Sharon Worcester

SALT LAKE CITY – Depression severity is a key factor in determining how to treat comorbid depression and restless legs syndrome, Dr. John Winkelman said at the annual meeting of the Associated Professional Sleep Societies.

The two conditions frequently occur together, and often it is unclear which is primary. Further complicating the matter of treatment is the fact that therapies for the two can be conflicting; for example, selective serotonin reuptake inhibitors (SSRIs) frequently used to treat depression have been shown to exacerbate RLS symptoms, explained Dr. Winkelman, who is associate director of the sleep disorders program at Brigham and Women's Hospital in Boston.

But the substantial morbidity and mortality that can be associated with severe depression take precedence when it comes to initiating treatment. In patients presenting with untreated severe depression and RLS, treat the depression first.

If possible, avoid SSRIs and try a nonserotonergic antidepressant such as bupropion instead, he advised.

The RLS symptoms should be treated shortly thereafter, because “the last thing a person with depression needs is to be up walking at night [as a result of RLS symptoms] and getting more and more agitated,” said Dr. Winkelman, who is also with Harvard Medical School, Boston.

In patients who have mild depression and RLS, treat the RLS first and see if the depressive symptoms improve, he suggested.

Given that about 10% of the U.S. population is on an antidepressant, it is likely that patients with RLS will present already on an SSRI for depression; in these cases, consider switching the patient to a nonserotonergic antidepressant only if the SSRI was the first drug tried in that patient.

In a patient who was treated with multiple drugs before finding one that worked for the depression or who was hospitalized for severe depression, don't rock the boat, Dr. Winkelman said. Rather, try adding a dopaminergic to treat the RLS symptoms in these patients, he said.

Another important factor to consider in patients with comorbid depression and restless legs syndrome is the effects of sleep quality and quantity on depression and RLS.

“There is quite a bit of data documenting that insomnia is an independent risk factor for incident, new-onset depression,” Dr. Winkelman noted. And there is good correlation between severity of RLS symptoms and sleep disturbance, as well.

Furthermore, in one study of more than 100 patients, there was a strong relationship between RLS-related sleep disturbance and depression, but RLS severity in itself did not predict depressive symptoms.

Similar findings have been noted in other neurologic diseases. In studies of patients with Parkinson's disease, for example, disease severity did not predict depressive symptoms, but the effects of the disease on quality of life and activities of daily living did predict depression, he explained.

This raises the question of whether sleep is a key mediator for RLS morbidity in regard to depressive symptomatology. Sleep optimization should therefore be one of the goals of treatment in these patients, Dr. Winkelman said.

SALT LAKE CITY – Depression severity is a key factor in determining how to treat comorbid depression and restless legs syndrome, Dr. John Winkelman said at the annual meeting of the Associated Professional Sleep Societies.

The two conditions frequently occur together, and often it is unclear which is primary. Further complicating the matter of treatment is the fact that therapies for the two can be conflicting; for example, selective serotonin reuptake inhibitors (SSRIs) frequently used to treat depression have been shown to exacerbate RLS symptoms, explained Dr. Winkelman, who is associate director of the sleep disorders program at Brigham and Women's Hospital in Boston.

But the substantial morbidity and mortality that can be associated with severe depression take precedence when it comes to initiating treatment. In patients presenting with untreated severe depression and RLS, treat the depression first.

If possible, avoid SSRIs and try a nonserotonergic antidepressant such as bupropion instead, he advised.

The RLS symptoms should be treated shortly thereafter, because “the last thing a person with depression needs is to be up walking at night [as a result of RLS symptoms] and getting more and more agitated,” said Dr. Winkelman, who is also with Harvard Medical School, Boston.

In patients who have mild depression and RLS, treat the RLS first and see if the depressive symptoms improve, he suggested.

Given that about 10% of the U.S. population is on an antidepressant, it is likely that patients with RLS will present already on an SSRI for depression; in these cases, consider switching the patient to a nonserotonergic antidepressant only if the SSRI was the first drug tried in that patient.

In a patient who was treated with multiple drugs before finding one that worked for the depression or who was hospitalized for severe depression, don't rock the boat, Dr. Winkelman said. Rather, try adding a dopaminergic to treat the RLS symptoms in these patients, he said.

Another important factor to consider in patients with comorbid depression and restless legs syndrome is the effects of sleep quality and quantity on depression and RLS.

“There is quite a bit of data documenting that insomnia is an independent risk factor for incident, new-onset depression,” Dr. Winkelman noted. And there is good correlation between severity of RLS symptoms and sleep disturbance, as well.

Furthermore, in one study of more than 100 patients, there was a strong relationship between RLS-related sleep disturbance and depression, but RLS severity in itself did not predict depressive symptoms.

Similar findings have been noted in other neurologic diseases. In studies of patients with Parkinson's disease, for example, disease severity did not predict depressive symptoms, but the effects of the disease on quality of life and activities of daily living did predict depression, he explained.

This raises the question of whether sleep is a key mediator for RLS morbidity in regard to depressive symptomatology. Sleep optimization should therefore be one of the goals of treatment in these patients, Dr. Winkelman said.

SALT LAKE CITY – Depression severity is a key factor in determining how to treat comorbid depression and restless legs syndrome, Dr. John Winkelman said at the annual meeting of the Associated Professional Sleep Societies.

The two conditions frequently occur together, and often it is unclear which is primary. Further complicating the matter of treatment is the fact that therapies for the two can be conflicting; for example, selective serotonin reuptake inhibitors (SSRIs) frequently used to treat depression have been shown to exacerbate RLS symptoms, explained Dr. Winkelman, who is associate director of the sleep disorders program at Brigham and Women's Hospital in Boston.

But the substantial morbidity and mortality that can be associated with severe depression take precedence when it comes to initiating treatment. In patients presenting with untreated severe depression and RLS, treat the depression first.

If possible, avoid SSRIs and try a nonserotonergic antidepressant such as bupropion instead, he advised.

The RLS symptoms should be treated shortly thereafter, because “the last thing a person with depression needs is to be up walking at night [as a result of RLS symptoms] and getting more and more agitated,” said Dr. Winkelman, who is also with Harvard Medical School, Boston.

In patients who have mild depression and RLS, treat the RLS first and see if the depressive symptoms improve, he suggested.

Given that about 10% of the U.S. population is on an antidepressant, it is likely that patients with RLS will present already on an SSRI for depression; in these cases, consider switching the patient to a nonserotonergic antidepressant only if the SSRI was the first drug tried in that patient.

In a patient who was treated with multiple drugs before finding one that worked for the depression or who was hospitalized for severe depression, don't rock the boat, Dr. Winkelman said. Rather, try adding a dopaminergic to treat the RLS symptoms in these patients, he said.

Another important factor to consider in patients with comorbid depression and restless legs syndrome is the effects of sleep quality and quantity on depression and RLS.

“There is quite a bit of data documenting that insomnia is an independent risk factor for incident, new-onset depression,” Dr. Winkelman noted. And there is good correlation between severity of RLS symptoms and sleep disturbance, as well.

Furthermore, in one study of more than 100 patients, there was a strong relationship between RLS-related sleep disturbance and depression, but RLS severity in itself did not predict depressive symptoms.

Similar findings have been noted in other neurologic diseases. In studies of patients with Parkinson's disease, for example, disease severity did not predict depressive symptoms, but the effects of the disease on quality of life and activities of daily living did predict depression, he explained.

This raises the question of whether sleep is a key mediator for RLS morbidity in regard to depressive symptomatology. Sleep optimization should therefore be one of the goals of treatment in these patients, Dr. Winkelman said.

SALT LAKE CITY — Depression severity is a key factor in determining how to treat comorbid depression and restless legs syndrome, Dr. John Winkelman said at the annual meeting of the Associated Professional Sleep Societies.

The two conditions frequently occur together, and often it is unclear which is primary. Further complicating the matter of treatment is the fact that therapies for the two can be conflicting; for example, SSRIs frequently used to treat depression have been shown to exacerbate RLS symptoms, said Dr. Winkelman, associate director of the Sleep Disorders Program at Brigham and Women's Hospital, Boston.

But the substantial morbidity and mortality that can be associated with severe depression take precedence when it comes to initiating treatment. In patients presenting with untreated severe depression and RLS, treat the depression first. If possible, avoid SSRIs and try a nonserotonergic antidepressant such as bupropion instead, he advised.

The RLS symptoms should be treated shortly thereafter, because “the last thing a person with depression needs is to be up walking at night [as a result of RLS symptoms] and getting more and more agitated,” said Dr. Winkelman, also of Harvard Medical School, Boston.

In patients with mild depression and RLS, treat the RLS first and see if the depressive symptoms improve, he suggested.

Given that about 10% of the U.S. population is on an antidepressant, it is likely that patients with RLS will present already on an SSRI for depression; in these cases, consider switching the patient to a nonserotonergic antidepressant only if the SSRI was the first drug tried.

In a patient who was treated with multiple drugs before finding one that worked for the depression or who was hospitalized for severe depression, don't rock the boat, Dr. Winkelman said. Rather, try adding a dopaminergic to treat the RLS symptoms in these patients, he said.

Another important factor to consider in patients with comorbid depression and RLS is the effects of sleep quality and quantity on depression and RLS.

“There is quite a bit of data documenting that insomnia is an independent risk factor for incident, new-onset depression,” Dr. Winkelman noted. And there is good correlation between RLS severity and sleep disturbance, as well.

In one study of more than 100 patients, there was a strong relationship between RLS-related sleep disturbance and depression, but RLS severity in itself did not predict depressive symptoms. Similar findings have been noted in other neurologic diseases. This raises the question of whether sleep is a key mediator for RLS morbidity in regard to depressive symptomatology. Sleep optimization should therefore be one of the goals of treatment in these patients, Dr. Winkelman said.

SALT LAKE CITY — Depression severity is a key factor in determining how to treat comorbid depression and restless legs syndrome, Dr. John Winkelman said at the annual meeting of the Associated Professional Sleep Societies.

The two conditions frequently occur together, and often it is unclear which is primary. Further complicating the matter of treatment is the fact that therapies for the two can be conflicting; for example, SSRIs frequently used to treat depression have been shown to exacerbate RLS symptoms, said Dr. Winkelman, associate director of the Sleep Disorders Program at Brigham and Women's Hospital, Boston.

