Position Development Panel and Scientific Advisory Committee. What is the role of serial bone mineral density measurements in patient management? J Clin Densitom 2002;5 Suppl:S29-S38.
5. Cummings SR, Bates D, Black DM. Clinical use of bone densitometry scientific review. JAMA 2002;288:1889-1897.Erratum in: JAMA 2002; 288:2825.
6. National steoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation, 2003. Available at: www.nof.org. Accessed on December 8, 2004.
7. Cranney A, Wells G, Willan A, et al. Meta-analysis of therapies for postmenopausal osteoporosis. II. Meta-analysis of alendronate for the treatment of postmenopausal women. Endocr Rev 2002;23:508-516.
8. Cranney A, Tugwell P, Adachi J, et al. Meta-analysis of therapies for postmenopausal osteoporosis. III. Meta-analysis of risedronate for the treatment of postmenopausal osteoporosis. Endocr Rev 2002;23:517-523.
9. Bone HG, Hosking D, Devogelaer JP, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004;350:1189-1199.
10. Bonnick SL. Monitoring osteoporosis therapy with bone densitometry: a vital tool or regression toward mediocrity. J Clin Endocrinol Metabl 2000;85:3493-3495.
11. Cummings SR, Palermo L, Browner W, et al. Monitoring osteoporosis therapy with bone densitometry: misleading changes and regression to the mean. Fracture Intervention Trial Research Group. JAMA 2000;283:1318-1321.
12. Hochberg MC, Ross PD, Black D, et al. Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Fracture Intervention Trial Research Group. Arthritis Rheum 1999;42:1246-1254.
13. Hodgson SF, Watts NB, Bilezikian JP, et al. American Association of Clinical Endocrinologists 2001 Medical Guidelines for Clinical Practice for the Prevention and Management of Postmenopausal Osteoporosis. Endocr Pract 2000;7:293-312.
14. Nelson HD, Morris CD, Kraemer DF, et al. Osteoporosis in Postmenopausal Women: Diagnosis and Monitoring. Evidence Report/Technology Assessment No. 28 (Prepared by the Oregon Health & Science University Evidence-based Practice Center under Contract No. 290-97-0018). AHRQ Publication No. 01-E032. Rockville, Md: Agency for Healthcare Research and Quality. January 2001. Available at: www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.Show Section&rid=hstat1.chapter.39885. Accessed on December 8, 2004.
15. Khan AA, Brown J, Faulkner K, et al. Standards and guidelines for performing central dual X-ray densitometry from the Canadian Panel of International Society for Clinical Densitometry. J Clin Densitom 2002;5:435-445.
16. Osteoporosis Prevention Diagnosis and Therapy. NIH Consensus Statement 2000; 17:1-36. Available at: consen-sus.nih.gov/cons/111/111_statement.htm. Accessed on December 8, 2004.
17. North American Menopause Society. Management of postmenopausal osteoporosis: position statement of the North American Menopause Society. Menopause 2002;9:84-101.
18. Sturtridge W, Lentle B, Hanley DA. Prevention and management of osteoporosis: consensus statements from the Scientific Advisory Board of the Osteoporosis Society of Canada. 2. The use of bone density measurement in the diagnosis and management of osteoporosis. CMAJ 1996;155:924-929.
19. University of Michigan Health System. Osteoporosis: Prevention and Treatment. Ann Arbor: University of Michigan Health System; 2002:1-12. Available at: cme.med.umich.edu/pdf/guideline/osteoporosis.pdf. Accessed on December 8, 2004.
Evidence-based answers from the Family Physicians Inquiries Network
How useful is ultrasound to evaluate patients with postmenopausal bleeding?
Using a threshold of ≤5 mm, transvaginal ultrasound (TVUS) can be used to identify those patients with postmenopausal bleeding who are at low risk for endometrial cancer, polyps, or atypical hyperplasia at a sensitivity comparable with that of endometrial biopsy and dilatation and curettage (D&C) (strength of recommendation: B, based on systematic reviews of consistent exploratory cohort studies.)
Evidence summary
A 1998 meta-analysis of 35 exploratory cohort studies published between 1966 and 1996 included a total of 5892 women with postmenopausal bleeding.1 TVUS evaluations were followed by endometrial tissue sampling and results were compared. Using endometrial thickness of ≤5 mm as the threshold, ultrasound was very accurate at ruling out patients with endometrial cancer but only fair at diagnosing cancer (likelihood ratio for a positive test [LR+]=2.5; LR for a negative test [LR–]=0.06). In addition, the 5-mm threshold was accurate at ruling out any endometrial abnormality (cancer, polyp, atypical hyperplasia: LR– = 0.01). The authors suggested that TVUS can reliably rule out significant endometrial disease among postmenopausal women with vaginal bleeding.
A 2002 meta-analysis of 57 cohort studies, without consistently applied reference standards, published between 1966 and 2000 included a total of 9031 women with postmenopausal bleeding.2 Because many of the studies were felt to use inadequately stringent criteria for diagnosis, the authors limited their final analysis to only 4 studies. They concluded that a negative result using a 5-mm threshold rules out endometrial pathology with fair certainty (LR– = 0.21).
Recommendations from others
A Consensus Conference Statement from the Society of Radiologists in Ultrasound recommended that either TVUS or endometrial biopsy could be used in the initial evaluation of patients with postmenopausal bleeding.3 Using a threshold of >5 mm as abnormal, they concluded that the sensitivities of TVUS and endometrial biopsy are comparable when “sufficient tissue” is obtained with endometrial biopsy. They felt that data was currently insufficient to clearly state which technique is more effective.
TVUS is an effective, relatively noninvasive way to rule out significant pathology
Postmenopausal women need accurate diagnostic evaluation when they have abnormal bleeding. While the majority have a benign cause of bleeding, such as atrophic endometrium, many have significant pathology, including cancer (Table). Many older patients are reluctant to undergo invasive sampling studies. Cervical stenosis, a common occurrence in this age group, further complicates matters. Evidence suggests that TVUS with a full endometrial thickness of 5 mm or less, full visualization of the cavity, and no other abnormal findings, can identify patients at low risk for significant abnormalities. The false negative rate for TVUS (8%) compares quite favorably with endometrial biopsy (5%–15%) and even D&C (2%–6%).1 TVUS is an effective and relatively noninvasive strategy for ruling out significant pathology. Given the false negative rates of these techniques, all patients with postmenopausal bleeding require close follow-up.
TABLE
Differential diagnosis of postmenopausal bleeding
| Histologic diagnosis | Incidence (n=1138) |
|---|---|
| Atrophy | 59% |
| Endometrial polyp | 12% |
| Hyperplasia | 10% |
| Endometrial cancer | 10% |
| Hormonal effect | 7% |
| Cervical cancer | 2% |
| Other | <1% |
| Source: Karlsson et al 1995.4 | |
1. Smith-Bindman R, Kerlikowske K, Feldstein VA, et al. Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA 1998;280:1510-1517.
2. Gupta JK, Chien PF, Voit D, Clark TJ, Khan KS. Ultrasonographic endometrial thickness for diagnosing endometrial pathology in women with postmenopausal bleeding: a meta-analysis. Acta Obstet Gynecol Scand 2002;81:799-816.
3. Evaluation of the woman with postmenopausal bleeding. Society of Radiologists in Ultrasound-Sponsored Consensus Conference statement. J Ultrasound Med 2001;20:1025-1036.
4. Karlsson B, Granberg S, Wikland M, et al. Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding—a Nordic multicenter study. Am J Obstet Gynecol 1995;172:1488-1494.
Using a threshold of ≤5 mm, transvaginal ultrasound (TVUS) can be used to identify those patients with postmenopausal bleeding who are at low risk for endometrial cancer, polyps, or atypical hyperplasia at a sensitivity comparable with that of endometrial biopsy and dilatation and curettage (D&C) (strength of recommendation: B, based on systematic reviews of consistent exploratory cohort studies.)
