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Can we prevent splenic rupture for patients with infectious mononucleosis?
All patients with infectious mononucleosis should be considered at risk for splenic rupture since clinical severity, laboratory results, and physical exam are not reliable predictors of rupture (strength of recommendation [SOR]: B, case-control study). Clinical evidence indicates that most splenic ruptures occur within 4 weeks of symptom onset, which correlates with ultrasound data showing resolution of splenomegaly by 30 days from symptom onset (SOR: B, case-control study). Given the morbidity and mortality associated with splenic rupture, instruct patients to refrain from vigorous physical activity for 1 month after symptom onset (SOR: C, expert opinion).
Evidence summary
The annual incidence of infectious mononucleosis is somewhere between 345 and 671 cases per 100,000 in the US; it is highest in the adolescent age group.1 Splenic rupture is the leading cause of death in infectious mononucleosis, occurring in 0.1% to 0.2% of all cases.1- 4 Based on this figure, approximately 100 cases of rupture may occur yearly in the US, only a few of which are reported.
A retrospective analysis of 8116 patients with infectious mononucleosis at the Mayo Clinic estimated the risk of spontaneous splenic rupture to be 0.1% of cases, correlating with rates found in other studies. The study’s criteria for definite spontaneous rupture are: no recent trauma; recent symptoms; hematologic, serologic, and histologic (splenic) evidence of infectious mononucleosis. Five patients with rupture (average age, 22) were identified; 3 were male. Splenectomy was performed for all patients. Follow-up over 33-years found all patients healthy with minimal subsequent illness.3
A review of 55 cases found almost all splenic ruptures occurred between the fourth and twenty-first days of illness, and that all affected spleens were enlarged, although only half were palpable on exam. Ninety percent of the ruptures occurred in males, and more than half were nontraumatic. There was no correlation between severity of illness and susceptibility to splenic rupture. No specifics were given on duration of illness or how splenomegaly was diagnosed.4
The best technique for identifying splenic enlargement and determining risk of rupture is unclear. In a case-control study, 29 patients were admitted to an ear, nose, and throat department with infectious mononucleosis and were evaluated serially for splenic and hepatic enlargement by ultrasound. Diagnosis was based on clinical picture, a positive heterophile test, and other blood tests. Four patients were included despite negative serology due to compelling clinical presentations and symptoms. Serial ultrasound imaging showed that all had enlarged spleens (mean enlargement 50%–60%); 50% had hepatic enlargement (5%–20% enlargement). The patients were compared with a control group of 8 patients admitted with peritonsillar abscess, as verified by tonsillectomy. No controls had hepatic or splenic enlargement. Physical examinations detected splenomegaly in only 17% of the study patients. The exams were conducted by house staff without blinding, randomization, or tests of reproducibility. Ultrasound scanning was completed on days 1, 3, 5, 10, 20, 90, and 120. The spleen was significantly larger in the infectious mononucleosis group than in the control group for the first 30 days, and no difference in size was found over the subsequent 3 months. No correlation existed between laboratory values and enlargement of the spleen or liver.5
No quality studies evaluate the risks of physical activity in infectious mononucleosis. Case reports of rupture have found comparable rates between traumatic and nontraumatic causes. In addition, no clinical trials evaluate imaging in decisions regarding return to activity and its effect on splenic rupture. Ultrasound is often used in the athletic setting for these decisions but no evidence supports its use as routine practice. The routine use of ultrasound for this purpose would cost more than $1 million to prevent 1 traumatic rupture.6
Recommendations from others
Clinical Sports Medicine recommends athletes refrain from sporting activities until all acute symptoms resolve and contact sports avoided while the spleen is enlarged. No recommendation is given on determining spleen size.7
Team Physician Handbook recommends athletes do no cardiovascular work, lifting, strength training, or contact sports for 2 weeks because of the risk of splenic rupture. Activity is then gradually increased as the athlete improves. Athletes are to avoid contact or weight-lifting for 4 weeks unless they feel well and ultrasound reveals a normal-sized spleen.8
Sports Medicine Secrets advises ultrasound or CT of the spleen to be obtained if there is any suspicion of splenomegaly or if return to play before 4 weeks is contemplated. Light athletic activity may be resumed approximately 3 weeks after symptom onset if the spleen is not tender or enlarged on examination, the patient is afebrile, liver enzymes are normal, and all other complications are resolved. Contact sports may be resumed 4 weeks after symptom onset if there is no documentation of splenomegaly, the athlete feels ready, and all other complications have resolved.9
Mononucleosis patients should restrict strenuous activity for 4 weeks from onset
Drew E. Malloy, MD
University of Arizona Campus Health Center, Tucson
At the University of Arizona student health center, we see over 120 new cases of mononucleosis each year. No clinicians in our group can recall a single splenic rupture in 18 years. The quoted rupture rate of 0.1% based on a study of 8116 patients may be a high estimate and it is likely that most physicians go through their entire career without seeing a single case.
For our group, the value of this review was to point out the lack of correlation with illness severity, lab abnormalities, or a palpable spleen in predicting this rare event. Based on this review, we amended our patient handout to make more specific our advice about restricting strenuous physical activity for 4 weeks from the onset of symptoms.
1. Auwaerter PG. Infectious mononucleosis in middle age. JAMA 1999;281:454-459.
2. Maki DG, Reich RM. Infectious mononucleosis in the athlete. Diagnosis, complications, and management. Am J Sports Med 1982;10:162-173.
3. Farley DR, Zietlow SP, Bannon MP, Farnell MB. Spontaneous rupture of the spleen due to infectious mononucleosis. Mayo Clin Proc 1992;67:846-853.
4. Asgari MM, Begos DG. Spontaneous splenic rupture in infectious mononucleosis: a review. Yale J Biol Med 1997;70:175-182.
5. Dommerby H, Stangerup SE, Stangerup M, Hancke S. Hepatosplenomegaly in infectious mononucleosis assessed by ultrasonic scanning. J Laryngol Otol 1986;100:573-579.
6. Ebell MH. Epstein-Barr virus infectious mononucleosis. Am Fam Physician 2004;70:1279-1287.
7. Brukner P, Khan K. Clinical Sports Medicine. 2nd ed, rev. Australia: McGraw-Hill; 2002.
8. Martin TJ. Infections in athletes. In: Mellion MB et al, eds. Team Physician’s Handbook. 3rd ed. Philadelphia, Pa: Hanley & Belfus; 2001;226-228.
9. Grindel SH, Shea MA. Infections in athletes. In: Mellion MB, Putukian M, Madden CC, eds. Sports MedicineSecrets. 3rd ed. Philadelphia, Pa: Hanley & Belfus; 2003:207.
All patients with infectious mononucleosis should be considered at risk for splenic rupture since clinical severity, laboratory results, and physical exam are not reliable predictors of rupture (strength of recommendation [SOR]: B, case-control study). Clinical evidence indicates that most splenic ruptures occur within 4 weeks of symptom onset, which correlates with ultrasound data showing resolution of splenomegaly by 30 days from symptom onset (SOR: B, case-control study). Given the morbidity and mortality associated with splenic rupture, instruct patients to refrain from vigorous physical activity for 1 month after symptom onset (SOR: C, expert opinion).