But the substantial morbidity and mortality that can be associated with severe depression take precedence when it comes to initiating treatment. In patients presenting with untreated severe depression and RLS, treat the depression first. If possible, avoid SSRIs and try a nonserotonergic antidepressant such as bupropion instead, he advised.

The RLS symptoms should be treated shortly thereafter, because “the last thing a person with depression needs is to be up walking at night [as a result of RLS symptoms] and getting more and more agitated,” said Dr. Winkelman, also of Harvard Medical School, Boston.

In patients with mild depression and RLS, treat the RLS first and see if the depressive symptoms improve, he suggested.

Given that about 10% of the U.S. population is on an antidepressant, it is likely that patients with RLS will present already on an SSRI for depression; in these cases, consider switching the patient to a nonserotonergic antidepressant only if the SSRI was the first drug tried.

In a patient who was treated with multiple drugs before finding one that worked for the depression or who was hospitalized for severe depression, don't rock the boat, Dr. Winkelman said. Rather, try adding a dopaminergic to treat the RLS symptoms in these patients, he said.

Another important factor to consider in patients with comorbid depression and RLS is the effects of sleep quality and quantity on depression and RLS.

“There is quite a bit of data documenting that insomnia is an independent risk factor for incident, new-onset depression,” Dr. Winkelman noted. And there is good correlation between RLS severity and sleep disturbance, as well.

In one study of more than 100 patients, there was a strong relationship between RLS-related sleep disturbance and depression, but RLS severity in itself did not predict depressive symptoms. Similar findings have been noted in other neurologic diseases. This raises the question of whether sleep is a key mediator for RLS morbidity in regard to depressive symptomatology. Sleep optimization should therefore be one of the goals of treatment in these patients, Dr. Winkelman said.

SALT LAKE CITY — Depression severity is a key factor in determining how to treat comorbid depression and restless legs syndrome, Dr. John Winkelman said at the annual meeting of the Associated Professional Sleep Societies.

The two conditions frequently occur together, and often it is unclear which is primary. Further complicating the matter of treatment is the fact that therapies for the two can be conflicting; for example, SSRIs frequently used to treat depression have been shown to exacerbate RLS symptoms, said Dr. Winkelman, associate director of the Sleep Disorders Program at Brigham and Women's Hospital, Boston.

But the substantial morbidity and mortality that can be associated with severe depression take precedence when it comes to initiating treatment. In patients presenting with untreated severe depression and RLS, treat the depression first. If possible, avoid SSRIs and try a nonserotonergic antidepressant such as bupropion instead, he advised.

The RLS symptoms should be treated shortly thereafter, because “the last thing a person with depression needs is to be up walking at night [as a result of RLS symptoms] and getting more and more agitated,” said Dr. Winkelman, also of Harvard Medical School, Boston.

In patients with mild depression and RLS, treat the RLS first and see if the depressive symptoms improve, he suggested.

Given that about 10% of the U.S. population is on an antidepressant, it is likely that patients with RLS will present already on an SSRI for depression; in these cases, consider switching the patient to a nonserotonergic antidepressant only if the SSRI was the first drug tried.

In a patient who was treated with multiple drugs before finding one that worked for the depression or who was hospitalized for severe depression, don't rock the boat, Dr. Winkelman said. Rather, try adding a dopaminergic to treat the RLS symptoms in these patients, he said.

Another important factor to consider in patients with comorbid depression and RLS is the effects of sleep quality and quantity on depression and RLS.

“There is quite a bit of data documenting that insomnia is an independent risk factor for incident, new-onset depression,” Dr. Winkelman noted. And there is good correlation between RLS severity and sleep disturbance, as well.

In one study of more than 100 patients, there was a strong relationship between RLS-related sleep disturbance and depression, but RLS severity in itself did not predict depressive symptoms. Similar findings have been noted in other neurologic diseases. This raises the question of whether sleep is a key mediator for RLS morbidity in regard to depressive symptomatology. Sleep optimization should therefore be one of the goals of treatment in these patients, Dr. Winkelman said.

SALT LAKE CITY — The prevalence of obstructive sleep apnea in patients with coronary heart disease may be higher than previously thought, according to data presented at the annual meeting of the Associated Professional Sleep Societies.

In a study of 132 patients with a history of myocardial infarction or angiographically verified coronary artery disease, the prevalence of obstructive sleep apnea was 70%, Robert M. Carney, Ph.D., reported in a poster presentation. The results of some previous studies have suggested prevalence rates in the 50% range in this population.

Patients in the current study underwent 2 nights of polysomnography. Obstructive sleep apnea was defined as at least five episodes of obstructive apnea or hypopnea per hour, said Dr. Carney, professor of psychiatry and director of the Behavioral Medicine Center at Washington University, St. Louis. The finding underscores the importance of screening heart disease patients for obstructive sleep apnea, which has been shown to increase the risk of myocardial infarction in this population, he concluded.

SALT LAKE CITY — The prevalence of obstructive sleep apnea in patients with coronary heart disease may be higher than previously thought, according to data presented at the annual meeting of the Associated Professional Sleep Societies.

In a study of 132 patients with a history of myocardial infarction or angiographically verified coronary artery disease, the prevalence of obstructive sleep apnea was 70%, Robert M. Carney, Ph.D., reported in a poster presentation. The results of some previous studies have suggested prevalence rates in the 50% range in this population.

Patients in the current study underwent 2 nights of polysomnography. Obstructive sleep apnea was defined as at least five episodes of obstructive apnea or hypopnea per hour, said Dr. Carney, professor of psychiatry and director of the Behavioral Medicine Center at Washington University, St. Louis. The finding underscores the importance of screening heart disease patients for obstructive sleep apnea, which has been shown to increase the risk of myocardial infarction in this population, he concluded.

SALT LAKE CITY — The prevalence of obstructive sleep apnea in patients with coronary heart disease may be higher than previously thought, according to data presented at the annual meeting of the Associated Professional Sleep Societies.

In a study of 132 patients with a history of myocardial infarction or angiographically verified coronary artery disease, the prevalence of obstructive sleep apnea was 70%, Robert M. Carney, Ph.D., reported in a poster presentation. The results of some previous studies have suggested prevalence rates in the 50% range in this population.

Patients in the current study underwent 2 nights of polysomnography. Obstructive sleep apnea was defined as at least five episodes of obstructive apnea or hypopnea per hour, said Dr. Carney, professor of psychiatry and director of the Behavioral Medicine Center at Washington University, St. Louis. The finding underscores the importance of screening heart disease patients for obstructive sleep apnea, which has been shown to increase the risk of myocardial infarction in this population, he concluded.

ATLANTA — A retrospective analysis of data from nearly 4,000 patients treated with intravenous bisphosphonates suggests that osteonecrosis of the jaw in patients with metastatic cancer is an important but rare event in these patients, Dr. Ana O. Hoff reported in a poster at the annual meeting of the American Society of Clinical Oncology.

Reports of an association between bisphosphonate treatment and osteonecrosis of the jaw (ONJ) in patients with metastatic bone disease prompted this study examining the frequency of and risk factors for ONJ, explained Dr. Hoff of the University of Texas M.D. Anderson Cancer Center, Houston.

The cohort studied included patients treated from September 1996 to February 2004. The most common diagnoses were breast cancer (in more than 1,300 patients) and multiple myeloma (in 550 patients), and the indications for intravenous bisphosphonate treatment included metastatic bone disease, hypercalcemia, and osteoporosis.

ONJ, which developed in 29 patients (0.73% overall, including about 1% of breast cancer patients and 2% of multiple myeloma patients), was defined as exposed nonhealing bone of at least 3 months' duration.

Mean cumulative doses of the bisphosphonates used (pamidronate and zoledronate) were significantly higher, and duration of disease and follow-up were significantly longer, in ONJ patients than in those who didn't develop ONJ.

Dental extractions, estrogen-receptor-positive tumors, and treatment with pamidronate and zoledronate were shown to be significant risk factors for ONJ in breast cancer patients. In multiple myeloma patients, significant risk factors were dental extractions, periodontal disease, and osteoporosis.

About 70% of ONJ patients reported no pain with bone exposure, Dr. Hoff noted.

Management of patients with ONJ included aggressive oral hygiene, oral rinses, debridement of necrotic bone, and antibiotic therapy. Of 15 ONJ patients followed longer than 6 months, 1 healed, 1 improved, 1 remained stable, and 9 experienced disease progression.

The finding of 0.73% ONJ occurrence in this population suggests that this is a rare, albeit important, event. Good dental care and avoidance of dental interventions are important recommendations for all patients being treated with intravenous bisphosphonates, Dr. Hoff concluded.

Race, Number of Infusions Possible Risks for Osteonecrosis

White cancer patients on intravenous bisphosphonate therapy for bone metastases may be at higher risk for osteonecrosis of the jaw, Dr. Tamer Aiti reported in a poster at the meeting.

A retrospective study by Dr. Aiti and his colleagues at John H. Stroger Jr. Cook County Hospital, Chicago, found that 6 (3.7%) of 161 patients with metastatic breast cancer developed this rare complication in the mandible bone. Five of the six patients were white. Yet whites accounted for less than a third of the population reviewed. All but 29 patients were nonwhite.

The investigators calculated that white patients had significantly more bisphosphonate infusions, 21 on average, compared with a mean of 13.5 infusions in nonwhite patients. Logistic regression analysis established that significantly more whites developed osteonecrosis of the jaw even after the study investigators controlled for dose (odds ratio 45.7).

The patients were treated with zoledronic acid and/or pamidronate between January 1, 2001, and October 30, 2005. None had prior glucocorticosteroid therapy.

As of Dec. 30, 2005, only two patients had resolution of their osteonecrosis of the jaw. Three patients had exposed bone—two with intermittent pain, and one with chronic pain. The lone African American patient with the complication developed sepsis and died.

Dr. Aiti of the department of surgical oncology at the University of Illinois at Chicago called for larger studies to consider not only race, but also confounding variables such as type of bisphosphonate therapy and cumulative dose, as well as other possible risk factors. Dr. Aiti and his colleagues also urged prospective imaging of high-risk patients, doing oral surgery before bisphosphonate treatment, and surveillance for osteonecrosis of the jaw.

“The study is small. I would not say it is confirmatory. We need larger numbers to see if this is really the fact,” he said in an interview.