Evidence summary
A 1998 meta-analysis of 35 exploratory cohort studies published between 1966 and 1996 included a total of 5892 women with postmenopausal bleeding.1 TVUS evaluations were followed by endometrial tissue sampling and results were compared. Using endometrial thickness of ≤5 mm as the threshold, ultrasound was very accurate at ruling out patients with endometrial cancer but only fair at diagnosing cancer (likelihood ratio for a positive test [LR+]=2.5; LR for a negative test [LR–]=0.06). In addition, the 5-mm threshold was accurate at ruling out any endometrial abnormality (cancer, polyp, atypical hyperplasia: LR– = 0.01). The authors suggested that TVUS can reliably rule out significant endometrial disease among postmenopausal women with vaginal bleeding.
A 2002 meta-analysis of 57 cohort studies, without consistently applied reference standards, published between 1966 and 2000 included a total of 9031 women with postmenopausal bleeding.2 Because many of the studies were felt to use inadequately stringent criteria for diagnosis, the authors limited their final analysis to only 4 studies. They concluded that a negative result using a 5-mm threshold rules out endometrial pathology with fair certainty (LR– = 0.21).
Recommendations from others
A Consensus Conference Statement from the Society of Radiologists in Ultrasound recommended that either TVUS or endometrial biopsy could be used in the initial evaluation of patients with postmenopausal bleeding.3 Using a threshold of >5 mm as abnormal, they concluded that the sensitivities of TVUS and endometrial biopsy are comparable when “sufficient tissue” is obtained with endometrial biopsy. They felt that data was currently insufficient to clearly state which technique is more effective.
TVUS is an effective, relatively noninvasive way to rule out significant pathology
Postmenopausal women need accurate diagnostic evaluation when they have abnormal bleeding. While the majority have a benign cause of bleeding, such as atrophic endometrium, many have significant pathology, including cancer (Table). Many older patients are reluctant to undergo invasive sampling studies. Cervical stenosis, a common occurrence in this age group, further complicates matters. Evidence suggests that TVUS with a full endometrial thickness of 5 mm or less, full visualization of the cavity, and no other abnormal findings, can identify patients at low risk for significant abnormalities. The false negative rate for TVUS (8%) compares quite favorably with endometrial biopsy (5%–15%) and even D&C (2%–6%).1 TVUS is an effective and relatively noninvasive strategy for ruling out significant pathology. Given the false negative rates of these techniques, all patients with postmenopausal bleeding require close follow-up.
TABLE
Differential diagnosis of postmenopausal bleeding
| Histologic diagnosis | Incidence (n=1138) |
|---|---|
| Atrophy | 59% |
| Endometrial polyp | 12% |
| Hyperplasia | 10% |
| Endometrial cancer | 10% |
| Hormonal effect | 7% |
| Cervical cancer | 2% |
| Other | <1% |
| Source: Karlsson et al 1995.4 | |
Using a threshold of ≤5 mm, transvaginal ultrasound (TVUS) can be used to identify those patients with postmenopausal bleeding who are at low risk for endometrial cancer, polyps, or atypical hyperplasia at a sensitivity comparable with that of endometrial biopsy and dilatation and curettage (D&C) (strength of recommendation: B, based on systematic reviews of consistent exploratory cohort studies.)
Evidence summary
A 1998 meta-analysis of 35 exploratory cohort studies published between 1966 and 1996 included a total of 5892 women with postmenopausal bleeding.1 TVUS evaluations were followed by endometrial tissue sampling and results were compared. Using endometrial thickness of ≤5 mm as the threshold, ultrasound was very accurate at ruling out patients with endometrial cancer but only fair at diagnosing cancer (likelihood ratio for a positive test [LR+]=2.5; LR for a negative test [LR–]=0.06). In addition, the 5-mm threshold was accurate at ruling out any endometrial abnormality (cancer, polyp, atypical hyperplasia: LR– = 0.01). The authors suggested that TVUS can reliably rule out significant endometrial disease among postmenopausal women with vaginal bleeding.
A 2002 meta-analysis of 57 cohort studies, without consistently applied reference standards, published between 1966 and 2000 included a total of 9031 women with postmenopausal bleeding.2 Because many of the studies were felt to use inadequately stringent criteria for diagnosis, the authors limited their final analysis to only 4 studies. They concluded that a negative result using a 5-mm threshold rules out endometrial pathology with fair certainty (LR– = 0.21).
Recommendations from others
A Consensus Conference Statement from the Society of Radiologists in Ultrasound recommended that either TVUS or endometrial biopsy could be used in the initial evaluation of patients with postmenopausal bleeding.3 Using a threshold of >5 mm as abnormal, they concluded that the sensitivities of TVUS and endometrial biopsy are comparable when “sufficient tissue” is obtained with endometrial biopsy. They felt that data was currently insufficient to clearly state which technique is more effective.
TVUS is an effective, relatively noninvasive way to rule out significant pathology
Postmenopausal women need accurate diagnostic evaluation when they have abnormal bleeding. While the majority have a benign cause of bleeding, such as atrophic endometrium, many have significant pathology, including cancer (Table). Many older patients are reluctant to undergo invasive sampling studies. Cervical stenosis, a common occurrence in this age group, further complicates matters. Evidence suggests that TVUS with a full endometrial thickness of 5 mm or less, full visualization of the cavity, and no other abnormal findings, can identify patients at low risk for significant abnormalities. The false negative rate for TVUS (8%) compares quite favorably with endometrial biopsy (5%–15%) and even D&C (2%–6%).1 TVUS is an effective and relatively noninvasive strategy for ruling out significant pathology. Given the false negative rates of these techniques, all patients with postmenopausal bleeding require close follow-up.
TABLE
Differential diagnosis of postmenopausal bleeding
| Histologic diagnosis | Incidence (n=1138) |
|---|---|
| Atrophy | 59% |
| Endometrial polyp | 12% |
| Hyperplasia | 10% |
| Endometrial cancer | 10% |
| Hormonal effect | 7% |
| Cervical cancer | 2% |
| Other | <1% |
| Source: Karlsson et al 1995.4 | |
1. Smith-Bindman R, Kerlikowske K, Feldstein VA, et al. Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA 1998;280:1510-1517.
2. Gupta JK, Chien PF, Voit D, Clark TJ, Khan KS. Ultrasonographic endometrial thickness for diagnosing endometrial pathology in women with postmenopausal bleeding: a meta-analysis. Acta Obstet Gynecol Scand 2002;81:799-816.
3. Evaluation of the woman with postmenopausal bleeding. Society of Radiologists in Ultrasound-Sponsored Consensus Conference statement. J Ultrasound Med 2001;20:1025-1036.
4. Karlsson B, Granberg S, Wikland M, et al. Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding—a Nordic multicenter study. Am J Obstet Gynecol 1995;172:1488-1494.
1. Smith-Bindman R, Kerlikowske K, Feldstein VA, et al. Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA 1998;280:1510-1517.
2. Gupta JK, Chien PF, Voit D, Clark TJ, Khan KS. Ultrasonographic endometrial thickness for diagnosing endometrial pathology in women with postmenopausal bleeding: a meta-analysis. Acta Obstet Gynecol Scand 2002;81:799-816.
3. Evaluation of the woman with postmenopausal bleeding. Society of Radiologists in Ultrasound-Sponsored Consensus Conference statement. J Ultrasound Med 2001;20:1025-1036.
4. Karlsson B, Granberg S, Wikland M, et al. Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding—a Nordic multicenter study. Am J Obstet Gynecol 1995;172:1488-1494.
Evidence-based answers from the Family Physicians Inquiries Network
Can transvaginal ultrasound detect endometrial disease among asymptomatic postmenopausal patients?
Transvaginal ultrasound should not replace endometrial biopsy for detection of endometrial disease among asymptomatic postmenopausal patients. Endometrial biopsy has been considered a standard for the clinical diagnosis of endometrial disease among asymptomatic patients, but it is invasive, may be uncomfortable, and may not be able to be performed for some patients with cervical stenosis. Ultrasound evaluation is less invasive and more comfortable and can be performed for patients with cervical stenosis. The positive predictive value of ultrasound is not adequate to allow it to replace endometrial biopsy for screening of asymptomatic women (strength of recommendation: B, based on cohort studies).
