Michele G. Sullivan

Medical therapy with antisecretory drugs should be the first-line treatment for gastroesophageal reflux disease, with antireflux surgery offered only to those whose symptoms are not controlled by medication or who can't tolerate the drugs, according to a new management guideline released by the AGA Institute.

Proton pump inhibitors remain the most effective medical therapy, followed by histamine2-receptor agonists, according to the position paper.

“There is ample evidence that, as a drug class, proton pump inhibitors are more effective in these patients than are histamine receptor blockers,” wrote lead author Dr. Peter J. Kahrilas of Northwestern University, Chicago.

The document addresses 12 broad issues concerning the diagnosis and management of gastroesophageal reflux disease (GERD), and was developed based on a technical review undertaken by Dr. Kahrilas and his colleagues Dr. Nicholas J. Shaheen and Dr. Michael Vaezi. For each question, the authors performed a comprehensive literature review.

While the authors said there is fair evidence that some lifestyle modifications can benefit patients with GERD, they found no strong evidence that such changes should be broadly recommended for all patients. Patients with nighttime symptoms may benefit from elevating the head of their bed, they wrote. Overweight or obese patients should be urged to lose weight, as this may prevent or delay the need for acid suppression.

The authors found strong evidence that antisecretory drugs, especially proton pump inhibitors, improve outcomes, and fair evidence to support twice-daily dosing for some patients. Although essentially all drug trials used once-daily dosing, expert opinion “is essentially unanimous in recommending twice-daily dosing of PPIs to improve symptom relief in patients with … an unsatisfactory response to once-daily dosing.” They found no evidence that metoclopramide is useful, either as mono- or adjunctive therapy, and recommend against its use because of its substantial side effect profile.

Strong evidence supported a three-tiered diagnostic algorithm. Patients with suspected GERD syndrome and troublesome dysphagia should undergo endoscopy with biopsy as an initial evaluation. Those with suspected GERD treated empirically who fail to respond to twice-daily PPIs may benefit from either an endoscopy or esophageal manometry to pursue alternative diagnoses. Ambulatory pH testing, off of PPI therapy, should be done to substantiate a GERD diagnosis for those who have not responded to empirical therapy, and who have had unremarkable endoscopy and manometry.

They found strong evidence that antisecretory drugs are also beneficial for patients with suspected extraesophageal reflux symptoms (cough, laryngitis, and asthma) when those patients also experience esophageal GERD symptoms. “Empirical therapy with twice-daily PPIs for 2 months remains a pragmatic clinical strategy for subsets of these patients if they have a concomitant esophageal GERD syndrome. Failing such a trial, etiologies other than GERD should be explored.”

No firm data suggest that GERD is always a progressive disease, going from nonerosive to erosive to Barrett's esophagus, the authors said. Therefore, routine endoscopy to monitor progression is not recommended. The limited data available suggest that any risk of progression is very small—less than 2% over 7 years—and endoscopic monitoring has not been shown to lessen the risk of cancer.

Regarding maintenance therapy, the authors found strong evidence that long-term PPIs are safe and effective, and can be titrated downward in many patients. However, daily therapy will still be necessary for most, as “the likelihood of spontaneous remission of disease is low.”

There was fair evidence supporting long-term maintenance therapy for patients with extraesophageal reflux symptoms, but only if they have concomitant esophageal GERD syndrome.

Medical therapy should be the first-line treatment. Surgery may be considered for those who can't tolerate the drugs, or whose symptoms are not controlled by them. However, the benefits of antireflux surgery need to be weighed carefully against the problems it can engender, the authors wrote.

Medical therapy with antisecretory drugs should be the first-line treatment for gastroesophageal reflux disease, with antireflux surgery offered only to those whose symptoms are not controlled by medication or who can't tolerate the drugs, according to a new management guideline released by the AGA Institute.

Proton pump inhibitors remain the most effective medical therapy, followed by histamine2-receptor agonists, according to the position paper.

“There is ample evidence that, as a drug class, proton pump inhibitors are more effective in these patients than are histamine receptor blockers,” wrote lead author Dr. Peter J. Kahrilas of Northwestern University, Chicago.

The document addresses 12 broad issues concerning the diagnosis and management of gastroesophageal reflux disease (GERD), and was developed based on a technical review undertaken by Dr. Kahrilas and his colleagues Dr. Nicholas J. Shaheen and Dr. Michael Vaezi. For each question, the authors performed a comprehensive literature review.

While the authors said there is fair evidence that some lifestyle modifications can benefit patients with GERD, they found no strong evidence that such changes should be broadly recommended for all patients. Patients with nighttime symptoms may benefit from elevating the head of their bed, they wrote. Overweight or obese patients should be urged to lose weight, as this may prevent or delay the need for acid suppression.

The authors found strong evidence that antisecretory drugs, especially proton pump inhibitors, improve outcomes, and fair evidence to support twice-daily dosing for some patients. Although essentially all drug trials used once-daily dosing, expert opinion “is essentially unanimous in recommending twice-daily dosing of PPIs to improve symptom relief in patients with … an unsatisfactory response to once-daily dosing.” They found no evidence that metoclopramide is useful, either as mono- or adjunctive therapy, and recommend against its use because of its substantial side effect profile.

Strong evidence supported a three-tiered diagnostic algorithm. Patients with suspected GERD syndrome and troublesome dysphagia should undergo endoscopy with biopsy as an initial evaluation. Those with suspected GERD treated empirically who fail to respond to twice-daily PPIs may benefit from either an endoscopy or esophageal manometry to pursue alternative diagnoses. Ambulatory pH testing, off of PPI therapy, should be done to substantiate a GERD diagnosis for those who have not responded to empirical therapy, and who have had unremarkable endoscopy and manometry.

They found strong evidence that antisecretory drugs are also beneficial for patients with suspected extraesophageal reflux symptoms (cough, laryngitis, and asthma) when those patients also experience esophageal GERD symptoms. “Empirical therapy with twice-daily PPIs for 2 months remains a pragmatic clinical strategy for subsets of these patients if they have a concomitant esophageal GERD syndrome. Failing such a trial, etiologies other than GERD should be explored.”

No firm data suggest that GERD is always a progressive disease, going from nonerosive to erosive to Barrett's esophagus, the authors said. Therefore, routine endoscopy to monitor progression is not recommended. The limited data available suggest that any risk of progression is very small—less than 2% over 7 years—and endoscopic monitoring has not been shown to lessen the risk of cancer.

Regarding maintenance therapy, the authors found strong evidence that long-term PPIs are safe and effective, and can be titrated downward in many patients. However, daily therapy will still be necessary for most, as “the likelihood of spontaneous remission of disease is low.”

There was fair evidence supporting long-term maintenance therapy for patients with extraesophageal reflux symptoms, but only if they have concomitant esophageal GERD syndrome.

Medical therapy should be the first-line treatment. Surgery may be considered for those who can't tolerate the drugs, or whose symptoms are not controlled by them. However, the benefits of antireflux surgery need to be weighed carefully against the problems it can engender, the authors wrote.

Medical therapy with antisecretory drugs should be the first-line treatment for gastroesophageal reflux disease, with antireflux surgery offered only to those whose symptoms are not controlled by medication or who can't tolerate the drugs, according to a new management guideline released by the AGA Institute.

Proton pump inhibitors remain the most effective medical therapy, followed by histamine2-receptor agonists, according to the position paper.

“There is ample evidence that, as a drug class, proton pump inhibitors are more effective in these patients than are histamine receptor blockers,” wrote lead author Dr. Peter J. Kahrilas of Northwestern University, Chicago.

The document addresses 12 broad issues concerning the diagnosis and management of gastroesophageal reflux disease (GERD), and was developed based on a technical review undertaken by Dr. Kahrilas and his colleagues Dr. Nicholas J. Shaheen and Dr. Michael Vaezi. For each question, the authors performed a comprehensive literature review.

While the authors said there is fair evidence that some lifestyle modifications can benefit patients with GERD, they found no strong evidence that such changes should be broadly recommended for all patients. Patients with nighttime symptoms may benefit from elevating the head of their bed, they wrote. Overweight or obese patients should be urged to lose weight, as this may prevent or delay the need for acid suppression.

The authors found strong evidence that antisecretory drugs, especially proton pump inhibitors, improve outcomes, and fair evidence to support twice-daily dosing for some patients. Although essentially all drug trials used once-daily dosing, expert opinion “is essentially unanimous in recommending twice-daily dosing of PPIs to improve symptom relief in patients with … an unsatisfactory response to once-daily dosing.” They found no evidence that metoclopramide is useful, either as mono- or adjunctive therapy, and recommend against its use because of its substantial side effect profile.

Strong evidence supported a three-tiered diagnostic algorithm. Patients with suspected GERD syndrome and troublesome dysphagia should undergo endoscopy with biopsy as an initial evaluation. Those with suspected GERD treated empirically who fail to respond to twice-daily PPIs may benefit from either an endoscopy or esophageal manometry to pursue alternative diagnoses. Ambulatory pH testing, off of PPI therapy, should be done to substantiate a GERD diagnosis for those who have not responded to empirical therapy, and who have had unremarkable endoscopy and manometry.

They found strong evidence that antisecretory drugs are also beneficial for patients with suspected extraesophageal reflux symptoms (cough, laryngitis, and asthma) when those patients also experience esophageal GERD symptoms. “Empirical therapy with twice-daily PPIs for 2 months remains a pragmatic clinical strategy for subsets of these patients if they have a concomitant esophageal GERD syndrome. Failing such a trial, etiologies other than GERD should be explored.”

No firm data suggest that GERD is always a progressive disease, going from nonerosive to erosive to Barrett's esophagus, the authors said. Therefore, routine endoscopy to monitor progression is not recommended. The limited data available suggest that any risk of progression is very small—less than 2% over 7 years—and endoscopic monitoring has not been shown to lessen the risk of cancer.

Regarding maintenance therapy, the authors found strong evidence that long-term PPIs are safe and effective, and can be titrated downward in many patients. However, daily therapy will still be necessary for most, as “the likelihood of spontaneous remission of disease is low.”

There was fair evidence supporting long-term maintenance therapy for patients with extraesophageal reflux symptoms, but only if they have concomitant esophageal GERD syndrome.

Medical therapy should be the first-line treatment. Surgery may be considered for those who can't tolerate the drugs, or whose symptoms are not controlled by them. However, the benefits of antireflux surgery need to be weighed carefully against the problems it can engender, the authors wrote.

BARCELONA — More than 20% of patients taking antipsychotic medications for schizophrenia were at risk for diabetes, more than 30% had undiagnosed hyperlipidemia, and more than 50% had undiagnosed hypertension, a large European epidemiologic study has found.

The findings drive home the need for continuous monitoring of patients taking these drugs, Dr. Marc de Hert and his colleagues wrote in a poster presented at the annual congress of the European College of Neuropsychopharmacology.

The observational study was launched in 2006; it included 2,270 patients with schizophrenia recruited in 12 European countries. Patients made a single clinic visit, during which they underwent a metabolic workup that included measurement of fasting blood glucose, weight, waist, hips, and blood pressure. The patients' median age was 41; 55% were male. Most (76%) had paranoid schizophrenia; the median duration of illness was 11 years.

The most frequently used typical antipsychotics were haloperidol (48%) and zuclopenthixol (20%). The most frequently used atypicals were risperidone (25%), olanzapine (23%), clozapine (19%), amisulpride (17%), and quetiapine (12%).

Only 4% of the patients had a diagnosis of diabetes, yet an additional 24% either had or were at risk of the disorder, wrote Dr. de Hert of the Catholic University Louvain (Belgium). Of these 559 patients, 75 had a fasting blood glucose of at least 126 mg/dL, consistent with diabetes, and 484 presented with an impaired fasting glucose of 100–126 mg/dL. Seven percent (161) previously had been diagnosed with hyperlipidemia. However, an additional 54% of the cohort had undiagnosed hyperlipidemia at the time of the exam.