—Jane Salodof MacNeil

ATLANTA — A retrospective analysis of data from nearly 4,000 patients treated with intravenous bisphosphonates suggests that osteonecrosis of the jaw in patients with metastatic cancer is an important but rare event in these patients, Dr. Ana O. Hoff reported in a poster at the annual meeting of the American Society of Clinical Oncology.

Reports of an association between bisphosphonate treatment and osteonecrosis of the jaw (ONJ) in patients with metastatic bone disease prompted this study examining the frequency of and risk factors for ONJ, explained Dr. Hoff of the University of Texas M.D. Anderson Cancer Center, Houston.

The cohort studied included patients treated from September 1996 to February 2004. The most common diagnoses were breast cancer (in more than 1,300 patients) and multiple myeloma (in 550 patients), and the indications for intravenous bisphosphonate treatment included metastatic bone disease, hypercalcemia, and osteoporosis.

ONJ, which developed in 29 patients (0.73% overall, including about 1% of breast cancer patients and 2% of multiple myeloma patients), was defined as exposed nonhealing bone of at least 3 months' duration.

Mean cumulative doses of the bisphosphonates used (pamidronate and zoledronate) were significantly higher, and duration of disease and follow-up were significantly longer, in ONJ patients than in those who didn't develop ONJ.

Dental extractions, estrogen-receptor-positive tumors, and treatment with pamidronate and zoledronate were shown to be significant risk factors for ONJ in breast cancer patients. In multiple myeloma patients, significant risk factors were dental extractions, periodontal disease, and osteoporosis.

About 70% of ONJ patients reported no pain with bone exposure, Dr. Hoff noted.

Management of patients with ONJ included aggressive oral hygiene, oral rinses, debridement of necrotic bone, and antibiotic therapy. Of 15 ONJ patients followed longer than 6 months, 1 healed, 1 improved, 1 remained stable, and 9 experienced disease progression.

The finding of 0.73% ONJ occurrence in this population suggests that this is a rare, albeit important, event. Good dental care and avoidance of dental interventions are important recommendations for all patients being treated with intravenous bisphosphonates, Dr. Hoff concluded.

Race, Number of Infusions Possible Risks for Osteonecrosis

White cancer patients on intravenous bisphosphonate therapy for bone metastases may be at higher risk for osteonecrosis of the jaw, Dr. Tamer Aiti reported in a poster at the meeting.

A retrospective study by Dr. Aiti and his colleagues at John H. Stroger Jr. Cook County Hospital, Chicago, found that 6 (3.7%) of 161 patients with metastatic breast cancer developed this rare complication in the mandible bone. Five of the six patients were white. Yet whites accounted for less than a third of the population reviewed. All but 29 patients were nonwhite.

The investigators calculated that white patients had significantly more bisphosphonate infusions, 21 on average, compared with a mean of 13.5 infusions in nonwhite patients. Logistic regression analysis established that significantly more whites developed osteonecrosis of the jaw even after the study investigators controlled for dose (odds ratio 45.7).

The patients were treated with zoledronic acid and/or pamidronate between January 1, 2001, and October 30, 2005. None had prior glucocorticosteroid therapy.

As of Dec. 30, 2005, only two patients had resolution of their osteonecrosis of the jaw. Three patients had exposed bone—two with intermittent pain, and one with chronic pain. The lone African American patient with the complication developed sepsis and died.

Dr. Aiti of the department of surgical oncology at the University of Illinois at Chicago called for larger studies to consider not only race, but also confounding variables such as type of bisphosphonate therapy and cumulative dose, as well as other possible risk factors. Dr. Aiti and his colleagues also urged prospective imaging of high-risk patients, doing oral surgery before bisphosphonate treatment, and surveillance for osteonecrosis of the jaw.

“The study is small. I would not say it is confirmatory. We need larger numbers to see if this is really the fact,” he said in an interview.

—Jane Salodof MacNeil

ATLANTA — A retrospective analysis of data from nearly 4,000 patients treated with intravenous bisphosphonates suggests that osteonecrosis of the jaw in patients with metastatic cancer is an important but rare event in these patients, Dr. Ana O. Hoff reported in a poster at the annual meeting of the American Society of Clinical Oncology.

Reports of an association between bisphosphonate treatment and osteonecrosis of the jaw (ONJ) in patients with metastatic bone disease prompted this study examining the frequency of and risk factors for ONJ, explained Dr. Hoff of the University of Texas M.D. Anderson Cancer Center, Houston.

The cohort studied included patients treated from September 1996 to February 2004. The most common diagnoses were breast cancer (in more than 1,300 patients) and multiple myeloma (in 550 patients), and the indications for intravenous bisphosphonate treatment included metastatic bone disease, hypercalcemia, and osteoporosis.

ONJ, which developed in 29 patients (0.73% overall, including about 1% of breast cancer patients and 2% of multiple myeloma patients), was defined as exposed nonhealing bone of at least 3 months' duration.

Mean cumulative doses of the bisphosphonates used (pamidronate and zoledronate) were significantly higher, and duration of disease and follow-up were significantly longer, in ONJ patients than in those who didn't develop ONJ.

Dental extractions, estrogen-receptor-positive tumors, and treatment with pamidronate and zoledronate were shown to be significant risk factors for ONJ in breast cancer patients. In multiple myeloma patients, significant risk factors were dental extractions, periodontal disease, and osteoporosis.

About 70% of ONJ patients reported no pain with bone exposure, Dr. Hoff noted.

Management of patients with ONJ included aggressive oral hygiene, oral rinses, debridement of necrotic bone, and antibiotic therapy. Of 15 ONJ patients followed longer than 6 months, 1 healed, 1 improved, 1 remained stable, and 9 experienced disease progression.

The finding of 0.73% ONJ occurrence in this population suggests that this is a rare, albeit important, event. Good dental care and avoidance of dental interventions are important recommendations for all patients being treated with intravenous bisphosphonates, Dr. Hoff concluded.

Race, Number of Infusions Possible Risks for Osteonecrosis

White cancer patients on intravenous bisphosphonate therapy for bone metastases may be at higher risk for osteonecrosis of the jaw, Dr. Tamer Aiti reported in a poster at the meeting.

A retrospective study by Dr. Aiti and his colleagues at John H. Stroger Jr. Cook County Hospital, Chicago, found that 6 (3.7%) of 161 patients with metastatic breast cancer developed this rare complication in the mandible bone. Five of the six patients were white. Yet whites accounted for less than a third of the population reviewed. All but 29 patients were nonwhite.

The investigators calculated that white patients had significantly more bisphosphonate infusions, 21 on average, compared with a mean of 13.5 infusions in nonwhite patients. Logistic regression analysis established that significantly more whites developed osteonecrosis of the jaw even after the study investigators controlled for dose (odds ratio 45.7).

The patients were treated with zoledronic acid and/or pamidronate between January 1, 2001, and October 30, 2005. None had prior glucocorticosteroid therapy.

As of Dec. 30, 2005, only two patients had resolution of their osteonecrosis of the jaw. Three patients had exposed bone—two with intermittent pain, and one with chronic pain. The lone African American patient with the complication developed sepsis and died.

Dr. Aiti of the department of surgical oncology at the University of Illinois at Chicago called for larger studies to consider not only race, but also confounding variables such as type of bisphosphonate therapy and cumulative dose, as well as other possible risk factors. Dr. Aiti and his colleagues also urged prospective imaging of high-risk patients, doing oral surgery before bisphosphonate treatment, and surveillance for osteonecrosis of the jaw.

“The study is small. I would not say it is confirmatory. We need larger numbers to see if this is really the fact,” he said in an interview.

—Jane Salodof MacNeil

SALT LAKE CITY – Patients with sleep-related eating disorder may benefit from topiramate treatment, a small study suggests.

Of 17 patients with chronic sleep-related eating disorder (SRED) who were treated with the anticonvulsant, 4 discontinued treatment due to lack of efficacy and 2 others stopped taking the drug because of side effects, including pruritus and weight gain.

The remaining 11 patients remained on therapy for a mean follow-up of 2 years, with all 11 achieving full or substantial control of SRED episodes. Ten of these 11 patients lost a substantial amount of weight (mean of 9.4 kg), Dr. Carlos H. Schenck reported in a poster at the annual meeting of the Associated Professional Sleep Societies.

Topiramate has been shown in previous studies to promote weight loss and control binge eating, and at least two case reports have suggested that it is helpful for controlling SRED. In the current study, the 17 patients presented with weight gain and nonrestorative sleep as a result of SRED; 9 had failed prior therapies for the condition; and the other 8 received topiramate as first-line therapy, noted Dr. Schenck of the Minnesota Regional Sleep Disorders Center and the University of Minnesota, both in Minneapolis.

Patients were initially treated with 25 mg topiramate at bedtime, with weekly increases of 25 mg as needed and as tolerated. The maximum dosage was 400 mg, with a mean dosage of 104.5 mg in the 11 patients who remained on therapy. Those patients had a mean age of 45 years, and nine were women. The duration of SRED ranged from 3 to 45 years, and 10 patients experienced nightly SRED episodes.

In 5 of the 11 patients, SRED was idiopathic, and in 6, the SRED was presumed symptomatic; eight other sleep disorders were present in these patients. These disorders included restless legs syndrome/periodic limb movement disorder in five patients and sleepwalking, narcolepsy, and primary insomnia in one patient each.

In addition, five patients had one or more Axis I psychiatric disorders, including four patients with a mood disorder, one with chemical dependency in remission, two with anxiety disorder, and one with a paranoid disorder.

Eight patients were using other medications at the time topiramate was initiated; these included benzodiazepines/agonists (five patients), dopaminergics (three patients), trazodone (three patients), antipsychotics (two patients), and daytime psychotropics (four patients).

SALT LAKE CITY – Patients with sleep-related eating disorder may benefit from topiramate treatment, a small study suggests.

Of 17 patients with chronic sleep-related eating disorder (SRED) who were treated with the anticonvulsant, 4 discontinued treatment due to lack of efficacy and 2 others stopped taking the drug because of side effects, including pruritus and weight gain.

The remaining 11 patients remained on therapy for a mean follow-up of 2 years, with all 11 achieving full or substantial control of SRED episodes. Ten of these 11 patients lost a substantial amount of weight (mean of 9.4 kg), Dr. Carlos H. Schenck reported in a poster at the annual meeting of the Associated Professional Sleep Societies.