Evidence summary
In a trial of postmenopausal estrogen use, 448 asymptomatic postmenopausal women were monitored with both endometrial biopsy and transvaginal ultrasound.1 Biopsy detected 11 cases of serious disease. At a threshold of 5 mm for endometrial thickness, ultrasound had a positive predictive value of 9% for detecting any abnormality with 90% sensitivity and 48% specificity. At this threshold, more than half of women evaluated with ultrasound would require endometrial biopsy as well, and only 4% of these patients would have serious disease. This study concludes that transvaginal ultrasound has a poor positive predictive value but a high negative predictive value for detecting serious endometrial disease for this asymptomatic population.
An additional study evaluated 1926 asymptomatic postmenopausal women with transvaginal ultrasound.2 Of these, 1833 had endometrial thickness <6 mm and 1750 of this cohort underwent biopsy. Five cases of serious endometrial abnormality were identified in this group (1 adenocarcinoma and 4 atypical hyperplasia). Specificity in this group was 98%, but sensitivity for accurately detecting an abnormality was low at 17%.
The negative predictive value was greater than 99%. An inadequate number of patients with endometrial thickness >6 mm were biopsied (45%) to allow for accurate calculation of positive predictive value in those with a >6 mm stripe. The study concludes that transvaginal ultrasonography may not be an effective screening procedure for this population.
The relevance of several other studies is affected by small sample size (range, 36–85).3-6 Other studies did not attempt to biopsy all patients screened with ultrasound.7,8
Recommendations from others
The National Cancer Institute states finds the evidence insufficient to recommend any routine screening for endometrial cancer with either endometrial biopsy or transvaginal ultrasound. The American Cancer Society does not recommend routine screening of asymptomatic patients for endometrial cancer. They recommend prompt recognition and evaluation of abnormal uterine bleeding. The US Preventive Services Task Force and American Academy of Family Physicians have not issued recommendations related to endometrial cancer screening.
No need to screen postmenopausal women for endometrial disease
Paul V. Aitken, Jr., MD, MPH
New Hanover Regional Medical Center, Wilmington, NC/University of North Carolina at Chapel Hill
This Clinical Inquiry appears to draw appropriate conclusions to the question as presented. However, the question implies tacit approval of the notion of screening asymptomatic postmenopausal women. As pointed out above, no major organization recommends screening of these women. When reviewing a study we must also ask if the original study question is similar to our own clinical question. A critical piece of information regarding this answer is that references 1 and 2 are “nested” studies done within the context of large drug trials originally designed to answer very different questions. These asymptomatic women were being screened as part of the study protocol to ensure drug safety. Any effort on our part to apply this data to our asymptomatic patients should be considered with this significant limitation in mind.
1. Langer RD, Pierce JJ, O’Hanlan KA, et al. Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. Postmenopausal Estrogen/Progestin Intervention Trial. N Engl J Med 1997;337:1792-1798.
2. Fleischer AC, Wheeler JE, Lindsay I, et al. An assessment of the value of ultrasonographic screening for endometrial disease in postmenopausal women without symptoms. Am J Obstet Gynecol 2001;184:70-75.
3. Hanggi W, Bersinger N, Altermatt HJ, Birkhauser MH. Comparison of transvaginal ultrasonography and endometrial biopsy in surveillance in postmenopausal HRT users. Maturitas 1997;27:133-143.
4. Shipley CF, 3rd, Simmons CL, Nelson GH. Comparison of transvaginal sonography with endometrial biopsy in asymptomatic postmenopausal women. J Ultrasound Med 1994;13:99-104.
5. Paraskevaidis E, Papadimitriou D, Kalantaridou SN, et al. Screening transvaginal uterine ultrasonography for identifying endometrial pathology in postmenopausal women. Anticancer Res 2002;22:1127-1130.
6. Castelo-Branco C, Puerto B, Duran M, et al. Transvaginal sonography of the endometrium in postmenopausal women: monitoring the effect of hormone replacement therapy. Maturitas 1994;19:59-65.
7. Vuento MH, Pirhonen JP, Makinen JI, et al. Screening for endometrial cancer in asymptomatic postmenopausal women with conventional and colour Doppler sonography. Br J Obstet Gynaecol 1999;106:14-20.
8. Ciatto S, Cecchini S, Bonardi R, Grazzini G, Mazotta A, Zappa M. A feasibility study of screening for endometrial carcinoma in postmenopausal women by ultrasonography. Tumori 1995;81:334-337.
Transvaginal ultrasound should not replace endometrial biopsy for detection of endometrial disease among asymptomatic postmenopausal patients. Endometrial biopsy has been considered a standard for the clinical diagnosis of endometrial disease among asymptomatic patients, but it is invasive, may be uncomfortable, and may not be able to be performed for some patients with cervical stenosis. Ultrasound evaluation is less invasive and more comfortable and can be performed for patients with cervical stenosis. The positive predictive value of ultrasound is not adequate to allow it to replace endometrial biopsy for screening of asymptomatic women (strength of recommendation: B, based on cohort studies).
Evidence summary
In a trial of postmenopausal estrogen use, 448 asymptomatic postmenopausal women were monitored with both endometrial biopsy and transvaginal ultrasound.1 Biopsy detected 11 cases of serious disease. At a threshold of 5 mm for endometrial thickness, ultrasound had a positive predictive value of 9% for detecting any abnormality with 90% sensitivity and 48% specificity. At this threshold, more than half of women evaluated with ultrasound would require endometrial biopsy as well, and only 4% of these patients would have serious disease. This study concludes that transvaginal ultrasound has a poor positive predictive value but a high negative predictive value for detecting serious endometrial disease for this asymptomatic population.
An additional study evaluated 1926 asymptomatic postmenopausal women with transvaginal ultrasound.2 Of these, 1833 had endometrial thickness <6 mm and 1750 of this cohort underwent biopsy. Five cases of serious endometrial abnormality were identified in this group (1 adenocarcinoma and 4 atypical hyperplasia). Specificity in this group was 98%, but sensitivity for accurately detecting an abnormality was low at 17%.
The negative predictive value was greater than 99%. An inadequate number of patients with endometrial thickness >6 mm were biopsied (45%) to allow for accurate calculation of positive predictive value in those with a >6 mm stripe. The study concludes that transvaginal ultrasonography may not be an effective screening procedure for this population.
The relevance of several other studies is affected by small sample size (range, 36–85).3-6 Other studies did not attempt to biopsy all patients screened with ultrasound.7,8
Recommendations from others
The National Cancer Institute states finds the evidence insufficient to recommend any routine screening for endometrial cancer with either endometrial biopsy or transvaginal ultrasound. The American Cancer Society does not recommend routine screening of asymptomatic patients for endometrial cancer. They recommend prompt recognition and evaluation of abnormal uterine bleeding. The US Preventive Services Task Force and American Academy of Family Physicians have not issued recommendations related to endometrial cancer screening.
No need to screen postmenopausal women for endometrial disease
Paul V. Aitken, Jr., MD, MPH
New Hanover Regional Medical Center, Wilmington, NC/University of North Carolina at Chapel Hill
This Clinical Inquiry appears to draw appropriate conclusions to the question as presented. However, the question implies tacit approval of the notion of screening asymptomatic postmenopausal women. As pointed out above, no major organization recommends screening of these women. When reviewing a study we must also ask if the original study question is similar to our own clinical question. A critical piece of information regarding this answer is that references 1 and 2 are “nested” studies done within the context of large drug trials originally designed to answer very different questions. These asymptomatic women were being screened as part of the study protocol to ensure drug safety. Any effort on our part to apply this data to our asymptomatic patients should be considered with this significant limitation in mind.
Transvaginal ultrasound should not replace endometrial biopsy for detection of endometrial disease among asymptomatic postmenopausal patients. Endometrial biopsy has been considered a standard for the clinical diagnosis of endometrial disease among asymptomatic patients, but it is invasive, may be uncomfortable, and may not be able to be performed for some patients with cervical stenosis. Ultrasound evaluation is less invasive and more comfortable and can be performed for patients with cervical stenosis. The positive predictive value of ultrasound is not adequate to allow it to replace endometrial biopsy for screening of asymptomatic women (strength of recommendation: B, based on cohort studies).