Evidence summary
The annual incidence of infectious mononucleosis is somewhere between 345 and 671 cases per 100,000 in the US; it is highest in the adolescent age group.1 Splenic rupture is the leading cause of death in infectious mononucleosis, occurring in 0.1% to 0.2% of all cases.1- 4 Based on this figure, approximately 100 cases of rupture may occur yearly in the US, only a few of which are reported.
A retrospective analysis of 8116 patients with infectious mononucleosis at the Mayo Clinic estimated the risk of spontaneous splenic rupture to be 0.1% of cases, correlating with rates found in other studies. The study’s criteria for definite spontaneous rupture are: no recent trauma; recent symptoms; hematologic, serologic, and histologic (splenic) evidence of infectious mononucleosis. Five patients with rupture (average age, 22) were identified; 3 were male. Splenectomy was performed for all patients. Follow-up over 33-years found all patients healthy with minimal subsequent illness.3
A review of 55 cases found almost all splenic ruptures occurred between the fourth and twenty-first days of illness, and that all affected spleens were enlarged, although only half were palpable on exam. Ninety percent of the ruptures occurred in males, and more than half were nontraumatic. There was no correlation between severity of illness and susceptibility to splenic rupture. No specifics were given on duration of illness or how splenomegaly was diagnosed.4
The best technique for identifying splenic enlargement and determining risk of rupture is unclear. In a case-control study, 29 patients were admitted to an ear, nose, and throat department with infectious mononucleosis and were evaluated serially for splenic and hepatic enlargement by ultrasound. Diagnosis was based on clinical picture, a positive heterophile test, and other blood tests. Four patients were included despite negative serology due to compelling clinical presentations and symptoms. Serial ultrasound imaging showed that all had enlarged spleens (mean enlargement 50%–60%); 50% had hepatic enlargement (5%–20% enlargement). The patients were compared with a control group of 8 patients admitted with peritonsillar abscess, as verified by tonsillectomy. No controls had hepatic or splenic enlargement. Physical examinations detected splenomegaly in only 17% of the study patients. The exams were conducted by house staff without blinding, randomization, or tests of reproducibility. Ultrasound scanning was completed on days 1, 3, 5, 10, 20, 90, and 120. The spleen was significantly larger in the infectious mononucleosis group than in the control group for the first 30 days, and no difference in size was found over the subsequent 3 months. No correlation existed between laboratory values and enlargement of the spleen or liver.5
No quality studies evaluate the risks of physical activity in infectious mononucleosis. Case reports of rupture have found comparable rates between traumatic and nontraumatic causes. In addition, no clinical trials evaluate imaging in decisions regarding return to activity and its effect on splenic rupture. Ultrasound is often used in the athletic setting for these decisions but no evidence supports its use as routine practice. The routine use of ultrasound for this purpose would cost more than $1 million to prevent 1 traumatic rupture.6
Recommendations from others
Clinical Sports Medicine recommends athletes refrain from sporting activities until all acute symptoms resolve and contact sports avoided while the spleen is enlarged. No recommendation is given on determining spleen size.7
Team Physician Handbook recommends athletes do no cardiovascular work, lifting, strength training, or contact sports for 2 weeks because of the risk of splenic rupture. Activity is then gradually increased as the athlete improves. Athletes are to avoid contact or weight-lifting for 4 weeks unless they feel well and ultrasound reveals a normal-sized spleen.8
Sports Medicine Secrets advises ultrasound or CT of the spleen to be obtained if there is any suspicion of splenomegaly or if return to play before 4 weeks is contemplated. Light athletic activity may be resumed approximately 3 weeks after symptom onset if the spleen is not tender or enlarged on examination, the patient is afebrile, liver enzymes are normal, and all other complications are resolved. Contact sports may be resumed 4 weeks after symptom onset if there is no documentation of splenomegaly, the athlete feels ready, and all other complications have resolved.9
Mononucleosis patients should restrict strenuous activity for 4 weeks from onset
Drew E. Malloy, MD
University of Arizona Campus Health Center, Tucson
At the University of Arizona student health center, we see over 120 new cases of mononucleosis each year. No clinicians in our group can recall a single splenic rupture in 18 years. The quoted rupture rate of 0.1% based on a study of 8116 patients may be a high estimate and it is likely that most physicians go through their entire career without seeing a single case.
For our group, the value of this review was to point out the lack of correlation with illness severity, lab abnormalities, or a palpable spleen in predicting this rare event. Based on this review, we amended our patient handout to make more specific our advice about restricting strenuous physical activity for 4 weeks from the onset of symptoms.
All patients with infectious mononucleosis should be considered at risk for splenic rupture since clinical severity, laboratory results, and physical exam are not reliable predictors of rupture (strength of recommendation [SOR]: B, case-control study). Clinical evidence indicates that most splenic ruptures occur within 4 weeks of symptom onset, which correlates with ultrasound data showing resolution of splenomegaly by 30 days from symptom onset (SOR: B, case-control study). Given the morbidity and mortality associated with splenic rupture, instruct patients to refrain from vigorous physical activity for 1 month after symptom onset (SOR: C, expert opinion).
Evidence summary
The annual incidence of infectious mononucleosis is somewhere between 345 and 671 cases per 100,000 in the US; it is highest in the adolescent age group.1 Splenic rupture is the leading cause of death in infectious mononucleosis, occurring in 0.1% to 0.2% of all cases.1- 4 Based on this figure, approximately 100 cases of rupture may occur yearly in the US, only a few of which are reported.
A retrospective analysis of 8116 patients with infectious mononucleosis at the Mayo Clinic estimated the risk of spontaneous splenic rupture to be 0.1% of cases, correlating with rates found in other studies. The study’s criteria for definite spontaneous rupture are: no recent trauma; recent symptoms; hematologic, serologic, and histologic (splenic) evidence of infectious mononucleosis. Five patients with rupture (average age, 22) were identified; 3 were male. Splenectomy was performed for all patients. Follow-up over 33-years found all patients healthy with minimal subsequent illness.3
A review of 55 cases found almost all splenic ruptures occurred between the fourth and twenty-first days of illness, and that all affected spleens were enlarged, although only half were palpable on exam. Ninety percent of the ruptures occurred in males, and more than half were nontraumatic. There was no correlation between severity of illness and susceptibility to splenic rupture. No specifics were given on duration of illness or how splenomegaly was diagnosed.4
The best technique for identifying splenic enlargement and determining risk of rupture is unclear. In a case-control study, 29 patients were admitted to an ear, nose, and throat department with infectious mononucleosis and were evaluated serially for splenic and hepatic enlargement by ultrasound. Diagnosis was based on clinical picture, a positive heterophile test, and other blood tests. Four patients were included despite negative serology due to compelling clinical presentations and symptoms. Serial ultrasound imaging showed that all had enlarged spleens (mean enlargement 50%–60%); 50% had hepatic enlargement (5%–20% enlargement). The patients were compared with a control group of 8 patients admitted with peritonsillar abscess, as verified by tonsillectomy. No controls had hepatic or splenic enlargement. Physical examinations detected splenomegaly in only 17% of the study patients. The exams were conducted by house staff without blinding, randomization, or tests of reproducibility. Ultrasound scanning was completed on days 1, 3, 5, 10, 20, 90, and 120. The spleen was significantly larger in the infectious mononucleosis group than in the control group for the first 30 days, and no difference in size was found over the subsequent 3 months. No correlation existed between laboratory values and enlargement of the spleen or liver.5
No quality studies evaluate the risks of physical activity in infectious mononucleosis. Case reports of rupture have found comparable rates between traumatic and nontraumatic causes. In addition, no clinical trials evaluate imaging in decisions regarding return to activity and its effect on splenic rupture. Ultrasound is often used in the athletic setting for these decisions but no evidence supports its use as routine practice. The routine use of ultrasound for this purpose would cost more than $1 million to prevent 1 traumatic rupture.6
Recommendations from others
Clinical Sports Medicine recommends athletes refrain from sporting activities until all acute symptoms resolve and contact sports avoided while the spleen is enlarged. No recommendation is given on determining spleen size.7
Team Physician Handbook recommends athletes do no cardiovascular work, lifting, strength training, or contact sports for 2 weeks because of the risk of splenic rupture. Activity is then gradually increased as the athlete improves. Athletes are to avoid contact or weight-lifting for 4 weeks unless they feel well and ultrasound reveals a normal-sized spleen.8
Sports Medicine Secrets advises ultrasound or CT of the spleen to be obtained if there is any suspicion of splenomegaly or if return to play before 4 weeks is contemplated. Light athletic activity may be resumed approximately 3 weeks after symptom onset if the spleen is not tender or enlarged on examination, the patient is afebrile, liver enzymes are normal, and all other complications are resolved. Contact sports may be resumed 4 weeks after symptom onset if there is no documentation of splenomegaly, the athlete feels ready, and all other complications have resolved.9
Mononucleosis patients should restrict strenuous activity for 4 weeks from onset
Drew E. Malloy, MD
University of Arizona Campus Health Center, Tucson
At the University of Arizona student health center, we see over 120 new cases of mononucleosis each year. No clinicians in our group can recall a single splenic rupture in 18 years. The quoted rupture rate of 0.1% based on a study of 8116 patients may be a high estimate and it is likely that most physicians go through their entire career without seeing a single case.