Topiramate has been shown in previous studies to promote weight loss and control binge eating, and at least two case reports have suggested that it is helpful for controlling SRED. In the current study, the 17 patients presented with weight gain and nonrestorative sleep as a result of SRED; 9 had failed prior therapies for the condition; and the other 8 received topiramate as first-line therapy, noted Dr. Schenck of the Minnesota Regional Sleep Disorders Center and the University of Minnesota, both in Minneapolis.

Patients were initially treated with 25 mg topiramate at bedtime, with weekly increases of 25 mg as needed and as tolerated. The maximum dosage was 400 mg, with a mean dosage of 104.5 mg in the 11 patients who remained on therapy. Those patients had a mean age of 45 years, and nine were women. The duration of SRED ranged from 3 to 45 years, and 10 patients experienced nightly SRED episodes.

In 5 of the 11 patients, SRED was idiopathic, and in 6, the SRED was presumed symptomatic; eight other sleep disorders were present in these patients. These disorders included restless legs syndrome/periodic limb movement disorder in five patients and sleepwalking, narcolepsy, and primary insomnia in one patient each.

In addition, five patients had one or more Axis I psychiatric disorders, including four patients with a mood disorder, one with chemical dependency in remission, two with anxiety disorder, and one with a paranoid disorder.

Eight patients were using other medications at the time topiramate was initiated; these included benzodiazepines/agonists (five patients), dopaminergics (three patients), trazodone (three patients), antipsychotics (two patients), and daytime psychotropics (four patients).

SALT LAKE CITY – Patients with sleep-related eating disorder may benefit from topiramate treatment, a small study suggests.

Of 17 patients with chronic sleep-related eating disorder (SRED) who were treated with the anticonvulsant, 4 discontinued treatment due to lack of efficacy and 2 others stopped taking the drug because of side effects, including pruritus and weight gain.

The remaining 11 patients remained on therapy for a mean follow-up of 2 years, with all 11 achieving full or substantial control of SRED episodes. Ten of these 11 patients lost a substantial amount of weight (mean of 9.4 kg), Dr. Carlos H. Schenck reported in a poster at the annual meeting of the Associated Professional Sleep Societies.

Topiramate has been shown in previous studies to promote weight loss and control binge eating, and at least two case reports have suggested that it is helpful for controlling SRED. In the current study, the 17 patients presented with weight gain and nonrestorative sleep as a result of SRED; 9 had failed prior therapies for the condition; and the other 8 received topiramate as first-line therapy, noted Dr. Schenck of the Minnesota Regional Sleep Disorders Center and the University of Minnesota, both in Minneapolis.

Patients were initially treated with 25 mg topiramate at bedtime, with weekly increases of 25 mg as needed and as tolerated. The maximum dosage was 400 mg, with a mean dosage of 104.5 mg in the 11 patients who remained on therapy. Those patients had a mean age of 45 years, and nine were women. The duration of SRED ranged from 3 to 45 years, and 10 patients experienced nightly SRED episodes.

In 5 of the 11 patients, SRED was idiopathic, and in 6, the SRED was presumed symptomatic; eight other sleep disorders were present in these patients. These disorders included restless legs syndrome/periodic limb movement disorder in five patients and sleepwalking, narcolepsy, and primary insomnia in one patient each.

In addition, five patients had one or more Axis I psychiatric disorders, including four patients with a mood disorder, one with chemical dependency in remission, two with anxiety disorder, and one with a paranoid disorder.

Eight patients were using other medications at the time topiramate was initiated; these included benzodiazepines/agonists (five patients), dopaminergics (three patients), trazodone (three patients), antipsychotics (two patients), and daytime psychotropics (four patients).

SALT LAKE CITY – The combination of obstructive sleep apnea and increased age may have an overwhelming effect on the brain's compensatory mechanisms, and early diagnosis and treatment of OSA in older patients may be important for preserving brain function, reported Liat Ayalon, Ph.D.

In a study Dr. Ayalon presented at the annual meeting of the Associated Professional Sleep Societies, 12 untreated OSA patients and 12 healthy good sleepers were studied with polysomnography and functional magnetic resonance imaging. The interaction between group and age in regard to effects on brain function during a verbal learning task was analyzed.

Imaging studies showed that patients' brains were able to recruit additional resources to maintain intact performance and compensate for either age or OSA. Increased brain activation was noted in both older patients and those with OSA, compared with controls, specifically in the left inferior parietal lobe, thalamus, caudate, middle temporal gyrus, and fusiform; in the right anterior cingulate; and in the bilateral precuneus and cerebellum.

But when patients had both increased age and OSA, decreased brain activation was noted, compared with younger patients, specifically in the right superior temporal gyrus and anterior cingulate, and in the bilateral parahippocampal gyri, caudate, precuneus, cerebellum, and fusiform gyrus, said Dr. Ayalon of the University of California, San Diego.

Patients ranged in age from 25 to 59 years. The groups were similar in age, gender, and body mass index. Average apnea-hypopnea index score–a measure of sleep apnea severity–was 35.1 in the OSA patients and 1.9 in the control group.

The findings suggest that OSA in older patients is associated with decreased functioning, as evidenced by deficiencies in word recall in this study.

Studies to address effects in even older patients (as this was a relatively young study population) and the effects of OSA treatment on brain function are planned, Dr. Ayalon said.

SALT LAKE CITY – The combination of obstructive sleep apnea and increased age may have an overwhelming effect on the brain's compensatory mechanisms, and early diagnosis and treatment of OSA in older patients may be important for preserving brain function, reported Liat Ayalon, Ph.D.

In a study Dr. Ayalon presented at the annual meeting of the Associated Professional Sleep Societies, 12 untreated OSA patients and 12 healthy good sleepers were studied with polysomnography and functional magnetic resonance imaging. The interaction between group and age in regard to effects on brain function during a verbal learning task was analyzed.

Imaging studies showed that patients' brains were able to recruit additional resources to maintain intact performance and compensate for either age or OSA. Increased brain activation was noted in both older patients and those with OSA, compared with controls, specifically in the left inferior parietal lobe, thalamus, caudate, middle temporal gyrus, and fusiform; in the right anterior cingulate; and in the bilateral precuneus and cerebellum.

But when patients had both increased age and OSA, decreased brain activation was noted, compared with younger patients, specifically in the right superior temporal gyrus and anterior cingulate, and in the bilateral parahippocampal gyri, caudate, precuneus, cerebellum, and fusiform gyrus, said Dr. Ayalon of the University of California, San Diego.

Patients ranged in age from 25 to 59 years. The groups were similar in age, gender, and body mass index. Average apnea-hypopnea index score–a measure of sleep apnea severity–was 35.1 in the OSA patients and 1.9 in the control group.

The findings suggest that OSA in older patients is associated with decreased functioning, as evidenced by deficiencies in word recall in this study.

Studies to address effects in even older patients (as this was a relatively young study population) and the effects of OSA treatment on brain function are planned, Dr. Ayalon said.

SALT LAKE CITY – The combination of obstructive sleep apnea and increased age may have an overwhelming effect on the brain's compensatory mechanisms, and early diagnosis and treatment of OSA in older patients may be important for preserving brain function, reported Liat Ayalon, Ph.D.

In a study Dr. Ayalon presented at the annual meeting of the Associated Professional Sleep Societies, 12 untreated OSA patients and 12 healthy good sleepers were studied with polysomnography and functional magnetic resonance imaging. The interaction between group and age in regard to effects on brain function during a verbal learning task was analyzed.

Imaging studies showed that patients' brains were able to recruit additional resources to maintain intact performance and compensate for either age or OSA. Increased brain activation was noted in both older patients and those with OSA, compared with controls, specifically in the left inferior parietal lobe, thalamus, caudate, middle temporal gyrus, and fusiform; in the right anterior cingulate; and in the bilateral precuneus and cerebellum.

But when patients had both increased age and OSA, decreased brain activation was noted, compared with younger patients, specifically in the right superior temporal gyrus and anterior cingulate, and in the bilateral parahippocampal gyri, caudate, precuneus, cerebellum, and fusiform gyrus, said Dr. Ayalon of the University of California, San Diego.

Patients ranged in age from 25 to 59 years. The groups were similar in age, gender, and body mass index. Average apnea-hypopnea index score–a measure of sleep apnea severity–was 35.1 in the OSA patients and 1.9 in the control group.

The findings suggest that OSA in older patients is associated with decreased functioning, as evidenced by deficiencies in word recall in this study.

Studies to address effects in even older patients (as this was a relatively young study population) and the effects of OSA treatment on brain function are planned, Dr. Ayalon said.

SALT LAKE CITY – Restless legs syndrome is common, troublesome, and rarely diagnosed in children and teens, Dr. Daniel Picchietti reported at the annual meeting of the Associated Professional Sleep Societies.

Multiple case reports, practice-based study findings, and adult studies showing that more than a third of patients report symptom onset prior to age 20 have hinted at a relatively high prevalence in children. Findings from the Peds REST Study–a large population-based study–provide confirmation of that, said Dr. Picchietti of the University of Illinois, Urbana.

In that study of children from more than 10,500 families in the United States and United Kingdom, the prevalence of definite restless legs syndrome (RLS) by the National Institutes of Health consensus criteria definition was 1.9% in children aged 8–11 years, and 2.0% in those aged 12–17 years, suggesting RLS occurs more often than epilepsy or diabetes in this population, he said.

Restless legs syndrome is a neurologic disorder characterized by unpleasant sensations in the legs, and an uncontrollable urge to move them for relief. Some affected individuals describe the sensations as burning, tugging, or creeping, or like insects crawling inside the legs, according to the National Institute of Neurological Disorders and Stroke.

To meet the official diagnosis, patients must meet these NIH criteria:

▸ A strong urge to move the legs, which patients may not be able to resist.

▸ RLS symptoms start or become worse when resting.

▸ Symptoms improve when patients move their legs. The relief can be complete or only partial, but generally starts very soon after activity.

▸ Symptoms are worse in the evening, especially when patients are lying down.

In the study, moderately to severely distressing symptoms that occurred more than twice weekly were reported by 0.5% of those aged 8–11 years, and by 1.0% of those aged 12–17 years. Furthermore, sleep disturbance and growing pains were significantly more common in those with RLS than in controls, 50% of those with RLS reported the condition had a negative effect on mood, and several medical diagnoses were reported more commonly in RLS patients than would be expected in the general population.