Evidence summary
In a trial of postmenopausal estrogen use, 448 asymptomatic postmenopausal women were monitored with both endometrial biopsy and transvaginal ultrasound.1 Biopsy detected 11 cases of serious disease. At a threshold of 5 mm for endometrial thickness, ultrasound had a positive predictive value of 9% for detecting any abnormality with 90% sensitivity and 48% specificity. At this threshold, more than half of women evaluated with ultrasound would require endometrial biopsy as well, and only 4% of these patients would have serious disease. This study concludes that transvaginal ultrasound has a poor positive predictive value but a high negative predictive value for detecting serious endometrial disease for this asymptomatic population.
An additional study evaluated 1926 asymptomatic postmenopausal women with transvaginal ultrasound.2 Of these, 1833 had endometrial thickness <6 mm and 1750 of this cohort underwent biopsy. Five cases of serious endometrial abnormality were identified in this group (1 adenocarcinoma and 4 atypical hyperplasia). Specificity in this group was 98%, but sensitivity for accurately detecting an abnormality was low at 17%.
The negative predictive value was greater than 99%. An inadequate number of patients with endometrial thickness >6 mm were biopsied (45%) to allow for accurate calculation of positive predictive value in those with a >6 mm stripe. The study concludes that transvaginal ultrasonography may not be an effective screening procedure for this population.
The relevance of several other studies is affected by small sample size (range, 36–85).3-6 Other studies did not attempt to biopsy all patients screened with ultrasound.7,8
Recommendations from others
The National Cancer Institute states finds the evidence insufficient to recommend any routine screening for endometrial cancer with either endometrial biopsy or transvaginal ultrasound. The American Cancer Society does not recommend routine screening of asymptomatic patients for endometrial cancer. They recommend prompt recognition and evaluation of abnormal uterine bleeding. The US Preventive Services Task Force and American Academy of Family Physicians have not issued recommendations related to endometrial cancer screening.
No need to screen postmenopausal women for endometrial disease
Paul V. Aitken, Jr., MD, MPH
New Hanover Regional Medical Center, Wilmington, NC/University of North Carolina at Chapel Hill
This Clinical Inquiry appears to draw appropriate conclusions to the question as presented. However, the question implies tacit approval of the notion of screening asymptomatic postmenopausal women. As pointed out above, no major organization recommends screening of these women. When reviewing a study we must also ask if the original study question is similar to our own clinical question. A critical piece of information regarding this answer is that references 1 and 2 are “nested” studies done within the context of large drug trials originally designed to answer very different questions. These asymptomatic women were being screened as part of the study protocol to ensure drug safety. Any effort on our part to apply this data to our asymptomatic patients should be considered with this significant limitation in mind.
1. Langer RD, Pierce JJ, O’Hanlan KA, et al. Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. Postmenopausal Estrogen/Progestin Intervention Trial. N Engl J Med 1997;337:1792-1798.
2. Fleischer AC, Wheeler JE, Lindsay I, et al. An assessment of the value of ultrasonographic screening for endometrial disease in postmenopausal women without symptoms. Am J Obstet Gynecol 2001;184:70-75.
3. Hanggi W, Bersinger N, Altermatt HJ, Birkhauser MH. Comparison of transvaginal ultrasonography and endometrial biopsy in surveillance in postmenopausal HRT users. Maturitas 1997;27:133-143.
4. Shipley CF, 3rd, Simmons CL, Nelson GH. Comparison of transvaginal sonography with endometrial biopsy in asymptomatic postmenopausal women. J Ultrasound Med 1994;13:99-104.
5. Paraskevaidis E, Papadimitriou D, Kalantaridou SN, et al. Screening transvaginal uterine ultrasonography for identifying endometrial pathology in postmenopausal women. Anticancer Res 2002;22:1127-1130.
6. Castelo-Branco C, Puerto B, Duran M, et al. Transvaginal sonography of the endometrium in postmenopausal women: monitoring the effect of hormone replacement therapy. Maturitas 1994;19:59-65.
7. Vuento MH, Pirhonen JP, Makinen JI, et al. Screening for endometrial cancer in asymptomatic postmenopausal women with conventional and colour Doppler sonography. Br J Obstet Gynaecol 1999;106:14-20.
8. Ciatto S, Cecchini S, Bonardi R, Grazzini G, Mazotta A, Zappa M. A feasibility study of screening for endometrial carcinoma in postmenopausal women by ultrasonography. Tumori 1995;81:334-337.
1. Langer RD, Pierce JJ, O’Hanlan KA, et al. Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. Postmenopausal Estrogen/Progestin Intervention Trial. N Engl J Med 1997;337:1792-1798.
2. Fleischer AC, Wheeler JE, Lindsay I, et al. An assessment of the value of ultrasonographic screening for endometrial disease in postmenopausal women without symptoms. Am J Obstet Gynecol 2001;184:70-75.
3. Hanggi W, Bersinger N, Altermatt HJ, Birkhauser MH. Comparison of transvaginal ultrasonography and endometrial biopsy in surveillance in postmenopausal HRT users. Maturitas 1997;27:133-143.
4. Shipley CF, 3rd, Simmons CL, Nelson GH. Comparison of transvaginal sonography with endometrial biopsy in asymptomatic postmenopausal women. J Ultrasound Med 1994;13:99-104.
5. Paraskevaidis E, Papadimitriou D, Kalantaridou SN, et al. Screening transvaginal uterine ultrasonography for identifying endometrial pathology in postmenopausal women. Anticancer Res 2002;22:1127-1130.
6. Castelo-Branco C, Puerto B, Duran M, et al. Transvaginal sonography of the endometrium in postmenopausal women: monitoring the effect of hormone replacement therapy. Maturitas 1994;19:59-65.
7. Vuento MH, Pirhonen JP, Makinen JI, et al. Screening for endometrial cancer in asymptomatic postmenopausal women with conventional and colour Doppler sonography. Br J Obstet Gynaecol 1999;106:14-20.
8. Ciatto S, Cecchini S, Bonardi R, Grazzini G, Mazotta A, Zappa M. A feasibility study of screening for endometrial carcinoma in postmenopausal women by ultrasonography. Tumori 1995;81:334-337.
Evidence-based answers from the Family Physicians Inquiries Network
What is the diagnostic approach to a 1-year-old with chronic cough?
Very few studies examine the evaluation of chronic cough among young children. Based on expert opinion, investigation of chronic cough should begin with a detailed history, physical examination, and chest radiograph (strength of recommendation [SOR]: C, expert opinion).1
Before pursuing additional studies, remove potential irritants from the patient’s environment. Work-up for persisting cough should consider congenital anomalies and then be directed toward common causes of chronic cough like those seen in older children and adults, including postnasal drip syndrome, gastroesophageal reflux disease (GERD), and asthma (SOR: C).
Evidence summary
The data on which expert opinion is based comes from case series of chronic cough in adults and older children in the setting of a specialty clinic.2,3 A detailed history should attend to the neonatal course, feeding concerns, sleep issues, potential for foreign-body aspiration, medications, infectious exposures, family history of atopy or asthma, and exposures to environmental irritants such as tobacco smoke.1 A dry, barking, or brassy cough in infants suggests large airway obstruction; in older children, it is likely psychogenic. A wet, productive cough is associated with an infectious cause. A cough associated with throat clearing suggests GERD or postnasal drip syndrome.3
Chest radiography, although universally recommended, was only abnormal for 4% of older patients (age 6 years through adult) from one series.2 Chest radiography may be most helpful for infants at increased risk for foreign-body aspiration. Cough from passive smoke exposure should improve with removal of exposure. There is no information on how long to wait for improvement.1
If the initial evaluation is not revealing, further investigation should focus on congenital anomalies, asthma, postnasal drip, and GERD. Aberrant innominate artery and asthma were the most frequent diagnoses among children aged <18 months old referred for otolaryngology consultation.3 Because pulmonary function testing is not practical for infants, a trial of aggressive therapy in combination with a “cough diary” kept by the parents may be used to diagnose asthma.1 Sinus computed tomography films are not routinely recommended to evaluate for postnasal drip, as sinusitis among children does not correlate well with postnasal drip.1 GERD may present with chronic cough; however, there is insufficient evidence for a uniform approach to diagnosis of cough associated with reflux.4
After evaluating infants for common causes of chronic cough (or if suggested by the history or physical), less common causes should be explored (Table). Consider a sweat chloride test first, followed by tuberculin testing. More than one cause for chronic cough was found 23% of the time in adults.2 Multiple causes of cough may be less common among infants, though no data confirm this.