For our group, the value of this review was to point out the lack of correlation with illness severity, lab abnormalities, or a palpable spleen in predicting this rare event. Based on this review, we amended our patient handout to make more specific our advice about restricting strenuous physical activity for 4 weeks from the onset of symptoms.
1. Auwaerter PG. Infectious mononucleosis in middle age. JAMA 1999;281:454-459.
2. Maki DG, Reich RM. Infectious mononucleosis in the athlete. Diagnosis, complications, and management. Am J Sports Med 1982;10:162-173.
3. Farley DR, Zietlow SP, Bannon MP, Farnell MB. Spontaneous rupture of the spleen due to infectious mononucleosis. Mayo Clin Proc 1992;67:846-853.
4. Asgari MM, Begos DG. Spontaneous splenic rupture in infectious mononucleosis: a review. Yale J Biol Med 1997;70:175-182.
5. Dommerby H, Stangerup SE, Stangerup M, Hancke S. Hepatosplenomegaly in infectious mononucleosis assessed by ultrasonic scanning. J Laryngol Otol 1986;100:573-579.
6. Ebell MH. Epstein-Barr virus infectious mononucleosis. Am Fam Physician 2004;70:1279-1287.
7. Brukner P, Khan K. Clinical Sports Medicine. 2nd ed, rev. Australia: McGraw-Hill; 2002.
8. Martin TJ. Infections in athletes. In: Mellion MB et al, eds. Team Physician’s Handbook. 3rd ed. Philadelphia, Pa: Hanley & Belfus; 2001;226-228.
9. Grindel SH, Shea MA. Infections in athletes. In: Mellion MB, Putukian M, Madden CC, eds. Sports MedicineSecrets. 3rd ed. Philadelphia, Pa: Hanley & Belfus; 2003:207.
1. Auwaerter PG. Infectious mononucleosis in middle age. JAMA 1999;281:454-459.
2. Maki DG, Reich RM. Infectious mononucleosis in the athlete. Diagnosis, complications, and management. Am J Sports Med 1982;10:162-173.
3. Farley DR, Zietlow SP, Bannon MP, Farnell MB. Spontaneous rupture of the spleen due to infectious mononucleosis. Mayo Clin Proc 1992;67:846-853.
4. Asgari MM, Begos DG. Spontaneous splenic rupture in infectious mononucleosis: a review. Yale J Biol Med 1997;70:175-182.
5. Dommerby H, Stangerup SE, Stangerup M, Hancke S. Hepatosplenomegaly in infectious mononucleosis assessed by ultrasonic scanning. J Laryngol Otol 1986;100:573-579.
6. Ebell MH. Epstein-Barr virus infectious mononucleosis. Am Fam Physician 2004;70:1279-1287.
7. Brukner P, Khan K. Clinical Sports Medicine. 2nd ed, rev. Australia: McGraw-Hill; 2002.
8. Martin TJ. Infections in athletes. In: Mellion MB et al, eds. Team Physician’s Handbook. 3rd ed. Philadelphia, Pa: Hanley & Belfus; 2001;226-228.
9. Grindel SH, Shea MA. Infections in athletes. In: Mellion MB, Putukian M, Madden CC, eds. Sports MedicineSecrets. 3rd ed. Philadelphia, Pa: Hanley & Belfus; 2003:207.
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 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
What is the best treatment for Osgood-Schlatter disease?
Osgood-Schlatter disease is a common cause of pain and tenderness at the tibial tuberosity in active adolescents. It is typically a self-limited condition that waxes and wanes, but which often takes months to years to resolve entirely. It is best managed with conservative measures (activity modification, ice, anti-inflammatory agents) and time (strength of recommendation [SOR]: B, several case series and retrospective studies).
In chronic cases that are refractory to conservative treatment, surgical intervention yields good results, particularly for patients with bony or cartilaginous ossicles. Excision of these ossicles produces resolution of symptoms and return to activity in several weeks (SOR: C, several case series). Corticosteroid injections are not recommended (SOR: C, case reports and expert opinion).