Hypertension previously had been diagnosed in 248 patients. But at the study visit, an additional 738 patients (32%) had elevated blood pressures; elevations were significantly more likely in those taking a typical than an atypical antipsychotic.

The incidence of metabolic syndrome was similar in both groups (37%).

This study was sponsored and funded by Sanofi-Aventis.

BARCELONA — More than 20% of patients taking antipsychotic medications for schizophrenia were at risk for diabetes, more than 30% had undiagnosed hyperlipidemia, and more than 50% had undiagnosed hypertension, a large European epidemiologic study has found.

The findings drive home the need for continuous monitoring of patients taking these drugs, Dr. Marc de Hert and his colleagues wrote in a poster presented at the annual congress of the European College of Neuropsychopharmacology.

The observational study was launched in 2006; it included 2,270 patients with schizophrenia recruited in 12 European countries. Patients made a single clinic visit, during which they underwent a metabolic workup that included measurement of fasting blood glucose, weight, waist, hips, and blood pressure. The patients' median age was 41; 55% were male. Most (76%) had paranoid schizophrenia; the median duration of illness was 11 years.

The most frequently used typical antipsychotics were haloperidol (48%) and zuclopenthixol (20%). The most frequently used atypicals were risperidone (25%), olanzapine (23%), clozapine (19%), amisulpride (17%), and quetiapine (12%).

Only 4% of the patients had a diagnosis of diabetes, yet an additional 24% either had or were at risk of the disorder, wrote Dr. de Hert of the Catholic University Louvain (Belgium). Of these 559 patients, 75 had a fasting blood glucose of at least 126 mg/dL, consistent with diabetes, and 484 presented with an impaired fasting glucose of 100–126 mg/dL. Seven percent (161) previously had been diagnosed with hyperlipidemia. However, an additional 54% of the cohort had undiagnosed hyperlipidemia at the time of the exam.

Hypertension previously had been diagnosed in 248 patients. But at the study visit, an additional 738 patients (32%) had elevated blood pressures; elevations were significantly more likely in those taking a typical than an atypical antipsychotic.

The incidence of metabolic syndrome was similar in both groups (37%).

This study was sponsored and funded by Sanofi-Aventis.

BARCELONA — More than 20% of patients taking antipsychotic medications for schizophrenia were at risk for diabetes, more than 30% had undiagnosed hyperlipidemia, and more than 50% had undiagnosed hypertension, a large European epidemiologic study has found.

The findings drive home the need for continuous monitoring of patients taking these drugs, Dr. Marc de Hert and his colleagues wrote in a poster presented at the annual congress of the European College of Neuropsychopharmacology.

The observational study was launched in 2006; it included 2,270 patients with schizophrenia recruited in 12 European countries. Patients made a single clinic visit, during which they underwent a metabolic workup that included measurement of fasting blood glucose, weight, waist, hips, and blood pressure. The patients' median age was 41; 55% were male. Most (76%) had paranoid schizophrenia; the median duration of illness was 11 years.

The most frequently used typical antipsychotics were haloperidol (48%) and zuclopenthixol (20%). The most frequently used atypicals were risperidone (25%), olanzapine (23%), clozapine (19%), amisulpride (17%), and quetiapine (12%).

Only 4% of the patients had a diagnosis of diabetes, yet an additional 24% either had or were at risk of the disorder, wrote Dr. de Hert of the Catholic University Louvain (Belgium). Of these 559 patients, 75 had a fasting blood glucose of at least 126 mg/dL, consistent with diabetes, and 484 presented with an impaired fasting glucose of 100–126 mg/dL. Seven percent (161) previously had been diagnosed with hyperlipidemia. However, an additional 54% of the cohort had undiagnosed hyperlipidemia at the time of the exam.

Hypertension previously had been diagnosed in 248 patients. But at the study visit, an additional 738 patients (32%) had elevated blood pressures; elevations were significantly more likely in those taking a typical than an atypical antipsychotic.

The incidence of metabolic syndrome was similar in both groups (37%).

This study was sponsored and funded by Sanofi-Aventis.

Early, aggressive insulin therapy is probably the optimal treatment for patients with newly diagnosed type 2 diabetes who present with severe hyperglycemia, because it provides better short-term glycemic control and β-cell recovery than a regimen of oral antidiabetes drugs, a study has found.

After being stabilized on insulin, patients in the controlled trial who were randomized to a further 6 months of insulin therapy had significantly better glucose levels and β-cell function, Dr. Harn-Shen Chen and colleagues concluded.

“Our data demonstrated that intensive insulin therapy … can achieve optimal glycemic control in [these patients], but cannot induce long-term glycemic control,” Dr. Chen of the Taipei Veterans General Hospital, Taiwan, and the coauthors wrote in Diabetes Care. “A 6-month course of further insulin therapy, compared with oral antidiabetes treatment, more effectively maintained adequate glycemic control accompanied with significant improvement of β-cell function” (Diabetes Care 2008;31:1927-32).

The investigators examined the effect of both treatments in 50 patients with newly diagnosed type 2 diabetes, all of whom were hospitalized with severe hyperglycemia—a fasting plasma glucose of more than 300 mg/dL, or random plasma glucose of more than 400 mg/dL. All patients received 10–14 days of intensive insulin treatment, with the goal of a preprandial blood glucose of 90–130 mg/dL and a bedtime blood glucose of 100–160 mg/dL. After stabilization, patients took an oral glucose tolerance test for baseline values, and were discharged on either insulin (30) or oral antidiabetic agents (20).

Insulin doses were titrated every 3 days to achieve a target blood glucose level of 90–130 mg/dL. Oral medications were titrated in several phases. Initially, overweight patients received metformin and lean patients received gliclazide-MR, both of which were titrated to achieve blood glucose of 90–130 mg/dL. In the second step, lean patients received metformin and overweight patients received gliclazide. In the third step, the drugs were titrated to a maximum of 120-mg/day gliclazide and 2,550-mg/day metformin in a split dose. After 6 months, the insulin-treated patients switched to an oral regimen. Both groups were assessed again at 12 months.

During the treatment period, the insulin dose decreased from a mean of 26 IU/day to 17 IU/day. Conversely, the oral medications had to be increased to achieve the target blood glucose level.

At the beginning of the treatment, both groups had stable hemoglobin A_1c (HbA_1c) of about 11%. At the end of the treatment, the HbA_1c level was significantly lower in the insulin group (6% vs 7.5%). At the 12-month follow-up visit, the HbA_1c level was still significantly better in the insulin group (6.8% vs 7.8%).

“The study showed that desired glycemic control was successfully achieved by intensive insulin therapy. … However, most of these subjects required pharmacologic therapy to maintain near-euglycemia in our study period,” the authors noted. “A 6-month course of further insulin therapy, compared with [oral antidiabetes drug] treatment, could more effectively achieve a near-normal A_1c level.”

β-Cell function was assessed by an oral glucose tolerance test at 6 months. All β-cell functions were significantly improved in both groups. However, when compared with the oral medications group, the insulin group had a significantly better insulin area under the curve, HOMA-β index, and insulinogenic index.

“Our results support the concept that correction of hyperglycemia can improve insulin secretion,” the authors wrote. “Another possibility is that β-cell secretory capacity may have been restored by 'rested' β-cells, induced by insulin injection.”

There were no severe hypoglycemic events in either group.

“Given the much greater efforts [required] on the part of both patients and physicians to initiate treatment with insulin, we need evidence, not hypotheses, to recommend this course,” Dr. Mayer B. Davidson of Charles R. Drew University of Medicine and Science, Los Angeles, cautioned in an accompanying editorial.

The study was funded by the Taipei Veterans General Hospital and the Taiwan Department of Health. The authors reported no conflicts of interest.

Early, aggressive insulin therapy is probably the optimal treatment for patients with newly diagnosed type 2 diabetes who present with severe hyperglycemia, because it provides better short-term glycemic control and β-cell recovery than a regimen of oral antidiabetes drugs, a study has found.

After being stabilized on insulin, patients in the controlled trial who were randomized to a further 6 months of insulin therapy had significantly better glucose levels and β-cell function, Dr. Harn-Shen Chen and colleagues concluded.

“Our data demonstrated that intensive insulin therapy … can achieve optimal glycemic control in [these patients], but cannot induce long-term glycemic control,” Dr. Chen of the Taipei Veterans General Hospital, Taiwan, and the coauthors wrote in Diabetes Care. “A 6-month course of further insulin therapy, compared with oral antidiabetes treatment, more effectively maintained adequate glycemic control accompanied with significant improvement of β-cell function” (Diabetes Care 2008;31:1927-32).

The investigators examined the effect of both treatments in 50 patients with newly diagnosed type 2 diabetes, all of whom were hospitalized with severe hyperglycemia—a fasting plasma glucose of more than 300 mg/dL, or random plasma glucose of more than 400 mg/dL. All patients received 10–14 days of intensive insulin treatment, with the goal of a preprandial blood glucose of 90–130 mg/dL and a bedtime blood glucose of 100–160 mg/dL. After stabilization, patients took an oral glucose tolerance test for baseline values, and were discharged on either insulin (30) or oral antidiabetic agents (20).

Insulin doses were titrated every 3 days to achieve a target blood glucose level of 90–130 mg/dL. Oral medications were titrated in several phases. Initially, overweight patients received metformin and lean patients received gliclazide-MR, both of which were titrated to achieve blood glucose of 90–130 mg/dL. In the second step, lean patients received metformin and overweight patients received gliclazide. In the third step, the drugs were titrated to a maximum of 120-mg/day gliclazide and 2,550-mg/day metformin in a split dose. After 6 months, the insulin-treated patients switched to an oral regimen. Both groups were assessed again at 12 months.

During the treatment period, the insulin dose decreased from a mean of 26 IU/day to 17 IU/day. Conversely, the oral medications had to be increased to achieve the target blood glucose level.

At the beginning of the treatment, both groups had stable hemoglobin A_1c (HbA_1c) of about 11%. At the end of the treatment, the HbA_1c level was significantly lower in the insulin group (6% vs 7.5%). At the 12-month follow-up visit, the HbA_1c level was still significantly better in the insulin group (6.8% vs 7.8%).

“The study showed that desired glycemic control was successfully achieved by intensive insulin therapy. … However, most of these subjects required pharmacologic therapy to maintain near-euglycemia in our study period,” the authors noted. “A 6-month course of further insulin therapy, compared with [oral antidiabetes drug] treatment, could more effectively achieve a near-normal A_1c level.”

β-Cell function was assessed by an oral glucose tolerance test at 6 months. All β-cell functions were significantly improved in both groups. However, when compared with the oral medications group, the insulin group had a significantly better insulin area under the curve, HOMA-β index, and insulinogenic index.

“Our results support the concept that correction of hyperglycemia can improve insulin secretion,” the authors wrote. “Another possibility is that β-cell secretory capacity may have been restored by 'rested' β-cells, induced by insulin injection.”

There were no severe hypoglycemic events in either group.

“Given the much greater efforts [required] on the part of both patients and physicians to initiate treatment with insulin, we need evidence, not hypotheses, to recommend this course,” Dr. Mayer B. Davidson of Charles R. Drew University of Medicine and Science, Los Angeles, cautioned in an accompanying editorial.

The study was funded by the Taipei Veterans General Hospital and the Taiwan Department of Health. The authors reported no conflicts of interest.

Early, aggressive insulin therapy is probably the optimal treatment for patients with newly diagnosed type 2 diabetes who present with severe hyperglycemia, because it provides better short-term glycemic control and β-cell recovery than a regimen of oral antidiabetes drugs, a study has found.

After being stabilized on insulin, patients in the controlled trial who were randomized to a further 6 months of insulin therapy had significantly better glucose levels and β-cell function, Dr. Harn-Shen Chen and colleagues concluded.

