Miriam E. Tucker

ATLANTA – All health care personnel should receive a single dose of the tetanus-diphtheria-acellular pertussis vaccine if they have not already, regardless of the duration since their last tetanus-diphtheria dose.

That recommendation, approved on Feb. 23 by the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention, updates a previous ACIP recommendation (MMWR 2006;55:RR-17).

©CDC

The committee also voted separately to recommend postexposure antimicrobial prophylaxis for all health care personnel (HCP) who have unprotected exposure to pertussis and are likely to expose high-risk patients – such as pregnant women or hospitalized newborns – to the disease, even if the HCP were previously vaccinated.

"Protecting HCP from acquiring and transmitting infectious diseases is a public health goal," said Dr. Jennifer Liang of the CDC’s National Center for Immunization and Respiratory Diseases.

In one hospital-based study of serum samples collected over 1-3 years, serologic evidence of pertussis infection was detected in 2 of 106 residents, for an annual incidence rate of 1.3%, and 3 of 39 emergency department employees, for annual incidence rate of 3.6%. Two of the five infected subjects had symptomatic disease (Infect. Control Hosp. Epidemiol. 1999;20:120-3).

The new Tdap recommendation removes a previous 2-year interval requirement since the last Td dose, and also includes HCP who are aged 65 years and older. Since Tdap is not currently licensed for multiple administrations, subsequent routine 10-year boosters should be given as Td, according to the language the committee approved by a near-unanimous vote of 14 members, with just one abstaining.

Also included was a recommendation that hospitals and ambulatory care facilities provide Tdap for HCP and use approaches that maximize vaccination rates, such as education about the benefits of vaccination, convenient access, and provision of the vaccine at no charge.

The second vote was aimed at addressing the fact that pertussis infection can occur even among those who are immunized. In an as-yet unpublished study from Vanderbilt University in Nashville, Tenn., of 116 exposures to pertussis among different HCP, pertussis infection did not occur in 40 of 44 (91%) of those who were monitored but did not receive postexposure prophylaxis (PEP) compared with 41 of 42 (98%) of those who received PEP.

While not conclusive, those findings suggested that there may be a benefit to both monitoring and PEP in vaccinated HCP, Dr. Liang said.

In addition to the PEP recommendation for HCP with unprotected exposure to pertussis who are likely to expose high-risk patients, ACIP also advised that other vaccinated HCP should either receive antimicrobial PEP or be monitored daily for 21 days after pertussis exposure and treated at the onset of signs and symptoms of pertussis.

Health care facilities should maximize efforts to prevent transmission of Bordetella pertussis, and take respiratory precautions to prevent unprotected exposure to pertussis, ACIP advised.

As an employee of the CDC, Dr. Liang has no relevant financial disclosures.

ATLANTA – All health care personnel should receive a single dose of the tetanus-diphtheria-acellular pertussis vaccine if they have not already, regardless of the duration since their last tetanus-diphtheria dose.

That recommendation, approved on Feb. 23 by the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention, updates a previous ACIP recommendation (MMWR 2006;55:RR-17).

©CDC

The committee also voted separately to recommend postexposure antimicrobial prophylaxis for all health care personnel (HCP) who have unprotected exposure to pertussis and are likely to expose high-risk patients – such as pregnant women or hospitalized newborns – to the disease, even if the HCP were previously vaccinated.

"Protecting HCP from acquiring and transmitting infectious diseases is a public health goal," said Dr. Jennifer Liang of the CDC’s National Center for Immunization and Respiratory Diseases.

In one hospital-based study of serum samples collected over 1-3 years, serologic evidence of pertussis infection was detected in 2 of 106 residents, for an annual incidence rate of 1.3%, and 3 of 39 emergency department employees, for annual incidence rate of 3.6%. Two of the five infected subjects had symptomatic disease (Infect. Control Hosp. Epidemiol. 1999;20:120-3).

The new Tdap recommendation removes a previous 2-year interval requirement since the last Td dose, and also includes HCP who are aged 65 years and older. Since Tdap is not currently licensed for multiple administrations, subsequent routine 10-year boosters should be given as Td, according to the language the committee approved by a near-unanimous vote of 14 members, with just one abstaining.

Also included was a recommendation that hospitals and ambulatory care facilities provide Tdap for HCP and use approaches that maximize vaccination rates, such as education about the benefits of vaccination, convenient access, and provision of the vaccine at no charge.