Evidence summary
No prospective, interventional studies evaluate the treatment of Osgood-Schlatter disease. One case series followed the natural course of the disease in 261 patients (365 symptomatic knees) for 12 to 24 months; 237 (90.8%) patients responded well to restriction of sports activity and nonsteroidal anti-inflammatory agents. The 24 patients who did not improve with conservative measures underwent surgical excision of ossicles, and all returned to normal activities (mean time, 4.5 weeks).1
In another case series of 118 patients (151 knees), 88% responded to intermittent limitation of activity (weeks to months) or cylinder casting if limiting activity was ineffective. The remaining 14 patients showed no improvement from these measures; all had surgical excision of an ossicle, sometimes combined with a tubercle-thinning procedure. Only 1 of these patients (7%) did not have complete relief and return to full activities at 6 weeks.2
Retrospective analyses also support a conservative approach. One retrospective survey of 68 young athletes with Osgood-Schlatter found they required an average of 3.2 months off all training and 7.3 months of some activity restrictions.3 In another survey, 20 of 22 (91%) adolescent athletes with Osgood-Schlatter were able to manage their symptoms with ice, aspirin, and mild activity modification. Only 2 needed to stop playing all sports for any period of time, and none required surgery.4
Another retrospective review analyzed 50 patients with Osgood-Schlatter (69 knees) for an average of 9 years. No treatments or activity restrictions were recommended. At time of follow-up, 36 (76%) had no limitations, but kneeling continued to be uncomfortable in 60%.5
No interventional studies have explicitly evaluated commonly recommended conservative treatments such as ice, analgesics, activity restriction, stretching, strengthening, or anti-inflammatory medication. Corticosteroid injections are generally not recommended, due to case reports of complications, primarily related to subcutaneous atrophy.6 One small case series demonstrated improvement in Osgood-Schlatter disease pain in 19 of 24 (79%) knees after using an infrapatellar strap for 6 to 8 weeks.7
Refractory cases have been treated with a variety of surgical interventions. In 1 case series, 67 patients (70 knees) (mean age 19.6, 77% male) with at least 18 months of symptoms despite conservative treatment underwent resection of an ossicle (62 cases) or excision of prominent tibial tubercle (8 cases). These patients were followed for 2.2 years, with 56 (90%) patients with ossicle-resection able to return to maximal sports activity without pain, tenderness, loss of motion, or atrophy.8
Another case series compared 22 patients who1 underwent drilling of the tibial tubercle (with or without the removal of the tibial tubercle) with 22 patients who had excision of loose ossicles or cartilage. Seventeen of the 22 (77%) patients with ossicle excision had complete resolution of symptoms compared with 8 of the 22 (36%) in the patients who underwent tibial tubercle drilling.9
One surgical series evaluated excision of tibial tuberosity in 35 patients (42 knees) who did not improve with conservative treatment for an average of 13.25 months. For 37 of 42 knees (88%), patients reported complete relief of pain, and all returned to activity without limitation. The average time to return to sports was 15.2 weeks.10
Recommendations from others
The American Academy of Orthopaedic Surgeons and the American Academy of Family Practice recommend activity limitation, ice, anti-inflammatories, protective padding, quadriceps/hamstring strengthening, and time in the management of Osgood-Schlatter disease.11,12
Few patients have poor results with conservative measures
James Barbee, MD
John Peter Smith Family Practice Residency Program, Ft. Worth, Tex
Osgood-Schlatter disease is a common problem that all primary care physicians must be ready to recognize and treat. While the research (primarily surgical series) indicates that 10% to 12% of patients may not improve with conservative measures, I have not had nearly that high a percentage of patients who require surgical intervention. Surgery is only offered after the tubercle attaches to the femur, or the tubercle fails to attach at all. In fact, I do not x-ray typical cases of Osgood-Schlatter disease unless evidence suggests patella tendon avulsion, or if parental concern is high. This means that, in most cases, the primary care physician has quite a while to try conservative measures before incurring the expense of radiography or an orthopedic consultation.
Drug brand names
- Candesartan • Atacand
- Felodipine • Plendil
- Spironolactone • Aldactone
- Valsartan • Diovan
1. Hussain A, Hagroo GA. Osgood-Schlatter disease. Sports Exer Injury 1996;2:202-206.
2. Mital MA, Matza RA, Cohen J. The so-called unresolved Osgood-Schlatter lesion. J Bone Joint Surg Am 1980;62:732-739.
3. Kujala UM, Kvist M, Heinonen O. Osgood-Schlatter’s disease in adolescent athletes. Retrospective study of incidence and duration. Am J Sports Med 1985;13:236-241.
4. Beovich R, Fricker PA. Osgood-Schlatter’s disease. A review of the literature and an Australian series. Aust J Sci Med Sport 1988;20:11-13.
5. Krause BL, Williams JP, Catterall A. Natural history of Osgood-Schlatter disease. J Pediatr Orthop 1990;10:65-68.
6. Rostron PK, Calver RF. Subcutaneous atrophy following methylprednisolone injection in Osgood-Schlatter epi-physitis. J Bone Joint Surg Am 1979;61:627-628.
7. Levine J, Kashyap S. A new conservative treatment of Osgood-Schlatter disease. Clin Orthop 1981;158:126-128.
8. Orava S, Malinen L, Karpakka JJ, et al. Results of surgical treatment of unresolved Osgood-Schlatter lesion. Ann Chir Gynaecol 2000;89:298-302.
9. Glynn MK, Regan BF. Surgical treatment of Osgood-Schlatter’s disease. J Pediatr Orthop 1983;3:216-219.
10. Flowers MJ, Bhadreshwar DR. Tibial tuberosity excision for symptomatic Osgood-Schlatter disease. J Pediatr Orthop 1995;15:292-297.
11. Osgood-Schlatter disease (knee pain). American Academy of Orthopaedic Surgeons Web site. Last updated July 2000. Available at: orthoinfo.aaos.org/fact/thr_report. cfm?Thread_ID=145&topcategory=Knee. Accessed on January 14, 2004.
12. Osgood-Schlatter. Disease: A cause of knee pain in children. American Academy of Family Physicians Web site. Last updated March 2002. Available at: familydoctor.org/handouts/135.html. Accessed on January 14, 2004.
Osgood-Schlatter disease is a common cause of pain and tenderness at the tibial tuberosity in active adolescents. It is typically a self-limited condition that waxes and wanes, but which often takes months to years to resolve entirely. It is best managed with conservative measures (activity modification, ice, anti-inflammatory agents) and time (strength of recommendation [SOR]: B, several case series and retrospective studies).
In chronic cases that are refractory to conservative treatment, surgical intervention yields good results, particularly for patients with bony or cartilaginous ossicles. Excision of these ossicles produces resolution of symptoms and return to activity in several weeks (SOR: C, several case series). Corticosteroid injections are not recommended (SOR: C, case reports and expert opinion).