“Our data demonstrated that intensive insulin therapy … can achieve optimal glycemic control in [these patients], but cannot induce long-term glycemic control,” Dr. Chen of the Taipei Veterans General Hospital, Taiwan, and the coauthors wrote in Diabetes Care. “A 6-month course of further insulin therapy, compared with oral antidiabetes treatment, more effectively maintained adequate glycemic control accompanied with significant improvement of β-cell function” (Diabetes Care 2008;31:1927-32).

The investigators examined the effect of both treatments in 50 patients with newly diagnosed type 2 diabetes, all of whom were hospitalized with severe hyperglycemia—a fasting plasma glucose of more than 300 mg/dL, or random plasma glucose of more than 400 mg/dL. All patients received 10–14 days of intensive insulin treatment, with the goal of a preprandial blood glucose of 90–130 mg/dL and a bedtime blood glucose of 100–160 mg/dL. After stabilization, patients took an oral glucose tolerance test for baseline values, and were discharged on either insulin (30) or oral antidiabetic agents (20).

Insulin doses were titrated every 3 days to achieve a target blood glucose level of 90–130 mg/dL. Oral medications were titrated in several phases. Initially, overweight patients received metformin and lean patients received gliclazide-MR, both of which were titrated to achieve blood glucose of 90–130 mg/dL. In the second step, lean patients received metformin and overweight patients received gliclazide. In the third step, the drugs were titrated to a maximum of 120-mg/day gliclazide and 2,550-mg/day metformin in a split dose. After 6 months, the insulin-treated patients switched to an oral regimen. Both groups were assessed again at 12 months.

During the treatment period, the insulin dose decreased from a mean of 26 IU/day to 17 IU/day. Conversely, the oral medications had to be increased to achieve the target blood glucose level.

At the beginning of the treatment, both groups had stable hemoglobin A_1c (HbA_1c) of about 11%. At the end of the treatment, the HbA_1c level was significantly lower in the insulin group (6% vs 7.5%). At the 12-month follow-up visit, the HbA_1c level was still significantly better in the insulin group (6.8% vs 7.8%).

“The study showed that desired glycemic control was successfully achieved by intensive insulin therapy. … However, most of these subjects required pharmacologic therapy to maintain near-euglycemia in our study period,” the authors noted. “A 6-month course of further insulin therapy, compared with [oral antidiabetes drug] treatment, could more effectively achieve a near-normal A_1c level.”

β-Cell function was assessed by an oral glucose tolerance test at 6 months. All β-cell functions were significantly improved in both groups. However, when compared with the oral medications group, the insulin group had a significantly better insulin area under the curve, HOMA-β index, and insulinogenic index.

“Our results support the concept that correction of hyperglycemia can improve insulin secretion,” the authors wrote. “Another possibility is that β-cell secretory capacity may have been restored by 'rested' β-cells, induced by insulin injection.”

There were no severe hypoglycemic events in either group.

“Given the much greater efforts [required] on the part of both patients and physicians to initiate treatment with insulin, we need evidence, not hypotheses, to recommend this course,” Dr. Mayer B. Davidson of Charles R. Drew University of Medicine and Science, Los Angeles, cautioned in an accompanying editorial.

The study was funded by the Taipei Veterans General Hospital and the Taiwan Department of Health. The authors reported no conflicts of interest.

CHICAGO – Smoking in midlife might increase the chance of Alzheimer's in later life among those who already carry an increased genetic risk.

A population-based Finnish study with more than 20 years of follow-up concluded that carriers of the apolipoprotein E4 allele who smoked in midlife were seven times more likely to develop Alzheimer's than were carriers who didn't smoke. Alcohol consumption seemed to exacerbate the smoking-associated risk; carriers who drank frequently and smoked at midlife were more than 11 times as likely to develop the disorder as were carriers who never indulged in either behavior, Dr. Minna Rusanen said at the International Conference on Alzheimer's Disease.

The news is actually good for apo E4 carriers, who are considered almost certain to develop the disorder at a relatively young age, she said in an interview. “Recent knowledge about the environmental risk factors of the disease is giving hope to genetically susceptible people,” said Dr. Rusanen of the Kuopio (Finland) University Hospital. “The risk of developing Alzheimer's may be lowered by adopting an overall healthy lifestyle early in life. Promoting smoking cessation should be one of the major issues in the public education; it could help to prevent, or at least delay, the onset of Alzheimer's, and thus help one to live a cognitively healthy life also through old age.”

The association between smoking and dementia has never been conclusively proved, Dr. Rusanen noted. “Several case-control studies in the 1980s and 1990s suggested an inverse relationship between smoking and dementia, but this was probably due to a survival bias.” Some studies found a positive association only among apo E4 noncarriers, but one concluded that apo E status didn't modify dementia risk among smokers. The connection between smoking and Alzheimer's risk, however, is biologically plausible. “Smoking is known to have negative vascular effects, and predispose to cerebrovascular disease by accelerating atherosclerosis and inducing oxidative stress and inflammation–mechanisms which are also thought to have relevance in the development of Alzheimer's.”

To further investigate this question, Dr. Rusanen and her colleagues extracted data from the Finnish Cardiovascular Risk Factors, Aging, and Dementia study. The study included 2,000 participants who had been examined during midlife in four separate samples (1972, 1977, 1982, and 1987). After an average follow-up of 21 years, 1,449 of these people took part in a reexamination held in 1998. At that time, subjects were aged 65–79 years; 61 had developed some type of dementia, with Alzheimer's accounting for 48 of those cases.

Information on smoking status was available for 1,419 subjects. Of these, 321 were smokers during midlife, 272 had smoked in their younger years, and 826 had never smoked.

After researchers controlled for socio-economic status, blood pressure, cholesterol, body mass index, heart disease, stroke, diabetes, and lung disease, there was no association between smoking and Alzheimer's disease in any group except apo E4 carriers. Carriers who smoked at midlife were almost seven times more likely to have developed the disorder than were the nonsmoking carriers.

The risk increased again when Dr. Rusanen factored in alcohol consumption at midlife. Again, apo E4 carriers fared significantly worse than any other group. Midlife smokers who drank either occasionally or frequently were 11 times more likely to develop Alzheimer's than were carriers who abstained from both behaviors.

Dr. Rusanen noted that her study differs slightly from other cohort studies in its timing. “The smoking habits of the subjects were investigated in midlife, [about] 21 years prior to the reexamination, which means that we can really examine smoking as a predisposing factor for dementia.”

Another matter that should be considered is that “the effect of apo E on dementia risk is believed to attenuate with increasing age. Our cohort is quite young, with a mean age of the participants at midlife of 50 years, so it is likely that the effect of apo E is more easily seen in our cohort than in a cohort with older persons,” Dr. Rusanen said at the meeting, which was sponsored by the Alzheimer's Association.

CHICAGO – Smoking in midlife might increase the chance of Alzheimer's in later life among those who already carry an increased genetic risk.

A population-based Finnish study with more than 20 years of follow-up concluded that carriers of the apolipoprotein E4 allele who smoked in midlife were seven times more likely to develop Alzheimer's than were carriers who didn't smoke. Alcohol consumption seemed to exacerbate the smoking-associated risk; carriers who drank frequently and smoked at midlife were more than 11 times as likely to develop the disorder as were carriers who never indulged in either behavior, Dr. Minna Rusanen said at the International Conference on Alzheimer's Disease.

The news is actually good for apo E4 carriers, who are considered almost certain to develop the disorder at a relatively young age, she said in an interview. “Recent knowledge about the environmental risk factors of the disease is giving hope to genetically susceptible people,” said Dr. Rusanen of the Kuopio (Finland) University Hospital. “The risk of developing Alzheimer's may be lowered by adopting an overall healthy lifestyle early in life. Promoting smoking cessation should be one of the major issues in the public education; it could help to prevent, or at least delay, the onset of Alzheimer's, and thus help one to live a cognitively healthy life also through old age.”

The association between smoking and dementia has never been conclusively proved, Dr. Rusanen noted. “Several case-control studies in the 1980s and 1990s suggested an inverse relationship between smoking and dementia, but this was probably due to a survival bias.” Some studies found a positive association only among apo E4 noncarriers, but one concluded that apo E status didn't modify dementia risk among smokers. The connection between smoking and Alzheimer's risk, however, is biologically plausible. “Smoking is known to have negative vascular effects, and predispose to cerebrovascular disease by accelerating atherosclerosis and inducing oxidative stress and inflammation–mechanisms which are also thought to have relevance in the development of Alzheimer's.”

To further investigate this question, Dr. Rusanen and her colleagues extracted data from the Finnish Cardiovascular Risk Factors, Aging, and Dementia study. The study included 2,000 participants who had been examined during midlife in four separate samples (1972, 1977, 1982, and 1987). After an average follow-up of 21 years, 1,449 of these people took part in a reexamination held in 1998. At that time, subjects were aged 65–79 years; 61 had developed some type of dementia, with Alzheimer's accounting for 48 of those cases.

Information on smoking status was available for 1,419 subjects. Of these, 321 were smokers during midlife, 272 had smoked in their younger years, and 826 had never smoked.

After researchers controlled for socio-economic status, blood pressure, cholesterol, body mass index, heart disease, stroke, diabetes, and lung disease, there was no association between smoking and Alzheimer's disease in any group except apo E4 carriers. Carriers who smoked at midlife were almost seven times more likely to have developed the disorder than were the nonsmoking carriers.

The risk increased again when Dr. Rusanen factored in alcohol consumption at midlife. Again, apo E4 carriers fared significantly worse than any other group. Midlife smokers who drank either occasionally or frequently were 11 times more likely to develop Alzheimer's than were carriers who abstained from both behaviors.

Dr. Rusanen noted that her study differs slightly from other cohort studies in its timing. “The smoking habits of the subjects were investigated in midlife, [about] 21 years prior to the reexamination, which means that we can really examine smoking as a predisposing factor for dementia.”

Another matter that should be considered is that “the effect of apo E on dementia risk is believed to attenuate with increasing age. Our cohort is quite young, with a mean age of the participants at midlife of 50 years, so it is likely that the effect of apo E is more easily seen in our cohort than in a cohort with older persons,” Dr. Rusanen said at the meeting, which was sponsored by the Alzheimer's Association.

CHICAGO – Smoking in midlife might increase the chance of Alzheimer's in later life among those who already carry an increased genetic risk.

A population-based Finnish study with more than 20 years of follow-up concluded that carriers of the apolipoprotein E4 allele who smoked in midlife were seven times more likely to develop Alzheimer's than were carriers who didn't smoke. Alcohol consumption seemed to exacerbate the smoking-associated risk; carriers who drank frequently and smoked at midlife were more than 11 times as likely to develop the disorder as were carriers who never indulged in either behavior, Dr. Minna Rusanen said at the International Conference on Alzheimer's Disease.

The news is actually good for apo E4 carriers, who are considered almost certain to develop the disorder at a relatively young age, she said in an interview. “Recent knowledge about the environmental risk factors of the disease is giving hope to genetically susceptible people,” said Dr. Rusanen of the Kuopio (Finland) University Hospital. “The risk of developing Alzheimer's may be lowered by adopting an overall healthy lifestyle early in life. Promoting smoking cessation should be one of the major issues in the public education; it could help to prevent, or at least delay, the onset of Alzheimer's, and thus help one to live a cognitively healthy life also through old age.”

The association between smoking and dementia has never been conclusively proved, Dr. Rusanen noted. “Several case-control studies in the 1980s and 1990s suggested an inverse relationship between smoking and dementia, but this was probably due to a survival bias.” Some studies found a positive association only among apo E4 noncarriers, but one concluded that apo E status didn't modify dementia risk among smokers. The connection between smoking and Alzheimer's risk, however, is biologically plausible. “Smoking is known to have negative vascular effects, and predispose to cerebrovascular disease by accelerating atherosclerosis and inducing oxidative stress and inflammation–mechanisms which are also thought to have relevance in the development of Alzheimer's.”