The second vote was aimed at addressing the fact that pertussis infection can occur even among those who are immunized. In an as-yet unpublished study from Vanderbilt University in Nashville, Tenn., of 116 exposures to pertussis among different HCP, pertussis infection did not occur in 40 of 44 (91%) of those who were monitored but did not receive postexposure prophylaxis (PEP) compared with 41 of 42 (98%) of those who received PEP.

While not conclusive, those findings suggested that there may be a benefit to both monitoring and PEP in vaccinated HCP, Dr. Liang said.

In addition to the PEP recommendation for HCP with unprotected exposure to pertussis who are likely to expose high-risk patients, ACIP also advised that other vaccinated HCP should either receive antimicrobial PEP or be monitored daily for 21 days after pertussis exposure and treated at the onset of signs and symptoms of pertussis.

Health care facilities should maximize efforts to prevent transmission of Bordetella pertussis, and take respiratory precautions to prevent unprotected exposure to pertussis, ACIP advised.

As an employee of the CDC, Dr. Liang has no relevant financial disclosures.

ATLANTA – All health care personnel should receive a single dose of the tetanus-diphtheria-acellular pertussis vaccine if they have not already, regardless of the duration since their last tetanus-diphtheria dose.

That recommendation, approved on Feb. 23 by the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention, updates a previous ACIP recommendation (MMWR 2006;55:RR-17).

©CDC

The committee also voted separately to recommend postexposure antimicrobial prophylaxis for all health care personnel (HCP) who have unprotected exposure to pertussis and are likely to expose high-risk patients – such as pregnant women or hospitalized newborns – to the disease, even if the HCP were previously vaccinated.

"Protecting HCP from acquiring and transmitting infectious diseases is a public health goal," said Dr. Jennifer Liang of the CDC’s National Center for Immunization and Respiratory Diseases.

In one hospital-based study of serum samples collected over 1-3 years, serologic evidence of pertussis infection was detected in 2 of 106 residents, for an annual incidence rate of 1.3%, and 3 of 39 emergency department employees, for annual incidence rate of 3.6%. Two of the five infected subjects had symptomatic disease (Infect. Control Hosp. Epidemiol. 1999;20:120-3).

The new Tdap recommendation removes a previous 2-year interval requirement since the last Td dose, and also includes HCP who are aged 65 years and older. Since Tdap is not currently licensed for multiple administrations, subsequent routine 10-year boosters should be given as Td, according to the language the committee approved by a near-unanimous vote of 14 members, with just one abstaining.

Also included was a recommendation that hospitals and ambulatory care facilities provide Tdap for HCP and use approaches that maximize vaccination rates, such as education about the benefits of vaccination, convenient access, and provision of the vaccine at no charge.

The second vote was aimed at addressing the fact that pertussis infection can occur even among those who are immunized. In an as-yet unpublished study from Vanderbilt University in Nashville, Tenn., of 116 exposures to pertussis among different HCP, pertussis infection did not occur in 40 of 44 (91%) of those who were monitored but did not receive postexposure prophylaxis (PEP) compared with 41 of 42 (98%) of those who received PEP.

While not conclusive, those findings suggested that there may be a benefit to both monitoring and PEP in vaccinated HCP, Dr. Liang said.

In addition to the PEP recommendation for HCP with unprotected exposure to pertussis who are likely to expose high-risk patients, ACIP also advised that other vaccinated HCP should either receive antimicrobial PEP or be monitored daily for 21 days after pertussis exposure and treated at the onset of signs and symptoms of pertussis.

Health care facilities should maximize efforts to prevent transmission of Bordetella pertussis, and take respiratory precautions to prevent unprotected exposure to pertussis, ACIP advised.

As an employee of the CDC, Dr. Liang has no relevant financial disclosures.

PITTSBURGH – Effective treatment of cognitive impairments in people with schizophrenia probably will require a combination of pharmacologic and psychosocial interventions, said Dr. Robert W. Buchanan.

His conclusion was based on data from a large body of previous studies that looked at potential cognitive-enhancing drugs with a variety of mechanisms.

"Given the pattern of observed effects of drugs on various cognitive processes to date, it seems unlikely to me that we’re going to find a drug that has broad spectrum effects. ... I think the best that we can hope for is to find a drug with a pronounced effect on a particular component of cognition. We’d then want to use that drug in combination with a psychosocial intervention to enhance cognition and functionality," said Dr. Buchanan, professor of psychiatry at the University of Maryland, Baltimore.