Evidence summary
No prospective, interventional studies evaluate the treatment of Osgood-Schlatter disease. One case series followed the natural course of the disease in 261 patients (365 symptomatic knees) for 12 to 24 months; 237 (90.8%) patients responded well to restriction of sports activity and nonsteroidal anti-inflammatory agents. The 24 patients who did not improve with conservative measures underwent surgical excision of ossicles, and all returned to normal activities (mean time, 4.5 weeks).1
In another case series of 118 patients (151 knees), 88% responded to intermittent limitation of activity (weeks to months) or cylinder casting if limiting activity was ineffective. The remaining 14 patients showed no improvement from these measures; all had surgical excision of an ossicle, sometimes combined with a tubercle-thinning procedure. Only 1 of these patients (7%) did not have complete relief and return to full activities at 6 weeks.2
Retrospective analyses also support a conservative approach. One retrospective survey of 68 young athletes with Osgood-Schlatter found they required an average of 3.2 months off all training and 7.3 months of some activity restrictions.3 In another survey, 20 of 22 (91%) adolescent athletes with Osgood-Schlatter were able to manage their symptoms with ice, aspirin, and mild activity modification. Only 2 needed to stop playing all sports for any period of time, and none required surgery.4
Another retrospective review analyzed 50 patients with Osgood-Schlatter (69 knees) for an average of 9 years. No treatments or activity restrictions were recommended. At time of follow-up, 36 (76%) had no limitations, but kneeling continued to be uncomfortable in 60%.5
No interventional studies have explicitly evaluated commonly recommended conservative treatments such as ice, analgesics, activity restriction, stretching, strengthening, or anti-inflammatory medication. Corticosteroid injections are generally not recommended, due to case reports of complications, primarily related to subcutaneous atrophy.6 One small case series demonstrated improvement in Osgood-Schlatter disease pain in 19 of 24 (79%) knees after using an infrapatellar strap for 6 to 8 weeks.7
Refractory cases have been treated with a variety of surgical interventions. In 1 case series, 67 patients (70 knees) (mean age 19.6, 77% male) with at least 18 months of symptoms despite conservative treatment underwent resection of an ossicle (62 cases) or excision of prominent tibial tubercle (8 cases). These patients were followed for 2.2 years, with 56 (90%) patients with ossicle-resection able to return to maximal sports activity without pain, tenderness, loss of motion, or atrophy.8
Another case series compared 22 patients who1 underwent drilling of the tibial tubercle (with or without the removal of the tibial tubercle) with 22 patients who had excision of loose ossicles or cartilage. Seventeen of the 22 (77%) patients with ossicle excision had complete resolution of symptoms compared with 8 of the 22 (36%) in the patients who underwent tibial tubercle drilling.9
One surgical series evaluated excision of tibial tuberosity in 35 patients (42 knees) who did not improve with conservative treatment for an average of 13.25 months. For 37 of 42 knees (88%), patients reported complete relief of pain, and all returned to activity without limitation. The average time to return to sports was 15.2 weeks.10
Recommendations from others
The American Academy of Orthopaedic Surgeons and the American Academy of Family Practice recommend activity limitation, ice, anti-inflammatories, protective padding, quadriceps/hamstring strengthening, and time in the management of Osgood-Schlatter disease.11,12
Few patients have poor results with conservative measures
James Barbee, MD
John Peter Smith Family Practice Residency Program, Ft. Worth, Tex
Osgood-Schlatter disease is a common problem that all primary care physicians must be ready to recognize and treat. While the research (primarily surgical series) indicates that 10% to 12% of patients may not improve with conservative measures, I have not had nearly that high a percentage of patients who require surgical intervention. Surgery is only offered after the tubercle attaches to the femur, or the tubercle fails to attach at all. In fact, I do not x-ray typical cases of Osgood-Schlatter disease unless evidence suggests patella tendon avulsion, or if parental concern is high. This means that, in most cases, the primary care physician has quite a while to try conservative measures before incurring the expense of radiography or an orthopedic consultation.
Drug brand names
- Candesartan • Atacand
- Felodipine • Plendil
- Spironolactone • Aldactone
- Valsartan • Diovan
Osgood-Schlatter disease is a common cause of pain and tenderness at the tibial tuberosity in active adolescents. It is typically a self-limited condition that waxes and wanes, but which often takes months to years to resolve entirely. It is best managed with conservative measures (activity modification, ice, anti-inflammatory agents) and time (strength of recommendation [SOR]: B, several case series and retrospective studies).
In chronic cases that are refractory to conservative treatment, surgical intervention yields good results, particularly for patients with bony or cartilaginous ossicles. Excision of these ossicles produces resolution of symptoms and return to activity in several weeks (SOR: C, several case series). Corticosteroid injections are not recommended (SOR: C, case reports and expert opinion).
Evidence summary
No prospective, interventional studies evaluate the treatment of Osgood-Schlatter disease. One case series followed the natural course of the disease in 261 patients (365 symptomatic knees) for 12 to 24 months; 237 (90.8%) patients responded well to restriction of sports activity and nonsteroidal anti-inflammatory agents. The 24 patients who did not improve with conservative measures underwent surgical excision of ossicles, and all returned to normal activities (mean time, 4.5 weeks).1
In another case series of 118 patients (151 knees), 88% responded to intermittent limitation of activity (weeks to months) or cylinder casting if limiting activity was ineffective. The remaining 14 patients showed no improvement from these measures; all had surgical excision of an ossicle, sometimes combined with a tubercle-thinning procedure. Only 1 of these patients (7%) did not have complete relief and return to full activities at 6 weeks.2
Retrospective analyses also support a conservative approach. One retrospective survey of 68 young athletes with Osgood-Schlatter found they required an average of 3.2 months off all training and 7.3 months of some activity restrictions.3 In another survey, 20 of 22 (91%) adolescent athletes with Osgood-Schlatter were able to manage their symptoms with ice, aspirin, and mild activity modification. Only 2 needed to stop playing all sports for any period of time, and none required surgery.4
Another retrospective review analyzed 50 patients with Osgood-Schlatter (69 knees) for an average of 9 years. No treatments or activity restrictions were recommended. At time of follow-up, 36 (76%) had no limitations, but kneeling continued to be uncomfortable in 60%.5
No interventional studies have explicitly evaluated commonly recommended conservative treatments such as ice, analgesics, activity restriction, stretching, strengthening, or anti-inflammatory medication. Corticosteroid injections are generally not recommended, due to case reports of complications, primarily related to subcutaneous atrophy.6 One small case series demonstrated improvement in Osgood-Schlatter disease pain in 19 of 24 (79%) knees after using an infrapatellar strap for 6 to 8 weeks.7
Refractory cases have been treated with a variety of surgical interventions. In 1 case series, 67 patients (70 knees) (mean age 19.6, 77% male) with at least 18 months of symptoms despite conservative treatment underwent resection of an ossicle (62 cases) or excision of prominent tibial tubercle (8 cases). These patients were followed for 2.2 years, with 56 (90%) patients with ossicle-resection able to return to maximal sports activity without pain, tenderness, loss of motion, or atrophy.8
Another case series compared 22 patients who1 underwent drilling of the tibial tubercle (with or without the removal of the tibial tubercle) with 22 patients who had excision of loose ossicles or cartilage. Seventeen of the 22 (77%) patients with ossicle excision had complete resolution of symptoms compared with 8 of the 22 (36%) in the patients who underwent tibial tubercle drilling.9
One surgical series evaluated excision of tibial tuberosity in 35 patients (42 knees) who did not improve with conservative treatment for an average of 13.25 months. For 37 of 42 knees (88%), patients reported complete relief of pain, and all returned to activity without limitation. The average time to return to sports was 15.2 weeks.10
Recommendations from others
The American Academy of Orthopaedic Surgeons and the American Academy of Family Practice recommend activity limitation, ice, anti-inflammatories, protective padding, quadriceps/hamstring strengthening, and time in the management of Osgood-Schlatter disease.11,12
Few patients have poor results with conservative measures
James Barbee, MD
John Peter Smith Family Practice Residency Program, Ft. Worth, Tex
Osgood-Schlatter disease is a common problem that all primary care physicians must be ready to recognize and treat. While the research (primarily surgical series) indicates that 10% to 12% of patients may not improve with conservative measures, I have not had nearly that high a percentage of patients who require surgical intervention. Surgery is only offered after the tubercle attaches to the femur, or the tubercle fails to attach at all. In fact, I do not x-ray typical cases of Osgood-Schlatter disease unless evidence suggests patella tendon avulsion, or if parental concern is high. This means that, in most cases, the primary care physician has quite a while to try conservative measures before incurring the expense of radiography or an orthopedic consultation.
Drug brand names
- Candesartan • Atacand
- Felodipine • Plendil
- Spironolactone • Aldactone
- Valsartan • Diovan
1. Hussain A, Hagroo GA. Osgood-Schlatter disease. Sports Exer Injury 1996;2:202-206.
2. Mital MA, Matza RA, Cohen J. The so-called unresolved Osgood-Schlatter lesion. J Bone Joint Surg Am 1980;62:732-739.
3. Kujala UM, Kvist M, Heinonen O. Osgood-Schlatter’s disease in adolescent athletes. Retrospective study of incidence and duration. Am J Sports Med 1985;13:236-241.