To further investigate this question, Dr. Rusanen and her colleagues extracted data from the Finnish Cardiovascular Risk Factors, Aging, and Dementia study. The study included 2,000 participants who had been examined during midlife in four separate samples (1972, 1977, 1982, and 1987). After an average follow-up of 21 years, 1,449 of these people took part in a reexamination held in 1998. At that time, subjects were aged 65–79 years; 61 had developed some type of dementia, with Alzheimer's accounting for 48 of those cases.

Information on smoking status was available for 1,419 subjects. Of these, 321 were smokers during midlife, 272 had smoked in their younger years, and 826 had never smoked.

After researchers controlled for socio-economic status, blood pressure, cholesterol, body mass index, heart disease, stroke, diabetes, and lung disease, there was no association between smoking and Alzheimer's disease in any group except apo E4 carriers. Carriers who smoked at midlife were almost seven times more likely to have developed the disorder than were the nonsmoking carriers.

The risk increased again when Dr. Rusanen factored in alcohol consumption at midlife. Again, apo E4 carriers fared significantly worse than any other group. Midlife smokers who drank either occasionally or frequently were 11 times more likely to develop Alzheimer's than were carriers who abstained from both behaviors.

Dr. Rusanen noted that her study differs slightly from other cohort studies in its timing. “The smoking habits of the subjects were investigated in midlife, [about] 21 years prior to the reexamination, which means that we can really examine smoking as a predisposing factor for dementia.”

Another matter that should be considered is that “the effect of apo E on dementia risk is believed to attenuate with increasing age. Our cohort is quite young, with a mean age of the participants at midlife of 50 years, so it is likely that the effect of apo E is more easily seen in our cohort than in a cohort with older persons,” Dr. Rusanen said at the meeting, which was sponsored by the Alzheimer's Association.

CHICAGO – Tarenflurbil, a drug designed to reduce toxic amyloid β levels in the brains of Alzheimer's disease patients, has failed its large phase III trial, Dr. Robert Green reported at the International Conference on Alzheimer's Disease.

Patients who received the drug (800 mg twice daily) exhibited virtually the same declines in cognition and function as did those who received placebo, said Dr. Green of the Boston University. “I think the results are definitive. There was no efficacy of the compound in this trial.”

In the wake of these results, Myriad Genetics Inc. of Salt Lake City, has decided to scrap its research on the drug, Dr. Green said at the meeting presented by the Alzheimer's Association.

Tarenflurbil had a somewhat encouraging phase II trial. In that study of 207 patients, those taking tarenflurbil experienced significant improvements in global functioning and activities of daily living, and near-significant improvements in cognition.

No such benefits occurred in the phase III trial, which comprised 1,653 patients with mild Alzheimer's. It was conducted at 133 sites across the United States.

Patients were randomized to equal groups to the study drug or placebo for 18 months; the treatment period was followed by a 30-day washout. Primary end points were the Alzheimer's Disease Assessment Scale-cognition (ADAS-Cog) and the Alzheimer's Disease Assessment Scale-activities of daily living (ADAS-ADL). Patients were evaluated every 3 months.

The groups were well matched at baseline, with an average age of 74 years and an average Mini-Mental State Exam score of 23; 51% were female. Most of the patients were on concomitant antidementia drugs: 33% were taking only cholinesterase inhibitors, 6% were on memantine alone, 19% were taking no antidementia drugs, and the rest were on combination therapy.

After 18 months of treatment, both the active and placebo groups showed a steady and almost identical decline in cognition. Both groups lost 7 points on the ADAS-Cog scale by the end of the study. In a secondary cognitive measure, the Clinical Dementia Rating sum of boxes, both groups lost 2.5 points by the end of the study.

A similar pattern appeared on the ADAS-ADL scale. Both groups followed an almost identical pattern of decline, each losing 10 points on the scale by 18 months.

Overall adverse events were similar in the tarenflurbil and placebo arms (88% vs. 86%). More patients taking the study drug discontinued because of adverse events (18% vs. 12%). Serious adverse events occurred in 23% of the active group and 20% of the placebo group.

The most common adverse event was anemia (10% tarenflurbil vs. 4% placebo–a significant difference). Infection was also significantly more common among the active group (7% vs. 3%), as was gastrointestinal ulcer (2% vs. 0.4%). There was no difference in the incidence of gastrointestinal bleeding.

Although the trial was a failure in terms of tarenflurbil efficacy, it did confirm an important observation–one that will be greatly helpful in future AD drug trials, Dr. Green said. “This study, which was well designed and well powered, proved that patients with mild Alzheimer's disease do decline enough over 18 months to actually look for a signal of efficacy.”

Tarenflurbil was the first gamma secretase modulator to be tested in a phase III trial. This class of drug is thought to reduce the levels of toxic amyloid β (Aβ₄₂) in the brain by changing the point at which the enzyme gamma secretase cuts the amyloid precursor protein. “This shifts the ratio to less of the toxic Aβ₄₂ and more of the less-toxic Aβ₄₀,” Dr. Green said.

Dr. Green said he did not receive compensation from Myriad Genetics for his role as a primary investigator on the study.

The drug had a somewhat encouraging phase II trial. But the phase III results fell short. DR. GREEN

CHICAGO – Tarenflurbil, a drug designed to reduce toxic amyloid β levels in the brains of Alzheimer's disease patients, has failed its large phase III trial, Dr. Robert Green reported at the International Conference on Alzheimer's Disease.

Patients who received the drug (800 mg twice daily) exhibited virtually the same declines in cognition and function as did those who received placebo, said Dr. Green of the Boston University. “I think the results are definitive. There was no efficacy of the compound in this trial.”

In the wake of these results, Myriad Genetics Inc. of Salt Lake City, has decided to scrap its research on the drug, Dr. Green said at the meeting presented by the Alzheimer's Association.

Tarenflurbil had a somewhat encouraging phase II trial. In that study of 207 patients, those taking tarenflurbil experienced significant improvements in global functioning and activities of daily living, and near-significant improvements in cognition.

No such benefits occurred in the phase III trial, which comprised 1,653 patients with mild Alzheimer's. It was conducted at 133 sites across the United States.

Patients were randomized to equal groups to the study drug or placebo for 18 months; the treatment period was followed by a 30-day washout. Primary end points were the Alzheimer's Disease Assessment Scale-cognition (ADAS-Cog) and the Alzheimer's Disease Assessment Scale-activities of daily living (ADAS-ADL). Patients were evaluated every 3 months.

The groups were well matched at baseline, with an average age of 74 years and an average Mini-Mental State Exam score of 23; 51% were female. Most of the patients were on concomitant antidementia drugs: 33% were taking only cholinesterase inhibitors, 6% were on memantine alone, 19% were taking no antidementia drugs, and the rest were on combination therapy.

After 18 months of treatment, both the active and placebo groups showed a steady and almost identical decline in cognition. Both groups lost 7 points on the ADAS-Cog scale by the end of the study. In a secondary cognitive measure, the Clinical Dementia Rating sum of boxes, both groups lost 2.5 points by the end of the study.

A similar pattern appeared on the ADAS-ADL scale. Both groups followed an almost identical pattern of decline, each losing 10 points on the scale by 18 months.

Overall adverse events were similar in the tarenflurbil and placebo arms (88% vs. 86%). More patients taking the study drug discontinued because of adverse events (18% vs. 12%). Serious adverse events occurred in 23% of the active group and 20% of the placebo group.

The most common adverse event was anemia (10% tarenflurbil vs. 4% placebo–a significant difference). Infection was also significantly more common among the active group (7% vs. 3%), as was gastrointestinal ulcer (2% vs. 0.4%). There was no difference in the incidence of gastrointestinal bleeding.

Although the trial was a failure in terms of tarenflurbil efficacy, it did confirm an important observation–one that will be greatly helpful in future AD drug trials, Dr. Green said. “This study, which was well designed and well powered, proved that patients with mild Alzheimer's disease do decline enough over 18 months to actually look for a signal of efficacy.”

Tarenflurbil was the first gamma secretase modulator to be tested in a phase III trial. This class of drug is thought to reduce the levels of toxic amyloid β (Aβ₄₂) in the brain by changing the point at which the enzyme gamma secretase cuts the amyloid precursor protein. “This shifts the ratio to less of the toxic Aβ₄₂ and more of the less-toxic Aβ₄₀,” Dr. Green said.

Dr. Green said he did not receive compensation from Myriad Genetics for his role as a primary investigator on the study.

The drug had a somewhat encouraging phase II trial. But the phase III results fell short. DR. GREEN

CHICAGO – Tarenflurbil, a drug designed to reduce toxic amyloid β levels in the brains of Alzheimer's disease patients, has failed its large phase III trial, Dr. Robert Green reported at the International Conference on Alzheimer's Disease.

Patients who received the drug (800 mg twice daily) exhibited virtually the same declines in cognition and function as did those who received placebo, said Dr. Green of the Boston University. “I think the results are definitive. There was no efficacy of the compound in this trial.”

In the wake of these results, Myriad Genetics Inc. of Salt Lake City, has decided to scrap its research on the drug, Dr. Green said at the meeting presented by the Alzheimer's Association.

Tarenflurbil had a somewhat encouraging phase II trial. In that study of 207 patients, those taking tarenflurbil experienced significant improvements in global functioning and activities of daily living, and near-significant improvements in cognition.

No such benefits occurred in the phase III trial, which comprised 1,653 patients with mild Alzheimer's. It was conducted at 133 sites across the United States.

Patients were randomized to equal groups to the study drug or placebo for 18 months; the treatment period was followed by a 30-day washout. Primary end points were the Alzheimer's Disease Assessment Scale-cognition (ADAS-Cog) and the Alzheimer's Disease Assessment Scale-activities of daily living (ADAS-ADL). Patients were evaluated every 3 months.

The groups were well matched at baseline, with an average age of 74 years and an average Mini-Mental State Exam score of 23; 51% were female. Most of the patients were on concomitant antidementia drugs: 33% were taking only cholinesterase inhibitors, 6% were on memantine alone, 19% were taking no antidementia drugs, and the rest were on combination therapy.

After 18 months of treatment, both the active and placebo groups showed a steady and almost identical decline in cognition. Both groups lost 7 points on the ADAS-Cog scale by the end of the study. In a secondary cognitive measure, the Clinical Dementia Rating sum of boxes, both groups lost 2.5 points by the end of the study.

A similar pattern appeared on the ADAS-ADL scale. Both groups followed an almost identical pattern of decline, each losing 10 points on the scale by 18 months.

Overall adverse events were similar in the tarenflurbil and placebo arms (88% vs. 86%). More patients taking the study drug discontinued because of adverse events (18% vs. 12%). Serious adverse events occurred in 23% of the active group and 20% of the placebo group.

The most common adverse event was anemia (10% tarenflurbil vs. 4% placebo–a significant difference). Infection was also significantly more common among the active group (7% vs. 3%), as was gastrointestinal ulcer (2% vs. 0.4%). There was no difference in the incidence of gastrointestinal bleeding.

Although the trial was a failure in terms of tarenflurbil efficacy, it did confirm an important observation–one that will be greatly helpful in future AD drug trials, Dr. Green said. “This study, which was well designed and well powered, proved that patients with mild Alzheimer's disease do decline enough over 18 months to actually look for a signal of efficacy.”

Tarenflurbil was the first gamma secretase modulator to be tested in a phase III trial. This class of drug is thought to reduce the levels of toxic amyloid β (Aβ₄₂) in the brain by changing the point at which the enzyme gamma secretase cuts the amyloid precursor protein. “This shifts the ratio to less of the toxic Aβ₄₂ and more of the less-toxic Aβ₄₀,” Dr. Green said.