First- and second-generation antipsychotics, although very effective in reducing hallucinations and delusions, have not demonstrated similar benefit in improving cognition. In a meta-analysis accounting for 208 effect sizes from 34 studies of first-generation antipsychotics, the overall effect size for nine cognitive measures was just 0.22. ("Small" was defined as 0.2, "moderate" was 0.5, and "large" was 0.7). Effect sizes for individual domains ranged from 0.13 (executive function) to 0.29 (automatic processing), to a negative effect of –0.11 for motor function (Biol. Psychiatry 2004;55:1013-22).

Initially, it had been hoped that through their unique pharmacologic profile, second-generation antipsychotics would be more beneficial than first-generation agents in improving cognition. But that was shown not to be the case in a substudy of 817 of the total 1,460 participants in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) project. At 2 months, patients who were randomized to the newer agents (olanzapine, quetiapine, risperidone, and ziprasidone) had similar, small neurocognitive improvements, compared with those taking the first-generation agent perphenazine (Arch. Gen. Psychiatry 2007;64:633-47).

"Second-generation antipsychotics offer little advantage vs. first-generation agents. Despite antipsychotic treatment, people with schizophrenia continue to exhibit marked cognitive impairments," Dr. Buchanan commented.

Indeed, it appears that there is a "cognitive cost" associated with medications – including antipsychotics – that raise serum anticholinergic activity. A study of 55 schizophrenia patients demonstrated a clear association between serum anticholinergic activity and impaired performance in verbal working memory and verbal learning and memory, independent of age, IQ, or symptom severity (Am. J. Psychiatry 2009;166:1055-62).

Various adjunctive pharmacologic approaches have been tried, with varying success. In a 12-week, double-blind, placebo-controlled, randomized trial, the acetylcholinesterase inhibitor galantamine had an insignificant overall effect on a composite of neuropsychological outcomes among 44 patients who received it, compared with 42 who got placebo. However, those taking galantamine did show significant improvements in certain measures, particularly processing speed and verbal memory (Am. J. Psychiatry 2008;165:82-9).

And in several small studies, galantamine appeared superior to placebo in improving attention, delayed memory, visual recognition, and emotional acuity.

The clinical observation that people with schizophrenia often appear to be self-medicating by cigarette smoking – as well as experimental findings of deficient expression of alpha(7)-nicotinic receptors in people with schizophrenia – led to interest in nicotinic acetylcholine receptors as possible therapeutic targets. In a 4-week, double-blind, crossover study of 31 nonsmoking people with schizophrenia, significant improvements over placebo were seen with a higher dose (150 mg twice daily) of the agent DMXBA (3-[2,4-dimethoxybenzylidene]-anabaseine) on SANS (Scale for the Assessment of Negative Symptoms) and BPRS (Brief Psychiatric Rating Scale) scores (Am. J. Psychiatry 2008;165:1040-7).

However, trials looking at other nicotinic receptor agonists, particularly the alpha4beta2 agent varenicline, have been uniformly negative, noted Dr. Buchanan, who was one of the authors of the DMXBA study.

Glutamatergic agents also have been studied. CONSIST (Cognitive and Negative Symptoms in Schizophrenia Trial), led by Dr. Buchanan, was a 16-week, double-blind, double-dummy, parallel group study of 157 patients who were randomized to adjunctive glycine, d-cycloserine, or placebo. There were no significant differences in the SANS scores or on a composite neuropsychological measure, suggesting that neither glycine nor d-cycloserine is effective for treating negative symptoms or cognitive impairments (Am. J. Psychiatry 2007;164:1593-602).

GABA (gamma aminobutyric acid) also has been looked at as a potential drug target. In another study led by Dr. Buchanan, the GABAA alpha2/alpha3 partial agonist MK-0777 was studied in 60 people in a 4-week, multicenter, double-blind, placebo-controlled randomized clinical trial. Again, results were negative: No significant group differences were found on the primary outcome measure, which was the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) consensus cognitive battery composite score. Moreover, secondary analysis suggested that patients who received placebo actually performed better on visual memory and reasoning/problem-solving tests than did those assigned to either of two MK-0777 doses (Biol. Psychiatry 2011;69:442-9).