In the U.S. population, for example, RLS patients were commonly diagnosed with ADHD (27%), anxiety disorder (11%), and depression (12%).

Data were collected randomly via Internet survey in April 2005 from a large volunteer research panel. Participants were initially blinded to the survey topic.

Responses were provided by the parents of those participants in the 8- to 11-year-old range, and by either parents or the adolescents themselves of those in the 12- to 17-year-old range. Only answers from biologically related parents and children were included in the analysis so the role of family history could be ascertained.

Descriptions of RLS symptoms that were provided by children in their own words were convincing in regard to whether they were truly affected by RLS.

“I really got the sense that this was restless legs syndrome–that we got exactly what we were measuring,” Dr. Picchietti said, explaining that there was concern about discerning RLS symptoms from other arthralgias and cramps of childhood.

The good news is that some of those with RLS were diagnosed, but the bad news is that even among those who were moderately to severely affected, fewer than one in six received a diagnosis. Also, treatment was very uncommon, he said.

In the present study RLS occurred equally in males and females in the pediatric population, while among adults, twice as many females as males are affected.

Another finding from Peds REST is that a family history of RLS (in at least one parent) is common in affected individuals. In one in six families with a child with RLS, both parents reported experiencing RLS symptoms, Dr. Picchietti noted.

SALT LAKE CITY – Restless legs syndrome is common, troublesome, and rarely diagnosed in children and teens, Dr. Daniel Picchietti reported at the annual meeting of the Associated Professional Sleep Societies.

Multiple case reports, practice-based study findings, and adult studies showing that more than a third of patients report symptom onset prior to age 20 have hinted at a relatively high prevalence in children. Findings from the Peds REST Study–a large population-based study–provide confirmation of that, said Dr. Picchietti of the University of Illinois, Urbana.

In that study of children from more than 10,500 families in the United States and United Kingdom, the prevalence of definite restless legs syndrome (RLS) by the National Institutes of Health consensus criteria definition was 1.9% in children aged 8–11 years, and 2.0% in those aged 12–17 years, suggesting RLS occurs more often than epilepsy or diabetes in this population, he said.

Restless legs syndrome is a neurologic disorder characterized by unpleasant sensations in the legs, and an uncontrollable urge to move them for relief. Some affected individuals describe the sensations as burning, tugging, or creeping, or like insects crawling inside the legs, according to the National Institute of Neurological Disorders and Stroke.

To meet the official diagnosis, patients must meet these NIH criteria:

▸ A strong urge to move the legs, which patients may not be able to resist.

▸ RLS symptoms start or become worse when resting.

▸ Symptoms improve when patients move their legs. The relief can be complete or only partial, but generally starts very soon after activity.

▸ Symptoms are worse in the evening, especially when patients are lying down.

In the study, moderately to severely distressing symptoms that occurred more than twice weekly were reported by 0.5% of those aged 8–11 years, and by 1.0% of those aged 12–17 years. Furthermore, sleep disturbance and growing pains were significantly more common in those with RLS than in controls, 50% of those with RLS reported the condition had a negative effect on mood, and several medical diagnoses were reported more commonly in RLS patients than would be expected in the general population.

In the U.S. population, for example, RLS patients were commonly diagnosed with ADHD (27%), anxiety disorder (11%), and depression (12%).

Data were collected randomly via Internet survey in April 2005 from a large volunteer research panel. Participants were initially blinded to the survey topic.

Responses were provided by the parents of those participants in the 8- to 11-year-old range, and by either parents or the adolescents themselves of those in the 12- to 17-year-old range. Only answers from biologically related parents and children were included in the analysis so the role of family history could be ascertained.

Descriptions of RLS symptoms that were provided by children in their own words were convincing in regard to whether they were truly affected by RLS.

“I really got the sense that this was restless legs syndrome–that we got exactly what we were measuring,” Dr. Picchietti said, explaining that there was concern about discerning RLS symptoms from other arthralgias and cramps of childhood.

The good news is that some of those with RLS were diagnosed, but the bad news is that even among those who were moderately to severely affected, fewer than one in six received a diagnosis. Also, treatment was very uncommon, he said.

In the present study RLS occurred equally in males and females in the pediatric population, while among adults, twice as many females as males are affected.

Another finding from Peds REST is that a family history of RLS (in at least one parent) is common in affected individuals. In one in six families with a child with RLS, both parents reported experiencing RLS symptoms, Dr. Picchietti noted.

SALT LAKE CITY – Restless legs syndrome is common, troublesome, and rarely diagnosed in children and teens, Dr. Daniel Picchietti reported at the annual meeting of the Associated Professional Sleep Societies.

Multiple case reports, practice-based study findings, and adult studies showing that more than a third of patients report symptom onset prior to age 20 have hinted at a relatively high prevalence in children. Findings from the Peds REST Study–a large population-based study–provide confirmation of that, said Dr. Picchietti of the University of Illinois, Urbana.

In that study of children from more than 10,500 families in the United States and United Kingdom, the prevalence of definite restless legs syndrome (RLS) by the National Institutes of Health consensus criteria definition was 1.9% in children aged 8–11 years, and 2.0% in those aged 12–17 years, suggesting RLS occurs more often than epilepsy or diabetes in this population, he said.

Restless legs syndrome is a neurologic disorder characterized by unpleasant sensations in the legs, and an uncontrollable urge to move them for relief. Some affected individuals describe the sensations as burning, tugging, or creeping, or like insects crawling inside the legs, according to the National Institute of Neurological Disorders and Stroke.

To meet the official diagnosis, patients must meet these NIH criteria:

▸ A strong urge to move the legs, which patients may not be able to resist.

▸ RLS symptoms start or become worse when resting.

▸ Symptoms improve when patients move their legs. The relief can be complete or only partial, but generally starts very soon after activity.

▸ Symptoms are worse in the evening, especially when patients are lying down.

In the study, moderately to severely distressing symptoms that occurred more than twice weekly were reported by 0.5% of those aged 8–11 years, and by 1.0% of those aged 12–17 years. Furthermore, sleep disturbance and growing pains were significantly more common in those with RLS than in controls, 50% of those with RLS reported the condition had a negative effect on mood, and several medical diagnoses were reported more commonly in RLS patients than would be expected in the general population.

In the U.S. population, for example, RLS patients were commonly diagnosed with ADHD (27%), anxiety disorder (11%), and depression (12%).

Data were collected randomly via Internet survey in April 2005 from a large volunteer research panel. Participants were initially blinded to the survey topic.

Responses were provided by the parents of those participants in the 8- to 11-year-old range, and by either parents or the adolescents themselves of those in the 12- to 17-year-old range. Only answers from biologically related parents and children were included in the analysis so the role of family history could be ascertained.

Descriptions of RLS symptoms that were provided by children in their own words were convincing in regard to whether they were truly affected by RLS.

“I really got the sense that this was restless legs syndrome–that we got exactly what we were measuring,” Dr. Picchietti said, explaining that there was concern about discerning RLS symptoms from other arthralgias and cramps of childhood.

The good news is that some of those with RLS were diagnosed, but the bad news is that even among those who were moderately to severely affected, fewer than one in six received a diagnosis. Also, treatment was very uncommon, he said.

In the present study RLS occurred equally in males and females in the pediatric population, while among adults, twice as many females as males are affected.

Another finding from Peds REST is that a family history of RLS (in at least one parent) is common in affected individuals. In one in six families with a child with RLS, both parents reported experiencing RLS symptoms, Dr. Picchietti noted.

ATLANTA — Lymphadenectomy improved survival in women with stage I, grade 3 through stage IV endometrioid uterine cancers in an analysis of more than 39,000 patients.

Although several studies have shown an association between lymphadenectomy and improved survival, questions remain about lymphadenectomy and staging, and whether there is a benefit for patients with stage I disease, said Dr. Nita Karnik Lee at the annual meeting of the American Society of Clinical Oncology.

The findings of the current study suggest lymphadenectomy performed during surgical staging is beneficial for women with stage I, grade 3 or higher endometrioid uterine cancers, Dr. Lee said.

The analysis focused on data from the U.S. National Cancer Institute's Surveillance Epidemiology and End Results (SEER) program during 1988–2001, including that from 12 registries. The data showed that of 39,396 women with endometrioid uterine cancers, 12,333 (31%) underwent surgical staging and lymphadenectomy. The remaining patients underwent hysterectomy and bilateral salpingo-oophorectomy without lymphadenectomy.

Overall 5-year disease-specific survival was 93% for stage I patients, 85% for stage II patients, 69% for stage III patients, and 38% for stage IV patients.

In the lymphadenectomy group, compared with the group without lymphadenectomy, 5-year disease-specific survival was 96% vs. 97% for those with stage I disease, 90% vs. 82% for those with stage II disease, 73% vs. 61% for stage III disease, and 52% vs. 28% for those with stage IV disease, said Dr. Lee, a clinical instructor at Stanford (Calif.) University Medical Center.

The differences were significant for those with stages II-IV disease, as well as for the subgroup of stage I patients with grade 3 disease. In this subgroup, 5-year disease-specific survival was 90% for those with lymphadenectomy vs. 85% in those without.

Also, in patients with deep myometrial invasion (stage IC, grade 3), there was a trend toward improved survival. The 5-year disease-specific survival was 82% in the lymphadenectomy group and 77% in the nonlymphadenectomy group; this difference was not statistically significant.

The proportion of patients with stage I disease was significantly higher in the group without lymphadenectomy (84% vs. 73%). In addition, there were about 20% more patients in the group without lymphadenectomy that had grade 1 disease. Perhaps consistent with these findings was the fact that this group received less radiation overall, compared with the lymphadenectomy group, she said.

On multivariate analysis, nonwhite race, advanced stage, advanced grade, and advanced age were prognostic factors associated with poorer survival. Year of diagnosis and presence of lymphadenectomy were independent prognostic factors associated with improved survival.

During a formal discussion of this study, Dr. Thomas Herzog of Columbia University, New York, noted that although it addresses the important question of the effect of lymphadenectomy on survival, the study is limited in a number of ways, including lack of randomization. Further, lymph node dissection was the only variable considered, minorities were underrepresented in the database, and the analysis fails to establish the role of lymph node dissection in all stage I cases, he added.