4. Beovich R, Fricker PA. Osgood-Schlatter’s disease. A review of the literature and an Australian series. Aust J Sci Med Sport 1988;20:11-13.
5. Krause BL, Williams JP, Catterall A. Natural history of Osgood-Schlatter disease. J Pediatr Orthop 1990;10:65-68.
6. Rostron PK, Calver RF. Subcutaneous atrophy following methylprednisolone injection in Osgood-Schlatter epi-physitis. J Bone Joint Surg Am 1979;61:627-628.
7. Levine J, Kashyap S. A new conservative treatment of Osgood-Schlatter disease. Clin Orthop 1981;158:126-128.
8. Orava S, Malinen L, Karpakka JJ, et al. Results of surgical treatment of unresolved Osgood-Schlatter lesion. Ann Chir Gynaecol 2000;89:298-302.
9. Glynn MK, Regan BF. Surgical treatment of Osgood-Schlatter’s disease. J Pediatr Orthop 1983;3:216-219.
10. Flowers MJ, Bhadreshwar DR. Tibial tuberosity excision for symptomatic Osgood-Schlatter disease. J Pediatr Orthop 1995;15:292-297.
11. Osgood-Schlatter disease (knee pain). American Academy of Orthopaedic Surgeons Web site. Last updated July 2000. Available at: orthoinfo.aaos.org/fact/thr_report. cfm?Thread_ID=145&topcategory=Knee. Accessed on January 14, 2004.
12. Osgood-Schlatter. Disease: A cause of knee pain in children. American Academy of Family Physicians Web site. Last updated March 2002. Available at: familydoctor.org/handouts/135.html. Accessed on January 14, 2004.
1. Hussain A, Hagroo GA. Osgood-Schlatter disease. Sports Exer Injury 1996;2:202-206.
2. Mital MA, Matza RA, Cohen J. The so-called unresolved Osgood-Schlatter lesion. J Bone Joint Surg Am 1980;62:732-739.
3. Kujala UM, Kvist M, Heinonen O. Osgood-Schlatter’s disease in adolescent athletes. Retrospective study of incidence and duration. Am J Sports Med 1985;13:236-241.
4. Beovich R, Fricker PA. Osgood-Schlatter’s disease. A review of the literature and an Australian series. Aust J Sci Med Sport 1988;20:11-13.
5. Krause BL, Williams JP, Catterall A. Natural history of Osgood-Schlatter disease. J Pediatr Orthop 1990;10:65-68.
6. Rostron PK, Calver RF. Subcutaneous atrophy following methylprednisolone injection in Osgood-Schlatter epi-physitis. J Bone Joint Surg Am 1979;61:627-628.
7. Levine J, Kashyap S. A new conservative treatment of Osgood-Schlatter disease. Clin Orthop 1981;158:126-128.
8. Orava S, Malinen L, Karpakka JJ, et al. Results of surgical treatment of unresolved Osgood-Schlatter lesion. Ann Chir Gynaecol 2000;89:298-302.
9. Glynn MK, Regan BF. Surgical treatment of Osgood-Schlatter’s disease. J Pediatr Orthop 1983;3:216-219.
10. Flowers MJ, Bhadreshwar DR. Tibial tuberosity excision for symptomatic Osgood-Schlatter disease. J Pediatr Orthop 1995;15:292-297.
11. Osgood-Schlatter disease (knee pain). American Academy of Orthopaedic Surgeons Web site. Last updated July 2000. Available at: orthoinfo.aaos.org/fact/thr_report. cfm?Thread_ID=145&topcategory=Knee. Accessed on January 14, 2004.
12. Osgood-Schlatter. Disease: A cause of knee pain in children. American Academy of Family Physicians Web site. Last updated March 2002. Available at: familydoctor.org/handouts/135.html. Accessed on January 14, 2004.
Evidence-based answers from the Family Physicians Inquiries Network
Is folate supplementation indicated for patients with CAD?
There is insufficient evidence to advocate the routine use of folate supplementation for the treatment of coronary artery disease (CAD). High levels of serum homocysteine have been associated in several studies with an increased risk for CAD (strength of recommendation [SOR]: B, associated in case-control studies). Folate supplementation decreases the level of serum homocysteine (SOR: A, meta-analysis of randomized controlled trials). This indirect evidence suggests that folate supplementation may be of benefit in slowing the progress of arteriosclerosis.
Two randomized controlled trials measuring the clinical benefits of folate supplementation for patients with CAD have been completed, with differing results. One study showed no benefit of 0.5 mg/d of folate for patients with stable CAD already on statin therapy. The other study found that patients given 1 mg/d of folate with vitamins B6 and B12 had a decreased restenosis rate after percutaneous coronary intervention (PCI) (SOR: B, conflicting randomized controlled trials).
It is possible that larger doses of folate are needed to be of clinical benefit, or that the addition of vitamins B6 and B12 are needed for synergy. Several randomized control trials are underway to further assess folate’s affect on CAD.
Evidence summary
Hyperhomocysteinemia is defined as a fasting plasma homocysteine level 15 μmol/L, although levels >10 μmol/L appear to have detrimental effects on risk profiles for CAD and arteriosclerosis.1 In 22 of 27 retrospective case-control studies, patients with CAD had significantly higher plasma homocysteine levels than control subjects (odds ratio [OR]=1.2–10.9, after adjustment for other CAD risk factors).2,3 However, only 4 of 7 prospective nested case-control trials showed a correlation between elevated homocysteine and myocardial infarction (MI) and coronary death.2
A meta-analysis of 12 randomized controlled trials found that folate supplementation, with vitamin B6 and B12, reduces plasma homocysteine levels.4 However, the long-term clinical cons quences of these interventions are unknown. At doses of 1 gm/d folate has no known side-effects.5
Two randomized, placebo-controlled trials of folate reporting clinical endpoints have been completed. One study analyzed folate supplementation in a patient population with known, stable CAD and found no difference in clinical endpoints at 24 months.6 In this study, 593 patients were randomized to receive either 0.5 mg/d of folic acid or placebo. The primary study endpoint was a composite of events including: overall mortality, sudden death, MI, stroke, and major vascular surgery. The study was powered to detect a 50% reduction in clinical events based on existing observational data in populations with CAD. An event rate of 15% for the 2-year interval was assumed.6 All patients in this study were on statin therapy prior to initiation of folate supplementation.
The second study analyzed folate supplementation in 553 post-PCI patients. Patients were treated with 1 mg of folate plus 10 mg of vitamin B6 and 400 μg of vitamin B12 for 6 months after the PCI. After a mean follow-up of 11 months, the rate of restenosis requiring revascularization was lower in the vitamin-treated study arm (9.9% vs 16% restenosis rate; relative risk [RR]=0.62; 95% confidence interval [CI], 0.40–0.97; number needed to treat=16).7 There was also a nonsignificant trend toward fewer deaths and MIs in the treated arm at both 6 and 12 months after intervention (death: 1.5% vs 2.8%; RR=0.54; 95% CI, 0.016–1.7; MI: 2.6% vs 4.3%; RR=0.60; 95% CI, 0.24–1.51). Statin use was similar in both control (71%) and treatment groups (69%).