Dr. Green said he did not receive compensation from Myriad Genetics for his role as a primary investigator on the study.

The drug had a somewhat encouraging phase II trial. But the phase III results fell short. DR. GREEN

BOSTON – Adolescents with undertreated chronic pain may develop pseudoaddiction to their pain medications, which would involve the demonstration of drug-seeking behaviors that are easy to confuse with true addiction.

“These symptoms can be very confusing,” Dr. John Knight said at the annual meeting of the American Academy of Pediatrics. “Virtually 100% of patients who get opioids for chronic pain will develop two signs of true drug dependence: physiologic tolerance and withdrawal symptoms if the drug is removed. But if you only have these two signs, that is not addiction.”

According to the Diagnostic and Statistical Manual IV, psychosocial symptoms must also be part of the clinical picture. These include the devotion of exorbitant amounts of time and energy to obtaining the drug; the relinquishment of important social, recreational, or occupational activities in favor of using the drug; and its continued use despite the understanding that it causes harmful effects. “Adolescents with pseudoaddiction are unlikely to engage in these sorts of behaviors,” said Dr. Knight, director of the Center for Adolescent Substance Abuse Research, Children's Hospital, Boston.

However, he said, the symptoms of pseudoaddiction can be alarming. Teens with pseudoaddiction will try to increase their drug supply to help better manage their pain. Behaviors commonly seen are hoarding of medication, requesting only specific drugs, increasing dosage without a physician consult, obtaining multiple prescriptions from different sources, and complaining about an increasing need for more drugs to obtain pain relief (J. Pain Symptom Manage. 1997;14:S27–35).

In cases of suspected pseudoaddiction, “I have a very low threshold for consultation. At a minimum, you need a pain management specialist and an addiction psychiatrist on your treatment team to help manage this,” he said. It's critical to maximize pain relief with supportive treatments. “Make sure you're providing adequate analgesia. You might need to add another narcotic, increase the dose, or switch to a longer-acting form or another medication.” Physical therapy can also play an important role in minimizing chronic pain, he added.

All chronic pain treatment plans require a monitoring component, he stressed. This includes parental pill counts and regular urine drug testing.

“These patients with insufficiently treated pain are going to try to ensure their supply of medication, but they are not usually going to engage in 'street behaviors' to get it,” Dr. Knight said.

“The street behaviors are much more suggestive of true drug dependence.” Patients with true addiction are more likely to sell their medication, steal medication or forge prescriptions, use illegal drugs or alcohol in combination with the prescribed drug, grind their pills for snorting or injecting, and obtain prescription drugs illegally.

Sometimes parents can unwittingly contribute to pseudoaddiction, he noted. Parents are understandably concerned when their child receives treatment with narcotic drugs and may limit the dosage to try to avoid addiction. When this happens, their children might have suboptimal pain relief and then display worrisome drug-seeking behaviors. Teens can also become resentful, feeling that the parent doesn't trust them to take medication appropriately and causes additional pain by withholding necessary medication. In cases like this, education is vital, Dr. Knight said.

“The parent needs to understand how important it is for the child to take the drug exactly as prescribed, and that although there is a risk of dependence, the risk is very low as long as we carefully monitor the amount of drug given.”

A written contract is a good way to help stress the importance of accurate dosing on both parents and patients, Dr. Knight suggested.

Patients with insufficiently treated pain usually won't engage in 'street behaviors.' DR. KNIGHT

BOSTON – Adolescents with undertreated chronic pain may develop pseudoaddiction to their pain medications, which would involve the demonstration of drug-seeking behaviors that are easy to confuse with true addiction.

“These symptoms can be very confusing,” Dr. John Knight said at the annual meeting of the American Academy of Pediatrics. “Virtually 100% of patients who get opioids for chronic pain will develop two signs of true drug dependence: physiologic tolerance and withdrawal symptoms if the drug is removed. But if you only have these two signs, that is not addiction.”

According to the Diagnostic and Statistical Manual IV, psychosocial symptoms must also be part of the clinical picture. These include the devotion of exorbitant amounts of time and energy to obtaining the drug; the relinquishment of important social, recreational, or occupational activities in favor of using the drug; and its continued use despite the understanding that it causes harmful effects. “Adolescents with pseudoaddiction are unlikely to engage in these sorts of behaviors,” said Dr. Knight, director of the Center for Adolescent Substance Abuse Research, Children's Hospital, Boston.

However, he said, the symptoms of pseudoaddiction can be alarming. Teens with pseudoaddiction will try to increase their drug supply to help better manage their pain. Behaviors commonly seen are hoarding of medication, requesting only specific drugs, increasing dosage without a physician consult, obtaining multiple prescriptions from different sources, and complaining about an increasing need for more drugs to obtain pain relief (J. Pain Symptom Manage. 1997;14:S27–35).

In cases of suspected pseudoaddiction, “I have a very low threshold for consultation. At a minimum, you need a pain management specialist and an addiction psychiatrist on your treatment team to help manage this,” he said. It's critical to maximize pain relief with supportive treatments. “Make sure you're providing adequate analgesia. You might need to add another narcotic, increase the dose, or switch to a longer-acting form or another medication.” Physical therapy can also play an important role in minimizing chronic pain, he added.

All chronic pain treatment plans require a monitoring component, he stressed. This includes parental pill counts and regular urine drug testing.

“These patients with insufficiently treated pain are going to try to ensure their supply of medication, but they are not usually going to engage in 'street behaviors' to get it,” Dr. Knight said.

“The street behaviors are much more suggestive of true drug dependence.” Patients with true addiction are more likely to sell their medication, steal medication or forge prescriptions, use illegal drugs or alcohol in combination with the prescribed drug, grind their pills for snorting or injecting, and obtain prescription drugs illegally.

Sometimes parents can unwittingly contribute to pseudoaddiction, he noted. Parents are understandably concerned when their child receives treatment with narcotic drugs and may limit the dosage to try to avoid addiction. When this happens, their children might have suboptimal pain relief and then display worrisome drug-seeking behaviors. Teens can also become resentful, feeling that the parent doesn't trust them to take medication appropriately and causes additional pain by withholding necessary medication. In cases like this, education is vital, Dr. Knight said.

“The parent needs to understand how important it is for the child to take the drug exactly as prescribed, and that although there is a risk of dependence, the risk is very low as long as we carefully monitor the amount of drug given.”

A written contract is a good way to help stress the importance of accurate dosing on both parents and patients, Dr. Knight suggested.

Patients with insufficiently treated pain usually won't engage in 'street behaviors.' DR. KNIGHT

BOSTON – Adolescents with undertreated chronic pain may develop pseudoaddiction to their pain medications, which would involve the demonstration of drug-seeking behaviors that are easy to confuse with true addiction.

“These symptoms can be very confusing,” Dr. John Knight said at the annual meeting of the American Academy of Pediatrics. “Virtually 100% of patients who get opioids for chronic pain will develop two signs of true drug dependence: physiologic tolerance and withdrawal symptoms if the drug is removed. But if you only have these two signs, that is not addiction.”

According to the Diagnostic and Statistical Manual IV, psychosocial symptoms must also be part of the clinical picture. These include the devotion of exorbitant amounts of time and energy to obtaining the drug; the relinquishment of important social, recreational, or occupational activities in favor of using the drug; and its continued use despite the understanding that it causes harmful effects. “Adolescents with pseudoaddiction are unlikely to engage in these sorts of behaviors,” said Dr. Knight, director of the Center for Adolescent Substance Abuse Research, Children's Hospital, Boston.

However, he said, the symptoms of pseudoaddiction can be alarming. Teens with pseudoaddiction will try to increase their drug supply to help better manage their pain. Behaviors commonly seen are hoarding of medication, requesting only specific drugs, increasing dosage without a physician consult, obtaining multiple prescriptions from different sources, and complaining about an increasing need for more drugs to obtain pain relief (J. Pain Symptom Manage. 1997;14:S27–35).

In cases of suspected pseudoaddiction, “I have a very low threshold for consultation. At a minimum, you need a pain management specialist and an addiction psychiatrist on your treatment team to help manage this,” he said. It's critical to maximize pain relief with supportive treatments. “Make sure you're providing adequate analgesia. You might need to add another narcotic, increase the dose, or switch to a longer-acting form or another medication.” Physical therapy can also play an important role in minimizing chronic pain, he added.

All chronic pain treatment plans require a monitoring component, he stressed. This includes parental pill counts and regular urine drug testing.

“These patients with insufficiently treated pain are going to try to ensure their supply of medication, but they are not usually going to engage in 'street behaviors' to get it,” Dr. Knight said.

“The street behaviors are much more suggestive of true drug dependence.” Patients with true addiction are more likely to sell their medication, steal medication or forge prescriptions, use illegal drugs or alcohol in combination with the prescribed drug, grind their pills for snorting or injecting, and obtain prescription drugs illegally.

Sometimes parents can unwittingly contribute to pseudoaddiction, he noted. Parents are understandably concerned when their child receives treatment with narcotic drugs and may limit the dosage to try to avoid addiction. When this happens, their children might have suboptimal pain relief and then display worrisome drug-seeking behaviors. Teens can also become resentful, feeling that the parent doesn't trust them to take medication appropriately and causes additional pain by withholding necessary medication. In cases like this, education is vital, Dr. Knight said.

“The parent needs to understand how important it is for the child to take the drug exactly as prescribed, and that although there is a risk of dependence, the risk is very low as long as we carefully monitor the amount of drug given.”

A written contract is a good way to help stress the importance of accurate dosing on both parents and patients, Dr. Knight suggested.

Patients with insufficiently treated pain usually won't engage in 'street behaviors.' DR. KNIGHT

Antisecretory drug therapy should be the first-line treatment for gastroesophageal reflux disease, with antireflux surgery offered only to those whose symptoms are not controlled by medication or who can't tolerate the drugs, according to a new management guideline from the American Gastroenterological Association.

Proton pump inhibitors remain the most effective medical therapy, followed by histamine₂-receptor agonists, according to the position paper (Gastroenterology 2008;135:1383–91).

“There is ample evidence that, as a drug class, proton pump inhibitors are more effective in these patients than are histamine receptor blockers,” wrote lead author Dr. Peter J. Kahrilas of Northwestern University, Chicago.

The document was based on a technical review by Dr. Kahrilas and his colleagues. Despite fair evidence that some lifestyle modifications can benefit patients with gastroesophageal reflux disease (GERD), the authors found no strong evidence that such changes should be broadly recommended. Patients with nighttime symptoms may benefit from elevating the head of their bed. Overweight or obese patients should be urged to lose weight, as this may prevent or delay the need for acid suppression.

The authors found strong evidence that antisecretory drugs, especially proton pump inhibitors, improve outcomes, and there is fair evidence to support twice-daily dosing for some patients. Expert opinion “is essentially unanimous in recommending twice-daily dosing of PPIs to improve symptom relief in patients with … an unsatisfactory response to once-daily dosing.” They found no evidence that metoclopramide is useful, and recommend against its use because of its substantial side effect profile.

Strong evidence supports a three-tiered diagnostic algorithm. Patients with suspected GERD syndrome and troublesome dysphagia should undergo endoscopy with biopsy as an initial evaluation. Those with suspected GERD who fail to respond to twice-daily PPIs may benefit from either an endoscopy or manometry. Ambulatory pH testing should be done to substantiate a GERD diagnosis for those who have not responded to empirical therapy and who have had unremarkable endoscopy and manometry.

There is no evidence that endoscopy used as a screening tool for Barrett's esophagus reduces mortality from esophageal adenocarcinoma in the setting of chronic GERD, the authors said.

They found strong evidence that antisecretory drugs also benefit patients with suspected extraesophageal reflux symptoms (cough, laryngitis, and asthma). But there was no evidence to support the drugs' use for extraesophageal symptoms in the absence of an esophageal GERD diagnosis. “Empirical therapy with twice-daily PPIs for 2 months remains a pragmatic clinical strategy for subsets of these patients if they have a concomitant esophageal GERD syndrome. Failing such a trial, etiologies other than GERD should be explored.”