He said the methodological limits failed to answer critical questions, such as whether there is a threshold node count, whether there is value of lymphadenectomy in stage I patients, and whether the effect seen is a therapeutic or diagnostic effect, such as stage migration.

Nonetheless, the findings are consistent with guidelines released earlier this year regarding the role of lymphadenectomy in endometrioid uterine cancers, and they appear to help boost the level of evidence in support of these guidelines, he said.

ATLANTA — Lymphadenectomy improved survival in women with stage I, grade 3 through stage IV endometrioid uterine cancers in an analysis of more than 39,000 patients.

Although several studies have shown an association between lymphadenectomy and improved survival, questions remain about lymphadenectomy and staging, and whether there is a benefit for patients with stage I disease, said Dr. Nita Karnik Lee at the annual meeting of the American Society of Clinical Oncology.

The findings of the current study suggest lymphadenectomy performed during surgical staging is beneficial for women with stage I, grade 3 or higher endometrioid uterine cancers, Dr. Lee said.

The analysis focused on data from the U.S. National Cancer Institute's Surveillance Epidemiology and End Results (SEER) program during 1988–2001, including that from 12 registries. The data showed that of 39,396 women with endometrioid uterine cancers, 12,333 (31%) underwent surgical staging and lymphadenectomy. The remaining patients underwent hysterectomy and bilateral salpingo-oophorectomy without lymphadenectomy.

Overall 5-year disease-specific survival was 93% for stage I patients, 85% for stage II patients, 69% for stage III patients, and 38% for stage IV patients.

In the lymphadenectomy group, compared with the group without lymphadenectomy, 5-year disease-specific survival was 96% vs. 97% for those with stage I disease, 90% vs. 82% for those with stage II disease, 73% vs. 61% for stage III disease, and 52% vs. 28% for those with stage IV disease, said Dr. Lee, a clinical instructor at Stanford (Calif.) University Medical Center.

The differences were significant for those with stages II-IV disease, as well as for the subgroup of stage I patients with grade 3 disease. In this subgroup, 5-year disease-specific survival was 90% for those with lymphadenectomy vs. 85% in those without.

Also, in patients with deep myometrial invasion (stage IC, grade 3), there was a trend toward improved survival. The 5-year disease-specific survival was 82% in the lymphadenectomy group and 77% in the nonlymphadenectomy group; this difference was not statistically significant.

The proportion of patients with stage I disease was significantly higher in the group without lymphadenectomy (84% vs. 73%). In addition, there were about 20% more patients in the group without lymphadenectomy that had grade 1 disease. Perhaps consistent with these findings was the fact that this group received less radiation overall, compared with the lymphadenectomy group, she said.

On multivariate analysis, nonwhite race, advanced stage, advanced grade, and advanced age were prognostic factors associated with poorer survival. Year of diagnosis and presence of lymphadenectomy were independent prognostic factors associated with improved survival.

During a formal discussion of this study, Dr. Thomas Herzog of Columbia University, New York, noted that although it addresses the important question of the effect of lymphadenectomy on survival, the study is limited in a number of ways, including lack of randomization. Further, lymph node dissection was the only variable considered, minorities were underrepresented in the database, and the analysis fails to establish the role of lymph node dissection in all stage I cases, he added.

He said the methodological limits failed to answer critical questions, such as whether there is a threshold node count, whether there is value of lymphadenectomy in stage I patients, and whether the effect seen is a therapeutic or diagnostic effect, such as stage migration.

Nonetheless, the findings are consistent with guidelines released earlier this year regarding the role of lymphadenectomy in endometrioid uterine cancers, and they appear to help boost the level of evidence in support of these guidelines, he said.

ATLANTA — Lymphadenectomy improved survival in women with stage I, grade 3 through stage IV endometrioid uterine cancers in an analysis of more than 39,000 patients.

Although several studies have shown an association between lymphadenectomy and improved survival, questions remain about lymphadenectomy and staging, and whether there is a benefit for patients with stage I disease, said Dr. Nita Karnik Lee at the annual meeting of the American Society of Clinical Oncology.

The findings of the current study suggest lymphadenectomy performed during surgical staging is beneficial for women with stage I, grade 3 or higher endometrioid uterine cancers, Dr. Lee said.

The analysis focused on data from the U.S. National Cancer Institute's Surveillance Epidemiology and End Results (SEER) program during 1988–2001, including that from 12 registries. The data showed that of 39,396 women with endometrioid uterine cancers, 12,333 (31%) underwent surgical staging and lymphadenectomy. The remaining patients underwent hysterectomy and bilateral salpingo-oophorectomy without lymphadenectomy.

Overall 5-year disease-specific survival was 93% for stage I patients, 85% for stage II patients, 69% for stage III patients, and 38% for stage IV patients.

In the lymphadenectomy group, compared with the group without lymphadenectomy, 5-year disease-specific survival was 96% vs. 97% for those with stage I disease, 90% vs. 82% for those with stage II disease, 73% vs. 61% for stage III disease, and 52% vs. 28% for those with stage IV disease, said Dr. Lee, a clinical instructor at Stanford (Calif.) University Medical Center.

The differences were significant for those with stages II-IV disease, as well as for the subgroup of stage I patients with grade 3 disease. In this subgroup, 5-year disease-specific survival was 90% for those with lymphadenectomy vs. 85% in those without.

Also, in patients with deep myometrial invasion (stage IC, grade 3), there was a trend toward improved survival. The 5-year disease-specific survival was 82% in the lymphadenectomy group and 77% in the nonlymphadenectomy group; this difference was not statistically significant.

The proportion of patients with stage I disease was significantly higher in the group without lymphadenectomy (84% vs. 73%). In addition, there were about 20% more patients in the group without lymphadenectomy that had grade 1 disease. Perhaps consistent with these findings was the fact that this group received less radiation overall, compared with the lymphadenectomy group, she said.

On multivariate analysis, nonwhite race, advanced stage, advanced grade, and advanced age were prognostic factors associated with poorer survival. Year of diagnosis and presence of lymphadenectomy were independent prognostic factors associated with improved survival.

During a formal discussion of this study, Dr. Thomas Herzog of Columbia University, New York, noted that although it addresses the important question of the effect of lymphadenectomy on survival, the study is limited in a number of ways, including lack of randomization. Further, lymph node dissection was the only variable considered, minorities were underrepresented in the database, and the analysis fails to establish the role of lymph node dissection in all stage I cases, he added.

He said the methodological limits failed to answer critical questions, such as whether there is a threshold node count, whether there is value of lymphadenectomy in stage I patients, and whether the effect seen is a therapeutic or diagnostic effect, such as stage migration.

Nonetheless, the findings are consistent with guidelines released earlier this year regarding the role of lymphadenectomy in endometrioid uterine cancers, and they appear to help boost the level of evidence in support of these guidelines, he said.

HOLLYWOOD, FLA. — Epidural analgesia given in early labor has been shown to have no significant effect on the risk of operative delivery in patients with spontaneous labor, and the same appears to hold true for patients with induced labor, according to data presented at the annual meeting of the Society for Obstetric Anesthesia and Perinatology.

In a series of 796 consecutive women with induced labor who requested early pain relief, the operative delivery rates were similar in those who did and did not receive early labor epidural analgesia (28% and 27%, respectively), Dr. Philip E. Hess reported in a poster at the meeting.

Because labor induction is known to be associated with higher operative delivery rates, there was concern that the effects of epidural analgesia in induced labor might be different than its effects in spontaneous labor, Dr. Hess wrote.

In the current study, patients undergoing labor induction who requested early pain relief (before 4-cm dilation) received parenteral opioid or labor epidural analgesia according to their obstetrician's protocol, reported Dr. Hess of Beth Israel Deaconess Medical Center, Boston.

A total of 350 women received epidural analgesia, and 446 received parenteral opioid. The groups were demographically similar, except the average body mass index was higher in the group that did not receive early epidural analgesia.

The groups were also similar demographically to a comparison group of 503 women with spontaneous labor. Consistent with the literature, that group had a 21% operative delivery rate, which was significantly lower than the rates in the induced labor groups, Dr. Hess noted.

HOLLYWOOD, FLA. — Epidural analgesia given in early labor has been shown to have no significant effect on the risk of operative delivery in patients with spontaneous labor, and the same appears to hold true for patients with induced labor, according to data presented at the annual meeting of the Society for Obstetric Anesthesia and Perinatology.

In a series of 796 consecutive women with induced labor who requested early pain relief, the operative delivery rates were similar in those who did and did not receive early labor epidural analgesia (28% and 27%, respectively), Dr. Philip E. Hess reported in a poster at the meeting.

Because labor induction is known to be associated with higher operative delivery rates, there was concern that the effects of epidural analgesia in induced labor might be different than its effects in spontaneous labor, Dr. Hess wrote.

In the current study, patients undergoing labor induction who requested early pain relief (before 4-cm dilation) received parenteral opioid or labor epidural analgesia according to their obstetrician's protocol, reported Dr. Hess of Beth Israel Deaconess Medical Center, Boston.

A total of 350 women received epidural analgesia, and 446 received parenteral opioid. The groups were demographically similar, except the average body mass index was higher in the group that did not receive early epidural analgesia.

The groups were also similar demographically to a comparison group of 503 women with spontaneous labor. Consistent with the literature, that group had a 21% operative delivery rate, which was significantly lower than the rates in the induced labor groups, Dr. Hess noted.

HOLLYWOOD, FLA. — Epidural analgesia given in early labor has been shown to have no significant effect on the risk of operative delivery in patients with spontaneous labor, and the same appears to hold true for patients with induced labor, according to data presented at the annual meeting of the Society for Obstetric Anesthesia and Perinatology.

In a series of 796 consecutive women with induced labor who requested early pain relief, the operative delivery rates were similar in those who did and did not receive early labor epidural analgesia (28% and 27%, respectively), Dr. Philip E. Hess reported in a poster at the meeting.

Because labor induction is known to be associated with higher operative delivery rates, there was concern that the effects of epidural analgesia in induced labor might be different than its effects in spontaneous labor, Dr. Hess wrote.

In the current study, patients undergoing labor induction who requested early pain relief (before 4-cm dilation) received parenteral opioid or labor epidural analgesia according to their obstetrician's protocol, reported Dr. Hess of Beth Israel Deaconess Medical Center, Boston.