Recommendations from others
The American Heart Association and American College of Cardiology do not recommend the routine use of high-dose folic acid or B-vitamin supplements for the primary or secondary prevention of cardiovascular events. The AHA recommendation is to meet recommended daily allowances of folate (400 μg), B12 (2.4 μg), and B6 (1.7 mg) primarily through a balanced diet, with use of supplements if diet alone does not meet the above requirements.8 Since 1998, wheat flour has been supplemented with folate, adding an estimated 100 μg/day to the average American diet.8
The Canadian Task Force on Preventive Health Care (CTFPHC) finds insufficient evidence to advocate screening for hyperhomocysteinemia and rely on expert opinion to advocate treatment in select, high-risk populations.2 Currently, the CTFPHC advocates meeting the recommended daily allowance of folate, B12, and B6.2
Folate for CAD an unanswered question
James M. Gill, MD, MPH
Christianacare Health System, Wilmington, Del
Folate seems like a simple, inexpensive, and relatively benign way to improve care. It is no wonder that many physicians have been recommending folate to their patients with CAD for years. However, as responsible physicians, we need more comprehensive evidence on the benefit of folate before making such universal recommendations.
Several points are important: first, most of the evidence on folate is from observational studies. Only 1 interventional study has shown benefit for patients with CAD, and this study used folate in combination with vitamins B6 and B12. Therefore, if physicians are going to recommend folate supplementation to their patients with CAD, they should recommend this combination rather than folate alone. Also, since this study only included patients who are post-PTCA, it may not apply to all patients with CAD. In short, there is still a fair amount of uncertainty in the answer to this clinical question. We should discuss this uncertainty with our patients, and come to a mutual decision based on preferences.
1. Ford ES, Smith SJ, Stroup DF, Steinberg KK, Mueller PW, Thacker SB. Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies. Int J Epidemiol 2002;31:59-70.
2. Booth GL, Wang EE. Preventive health care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary artery disease events. The Canadian Task Force on Preventive Health Care. CMAJ 2000;163:21-29.
3. Bandolier Library. Homocysteine and heart disease: an update. Available at: http://www.jr2.ox.ac.uk/bandolier/booth/cardiac/homheart.html. Accessed on May 29, 2003.
4. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration. BMJ 1998;316:894-898.
5. Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. JAMA 2002;287:3116-3126.
6. Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ. Secondary prevention with folic acid: Effects on clinical outcomes. J Am Coll Cardiol 2003;41:2105-2113.
7. Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA 2002;288:973-979.
8. American Heart Association. AHA Science Advisory: Homocyst(e)ine, Diet, and Cardiovascular Diseases. Available at: http://www.americanheart.org. Accessed on May 29, 2003.
There is insufficient evidence to advocate the routine use of folate supplementation for the treatment of coronary artery disease (CAD). High levels of serum homocysteine have been associated in several studies with an increased risk for CAD (strength of recommendation [SOR]: B, associated in case-control studies). Folate supplementation decreases the level of serum homocysteine (SOR: A, meta-analysis of randomized controlled trials). This indirect evidence suggests that folate supplementation may be of benefit in slowing the progress of arteriosclerosis.
Two randomized controlled trials measuring the clinical benefits of folate supplementation for patients with CAD have been completed, with differing results. One study showed no benefit of 0.5 mg/d of folate for patients with stable CAD already on statin therapy. The other study found that patients given 1 mg/d of folate with vitamins B6 and B12 had a decreased restenosis rate after percutaneous coronary intervention (PCI) (SOR: B, conflicting randomized controlled trials).
It is possible that larger doses of folate are needed to be of clinical benefit, or that the addition of vitamins B6 and B12 are needed for synergy. Several randomized control trials are underway to further assess folate’s affect on CAD.
Evidence summary
Hyperhomocysteinemia is defined as a fasting plasma homocysteine level 15 μmol/L, although levels >10 μmol/L appear to have detrimental effects on risk profiles for CAD and arteriosclerosis.1 In 22 of 27 retrospective case-control studies, patients with CAD had significantly higher plasma homocysteine levels than control subjects (odds ratio [OR]=1.2–10.9, after adjustment for other CAD risk factors).2,3 However, only 4 of 7 prospective nested case-control trials showed a correlation between elevated homocysteine and myocardial infarction (MI) and coronary death.2
A meta-analysis of 12 randomized controlled trials found that folate supplementation, with vitamin B6 and B12, reduces plasma homocysteine levels.4 However, the long-term clinical cons quences of these interventions are unknown. At doses of 1 gm/d folate has no known side-effects.5
Two randomized, placebo-controlled trials of folate reporting clinical endpoints have been completed. One study analyzed folate supplementation in a patient population with known, stable CAD and found no difference in clinical endpoints at 24 months.6 In this study, 593 patients were randomized to receive either 0.5 mg/d of folic acid or placebo. The primary study endpoint was a composite of events including: overall mortality, sudden death, MI, stroke, and major vascular surgery. The study was powered to detect a 50% reduction in clinical events based on existing observational data in populations with CAD. An event rate of 15% for the 2-year interval was assumed.6 All patients in this study were on statin therapy prior to initiation of folate supplementation.
The second study analyzed folate supplementation in 553 post-PCI patients. Patients were treated with 1 mg of folate plus 10 mg of vitamin B6 and 400 μg of vitamin B12 for 6 months after the PCI. After a mean follow-up of 11 months, the rate of restenosis requiring revascularization was lower in the vitamin-treated study arm (9.9% vs 16% restenosis rate; relative risk [RR]=0.62; 95% confidence interval [CI], 0.40–0.97; number needed to treat=16).7 There was also a nonsignificant trend toward fewer deaths and MIs in the treated arm at both 6 and 12 months after intervention (death: 1.5% vs 2.8%; RR=0.54; 95% CI, 0.016–1.7; MI: 2.6% vs 4.3%; RR=0.60; 95% CI, 0.24–1.51). Statin use was similar in both control (71%) and treatment groups (69%).
Recommendations from others
The American Heart Association and American College of Cardiology do not recommend the routine use of high-dose folic acid or B-vitamin supplements for the primary or secondary prevention of cardiovascular events. The AHA recommendation is to meet recommended daily allowances of folate (400 μg), B12 (2.4 μg), and B6 (1.7 mg) primarily through a balanced diet, with use of supplements if diet alone does not meet the above requirements.8 Since 1998, wheat flour has been supplemented with folate, adding an estimated 100 μg/day to the average American diet.8
The Canadian Task Force on Preventive Health Care (CTFPHC) finds insufficient evidence to advocate screening for hyperhomocysteinemia and rely on expert opinion to advocate treatment in select, high-risk populations.2 Currently, the CTFPHC advocates meeting the recommended daily allowance of folate, B12, and B6.2
Folate for CAD an unanswered question
James M. Gill, MD, MPH
Christianacare Health System, Wilmington, Del
Folate seems like a simple, inexpensive, and relatively benign way to improve care. It is no wonder that many physicians have been recommending folate to their patients with CAD for years. However, as responsible physicians, we need more comprehensive evidence on the benefit of folate before making such universal recommendations.