There are no firm data suggesting that GERD is always a progressive disease, going from nonerosive to erosive to Barrett's esophagus, the authors said. Therefore, routine endoscopy to monitor progression is not recommended.

For maintenance therapy, the authors found strong evidence that long-term PPIs are safe and effective and can be titrated downward in many patients. But most patients need daily therapy, as “the likelihood of spontaneous remission of disease is low.”

There was fair evidence supporting long-term maintenance therapy for patients with extraesophageal reflux symptoms, but only if they have concomitant esophageal GERD syndrome.

The authors found no significant safety issues with long-term use of antisecretory drugs. There is no need for routine bone studies or calcium supplementation, beyond that which would normally be recommended based on individual risk factors.

Surgery may be considered for those who can't tolerate the drugs or whose symptoms are not controlled by them. Dysphagia severe enough to require surgical correction occurs in up to 6% of surgical cases, and “both controlled and uncontrolled trials have shown a significant increase in flatulence, an inability to belch, and increased bowel symptoms after antireflux surgery,” the authors wrote.

Antisecretory drug therapy should be the first-line treatment for gastroesophageal reflux disease, with antireflux surgery offered only to those whose symptoms are not controlled by medication or who can't tolerate the drugs, according to a new management guideline from the American Gastroenterological Association.

Proton pump inhibitors remain the most effective medical therapy, followed by histamine₂-receptor agonists, according to the position paper (Gastroenterology 2008;135:1383–91).

“There is ample evidence that, as a drug class, proton pump inhibitors are more effective in these patients than are histamine receptor blockers,” wrote lead author Dr. Peter J. Kahrilas of Northwestern University, Chicago.

The document was based on a technical review by Dr. Kahrilas and his colleagues. Despite fair evidence that some lifestyle modifications can benefit patients with gastroesophageal reflux disease (GERD), the authors found no strong evidence that such changes should be broadly recommended. Patients with nighttime symptoms may benefit from elevating the head of their bed. Overweight or obese patients should be urged to lose weight, as this may prevent or delay the need for acid suppression.

The authors found strong evidence that antisecretory drugs, especially proton pump inhibitors, improve outcomes, and there is fair evidence to support twice-daily dosing for some patients. Expert opinion “is essentially unanimous in recommending twice-daily dosing of PPIs to improve symptom relief in patients with … an unsatisfactory response to once-daily dosing.” They found no evidence that metoclopramide is useful, and recommend against its use because of its substantial side effect profile.

Strong evidence supports a three-tiered diagnostic algorithm. Patients with suspected GERD syndrome and troublesome dysphagia should undergo endoscopy with biopsy as an initial evaluation. Those with suspected GERD who fail to respond to twice-daily PPIs may benefit from either an endoscopy or manometry. Ambulatory pH testing should be done to substantiate a GERD diagnosis for those who have not responded to empirical therapy and who have had unremarkable endoscopy and manometry.

There is no evidence that endoscopy used as a screening tool for Barrett's esophagus reduces mortality from esophageal adenocarcinoma in the setting of chronic GERD, the authors said.

They found strong evidence that antisecretory drugs also benefit patients with suspected extraesophageal reflux symptoms (cough, laryngitis, and asthma). But there was no evidence to support the drugs' use for extraesophageal symptoms in the absence of an esophageal GERD diagnosis. “Empirical therapy with twice-daily PPIs for 2 months remains a pragmatic clinical strategy for subsets of these patients if they have a concomitant esophageal GERD syndrome. Failing such a trial, etiologies other than GERD should be explored.”

There are no firm data suggesting that GERD is always a progressive disease, going from nonerosive to erosive to Barrett's esophagus, the authors said. Therefore, routine endoscopy to monitor progression is not recommended.

For maintenance therapy, the authors found strong evidence that long-term PPIs are safe and effective and can be titrated downward in many patients. But most patients need daily therapy, as “the likelihood of spontaneous remission of disease is low.”

There was fair evidence supporting long-term maintenance therapy for patients with extraesophageal reflux symptoms, but only if they have concomitant esophageal GERD syndrome.

The authors found no significant safety issues with long-term use of antisecretory drugs. There is no need for routine bone studies or calcium supplementation, beyond that which would normally be recommended based on individual risk factors.

Surgery may be considered for those who can't tolerate the drugs or whose symptoms are not controlled by them. Dysphagia severe enough to require surgical correction occurs in up to 6% of surgical cases, and “both controlled and uncontrolled trials have shown a significant increase in flatulence, an inability to belch, and increased bowel symptoms after antireflux surgery,” the authors wrote.

Antisecretory drug therapy should be the first-line treatment for gastroesophageal reflux disease, with antireflux surgery offered only to those whose symptoms are not controlled by medication or who can't tolerate the drugs, according to a new management guideline from the American Gastroenterological Association.

Proton pump inhibitors remain the most effective medical therapy, followed by histamine₂-receptor agonists, according to the position paper (Gastroenterology 2008;135:1383–91).

“There is ample evidence that, as a drug class, proton pump inhibitors are more effective in these patients than are histamine receptor blockers,” wrote lead author Dr. Peter J. Kahrilas of Northwestern University, Chicago.

The document was based on a technical review by Dr. Kahrilas and his colleagues. Despite fair evidence that some lifestyle modifications can benefit patients with gastroesophageal reflux disease (GERD), the authors found no strong evidence that such changes should be broadly recommended. Patients with nighttime symptoms may benefit from elevating the head of their bed. Overweight or obese patients should be urged to lose weight, as this may prevent or delay the need for acid suppression.

The authors found strong evidence that antisecretory drugs, especially proton pump inhibitors, improve outcomes, and there is fair evidence to support twice-daily dosing for some patients. Expert opinion “is essentially unanimous in recommending twice-daily dosing of PPIs to improve symptom relief in patients with … an unsatisfactory response to once-daily dosing.” They found no evidence that metoclopramide is useful, and recommend against its use because of its substantial side effect profile.

Strong evidence supports a three-tiered diagnostic algorithm. Patients with suspected GERD syndrome and troublesome dysphagia should undergo endoscopy with biopsy as an initial evaluation. Those with suspected GERD who fail to respond to twice-daily PPIs may benefit from either an endoscopy or manometry. Ambulatory pH testing should be done to substantiate a GERD diagnosis for those who have not responded to empirical therapy and who have had unremarkable endoscopy and manometry.

There is no evidence that endoscopy used as a screening tool for Barrett's esophagus reduces mortality from esophageal adenocarcinoma in the setting of chronic GERD, the authors said.

They found strong evidence that antisecretory drugs also benefit patients with suspected extraesophageal reflux symptoms (cough, laryngitis, and asthma). But there was no evidence to support the drugs' use for extraesophageal symptoms in the absence of an esophageal GERD diagnosis. “Empirical therapy with twice-daily PPIs for 2 months remains a pragmatic clinical strategy for subsets of these patients if they have a concomitant esophageal GERD syndrome. Failing such a trial, etiologies other than GERD should be explored.”

There are no firm data suggesting that GERD is always a progressive disease, going from nonerosive to erosive to Barrett's esophagus, the authors said. Therefore, routine endoscopy to monitor progression is not recommended.

For maintenance therapy, the authors found strong evidence that long-term PPIs are safe and effective and can be titrated downward in many patients. But most patients need daily therapy, as “the likelihood of spontaneous remission of disease is low.”

There was fair evidence supporting long-term maintenance therapy for patients with extraesophageal reflux symptoms, but only if they have concomitant esophageal GERD syndrome.

The authors found no significant safety issues with long-term use of antisecretory drugs. There is no need for routine bone studies or calcium supplementation, beyond that which would normally be recommended based on individual risk factors.

Surgery may be considered for those who can't tolerate the drugs or whose symptoms are not controlled by them. Dysphagia severe enough to require surgical correction occurs in up to 6% of surgical cases, and “both controlled and uncontrolled trials have shown a significant increase in flatulence, an inability to belch, and increased bowel symptoms after antireflux surgery,” the authors wrote.

BARCELONA — Despite long-term treatment with selective serotonin reuptake inhibitors, many depressed patients cared for by primary care physicians continue to experience symptoms that affect their daily lives, according to a survey conducted in the United Kingdom.

Only a minority of these patients were satisfied with their current sleep, while 52% reported moderate-severe anxiety and 37% moderate-severe depression, although most had been on treatment for 6 months to more than 1 year, Dr. Alan G. Wade wrote in a poster presented at the annual congress of the European College of Neuropsychopharmacology.

“If patients are to have a good quality of life with the maximum possibility of remaining free from subsequent episodes of depression, it's important that treatment results in patients who are in remission with a minimal number of symptoms,” wrote Dr. Wade, a founder of Patients Direct in Glasgow, Scotland. “But despite long-term SSRI treatment, few of these patients were in true remission.”

Patients Direct operates in tandem with the Robertson Centre for Biostatistics at the University of Glasgow. The company obtains postmarketing drug data by direct patient survey and supplies this information to health care providers, the pharmaceutical industry, and other interested groups, according to the company Web site. Dr. Wade's analysis was based on surveys completed by 256 patients in western Scotland whose general practitioners were treating them for depression with SSRIs.

Prescribing information was obtained from a large regional database, and each patient filled out a questionnaire about treatment. The survey included the Hospital Anxiety and Depression Scale (HADS), and specific questions about sleep. The group was primarily composed of women (79%). Most of the patients (190) were aged 36–70 years, with the remainder aged 18–35 years. The primary indication for SSRI was depression (80%). Other indications were anxiety and pain.

Length of treatment varied, with 56% having taken the drugs for more than a year; 13% for 7–12 months; 18% for 4–6 months; and 12% for 1–3 months. The rest had been on an SSRI for a month or less. Most (90%) said that they took the medication as directed.

HADS scores showed that depression and anxiety persisted in many patients, despite the medication. Fewer than half (42%) scored “normal” on the scale; 21% reported minor symptoms. Among the participants, 20% reported moderate depression, while 17% reported severe depression.

Symptoms of anxiety did not respond even that well to the medication. Just 20% of patients had normal scores on the HADS anxiety subscale. Mild symptoms occurred in 22%, moderate symptoms in 23%, and severe symptoms in 29%.

About a third of patients complained of poor sleep—32% felt their sleep problems were so severe that others could notice them, and 29% said the sleep issues interfered with their daily life and were a source of significant distress. This finding was significantly associated with higher depression and anxiety scores.

Most patients with sleep problems (62%) never mentioned the issue to their general practitioner, although of those who did, 51% got a prescription for a sleep aid. However, more than half of those who received a hypnotic prescription ended up taking it for longer than the recommended 4-week period.

“The long-term use of hypnotics presents its own problems,” Dr. Wade pointed out, “but there is some evidence that addressing sleep as a symptom of depression can provide benefit.”

He noted that the survey results are similar to findings in a recent paper addressing remission in depression. The review found that many patients treated for depression report residual symptoms despite apparently successful treatment (Psychol. Med. 2007;37:307-17).

Dr. Wade's study was sponsored by an unrestricted educational grant from Servier Laboratories Ltd., a European company that is developing a new antidepressant, agomelatine, for the U.S. market.

BARCELONA — Despite long-term treatment with selective serotonin reuptake inhibitors, many depressed patients cared for by primary care physicians continue to experience symptoms that affect their daily lives, according to a survey conducted in the United Kingdom.

Only a minority of these patients were satisfied with their current sleep, while 52% reported moderate-severe anxiety and 37% moderate-severe depression, although most had been on treatment for 6 months to more than 1 year, Dr. Alan G. Wade wrote in a poster presented at the annual congress of the European College of Neuropsychopharmacology.