Though it includes a mixture of adults and older children, a case series from pulmonary specialists finds pulmonary function tests with methacholine challenge the most helpful test.2 Case series from otolaryngology find endoscopy to be the most helpful, but it also includes a mix of older patients.3 Therefore, it seems likely that primary care physicians already appropriately refer patients to the correct specialists for evaluation. The optimal time to refer patients is unknown. We identified no reports from primary care settings. The question is an appropriate topic for primary care research.
TABLE
Causes of chronic cough among children with normal chest radiograph
| Category | Diagnoses |
|---|---|
| Asthma | Cough-variant asthma, hyperactive airways after infection |
| Infectious | Chronic sinusitis, otitis media with effusion, chronic bronchitis, bronchiectasis, chronic Waldeyer’s ring infection, pertussis, parapertussis, adenovirus, tuberculosis |
Congenital
| Aberrant innominate artery, vascular rings, bronchogenic cyst, esophageal duplication, subglottic stenosis, tracheomalacia, tracheal and bronchial stenosis Gastroesophageal reflux, esophageal incoordination, tracheoesophageal fistula, cleft larynx, vocal cord paralysis, pharyngeal incoordination, achalasia, cricopharyngeal achalasia Tracheobronchial tree abnormalities, cystic fibrosis, immotile cilia syndrome, congenital heart disease, bronchopulmonary dysplasia |
| Psychogenic | Psychogenic cough |
| Traumatic | Foreign bodies of bronchus, trachea, larynx, nose, external auditory canal |
| Environmental | Tobacco exposure, low humidity, overheating, allergens, industrial pollutants |
| Otologic | Cerumen, foreign body, infection, neoplasm, hair |
| Neoplastic | Larynx: Subglottic hemangioma, papillomatosis Tracheobronchial tree: Papillomatosis, bronchial adenoma Mediastinal tumor causing tracheobronchial compression |
| Cardiovascular | Rheumatic fever, congestive heart failure, mitral stenosis |
| Adapted from: Holinger 1986.3 | |
Recommendations from others
A guideline from Finaldn suggests referral for investigations of asthma, allergy, and GERD. Infectious diseases, the presence of foreign bodies, and psychogenic causes should also be considered.5
Inquire about exposure to irritants, feeding habits, infection, family history of asthma
Phong Luu, MD
Baylor College of Medicine, Houston, Tex
A comprehensive detailed history is the first important diagnostic step in the approach to a chronic cough in a 1-year old. The primary care provider should inquire about the infant’s exposure to environmental irritants such as tobacco smoke, their feeding habits, possible foreign-body aspiration, infectious exposure, and the family history of asthma. Environmental pollution in areas such as where I practice (Houston, Texas) can be a significant factor in evaluating infant with chronic cough. A chest radiograph should be considered after a thorough physical examination.
After an initial evaluation, further investigation should focus on the common causes of chronic cough such as postnasal drip, asthma, and GERD. Because of the high frequency of postnasal drip, the patient can be empirically started on antihistamine/decongestion combination. The primary care provider may consider an empirical treatment for gastroesophageal reflux disease if suggested by the history and physical examination. If no improvement is seen after several weeks, the patient should be referred to the appropriate specialist for evaluation of asthma, congenital anomalies, or other less common cause of chronic cough.
1. Irwin RS, Boulet LP, Cloutier MM, et al. Managing cough as a defense mechanism and as a symptom. A consensus panel report of the American College of Chest Physicians. Chest 1998;114(2 Suppl):133S-181S.
2. Irwin RS, Curley FJ, French CL. Chronic cough. The spectrum and frequency of causes, key components of diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis 1990;141:640-647.
3. Holinger LD. Chronic cough in infants and children. Laryngoscope 1986;96:316-322.
4. Rudolph CD, Mazur LJ, Liptak GS, et al. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 2001;32 Suppl 2:S1-31.
5. Finnish Medical Society Duodecim. Prolonged cough in children. Helsinki, Finland: Duodecim Medical Publications; 2001. Available at: www.guideline.gov/guidelines/FTNGC-2602.html. Accessed on November 11, 2004.
Very few studies examine the evaluation of chronic cough among young children. Based on expert opinion, investigation of chronic cough should begin with a detailed history, physical examination, and chest radiograph (strength of recommendation [SOR]: C, expert opinion).1
Before pursuing additional studies, remove potential irritants from the patient’s environment. Work-up for persisting cough should consider congenital anomalies and then be directed toward common causes of chronic cough like those seen in older children and adults, including postnasal drip syndrome, gastroesophageal reflux disease (GERD), and asthma (SOR: C).
Evidence summary
The data on which expert opinion is based comes from case series of chronic cough in adults and older children in the setting of a specialty clinic.2,3 A detailed history should attend to the neonatal course, feeding concerns, sleep issues, potential for foreign-body aspiration, medications, infectious exposures, family history of atopy or asthma, and exposures to environmental irritants such as tobacco smoke.1 A dry, barking, or brassy cough in infants suggests large airway obstruction; in older children, it is likely psychogenic. A wet, productive cough is associated with an infectious cause. A cough associated with throat clearing suggests GERD or postnasal drip syndrome.3
Chest radiography, although universally recommended, was only abnormal for 4% of older patients (age 6 years through adult) from one series.2 Chest radiography may be most helpful for infants at increased risk for foreign-body aspiration. Cough from passive smoke exposure should improve with removal of exposure. There is no information on how long to wait for improvement.1
If the initial evaluation is not revealing, further investigation should focus on congenital anomalies, asthma, postnasal drip, and GERD. Aberrant innominate artery and asthma were the most frequent diagnoses among children aged <18 months old referred for otolaryngology consultation.3 Because pulmonary function testing is not practical for infants, a trial of aggressive therapy in combination with a “cough diary” kept by the parents may be used to diagnose asthma.1 Sinus computed tomography films are not routinely recommended to evaluate for postnasal drip, as sinusitis among children does not correlate well with postnasal drip.1 GERD may present with chronic cough; however, there is insufficient evidence for a uniform approach to diagnosis of cough associated with reflux.4
After evaluating infants for common causes of chronic cough (or if suggested by the history or physical), less common causes should be explored (Table). Consider a sweat chloride test first, followed by tuberculin testing. More than one cause for chronic cough was found 23% of the time in adults.2 Multiple causes of cough may be less common among infants, though no data confirm this.
Though it includes a mixture of adults and older children, a case series from pulmonary specialists finds pulmonary function tests with methacholine challenge the most helpful test.2 Case series from otolaryngology find endoscopy to be the most helpful, but it also includes a mix of older patients.3 Therefore, it seems likely that primary care physicians already appropriately refer patients to the correct specialists for evaluation. The optimal time to refer patients is unknown. We identified no reports from primary care settings. The question is an appropriate topic for primary care research.