A total of 350 women received epidural analgesia, and 446 received parenteral opioid. The groups were demographically similar, except the average body mass index was higher in the group that did not receive early epidural analgesia.

The groups were also similar demographically to a comparison group of 503 women with spontaneous labor. Consistent with the literature, that group had a 21% operative delivery rate, which was significantly lower than the rates in the induced labor groups, Dr. Hess noted.

MIAMI BEACH – Three variables–medicine characteristics, efficacy study characteristics, and patient characteristics–should be considered when prescribing for attention-deficit hyperactivity disorder, said Dr. Richard Rubin at the annual meeting of the American Society for Adolescent Psychiatry.

Medicine characteristics include effect duration, influence on comorbidities, individual safety risk, patient acceptance, cost, and access for continuous adherence, said Dr. Rubin, director of the private practice-based Clinical Study Center in Burlington, Vt.

Efficacy study characteristics–such as patient selection, rating measurements used, dosing, and treatment duration–should be considered in regard to how they might limit the findings and apply to patient care.

Patient characteristics important to consider include potential response mediators and moderators.

Compliance, for example, is a mediator that frequently causes problems in achieving desired outcomes. Data from 2004 on the three most commonly prescribed ADHD medications show that refill adherence after 2 months is only 50%. Patient/parent benefit expectations, subjective discomfort complaints, and side-effect fears appear to play an important role in compliance, and should be addressed by prescribers.

Comorbid disorders are common moderators that also require careful evaluation and consideration in ADHD prescribing, said Dr. Rubin at the meeting cosponsored by the University of Texas at Dallas.

Medications specifically approved for ADHD included amphetamine formulations, various methylphenidate products, and atomoxetine (Strattera). Useful medications not approved for ADHD include the antidepressants bupropion, imipramine, and nortriptyline, and the α₂-adrenergic agonists clonidine and guanfacine. Pemoline was withdrawn from the market, Dr. Rubin noted.

In the past year, new FDA approvals for adolescents were granted for a 72-g dose of osmotic-release oral system (OROS) methylphenidate, a methylphenidate transdermal system (Daytrana), and extended-release mixed amphetamine salts. An extended-release formulation for dexmethylphenidate (Focalin XR) was also approved for children, adolescents, and adults.

In addition, an “FDA approvable” letter was issued for an ADHD formulation of modafinil (Provigil), he noted.

Other topics Dr. Rubin addressed included:

▸ Stimulant pharmacokinetics and efficacy. One study looking at the effects of weight, age, and gender on mixed amphetamine salts (MAS) pharmacokinetics showed that the area under the curve and Cmax decreased, and half-life increased as weight increased in children, adolescents, and adults. Age and gender had no effect on the parameters, independent of weight.

A 4-week randomized, placebo-controlled study of MAS in 318 adolescents showed those treated with 10–40 mg/day had a mean 17.8-point decrease on the ADHD Rating Scale (ADHD-RS), those treated with 50 mg/day had a mean 16.9-point decrease, and those in the 60-mg group had a mean 14-point decrease, compared with a mean 9.4-point decrease in the placebo group. An OROS methylphenidate dosing study of 177 13- to 18-year-olds with combined type ADHD showed that 38% required the 72-mg dose to achieve at least a 30% ADHD-RS improvement, with a mean change of 15.3.

▸ Schedule II prescribing rules. Federal regulations updated in November 2005 to clarify physician responsibilities state that physicians are not required to see a patient every month or whenever schedule II drugs are prescribed. Prescriptions due for a refill can be mailed to a patient, or mailed or faxed to a pharmacy, but the physician should have a contact with the patient to verify ongoing safety. Physicians cannot provide refill prescriptions dated in advance. The amount of medicine that can be prescribed (for example, a 30- or 90-day supply) is regulated by the state or a third-party payer.

▸ Tricyclics for ADHD. These drugs may still have some selected use in ADHD, for example, with comorbid tics, but the risks for overdose fatality remain. Also, case reports suggest there is a risk for tricyclic-marijuana adverse interactions.

▸ α₂ Noradrenergic agonists for ADHD. Clonidine and guanfacine have been shown to be effective when added to stimulants for aggression with ADHD, and also appear effective for tics with ADHD. While the sedative properties of clonidine are commonly used at bedtime after daytime stimulants, physicians should be conscientious about the differential diagnosis and treatment of sleep problems in ADHD adolescents, Dr. Rubin advised.

For example, the ADHD itself, or comorbidities such as anxiety, oppositional defiant disorder, and substance abuse might play a role in sleep problems. Stimulant side effects, a primary sleep disorder such as obstructive apnea, restless legs, or poor sleep-hygiene practices may also be to blame.

▸ Bupropion. This drug is still a useful off-label treatment option for ADHD, particularly in those with substance use disorder, mood disorder, and/or conduct disorder, recent studies suggest. The dose needs to be high enough (450 mg/day for the XL form and 400 mg/day for SR form), and with duration of at least 4 weeks to achieve a 50% reduction in symptoms. The XL once-daily dose is associated with better adherence than the twice-daily SR dose, he noted.

▸ Atomoxetine initiation. The use of atomoxetine can be simplified and compliance might be improved with small deviations from the original package insert instructions.

Dr. Rubin recommended a titration schedule of 0.5 mg/kg per day the first week, 1.0 mg/kg per day the second week, and 1.5 mg/kg per day the third week. He said this allows only one pill size, but noted that the titration can be done as 40, then 80, then 120 mg in larger patients.

The basic visit schedule should include a visit at week 2 to evaluate tolerability and compliance, a visit at week 4 to look for response signals. Early tolerability problems can often be ameliorated with slower titrations, dose time change, or dose splitting to b.i.d., and a visit at week 6 to evaluate for extent of response and treatment moderators. Stimulant augmentation is useful for partial responders.

An alternate treatment should be considered in nonresponders. Initial evening postdinner dosing has the best tolerability, but a later switch to morning or twice-daily dosing may provide better efficacy. Some late adolescents, particularly college students, may adhere best with noon dosing along with lunch. While rare in adolescents, noradrenergic side effects are relieved by a 50% slower titration.

▸ Long-term stimulant side effects. There is no evidence of major adverse events with long-term stimulant use. Side effects that tend to persist include insomnia, decreased appetite and/or weight loss, and headache. Growth rate may be affected, but no evidence exists of an ultimate adult height reduction. However, if weight or height drops 10 or more percentile points after 1 year of treatment, a medication change should be considered.

▸ Sudden cardiac death and ADHD treatment. After Canada's withdrawal of MAS because of sudden cardiac death concerns and the drug's subsequent reinstatement, a Canadian physician advisory report advised strenuous exercise, use of other stimulants, and family history should be considered in risk-benefit assessment for individual patients.

▸ Atomoxetine and liver injury. Although a package insert warning was announced in December 2004, no Food and Drug Administration or psychiatric guideline for screening in healthy individuals has been issued.

If liver enzymes are measured, it is important to recognize that other factors, such as alcohol intake, acetaminophen, viral syndromes, and obesity can cause temporary changes.

An increase in liver enzymes to more than two times the baseline is a guide used in clinical trials for determining clinical significance. Any increase in bilirubin level is a red flag needing further evaluation.

MIAMI BEACH – Three variables–medicine characteristics, efficacy study characteristics, and patient characteristics–should be considered when prescribing for attention-deficit hyperactivity disorder, said Dr. Richard Rubin at the annual meeting of the American Society for Adolescent Psychiatry.

Medicine characteristics include effect duration, influence on comorbidities, individual safety risk, patient acceptance, cost, and access for continuous adherence, said Dr. Rubin, director of the private practice-based Clinical Study Center in Burlington, Vt.

Efficacy study characteristics–such as patient selection, rating measurements used, dosing, and treatment duration–should be considered in regard to how they might limit the findings and apply to patient care.

Patient characteristics important to consider include potential response mediators and moderators.

Compliance, for example, is a mediator that frequently causes problems in achieving desired outcomes. Data from 2004 on the three most commonly prescribed ADHD medications show that refill adherence after 2 months is only 50%. Patient/parent benefit expectations, subjective discomfort complaints, and side-effect fears appear to play an important role in compliance, and should be addressed by prescribers.

Comorbid disorders are common moderators that also require careful evaluation and consideration in ADHD prescribing, said Dr. Rubin at the meeting cosponsored by the University of Texas at Dallas.

Medications specifically approved for ADHD included amphetamine formulations, various methylphenidate products, and atomoxetine (Strattera). Useful medications not approved for ADHD include the antidepressants bupropion, imipramine, and nortriptyline, and the α₂-adrenergic agonists clonidine and guanfacine. Pemoline was withdrawn from the market, Dr. Rubin noted.

In the past year, new FDA approvals for adolescents were granted for a 72-g dose of osmotic-release oral system (OROS) methylphenidate, a methylphenidate transdermal system (Daytrana), and extended-release mixed amphetamine salts. An extended-release formulation for dexmethylphenidate (Focalin XR) was also approved for children, adolescents, and adults.

In addition, an “FDA approvable” letter was issued for an ADHD formulation of modafinil (Provigil), he noted.

Other topics Dr. Rubin addressed included:

▸ Stimulant pharmacokinetics and efficacy. One study looking at the effects of weight, age, and gender on mixed amphetamine salts (MAS) pharmacokinetics showed that the area under the curve and Cmax decreased, and half-life increased as weight increased in children, adolescents, and adults. Age and gender had no effect on the parameters, independent of weight.

A 4-week randomized, placebo-controlled study of MAS in 318 adolescents showed those treated with 10–40 mg/day had a mean 17.8-point decrease on the ADHD Rating Scale (ADHD-RS), those treated with 50 mg/day had a mean 16.9-point decrease, and those in the 60-mg group had a mean 14-point decrease, compared with a mean 9.4-point decrease in the placebo group. An OROS methylphenidate dosing study of 177 13- to 18-year-olds with combined type ADHD showed that 38% required the 72-mg dose to achieve at least a 30% ADHD-RS improvement, with a mean change of 15.3.

▸ Schedule II prescribing rules. Federal regulations updated in November 2005 to clarify physician responsibilities state that physicians are not required to see a patient every month or whenever schedule II drugs are prescribed. Prescriptions due for a refill can be mailed to a patient, or mailed or faxed to a pharmacy, but the physician should have a contact with the patient to verify ongoing safety. Physicians cannot provide refill prescriptions dated in advance. The amount of medicine that can be prescribed (for example, a 30- or 90-day supply) is regulated by the state or a third-party payer.