Why so many negative studies? It might be that the best targets have not yet been identified. Alternative agents might include allosteric modulators, reuptake inhibitors, or enzyme inhibitors. Perhaps the problem has been in the choice of dose or dosing schedule, as there are data suggesting that intermittent or once-weekly dosing might better hit the "sweet spot" of drug efficacy, Dr. Buchanan postulated.

Or, it’s possible that drugs require "practice," in the form of cognitive remediation, to be effective. "Rather than continue to search for the miracle drug that will single-handedly reverse the various cognitive impairments, should we be examining the extent to which pharmacological agents can enhance the therapeutic effects of nonpharmacological approaches for the enhancement of cognition?" he asked.

Such interventions might include cognitive remediation such as PositScience (www.positscience.com), cognitive enhancement therapy, cognitive-behavioral therapy (CBT), and even exercise.

In an interview, Dr. Buchanan said that studies are underway using d-cycloserine to enhance CBT and cognitive remediation, and his own group has proposed a study using nicotine to enhance cognitive remediation. Another potential agent that could be used with psychosocial treatment is oxytocin, a naturally occurring hormone, which might facilitate social interactions.

Dr. Buchanan has received grant/research support from Janssen and is a consultant to Abbott Laboratories, GlaxoSmithKline, Sanofi-Aventis, Schering-Plough, and Takeda. He serves on advisory boards for Abbott, Astellas Pharma, AstraZeneca, Cypress Bioscience, Merck, Pfizer, Roche, Solvay Pharmaceuticals, and Wyeth. He also is a data and safety monitoring board member for Cephalon, Otsuka, and Pfizer.

PITTSBURGH – Effective treatment of cognitive impairments in people with schizophrenia probably will require a combination of pharmacologic and psychosocial interventions, said Dr. Robert W. Buchanan.

His conclusion was based on data from a large body of previous studies that looked at potential cognitive-enhancing drugs with a variety of mechanisms.

"Given the pattern of observed effects of drugs on various cognitive processes to date, it seems unlikely to me that we’re going to find a drug that has broad spectrum effects. ... I think the best that we can hope for is to find a drug with a pronounced effect on a particular component of cognition. We’d then want to use that drug in combination with a psychosocial intervention to enhance cognition and functionality," said Dr. Buchanan, professor of psychiatry at the University of Maryland, Baltimore.

First- and second-generation antipsychotics, although very effective in reducing hallucinations and delusions, have not demonstrated similar benefit in improving cognition. In a meta-analysis accounting for 208 effect sizes from 34 studies of first-generation antipsychotics, the overall effect size for nine cognitive measures was just 0.22. ("Small" was defined as 0.2, "moderate" was 0.5, and "large" was 0.7). Effect sizes for individual domains ranged from 0.13 (executive function) to 0.29 (automatic processing), to a negative effect of –0.11 for motor function (Biol. Psychiatry 2004;55:1013-22).

Initially, it had been hoped that through their unique pharmacologic profile, second-generation antipsychotics would be more beneficial than first-generation agents in improving cognition. But that was shown not to be the case in a substudy of 817 of the total 1,460 participants in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) project. At 2 months, patients who were randomized to the newer agents (olanzapine, quetiapine, risperidone, and ziprasidone) had similar, small neurocognitive improvements, compared with those taking the first-generation agent perphenazine (Arch. Gen. Psychiatry 2007;64:633-47).

"Second-generation antipsychotics offer little advantage vs. first-generation agents. Despite antipsychotic treatment, people with schizophrenia continue to exhibit marked cognitive impairments," Dr. Buchanan commented.

Indeed, it appears that there is a "cognitive cost" associated with medications – including antipsychotics – that raise serum anticholinergic activity. A study of 55 schizophrenia patients demonstrated a clear association between serum anticholinergic activity and impaired performance in verbal working memory and verbal learning and memory, independent of age, IQ, or symptom severity (Am. J. Psychiatry 2009;166:1055-62).

Various adjunctive pharmacologic approaches have been tried, with varying success. In a 12-week, double-blind, placebo-controlled, randomized trial, the acetylcholinesterase inhibitor galantamine had an insignificant overall effect on a composite of neuropsychological outcomes among 44 patients who received it, compared with 42 who got placebo. However, those taking galantamine did show significant improvements in certain measures, particularly processing speed and verbal memory (Am. J. Psychiatry 2008;165:82-9).