TABLE
Causes of chronic cough among children with normal chest radiograph
| Category | Diagnoses |
|---|---|
| Asthma | Cough-variant asthma, hyperactive airways after infection |
| Infectious | Chronic sinusitis, otitis media with effusion, chronic bronchitis, bronchiectasis, chronic Waldeyer’s ring infection, pertussis, parapertussis, adenovirus, tuberculosis |
Congenital
| Aberrant innominate artery, vascular rings, bronchogenic cyst, esophageal duplication, subglottic stenosis, tracheomalacia, tracheal and bronchial stenosis Gastroesophageal reflux, esophageal incoordination, tracheoesophageal fistula, cleft larynx, vocal cord paralysis, pharyngeal incoordination, achalasia, cricopharyngeal achalasia Tracheobronchial tree abnormalities, cystic fibrosis, immotile cilia syndrome, congenital heart disease, bronchopulmonary dysplasia |
| Psychogenic | Psychogenic cough |
| Traumatic | Foreign bodies of bronchus, trachea, larynx, nose, external auditory canal |
| Environmental | Tobacco exposure, low humidity, overheating, allergens, industrial pollutants |
| Otologic | Cerumen, foreign body, infection, neoplasm, hair |
| Neoplastic | Larynx: Subglottic hemangioma, papillomatosis Tracheobronchial tree: Papillomatosis, bronchial adenoma Mediastinal tumor causing tracheobronchial compression |
| Cardiovascular | Rheumatic fever, congestive heart failure, mitral stenosis |
| Adapted from: Holinger 1986.3 | |
Recommendations from others
A guideline from Finaldn suggests referral for investigations of asthma, allergy, and GERD. Infectious diseases, the presence of foreign bodies, and psychogenic causes should also be considered.5
Inquire about exposure to irritants, feeding habits, infection, family history of asthma
Phong Luu, MD
Baylor College of Medicine, Houston, Tex
A comprehensive detailed history is the first important diagnostic step in the approach to a chronic cough in a 1-year old. The primary care provider should inquire about the infant’s exposure to environmental irritants such as tobacco smoke, their feeding habits, possible foreign-body aspiration, infectious exposure, and the family history of asthma. Environmental pollution in areas such as where I practice (Houston, Texas) can be a significant factor in evaluating infant with chronic cough. A chest radiograph should be considered after a thorough physical examination.
After an initial evaluation, further investigation should focus on the common causes of chronic cough such as postnasal drip, asthma, and GERD. Because of the high frequency of postnasal drip, the patient can be empirically started on antihistamine/decongestion combination. The primary care provider may consider an empirical treatment for gastroesophageal reflux disease if suggested by the history and physical examination. If no improvement is seen after several weeks, the patient should be referred to the appropriate specialist for evaluation of asthma, congenital anomalies, or other less common cause of chronic cough.
Very few studies examine the evaluation of chronic cough among young children. Based on expert opinion, investigation of chronic cough should begin with a detailed history, physical examination, and chest radiograph (strength of recommendation [SOR]: C, expert opinion).1
Before pursuing additional studies, remove potential irritants from the patient’s environment. Work-up for persisting cough should consider congenital anomalies and then be directed toward common causes of chronic cough like those seen in older children and adults, including postnasal drip syndrome, gastroesophageal reflux disease (GERD), and asthma (SOR: C).
Evidence summary
The data on which expert opinion is based comes from case series of chronic cough in adults and older children in the setting of a specialty clinic.2,3 A detailed history should attend to the neonatal course, feeding concerns, sleep issues, potential for foreign-body aspiration, medications, infectious exposures, family history of atopy or asthma, and exposures to environmental irritants such as tobacco smoke.1 A dry, barking, or brassy cough in infants suggests large airway obstruction; in older children, it is likely psychogenic. A wet, productive cough is associated with an infectious cause. A cough associated with throat clearing suggests GERD or postnasal drip syndrome.3
Chest radiography, although universally recommended, was only abnormal for 4% of older patients (age 6 years through adult) from one series.2 Chest radiography may be most helpful for infants at increased risk for foreign-body aspiration. Cough from passive smoke exposure should improve with removal of exposure. There is no information on how long to wait for improvement.1
If the initial evaluation is not revealing, further investigation should focus on congenital anomalies, asthma, postnasal drip, and GERD. Aberrant innominate artery and asthma were the most frequent diagnoses among children aged <18 months old referred for otolaryngology consultation.3 Because pulmonary function testing is not practical for infants, a trial of aggressive therapy in combination with a “cough diary” kept by the parents may be used to diagnose asthma.1 Sinus computed tomography films are not routinely recommended to evaluate for postnasal drip, as sinusitis among children does not correlate well with postnasal drip.1 GERD may present with chronic cough; however, there is insufficient evidence for a uniform approach to diagnosis of cough associated with reflux.4
After evaluating infants for common causes of chronic cough (or if suggested by the history or physical), less common causes should be explored (Table). Consider a sweat chloride test first, followed by tuberculin testing. More than one cause for chronic cough was found 23% of the time in adults.2 Multiple causes of cough may be less common among infants, though no data confirm this.
Though it includes a mixture of adults and older children, a case series from pulmonary specialists finds pulmonary function tests with methacholine challenge the most helpful test.2 Case series from otolaryngology find endoscopy to be the most helpful, but it also includes a mix of older patients.3 Therefore, it seems likely that primary care physicians already appropriately refer patients to the correct specialists for evaluation. The optimal time to refer patients is unknown. We identified no reports from primary care settings. The question is an appropriate topic for primary care research.
TABLE
Causes of chronic cough among children with normal chest radiograph
| Category | Diagnoses |
|---|---|
| Asthma | Cough-variant asthma, hyperactive airways after infection |
| Infectious | Chronic sinusitis, otitis media with effusion, chronic bronchitis, bronchiectasis, chronic Waldeyer’s ring infection, pertussis, parapertussis, adenovirus, tuberculosis |
Congenital
| Aberrant innominate artery, vascular rings, bronchogenic cyst, esophageal duplication, subglottic stenosis, tracheomalacia, tracheal and bronchial stenosis Gastroesophageal reflux, esophageal incoordination, tracheoesophageal fistula, cleft larynx, vocal cord paralysis, pharyngeal incoordination, achalasia, cricopharyngeal achalasia Tracheobronchial tree abnormalities, cystic fibrosis, immotile cilia syndrome, congenital heart disease, bronchopulmonary dysplasia |
| Psychogenic | Psychogenic cough |
| Traumatic | Foreign bodies of bronchus, trachea, larynx, nose, external auditory canal |
| Environmental | Tobacco exposure, low humidity, overheating, allergens, industrial pollutants |
| Otologic | Cerumen, foreign body, infection, neoplasm, hair |
| Neoplastic | Larynx: Subglottic hemangioma, papillomatosis Tracheobronchial tree: Papillomatosis, bronchial adenoma Mediastinal tumor causing tracheobronchial compression |
| Cardiovascular | Rheumatic fever, congestive heart failure, mitral stenosis |
| Adapted from: Holinger 1986.3 | |
Recommendations from others
A guideline from Finaldn suggests referral for investigations of asthma, allergy, and GERD. Infectious diseases, the presence of foreign bodies, and psychogenic causes should also be considered.5
Inquire about exposure to irritants, feeding habits, infection, family history of asthma
Phong Luu, MD
Baylor College of Medicine, Houston, Tex
A comprehensive detailed history is the first important diagnostic step in the approach to a chronic cough in a 1-year old. The primary care provider should inquire about the infant’s exposure to environmental irritants such as tobacco smoke, their feeding habits, possible foreign-body aspiration, infectious exposure, and the family history of asthma. Environmental pollution in areas such as where I practice (Houston, Texas) can be a significant factor in evaluating infant with chronic cough. A chest radiograph should be considered after a thorough physical examination.
After an initial evaluation, further investigation should focus on the common causes of chronic cough such as postnasal drip, asthma, and GERD. Because of the high frequency of postnasal drip, the patient can be empirically started on antihistamine/decongestion combination. The primary care provider may consider an empirical treatment for gastroesophageal reflux disease if suggested by the history and physical examination. If no improvement is seen after several weeks, the patient should be referred to the appropriate specialist for evaluation of asthma, congenital anomalies, or other less common cause of chronic cough.
1. Irwin RS, Boulet LP, Cloutier MM, et al. Managing cough as a defense mechanism and as a symptom. A consensus panel report of the American College of Chest Physicians. Chest 1998;114(2 Suppl):133S-181S.
2. Irwin RS, Curley FJ, French CL. Chronic cough. The spectrum and frequency of causes, key components of diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis 1990;141:640-647.