“If patients are to have a good quality of life with the maximum possibility of remaining free from subsequent episodes of depression, it's important that treatment results in patients who are in remission with a minimal number of symptoms,” wrote Dr. Wade, a founder of Patients Direct in Glasgow, Scotland. “But despite long-term SSRI treatment, few of these patients were in true remission.”

Patients Direct operates in tandem with the Robertson Centre for Biostatistics at the University of Glasgow. The company obtains postmarketing drug data by direct patient survey and supplies this information to health care providers, the pharmaceutical industry, and other interested groups, according to the company Web site. Dr. Wade's analysis was based on surveys completed by 256 patients in western Scotland whose general practitioners were treating them for depression with SSRIs.

Prescribing information was obtained from a large regional database, and each patient filled out a questionnaire about treatment. The survey included the Hospital Anxiety and Depression Scale (HADS), and specific questions about sleep. The group was primarily composed of women (79%). Most of the patients (190) were aged 36–70 years, with the remainder aged 18–35 years. The primary indication for SSRI was depression (80%). Other indications were anxiety and pain.

Length of treatment varied, with 56% having taken the drugs for more than a year; 13% for 7–12 months; 18% for 4–6 months; and 12% for 1–3 months. The rest had been on an SSRI for a month or less. Most (90%) said that they took the medication as directed.

HADS scores showed that depression and anxiety persisted in many patients, despite the medication. Fewer than half (42%) scored “normal” on the scale; 21% reported minor symptoms. Among the participants, 20% reported moderate depression, while 17% reported severe depression.

Symptoms of anxiety did not respond even that well to the medication. Just 20% of patients had normal scores on the HADS anxiety subscale. Mild symptoms occurred in 22%, moderate symptoms in 23%, and severe symptoms in 29%.

About a third of patients complained of poor sleep—32% felt their sleep problems were so severe that others could notice them, and 29% said the sleep issues interfered with their daily life and were a source of significant distress. This finding was significantly associated with higher depression and anxiety scores.

Most patients with sleep problems (62%) never mentioned the issue to their general practitioner, although of those who did, 51% got a prescription for a sleep aid. However, more than half of those who received a hypnotic prescription ended up taking it for longer than the recommended 4-week period.

“The long-term use of hypnotics presents its own problems,” Dr. Wade pointed out, “but there is some evidence that addressing sleep as a symptom of depression can provide benefit.”

He noted that the survey results are similar to findings in a recent paper addressing remission in depression. The review found that many patients treated for depression report residual symptoms despite apparently successful treatment (Psychol. Med. 2007;37:307-17).

Dr. Wade's study was sponsored by an unrestricted educational grant from Servier Laboratories Ltd., a European company that is developing a new antidepressant, agomelatine, for the U.S. market.

BARCELONA — Despite long-term treatment with selective serotonin reuptake inhibitors, many depressed patients cared for by primary care physicians continue to experience symptoms that affect their daily lives, according to a survey conducted in the United Kingdom.

Only a minority of these patients were satisfied with their current sleep, while 52% reported moderate-severe anxiety and 37% moderate-severe depression, although most had been on treatment for 6 months to more than 1 year, Dr. Alan G. Wade wrote in a poster presented at the annual congress of the European College of Neuropsychopharmacology.

“If patients are to have a good quality of life with the maximum possibility of remaining free from subsequent episodes of depression, it's important that treatment results in patients who are in remission with a minimal number of symptoms,” wrote Dr. Wade, a founder of Patients Direct in Glasgow, Scotland. “But despite long-term SSRI treatment, few of these patients were in true remission.”

Patients Direct operates in tandem with the Robertson Centre for Biostatistics at the University of Glasgow. The company obtains postmarketing drug data by direct patient survey and supplies this information to health care providers, the pharmaceutical industry, and other interested groups, according to the company Web site. Dr. Wade's analysis was based on surveys completed by 256 patients in western Scotland whose general practitioners were treating them for depression with SSRIs.

Prescribing information was obtained from a large regional database, and each patient filled out a questionnaire about treatment. The survey included the Hospital Anxiety and Depression Scale (HADS), and specific questions about sleep. The group was primarily composed of women (79%). Most of the patients (190) were aged 36–70 years, with the remainder aged 18–35 years. The primary indication for SSRI was depression (80%). Other indications were anxiety and pain.

Length of treatment varied, with 56% having taken the drugs for more than a year; 13% for 7–12 months; 18% for 4–6 months; and 12% for 1–3 months. The rest had been on an SSRI for a month or less. Most (90%) said that they took the medication as directed.

HADS scores showed that depression and anxiety persisted in many patients, despite the medication. Fewer than half (42%) scored “normal” on the scale; 21% reported minor symptoms. Among the participants, 20% reported moderate depression, while 17% reported severe depression.

Symptoms of anxiety did not respond even that well to the medication. Just 20% of patients had normal scores on the HADS anxiety subscale. Mild symptoms occurred in 22%, moderate symptoms in 23%, and severe symptoms in 29%.

About a third of patients complained of poor sleep—32% felt their sleep problems were so severe that others could notice them, and 29% said the sleep issues interfered with their daily life and were a source of significant distress. This finding was significantly associated with higher depression and anxiety scores.

Most patients with sleep problems (62%) never mentioned the issue to their general practitioner, although of those who did, 51% got a prescription for a sleep aid. However, more than half of those who received a hypnotic prescription ended up taking it for longer than the recommended 4-week period.

“The long-term use of hypnotics presents its own problems,” Dr. Wade pointed out, “but there is some evidence that addressing sleep as a symptom of depression can provide benefit.”

He noted that the survey results are similar to findings in a recent paper addressing remission in depression. The review found that many patients treated for depression report residual symptoms despite apparently successful treatment (Psychol. Med. 2007;37:307-17).

Dr. Wade's study was sponsored by an unrestricted educational grant from Servier Laboratories Ltd., a European company that is developing a new antidepressant, agomelatine, for the U.S. market.

CHICAGO — A postmortem analysis of subjects with both Alzheimer's disease and diabetes found up to 80% fewer amyloid β plaques in the brains of those who took both insulin and oral diabetic medication while alive.

The finding might shed some light on a discrepancy that has puzzled Alzheimer's researchers: Although epidemiological studies confirm a significantly increased risk of Alzheimer's and other dementias in subjects with diabetes, their brains generally appear less physically ravaged by the disease, Michal Schnaider Beeri, Ph.D., said at the International Conference on Alzheimer's Disease.

“Medication might be one explanation for this apparent discrepancy between [epidemiological] and neuropathology studies,” said Dr. Beeri of the Mount Sinai School of Medicine, New York.

The study involved 148 brains from the Mount Sinai School of Medicine brain bank. All were from subjects with Alzheimer's disease, half of whom also had diabetes. The subjects were matched for age (mean age, 81 years), sex (57% female), and dementia severity (mean clinical dementia rating score, 2.4).

Dr. Beeri and her colleagues divided the subjects according to use of diabetic medications. Of the 124 subjects with diabetes, 49 were on insulin only, 28 were on oral diabetes medications only, 18 were on a combination of agents, and 29 weren't on medications. The groups were compared with each other and with those without diabetes.

The researchers saw no significant links between medication and the presence of tau neurofibrillary tangles. But they found a strong interaction between medication and amyloid β₄₂ plaques—a diagnostic hallmark of Alzheimer's—in the hippocampus, amygdala, and entorhinal cortex.

Plaque presence was rated from 0 (none) to 2 (severe). Subjects without diabetes had a rating of about 1.5, as did those with diabetes who were taking only oral medications. Diabetics who took no diabetes medications had a rating of about 1.25. Subjects taking insulin had a lower, but not significantly lower, plaque rating (1, considered sparse), compared with those without diabetes, diabetics not on medications, and those on only oral agents, Dr. Beeri said.

The largest differences were between subjects on combination therapy (insulin and oral medications) and those who took only oral agents and subjects without diabetes. Combination therapy subjects had a plaque rating of about 0.25, or 80% lower than ratings for subjects in the other two groups. Those who had taken combination therapy also had significantly fewer plaques than did those who took no medications, as well as those who took only insulin.

These relationships remained significant even after controlling for age at death, sex, dementia severity, fasting glucose level at last admission, and apo E4 status. There were no significant changes when subjects with other comorbidities were excluded.

“The results suggest insulin combined with other diabetes medication is associated with a substantial reduction in brain neuritic plaque density, consistent with the effects of both on the neurobiology of insulin,” Dr. Beeri said at the meeting, which was presented by the Alzheimer's Association. “Insulin and insulin sensitizers (oral hypoglycemics) target organs at the periphery but also seem to have an effect on the brain, [suggesting] the possibility of therapeutic targeting of insulin signaling pathways of the brain for reducing amyloid β-associated neuropathology of Alzheimer's.”

Brains of patients taking both insulin and oral hypoglycemic drugs had fewer plaques (white arrows) than those of nondiabetics, but equal neurofibrillary tangles (black). Courtesy Dr. Vahram Haroutunian

The link between diabetes drugs (like insulin) and fewer plaques echos the effects of both on insulin neurobiology. DR. BEERI

CHICAGO — A postmortem analysis of subjects with both Alzheimer's disease and diabetes found up to 80% fewer amyloid β plaques in the brains of those who took both insulin and oral diabetic medication while alive.

The finding might shed some light on a discrepancy that has puzzled Alzheimer's researchers: Although epidemiological studies confirm a significantly increased risk of Alzheimer's and other dementias in subjects with diabetes, their brains generally appear less physically ravaged by the disease, Michal Schnaider Beeri, Ph.D., said at the International Conference on Alzheimer's Disease.

“Medication might be one explanation for this apparent discrepancy between [epidemiological] and neuropathology studies,” said Dr. Beeri of the Mount Sinai School of Medicine, New York.

The study involved 148 brains from the Mount Sinai School of Medicine brain bank. All were from subjects with Alzheimer's disease, half of whom also had diabetes. The subjects were matched for age (mean age, 81 years), sex (57% female), and dementia severity (mean clinical dementia rating score, 2.4).

Dr. Beeri and her colleagues divided the subjects according to use of diabetic medications. Of the 124 subjects with diabetes, 49 were on insulin only, 28 were on oral diabetes medications only, 18 were on a combination of agents, and 29 weren't on medications. The groups were compared with each other and with those without diabetes.

The researchers saw no significant links between medication and the presence of tau neurofibrillary tangles. But they found a strong interaction between medication and amyloid β₄₂ plaques—a diagnostic hallmark of Alzheimer's—in the hippocampus, amygdala, and entorhinal cortex.

Plaque presence was rated from 0 (none) to 2 (severe). Subjects without diabetes had a rating of about 1.5, as did those with diabetes who were taking only oral medications. Diabetics who took no diabetes medications had a rating of about 1.25. Subjects taking insulin had a lower, but not significantly lower, plaque rating (1, considered sparse), compared with those without diabetes, diabetics not on medications, and those on only oral agents, Dr. Beeri said.

The largest differences were between subjects on combination therapy (insulin and oral medications) and those who took only oral agents and subjects without diabetes. Combination therapy subjects had a plaque rating of about 0.25, or 80% lower than ratings for subjects in the other two groups. Those who had taken combination therapy also had significantly fewer plaques than did those who took no medications, as well as those who took only insulin.

These relationships remained significant even after controlling for age at death, sex, dementia severity, fasting glucose level at last admission, and apo E4 status. There were no significant changes when subjects with other comorbidities were excluded.

“The results suggest insulin combined with other diabetes medication is associated with a substantial reduction in brain neuritic plaque density, consistent with the effects of both on the neurobiology of insulin,” Dr. Beeri said at the meeting, which was presented by the Alzheimer's Association. “Insulin and insulin sensitizers (oral hypoglycemics) target organs at the periphery but also seem to have an effect on the brain, [suggesting] the possibility of therapeutic targeting of insulin signaling pathways of the brain for reducing amyloid β-associated neuropathology of Alzheimer's.”