▸ Tricyclics for ADHD. These drugs may still have some selected use in ADHD, for example, with comorbid tics, but the risks for overdose fatality remain. Also, case reports suggest there is a risk for tricyclic-marijuana adverse interactions.

▸ α₂ Noradrenergic agonists for ADHD. Clonidine and guanfacine have been shown to be effective when added to stimulants for aggression with ADHD, and also appear effective for tics with ADHD. While the sedative properties of clonidine are commonly used at bedtime after daytime stimulants, physicians should be conscientious about the differential diagnosis and treatment of sleep problems in ADHD adolescents, Dr. Rubin advised.

For example, the ADHD itself, or comorbidities such as anxiety, oppositional defiant disorder, and substance abuse might play a role in sleep problems. Stimulant side effects, a primary sleep disorder such as obstructive apnea, restless legs, or poor sleep-hygiene practices may also be to blame.

▸ Bupropion. This drug is still a useful off-label treatment option for ADHD, particularly in those with substance use disorder, mood disorder, and/or conduct disorder, recent studies suggest. The dose needs to be high enough (450 mg/day for the XL form and 400 mg/day for SR form), and with duration of at least 4 weeks to achieve a 50% reduction in symptoms. The XL once-daily dose is associated with better adherence than the twice-daily SR dose, he noted.

▸ Atomoxetine initiation. The use of atomoxetine can be simplified and compliance might be improved with small deviations from the original package insert instructions.

Dr. Rubin recommended a titration schedule of 0.5 mg/kg per day the first week, 1.0 mg/kg per day the second week, and 1.5 mg/kg per day the third week. He said this allows only one pill size, but noted that the titration can be done as 40, then 80, then 120 mg in larger patients.

The basic visit schedule should include a visit at week 2 to evaluate tolerability and compliance, a visit at week 4 to look for response signals. Early tolerability problems can often be ameliorated with slower titrations, dose time change, or dose splitting to b.i.d., and a visit at week 6 to evaluate for extent of response and treatment moderators. Stimulant augmentation is useful for partial responders.

An alternate treatment should be considered in nonresponders. Initial evening postdinner dosing has the best tolerability, but a later switch to morning or twice-daily dosing may provide better efficacy. Some late adolescents, particularly college students, may adhere best with noon dosing along with lunch. While rare in adolescents, noradrenergic side effects are relieved by a 50% slower titration.

▸ Long-term stimulant side effects. There is no evidence of major adverse events with long-term stimulant use. Side effects that tend to persist include insomnia, decreased appetite and/or weight loss, and headache. Growth rate may be affected, but no evidence exists of an ultimate adult height reduction. However, if weight or height drops 10 or more percentile points after 1 year of treatment, a medication change should be considered.

▸ Sudden cardiac death and ADHD treatment. After Canada's withdrawal of MAS because of sudden cardiac death concerns and the drug's subsequent reinstatement, a Canadian physician advisory report advised strenuous exercise, use of other stimulants, and family history should be considered in risk-benefit assessment for individual patients.

▸ Atomoxetine and liver injury. Although a package insert warning was announced in December 2004, no Food and Drug Administration or psychiatric guideline for screening in healthy individuals has been issued.

If liver enzymes are measured, it is important to recognize that other factors, such as alcohol intake, acetaminophen, viral syndromes, and obesity can cause temporary changes.

An increase in liver enzymes to more than two times the baseline is a guide used in clinical trials for determining clinical significance. Any increase in bilirubin level is a red flag needing further evaluation.

MIAMI BEACH – Three variables–medicine characteristics, efficacy study characteristics, and patient characteristics–should be considered when prescribing for attention-deficit hyperactivity disorder, said Dr. Richard Rubin at the annual meeting of the American Society for Adolescent Psychiatry.

Medicine characteristics include effect duration, influence on comorbidities, individual safety risk, patient acceptance, cost, and access for continuous adherence, said Dr. Rubin, director of the private practice-based Clinical Study Center in Burlington, Vt.

Efficacy study characteristics–such as patient selection, rating measurements used, dosing, and treatment duration–should be considered in regard to how they might limit the findings and apply to patient care.

Patient characteristics important to consider include potential response mediators and moderators.

Compliance, for example, is a mediator that frequently causes problems in achieving desired outcomes. Data from 2004 on the three most commonly prescribed ADHD medications show that refill adherence after 2 months is only 50%. Patient/parent benefit expectations, subjective discomfort complaints, and side-effect fears appear to play an important role in compliance, and should be addressed by prescribers.

Comorbid disorders are common moderators that also require careful evaluation and consideration in ADHD prescribing, said Dr. Rubin at the meeting cosponsored by the University of Texas at Dallas.

Medications specifically approved for ADHD included amphetamine formulations, various methylphenidate products, and atomoxetine (Strattera). Useful medications not approved for ADHD include the antidepressants bupropion, imipramine, and nortriptyline, and the α₂-adrenergic agonists clonidine and guanfacine. Pemoline was withdrawn from the market, Dr. Rubin noted.

In the past year, new FDA approvals for adolescents were granted for a 72-g dose of osmotic-release oral system (OROS) methylphenidate, a methylphenidate transdermal system (Daytrana), and extended-release mixed amphetamine salts. An extended-release formulation for dexmethylphenidate (Focalin XR) was also approved for children, adolescents, and adults.

In addition, an “FDA approvable” letter was issued for an ADHD formulation of modafinil (Provigil), he noted.

Other topics Dr. Rubin addressed included:

▸ Stimulant pharmacokinetics and efficacy. One study looking at the effects of weight, age, and gender on mixed amphetamine salts (MAS) pharmacokinetics showed that the area under the curve and Cmax decreased, and half-life increased as weight increased in children, adolescents, and adults. Age and gender had no effect on the parameters, independent of weight.

A 4-week randomized, placebo-controlled study of MAS in 318 adolescents showed those treated with 10–40 mg/day had a mean 17.8-point decrease on the ADHD Rating Scale (ADHD-RS), those treated with 50 mg/day had a mean 16.9-point decrease, and those in the 60-mg group had a mean 14-point decrease, compared with a mean 9.4-point decrease in the placebo group. An OROS methylphenidate dosing study of 177 13- to 18-year-olds with combined type ADHD showed that 38% required the 72-mg dose to achieve at least a 30% ADHD-RS improvement, with a mean change of 15.3.

▸ Schedule II prescribing rules. Federal regulations updated in November 2005 to clarify physician responsibilities state that physicians are not required to see a patient every month or whenever schedule II drugs are prescribed. Prescriptions due for a refill can be mailed to a patient, or mailed or faxed to a pharmacy, but the physician should have a contact with the patient to verify ongoing safety. Physicians cannot provide refill prescriptions dated in advance. The amount of medicine that can be prescribed (for example, a 30- or 90-day supply) is regulated by the state or a third-party payer.

▸ Tricyclics for ADHD. These drugs may still have some selected use in ADHD, for example, with comorbid tics, but the risks for overdose fatality remain. Also, case reports suggest there is a risk for tricyclic-marijuana adverse interactions.

▸ α₂ Noradrenergic agonists for ADHD. Clonidine and guanfacine have been shown to be effective when added to stimulants for aggression with ADHD, and also appear effective for tics with ADHD. While the sedative properties of clonidine are commonly used at bedtime after daytime stimulants, physicians should be conscientious about the differential diagnosis and treatment of sleep problems in ADHD adolescents, Dr. Rubin advised.

For example, the ADHD itself, or comorbidities such as anxiety, oppositional defiant disorder, and substance abuse might play a role in sleep problems. Stimulant side effects, a primary sleep disorder such as obstructive apnea, restless legs, or poor sleep-hygiene practices may also be to blame.

▸ Bupropion. This drug is still a useful off-label treatment option for ADHD, particularly in those with substance use disorder, mood disorder, and/or conduct disorder, recent studies suggest. The dose needs to be high enough (450 mg/day for the XL form and 400 mg/day for SR form), and with duration of at least 4 weeks to achieve a 50% reduction in symptoms. The XL once-daily dose is associated with better adherence than the twice-daily SR dose, he noted.

▸ Atomoxetine initiation. The use of atomoxetine can be simplified and compliance might be improved with small deviations from the original package insert instructions.

Dr. Rubin recommended a titration schedule of 0.5 mg/kg per day the first week, 1.0 mg/kg per day the second week, and 1.5 mg/kg per day the third week. He said this allows only one pill size, but noted that the titration can be done as 40, then 80, then 120 mg in larger patients.

The basic visit schedule should include a visit at week 2 to evaluate tolerability and compliance, a visit at week 4 to look for response signals. Early tolerability problems can often be ameliorated with slower titrations, dose time change, or dose splitting to b.i.d., and a visit at week 6 to evaluate for extent of response and treatment moderators. Stimulant augmentation is useful for partial responders.

An alternate treatment should be considered in nonresponders. Initial evening postdinner dosing has the best tolerability, but a later switch to morning or twice-daily dosing may provide better efficacy. Some late adolescents, particularly college students, may adhere best with noon dosing along with lunch. While rare in adolescents, noradrenergic side effects are relieved by a 50% slower titration.

▸ Long-term stimulant side effects. There is no evidence of major adverse events with long-term stimulant use. Side effects that tend to persist include insomnia, decreased appetite and/or weight loss, and headache. Growth rate may be affected, but no evidence exists of an ultimate adult height reduction. However, if weight or height drops 10 or more percentile points after 1 year of treatment, a medication change should be considered.

▸ Sudden cardiac death and ADHD treatment. After Canada's withdrawal of MAS because of sudden cardiac death concerns and the drug's subsequent reinstatement, a Canadian physician advisory report advised strenuous exercise, use of other stimulants, and family history should be considered in risk-benefit assessment for individual patients.

▸ Atomoxetine and liver injury. Although a package insert warning was announced in December 2004, no Food and Drug Administration or psychiatric guideline for screening in healthy individuals has been issued.

If liver enzymes are measured, it is important to recognize that other factors, such as alcohol intake, acetaminophen, viral syndromes, and obesity can cause temporary changes.

An increase in liver enzymes to more than two times the baseline is a guide used in clinical trials for determining clinical significance. Any increase in bilirubin level is a red flag needing further evaluation.