3. Holinger LD. Chronic cough in infants and children. Laryngoscope 1986;96:316-322.
4. Rudolph CD, Mazur LJ, Liptak GS, et al. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 2001;32 Suppl 2:S1-31.
5. Finnish Medical Society Duodecim. Prolonged cough in children. Helsinki, Finland: Duodecim Medical Publications; 2001. Available at: www.guideline.gov/guidelines/FTNGC-2602.html. Accessed on November 11, 2004.
1. Irwin RS, Boulet LP, Cloutier MM, et al. Managing cough as a defense mechanism and as a symptom. A consensus panel report of the American College of Chest Physicians. Chest 1998;114(2 Suppl):133S-181S.
2. Irwin RS, Curley FJ, French CL. Chronic cough. The spectrum and frequency of causes, key components of diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis 1990;141:640-647.
3. Holinger LD. Chronic cough in infants and children. Laryngoscope 1986;96:316-322.
4. Rudolph CD, Mazur LJ, Liptak GS, et al. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 2001;32 Suppl 2:S1-31.
5. Finnish Medical Society Duodecim. Prolonged cough in children. Helsinki, Finland: Duodecim Medical Publications; 2001. Available at: www.guideline.gov/guidelines/FTNGC-2602.html. Accessed on November 11, 2004.
Evidence-based answers from the Family Physicians Inquiries Network
Is antibiotic prophylaxis effective for recurrent acute otitis media?
For children who have recurrent episodes of clinically diagnosed acute otitis media (AOM), antibiotic prophylaxis significantly reduces recurrence, although the effect is not large (strength of recommendation: A–, based on 1 systematic review of randomized controlled trials [RCTs] with below-average quality and 1 subsequent RCT with conflicting results). Evidence is insufficient to suggest which antibiotic is most appropriate, the optimal length of prophylaxis, or the number of episodes of AOM needed to justify prophylactic treatment. Possible harms of antibiotics include vomiting, diarrhea, rash, and infection with antibiotic-resistant organisms.
Evidence summary
A systematic review of antibiotic prophylaxis for recurrent AOM examined 9 RCTs with a total of 958 children. Recurrent AOM was defined as 3 or more episodes per 6 to 18 months. The studies were low to moderate in quality (mean methodologic quality score of 11.8 out of 29 possible points). The most commonly used antibiotics were amoxicillin, cotrimoxazole, and sulfamethoxazole, given for 3 to 24 months (dosing not reported).
Children taking antibiotics had 0.11 (95% confidence interval [CI], 0.03–0.19) fewer episodes of recurrent AOM per patient-month than those taking placebo. The rate in the control group was 0.19 (95% CI, 0.13–0.26). Nine children would have to be treated per month to prevent 1 ear infection (NNT=9; 95% CI, 5–33). Only 2 of the 9 studies had statistically significant results; both used sulfisoxazole for 10 to 12 weeks and were of similar methodologic quality (12.5 out 29 points).
A trend towards a better outcome in studies that used sulfisoxazole did not reach significance compared with those using other medications (ie, ampicillin, amoxicillin, cotrimoxazole). Shorter treatment intervals (<6 months) trended toward being more effective than longer intervals, but this also did not reach significance. Children with more frequent episodes of AOM did no better than those with less frequent episodes.1
Since that review was published, another study of prophylaxis for ear infections had been published. This randomized, double blind, placebo-controlled study enrolled 194 children aged 3 months to 6 years with at least 3 documented AOM episodes in the preceding 6 months. The children were given amoxicillin (20 mg/kg/d) either once daily (n=55) or divided twice daily (n=44) or placebo (n=59). Excluding 36 noncompliant subjects, the percentages without a recurrent episode were 63% for the placebo group, 64% for the once-daily amoxicillin group, and 61% for the twice-daily amoxicillin group. There was no significant difference in the incidence of new AOM episodes among the children in the 3 groups.2
A review article states: “Many children with acute otitis media do not benefit from antimicrobial therapy because the cause of their illness is not bacterial or the infection is cleared by the immune system without use of a drug. At present, we do not have clinical criteria for distinguishing which children are in need of antibiotic therapy for AOM.”3 The lack of criteria for determining which children need antibiotic therapy for AOM makes it more difficult to select children for antibiotic prophylaxis against recurrent AOM.
Recommendations from others
The American Academy of Pediatrics and the American Academy of Family Physicians do not address antibiotic prophylaxis for recurrent episodes of otitis media in their guidelines. Both groups recommend modification of risk factors to decrease recurrent AOM, including promoting breastfeeding during the first 6 months, avoiding bottle-propping, reducing or eliminating pacifier use in the second 6 months of life, and eliminating exposure to secondhand smoke.
They also recommend pneumococcal conjugate vaccine to reduce vaccine-serotype pneumococcal otitis and live-attenuated influenza vaccine during respiratory virus season for children aged >2 years.
Treatment options include observation, antibiotic prophylaxis, tympanostomy tubes; no option is ideal for all
Alex Krist, MD
Fairfax Family Practice Residency, Virginia Commonwealth University, Fairfax, Va
Treatment options for children with recurrent acute otitis media include observation with treatment of recurrences, antibiotic prophylaxis, or tympanostomy tubes. No option is ideal for all children.
Multiple factors can be weighed to choose more or less aggressive treatment including frequency and severity of infections, exposure to secondhand smoke, day care enrollment, sibling history, parental comfort and anxiety, presence of serous otitis media between episodes, time of year, and effect on overall hearing. Measures to prevent otitis media and reserving the diagnosis of acute otitis media for “true” purulent infections can help limit the number of children diagnosed with recurrent disease.
1. Williams RL, Chalmers TC, Stange KC, Chalmers FT, Bowlin SJ. Use of antibiotics in preventing recurrent acute otitis media and in treating otitis media with effusion. A meta-analytic attempt to resolve the brouhaha. JAMA 1993;270:1344-1351.
2. Roark R, Berman S. Continuous twice daily or once daily amoxicillin prophylaxis compared with placebo for children with recurrent acute otitis media. Pediatr Infect Dis 1997;16:376-381.
3. Pichichero ME. Acute otitis media: part II. Treatment in an era of increasing antibiotic resistance. Am Fam Physician 2000;61:2410-2416.
4. American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. Diagnosis and management of acute otitis media. Pediatrics 2004;113:1451-1465.
For children who have recurrent episodes of clinically diagnosed acute otitis media (AOM), antibiotic prophylaxis significantly reduces recurrence, although the effect is not large (strength of recommendation: A–, based on 1 systematic review of randomized controlled trials [RCTs] with below-average quality and 1 subsequent RCT with conflicting results). Evidence is insufficient to suggest which antibiotic is most appropriate, the optimal length of prophylaxis, or the number of episodes of AOM needed to justify prophylactic treatment. Possible harms of antibiotics include vomiting, diarrhea, rash, and infection with antibiotic-resistant organisms.
Evidence summary
A systematic review of antibiotic prophylaxis for recurrent AOM examined 9 RCTs with a total of 958 children. Recurrent AOM was defined as 3 or more episodes per 6 to 18 months. The studies were low to moderate in quality (mean methodologic quality score of 11.8 out of 29 possible points). The most commonly used antibiotics were amoxicillin, cotrimoxazole, and sulfamethoxazole, given for 3 to 24 months (dosing not reported).
Children taking antibiotics had 0.11 (95% confidence interval [CI], 0.03–0.19) fewer episodes of recurrent AOM per patient-month than those taking placebo. The rate in the control group was 0.19 (95% CI, 0.13–0.26). Nine children would have to be treated per month to prevent 1 ear infection (NNT=9; 95% CI, 5–33). Only 2 of the 9 studies had statistically significant results; both used sulfisoxazole for 10 to 12 weeks and were of similar methodologic quality (12.5 out 29 points).