Brains of patients taking both insulin and oral hypoglycemic drugs had fewer plaques (white arrows) than those of nondiabetics, but equal neurofibrillary tangles (black). Courtesy Dr. Vahram Haroutunian

The link between diabetes drugs (like insulin) and fewer plaques echos the effects of both on insulin neurobiology. DR. BEERI

CHICAGO — A postmortem analysis of subjects with both Alzheimer's disease and diabetes found up to 80% fewer amyloid β plaques in the brains of those who took both insulin and oral diabetic medication while alive.

The finding might shed some light on a discrepancy that has puzzled Alzheimer's researchers: Although epidemiological studies confirm a significantly increased risk of Alzheimer's and other dementias in subjects with diabetes, their brains generally appear less physically ravaged by the disease, Michal Schnaider Beeri, Ph.D., said at the International Conference on Alzheimer's Disease.

“Medication might be one explanation for this apparent discrepancy between [epidemiological] and neuropathology studies,” said Dr. Beeri of the Mount Sinai School of Medicine, New York.

The study involved 148 brains from the Mount Sinai School of Medicine brain bank. All were from subjects with Alzheimer's disease, half of whom also had diabetes. The subjects were matched for age (mean age, 81 years), sex (57% female), and dementia severity (mean clinical dementia rating score, 2.4).

Dr. Beeri and her colleagues divided the subjects according to use of diabetic medications. Of the 124 subjects with diabetes, 49 were on insulin only, 28 were on oral diabetes medications only, 18 were on a combination of agents, and 29 weren't on medications. The groups were compared with each other and with those without diabetes.

The researchers saw no significant links between medication and the presence of tau neurofibrillary tangles. But they found a strong interaction between medication and amyloid β₄₂ plaques—a diagnostic hallmark of Alzheimer's—in the hippocampus, amygdala, and entorhinal cortex.

Plaque presence was rated from 0 (none) to 2 (severe). Subjects without diabetes had a rating of about 1.5, as did those with diabetes who were taking only oral medications. Diabetics who took no diabetes medications had a rating of about 1.25. Subjects taking insulin had a lower, but not significantly lower, plaque rating (1, considered sparse), compared with those without diabetes, diabetics not on medications, and those on only oral agents, Dr. Beeri said.

The largest differences were between subjects on combination therapy (insulin and oral medications) and those who took only oral agents and subjects without diabetes. Combination therapy subjects had a plaque rating of about 0.25, or 80% lower than ratings for subjects in the other two groups. Those who had taken combination therapy also had significantly fewer plaques than did those who took no medications, as well as those who took only insulin.

These relationships remained significant even after controlling for age at death, sex, dementia severity, fasting glucose level at last admission, and apo E4 status. There were no significant changes when subjects with other comorbidities were excluded.

“The results suggest insulin combined with other diabetes medication is associated with a substantial reduction in brain neuritic plaque density, consistent with the effects of both on the neurobiology of insulin,” Dr. Beeri said at the meeting, which was presented by the Alzheimer's Association. “Insulin and insulin sensitizers (oral hypoglycemics) target organs at the periphery but also seem to have an effect on the brain, [suggesting] the possibility of therapeutic targeting of insulin signaling pathways of the brain for reducing amyloid β-associated neuropathology of Alzheimer's.”

Brains of patients taking both insulin and oral hypoglycemic drugs had fewer plaques (white arrows) than those of nondiabetics, but equal neurofibrillary tangles (black). Courtesy Dr. Vahram Haroutunian

The link between diabetes drugs (like insulin) and fewer plaques echos the effects of both on insulin neurobiology. DR. BEERI

MADRID — Adverse events are more common in patients who take older antiepileptic drugs or who take more than one antiepileptic, compared with patients on monotherapy or newer agents.

“The adverse effect profiles of anti-epileptic drugs are often determining factors in drug selection, and yet adverse effects may be overlooked in everyday clinical practice,” Joyce A. Cramer wrote in a poster presented at the annual congress of the European Federation of Neurological Societies.

Ms. Cramer, a research scientist at Yale University, New Haven, Conn., conducted a population surveillance study to evaluate the adverse effects of both newer and older antiepileptic drugs (AEDs). The cross-sectional study was conducted in six European countries and consisted of a single clinical examination and structured interview.

The study population comprised 1,019 patients (mean age, 31 years) who had been on a stable dosing regimen for a median of 13 months. Of those, 57% were on monotherapy, and 43% were on polytherapy.

Most of the patients (71%) were taking at least one older AED (carbamazepine, clobazam, clonazepam, phenobarbital, phenytoin, or valproate). The rest were taking at least one newer AED (gaba- pentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, and zonisamide).

At least one adverse effect occurred in 68% of the patients. Newer AEDs were associated with fewer reports of adverse effects than were older drugs (61%, compared with 71%, respectively), and mono- therapy was associated with fewer reports of adverse effects than was polytherapy (66%, compared with 71%).

Neurologic adverse effects were more common in those taking older AEDs than in those taking newer AEDs (60% vs. 54%, respectively), as were systemic adverse effects (42%, compared with 33%).

Neurologic adverse effects were also more common in patients on polytherapy than in those on monotherapy (64% vs. 53%), although the percentage of patients reporting systemic adverse effects was equal in these two groups (40%).

Adverse effects that were significantly more common in those taking the older drugs, compared with the newer drugs, were cognitive slowing (30% vs. 22%), sedation (30% vs. 23%), and tremor (18% vs. 10%).

Adverse effects that were significantly more common in those taking polytherapy, compared with monotherapy, were cognitive slowing (36% vs. 22%), psychological problems (31% vs. 22%), tremor (21% vs. 11%), and gait disturbances (12% vs. 7%).

A logistic regression analysis concluded that patients on newer AEDs were 36% less likely than were those on the older drugs to report at least one adverse effect. Treatment modifications were 52% more likely in those reporting adverse effects; at the study visit, 23% of patients changed therapy, mostly because of an adverse effect.

Ms. Cramer noted that patients who were taking levetiracetam were 67% less likely to report an adverse effect than were those who were not taking the drug, and those taking lamotrigine were 49% less likely to report an adverse effect than were those not taking lamotrigine.

The study was sponsored by UCB Pharma Inc., the company that manufactures levetiracetam. Ms. Cramer is a consultant for the company.

ELSEVIER GLOBAL MEDICAL NEWS

MADRID — Adverse events are more common in patients who take older antiepileptic drugs or who take more than one antiepileptic, compared with patients on monotherapy or newer agents.

“The adverse effect profiles of anti-epileptic drugs are often determining factors in drug selection, and yet adverse effects may be overlooked in everyday clinical practice,” Joyce A. Cramer wrote in a poster presented at the annual congress of the European Federation of Neurological Societies.

Ms. Cramer, a research scientist at Yale University, New Haven, Conn., conducted a population surveillance study to evaluate the adverse effects of both newer and older antiepileptic drugs (AEDs). The cross-sectional study was conducted in six European countries and consisted of a single clinical examination and structured interview.

The study population comprised 1,019 patients (mean age, 31 years) who had been on a stable dosing regimen for a median of 13 months. Of those, 57% were on monotherapy, and 43% were on polytherapy.

Most of the patients (71%) were taking at least one older AED (carbamazepine, clobazam, clonazepam, phenobarbital, phenytoin, or valproate). The rest were taking at least one newer AED (gaba- pentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, and zonisamide).

At least one adverse effect occurred in 68% of the patients. Newer AEDs were associated with fewer reports of adverse effects than were older drugs (61%, compared with 71%, respectively), and mono- therapy was associated with fewer reports of adverse effects than was polytherapy (66%, compared with 71%).

Neurologic adverse effects were more common in those taking older AEDs than in those taking newer AEDs (60% vs. 54%, respectively), as were systemic adverse effects (42%, compared with 33%).

Neurologic adverse effects were also more common in patients on polytherapy than in those on monotherapy (64% vs. 53%), although the percentage of patients reporting systemic adverse effects was equal in these two groups (40%).

Adverse effects that were significantly more common in those taking the older drugs, compared with the newer drugs, were cognitive slowing (30% vs. 22%), sedation (30% vs. 23%), and tremor (18% vs. 10%).

Adverse effects that were significantly more common in those taking polytherapy, compared with monotherapy, were cognitive slowing (36% vs. 22%), psychological problems (31% vs. 22%), tremor (21% vs. 11%), and gait disturbances (12% vs. 7%).

A logistic regression analysis concluded that patients on newer AEDs were 36% less likely than were those on the older drugs to report at least one adverse effect. Treatment modifications were 52% more likely in those reporting adverse effects; at the study visit, 23% of patients changed therapy, mostly because of an adverse effect.

Ms. Cramer noted that patients who were taking levetiracetam were 67% less likely to report an adverse effect than were those who were not taking the drug, and those taking lamotrigine were 49% less likely to report an adverse effect than were those not taking lamotrigine.

The study was sponsored by UCB Pharma Inc., the company that manufactures levetiracetam. Ms. Cramer is a consultant for the company.

ELSEVIER GLOBAL MEDICAL NEWS

MADRID — Adverse events are more common in patients who take older antiepileptic drugs or who take more than one antiepileptic, compared with patients on monotherapy or newer agents.

“The adverse effect profiles of anti-epileptic drugs are often determining factors in drug selection, and yet adverse effects may be overlooked in everyday clinical practice,” Joyce A. Cramer wrote in a poster presented at the annual congress of the European Federation of Neurological Societies.

Ms. Cramer, a research scientist at Yale University, New Haven, Conn., conducted a population surveillance study to evaluate the adverse effects of both newer and older antiepileptic drugs (AEDs). The cross-sectional study was conducted in six European countries and consisted of a single clinical examination and structured interview.

The study population comprised 1,019 patients (mean age, 31 years) who had been on a stable dosing regimen for a median of 13 months. Of those, 57% were on monotherapy, and 43% were on polytherapy.

Most of the patients (71%) were taking at least one older AED (carbamazepine, clobazam, clonazepam, phenobarbital, phenytoin, or valproate). The rest were taking at least one newer AED (gaba- pentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, and zonisamide).

At least one adverse effect occurred in 68% of the patients. Newer AEDs were associated with fewer reports of adverse effects than were older drugs (61%, compared with 71%, respectively), and mono- therapy was associated with fewer reports of adverse effects than was polytherapy (66%, compared with 71%).

Neurologic adverse effects were more common in those taking older AEDs than in those taking newer AEDs (60% vs. 54%, respectively), as were systemic adverse effects (42%, compared with 33%).

Neurologic adverse effects were also more common in patients on polytherapy than in those on monotherapy (64% vs. 53%), although the percentage of patients reporting systemic adverse effects was equal in these two groups (40%).

Adverse effects that were significantly more common in those taking the older drugs, compared with the newer drugs, were cognitive slowing (30% vs. 22%), sedation (30% vs. 23%), and tremor (18% vs. 10%).

Adverse effects that were significantly more common in those taking polytherapy, compared with monotherapy, were cognitive slowing (36% vs. 22%), psychological problems (31% vs. 22%), tremor (21% vs. 11%), and gait disturbances (12% vs. 7%).

A logistic regression analysis concluded that patients on newer AEDs were 36% less likely than were those on the older drugs to report at least one adverse effect. Treatment modifications were 52% more likely in those reporting adverse effects; at the study visit, 23% of patients changed therapy, mostly because of an adverse effect.

Ms. Cramer noted that patients who were taking levetiracetam were 67% less likely to report an adverse effect than were those who were not taking the drug, and those taking lamotrigine were 49% less likely to report an adverse effect than were those not taking lamotrigine.

The study was sponsored by UCB Pharma Inc., the company that manufactures levetiracetam. Ms. Cramer is a consultant for the company.

ELSEVIER GLOBAL MEDICAL NEWS