Several points are important: first, most of the evidence on folate is from observational studies. Only 1 interventional study has shown benefit for patients with CAD, and this study used folate in combination with vitamins B6 and B12. Therefore, if physicians are going to recommend folate supplementation to their patients with CAD, they should recommend this combination rather than folate alone. Also, since this study only included patients who are post-PTCA, it may not apply to all patients with CAD. In short, there is still a fair amount of uncertainty in the answer to this clinical question. We should discuss this uncertainty with our patients, and come to a mutual decision based on preferences.
There is insufficient evidence to advocate the routine use of folate supplementation for the treatment of coronary artery disease (CAD). High levels of serum homocysteine have been associated in several studies with an increased risk for CAD (strength of recommendation [SOR]: B, associated in case-control studies). Folate supplementation decreases the level of serum homocysteine (SOR: A, meta-analysis of randomized controlled trials). This indirect evidence suggests that folate supplementation may be of benefit in slowing the progress of arteriosclerosis.
Two randomized controlled trials measuring the clinical benefits of folate supplementation for patients with CAD have been completed, with differing results. One study showed no benefit of 0.5 mg/d of folate for patients with stable CAD already on statin therapy. The other study found that patients given 1 mg/d of folate with vitamins B6 and B12 had a decreased restenosis rate after percutaneous coronary intervention (PCI) (SOR: B, conflicting randomized controlled trials).
It is possible that larger doses of folate are needed to be of clinical benefit, or that the addition of vitamins B6 and B12 are needed for synergy. Several randomized control trials are underway to further assess folate’s affect on CAD.
Evidence summary
Hyperhomocysteinemia is defined as a fasting plasma homocysteine level 15 μmol/L, although levels >10 μmol/L appear to have detrimental effects on risk profiles for CAD and arteriosclerosis.1 In 22 of 27 retrospective case-control studies, patients with CAD had significantly higher plasma homocysteine levels than control subjects (odds ratio [OR]=1.2–10.9, after adjustment for other CAD risk factors).2,3 However, only 4 of 7 prospective nested case-control trials showed a correlation between elevated homocysteine and myocardial infarction (MI) and coronary death.2
A meta-analysis of 12 randomized controlled trials found that folate supplementation, with vitamin B6 and B12, reduces plasma homocysteine levels.4 However, the long-term clinical cons quences of these interventions are unknown. At doses of 1 gm/d folate has no known side-effects.5
Two randomized, placebo-controlled trials of folate reporting clinical endpoints have been completed. One study analyzed folate supplementation in a patient population with known, stable CAD and found no difference in clinical endpoints at 24 months.6 In this study, 593 patients were randomized to receive either 0.5 mg/d of folic acid or placebo. The primary study endpoint was a composite of events including: overall mortality, sudden death, MI, stroke, and major vascular surgery. The study was powered to detect a 50% reduction in clinical events based on existing observational data in populations with CAD. An event rate of 15% for the 2-year interval was assumed.6 All patients in this study were on statin therapy prior to initiation of folate supplementation.
The second study analyzed folate supplementation in 553 post-PCI patients. Patients were treated with 1 mg of folate plus 10 mg of vitamin B6 and 400 μg of vitamin B12 for 6 months after the PCI. After a mean follow-up of 11 months, the rate of restenosis requiring revascularization was lower in the vitamin-treated study arm (9.9% vs 16% restenosis rate; relative risk [RR]=0.62; 95% confidence interval [CI], 0.40–0.97; number needed to treat=16).7 There was also a nonsignificant trend toward fewer deaths and MIs in the treated arm at both 6 and 12 months after intervention (death: 1.5% vs 2.8%; RR=0.54; 95% CI, 0.016–1.7; MI: 2.6% vs 4.3%; RR=0.60; 95% CI, 0.24–1.51). Statin use was similar in both control (71%) and treatment groups (69%).
Recommendations from others
The American Heart Association and American College of Cardiology do not recommend the routine use of high-dose folic acid or B-vitamin supplements for the primary or secondary prevention of cardiovascular events. The AHA recommendation is to meet recommended daily allowances of folate (400 μg), B12 (2.4 μg), and B6 (1.7 mg) primarily through a balanced diet, with use of supplements if diet alone does not meet the above requirements.8 Since 1998, wheat flour has been supplemented with folate, adding an estimated 100 μg/day to the average American diet.8
The Canadian Task Force on Preventive Health Care (CTFPHC) finds insufficient evidence to advocate screening for hyperhomocysteinemia and rely on expert opinion to advocate treatment in select, high-risk populations.2 Currently, the CTFPHC advocates meeting the recommended daily allowance of folate, B12, and B6.2
Folate for CAD an unanswered question
James M. Gill, MD, MPH
Christianacare Health System, Wilmington, Del
Folate seems like a simple, inexpensive, and relatively benign way to improve care. It is no wonder that many physicians have been recommending folate to their patients with CAD for years. However, as responsible physicians, we need more comprehensive evidence on the benefit of folate before making such universal recommendations.
Several points are important: first, most of the evidence on folate is from observational studies. Only 1 interventional study has shown benefit for patients with CAD, and this study used folate in combination with vitamins B6 and B12. Therefore, if physicians are going to recommend folate supplementation to their patients with CAD, they should recommend this combination rather than folate alone. Also, since this study only included patients who are post-PTCA, it may not apply to all patients with CAD. In short, there is still a fair amount of uncertainty in the answer to this clinical question. We should discuss this uncertainty with our patients, and come to a mutual decision based on preferences.
1. Ford ES, Smith SJ, Stroup DF, Steinberg KK, Mueller PW, Thacker SB. Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies. Int J Epidemiol 2002;31:59-70.
2. Booth GL, Wang EE. Preventive health care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary artery disease events. The Canadian Task Force on Preventive Health Care. CMAJ 2000;163:21-29.
3. Bandolier Library. Homocysteine and heart disease: an update. Available at: http://www.jr2.ox.ac.uk/bandolier/booth/cardiac/homheart.html. Accessed on May 29, 2003.
4. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration. BMJ 1998;316:894-898.
5. Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. JAMA 2002;287:3116-3126.
6. Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ. Secondary prevention with folic acid: Effects on clinical outcomes. J Am Coll Cardiol 2003;41:2105-2113.
7. Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA 2002;288:973-979.
8. American Heart Association. AHA Science Advisory: Homocyst(e)ine, Diet, and Cardiovascular Diseases. Available at: http://www.americanheart.org. Accessed on May 29, 2003.
1. Ford ES, Smith SJ, Stroup DF, Steinberg KK, Mueller PW, Thacker SB. Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies. Int J Epidemiol 2002;31:59-70.
2. Booth GL, Wang EE. Preventive health care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary artery disease events. The Canadian Task Force on Preventive Health Care. CMAJ 2000;163:21-29.
3. Bandolier Library. Homocysteine and heart disease: an update. Available at: http://www.jr2.ox.ac.uk/bandolier/booth/cardiac/homheart.html. Accessed on May 29, 2003.
4. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration. BMJ 1998;316:894-898.
5. Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. JAMA 2002;287:3116-3126.
6. Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ. Secondary prevention with folic acid: Effects on clinical outcomes. J Am Coll Cardiol 2003;41:2105-2113.
7. Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA 2002;288:973-979.
8. American Heart Association. AHA Science Advisory: Homocyst(e)ine, Diet, and Cardiovascular Diseases. Available at: http://www.americanheart.org. Accessed on May 29, 2003.
Evidence-based answers from the Family Physicians Inquiries Network