A trend towards a better outcome in studies that used sulfisoxazole did not reach significance compared with those using other medications (ie, ampicillin, amoxicillin, cotrimoxazole). Shorter treatment intervals (<6 months) trended toward being more effective than longer intervals, but this also did not reach significance. Children with more frequent episodes of AOM did no better than those with less frequent episodes.1
Since that review was published, another study of prophylaxis for ear infections had been published. This randomized, double blind, placebo-controlled study enrolled 194 children aged 3 months to 6 years with at least 3 documented AOM episodes in the preceding 6 months. The children were given amoxicillin (20 mg/kg/d) either once daily (n=55) or divided twice daily (n=44) or placebo (n=59). Excluding 36 noncompliant subjects, the percentages without a recurrent episode were 63% for the placebo group, 64% for the once-daily amoxicillin group, and 61% for the twice-daily amoxicillin group. There was no significant difference in the incidence of new AOM episodes among the children in the 3 groups.2
A review article states: “Many children with acute otitis media do not benefit from antimicrobial therapy because the cause of their illness is not bacterial or the infection is cleared by the immune system without use of a drug. At present, we do not have clinical criteria for distinguishing which children are in need of antibiotic therapy for AOM.”3 The lack of criteria for determining which children need antibiotic therapy for AOM makes it more difficult to select children for antibiotic prophylaxis against recurrent AOM.
Recommendations from others
The American Academy of Pediatrics and the American Academy of Family Physicians do not address antibiotic prophylaxis for recurrent episodes of otitis media in their guidelines. Both groups recommend modification of risk factors to decrease recurrent AOM, including promoting breastfeeding during the first 6 months, avoiding bottle-propping, reducing or eliminating pacifier use in the second 6 months of life, and eliminating exposure to secondhand smoke.
They also recommend pneumococcal conjugate vaccine to reduce vaccine-serotype pneumococcal otitis and live-attenuated influenza vaccine during respiratory virus season for children aged >2 years.
Treatment options include observation, antibiotic prophylaxis, tympanostomy tubes; no option is ideal for all
Alex Krist, MD
Fairfax Family Practice Residency, Virginia Commonwealth University, Fairfax, Va
Treatment options for children with recurrent acute otitis media include observation with treatment of recurrences, antibiotic prophylaxis, or tympanostomy tubes. No option is ideal for all children.
Multiple factors can be weighed to choose more or less aggressive treatment including frequency and severity of infections, exposure to secondhand smoke, day care enrollment, sibling history, parental comfort and anxiety, presence of serous otitis media between episodes, time of year, and effect on overall hearing. Measures to prevent otitis media and reserving the diagnosis of acute otitis media for “true” purulent infections can help limit the number of children diagnosed with recurrent disease.
For children who have recurrent episodes of clinically diagnosed acute otitis media (AOM), antibiotic prophylaxis significantly reduces recurrence, although the effect is not large (strength of recommendation: A–, based on 1 systematic review of randomized controlled trials [RCTs] with below-average quality and 1 subsequent RCT with conflicting results). Evidence is insufficient to suggest which antibiotic is most appropriate, the optimal length of prophylaxis, or the number of episodes of AOM needed to justify prophylactic treatment. Possible harms of antibiotics include vomiting, diarrhea, rash, and infection with antibiotic-resistant organisms.
Evidence summary
A systematic review of antibiotic prophylaxis for recurrent AOM examined 9 RCTs with a total of 958 children. Recurrent AOM was defined as 3 or more episodes per 6 to 18 months. The studies were low to moderate in quality (mean methodologic quality score of 11.8 out of 29 possible points). The most commonly used antibiotics were amoxicillin, cotrimoxazole, and sulfamethoxazole, given for 3 to 24 months (dosing not reported).
Children taking antibiotics had 0.11 (95% confidence interval [CI], 0.03–0.19) fewer episodes of recurrent AOM per patient-month than those taking placebo. The rate in the control group was 0.19 (95% CI, 0.13–0.26). Nine children would have to be treated per month to prevent 1 ear infection (NNT=9; 95% CI, 5–33). Only 2 of the 9 studies had statistically significant results; both used sulfisoxazole for 10 to 12 weeks and were of similar methodologic quality (12.5 out 29 points).
A trend towards a better outcome in studies that used sulfisoxazole did not reach significance compared with those using other medications (ie, ampicillin, amoxicillin, cotrimoxazole). Shorter treatment intervals (<6 months) trended toward being more effective than longer intervals, but this also did not reach significance. Children with more frequent episodes of AOM did no better than those with less frequent episodes.1
Since that review was published, another study of prophylaxis for ear infections had been published. This randomized, double blind, placebo-controlled study enrolled 194 children aged 3 months to 6 years with at least 3 documented AOM episodes in the preceding 6 months. The children were given amoxicillin (20 mg/kg/d) either once daily (n=55) or divided twice daily (n=44) or placebo (n=59). Excluding 36 noncompliant subjects, the percentages without a recurrent episode were 63% for the placebo group, 64% for the once-daily amoxicillin group, and 61% for the twice-daily amoxicillin group. There was no significant difference in the incidence of new AOM episodes among the children in the 3 groups.2
A review article states: “Many children with acute otitis media do not benefit from antimicrobial therapy because the cause of their illness is not bacterial or the infection is cleared by the immune system without use of a drug. At present, we do not have clinical criteria for distinguishing which children are in need of antibiotic therapy for AOM.”3 The lack of criteria for determining which children need antibiotic therapy for AOM makes it more difficult to select children for antibiotic prophylaxis against recurrent AOM.
Recommendations from others
The American Academy of Pediatrics and the American Academy of Family Physicians do not address antibiotic prophylaxis for recurrent episodes of otitis media in their guidelines. Both groups recommend modification of risk factors to decrease recurrent AOM, including promoting breastfeeding during the first 6 months, avoiding bottle-propping, reducing or eliminating pacifier use in the second 6 months of life, and eliminating exposure to secondhand smoke.
They also recommend pneumococcal conjugate vaccine to reduce vaccine-serotype pneumococcal otitis and live-attenuated influenza vaccine during respiratory virus season for children aged >2 years.
Treatment options include observation, antibiotic prophylaxis, tympanostomy tubes; no option is ideal for all
Alex Krist, MD
Fairfax Family Practice Residency, Virginia Commonwealth University, Fairfax, Va
Treatment options for children with recurrent acute otitis media include observation with treatment of recurrences, antibiotic prophylaxis, or tympanostomy tubes. No option is ideal for all children.
Multiple factors can be weighed to choose more or less aggressive treatment including frequency and severity of infections, exposure to secondhand smoke, day care enrollment, sibling history, parental comfort and anxiety, presence of serous otitis media between episodes, time of year, and effect on overall hearing. Measures to prevent otitis media and reserving the diagnosis of acute otitis media for “true” purulent infections can help limit the number of children diagnosed with recurrent disease.
1. Williams RL, Chalmers TC, Stange KC, Chalmers FT, Bowlin SJ. Use of antibiotics in preventing recurrent acute otitis media and in treating otitis media with effusion. A meta-analytic attempt to resolve the brouhaha. JAMA 1993;270:1344-1351.
2. Roark R, Berman S. Continuous twice daily or once daily amoxicillin prophylaxis compared with placebo for children with recurrent acute otitis media. Pediatr Infect Dis 1997;16:376-381.
3. Pichichero ME. Acute otitis media: part II. Treatment in an era of increasing antibiotic resistance. Am Fam Physician 2000;61:2410-2416.
4. American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. Diagnosis and management of acute otitis media. Pediatrics 2004;113:1451-1465.
1. Williams RL, Chalmers TC, Stange KC, Chalmers FT, Bowlin SJ. Use of antibiotics in preventing recurrent acute otitis media and in treating otitis media with effusion. A meta-analytic attempt to resolve the brouhaha. JAMA 1993;270:1344-1351.
2. Roark R, Berman S. Continuous twice daily or once daily amoxicillin prophylaxis compared with placebo for children with recurrent acute otitis media. Pediatr Infect Dis 1997;16:376-381.
3. Pichichero ME. Acute otitis media: part II. Treatment in an era of increasing antibiotic resistance. Am Fam Physician 2000;61:2410-2416.
4. American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. Diagnosis and management of acute otitis media. Pediatrics 2004;113:1451-1465.
Evidence-based answers from the Family Physicians Inquiries Network