And in several small studies, galantamine appeared superior to placebo in improving attention, delayed memory, visual recognition, and emotional acuity.

The clinical observation that people with schizophrenia often appear to be self-medicating by cigarette smoking – as well as experimental findings of deficient expression of alpha(7)-nicotinic receptors in people with schizophrenia – led to interest in nicotinic acetylcholine receptors as possible therapeutic targets. In a 4-week, double-blind, crossover study of 31 nonsmoking people with schizophrenia, significant improvements over placebo were seen with a higher dose (150 mg twice daily) of the agent DMXBA (3-[2,4-dimethoxybenzylidene]-anabaseine) on SANS (Scale for the Assessment of Negative Symptoms) and BPRS (Brief Psychiatric Rating Scale) scores (Am. J. Psychiatry 2008;165:1040-7).

However, trials looking at other nicotinic receptor agonists, particularly the alpha4beta2 agent varenicline, have been uniformly negative, noted Dr. Buchanan, who was one of the authors of the DMXBA study.

Glutamatergic agents also have been studied. CONSIST (Cognitive and Negative Symptoms in Schizophrenia Trial), led by Dr. Buchanan, was a 16-week, double-blind, double-dummy, parallel group study of 157 patients who were randomized to adjunctive glycine, d-cycloserine, or placebo. There were no significant differences in the SANS scores or on a composite neuropsychological measure, suggesting that neither glycine nor d-cycloserine is effective for treating negative symptoms or cognitive impairments (Am. J. Psychiatry 2007;164:1593-602).

GABA (gamma aminobutyric acid) also has been looked at as a potential drug target. In another study led by Dr. Buchanan, the GABAA alpha2/alpha3 partial agonist MK-0777 was studied in 60 people in a 4-week, multicenter, double-blind, placebo-controlled randomized clinical trial. Again, results were negative: No significant group differences were found on the primary outcome measure, which was the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) consensus cognitive battery composite score. Moreover, secondary analysis suggested that patients who received placebo actually performed better on visual memory and reasoning/problem-solving tests than did those assigned to either of two MK-0777 doses (Biol. Psychiatry 2011;69:442-9).

Why so many negative studies? It might be that the best targets have not yet been identified. Alternative agents might include allosteric modulators, reuptake inhibitors, or enzyme inhibitors. Perhaps the problem has been in the choice of dose or dosing schedule, as there are data suggesting that intermittent or once-weekly dosing might better hit the "sweet spot" of drug efficacy, Dr. Buchanan postulated.

Or, it’s possible that drugs require "practice," in the form of cognitive remediation, to be effective. "Rather than continue to search for the miracle drug that will single-handedly reverse the various cognitive impairments, should we be examining the extent to which pharmacological agents can enhance the therapeutic effects of nonpharmacological approaches for the enhancement of cognition?" he asked.

Such interventions might include cognitive remediation such as PositScience (www.positscience.com), cognitive enhancement therapy, cognitive-behavioral therapy (CBT), and even exercise.

In an interview, Dr. Buchanan said that studies are underway using d-cycloserine to enhance CBT and cognitive remediation, and his own group has proposed a study using nicotine to enhance cognitive remediation. Another potential agent that could be used with psychosocial treatment is oxytocin, a naturally occurring hormone, which might facilitate social interactions.

Dr. Buchanan has received grant/research support from Janssen and is a consultant to Abbott Laboratories, GlaxoSmithKline, Sanofi-Aventis, Schering-Plough, and Takeda. He serves on advisory boards for Abbott, Astellas Pharma, AstraZeneca, Cypress Bioscience, Merck, Pfizer, Roche, Solvay Pharmaceuticals, and Wyeth. He also is a data and safety monitoring board member for Cephalon, Otsuka, and Pfizer.

PITTSBURGH – Effective treatment of cognitive impairments in people with schizophrenia probably will require a combination of pharmacologic and psychosocial interventions, said Dr. Robert W. Buchanan.

His conclusion was based on data from a large body of previous studies that looked at potential cognitive-enhancing drugs with a variety of mechanisms.

"Given the pattern of observed effects of drugs on various cognitive processes to date, it seems unlikely to me that we’re going to find a drug that has broad spectrum effects. ... I think the best that we can hope for is to find a drug with a pronounced effect on a particular component of cognition. We’d then want to use that drug in combination with a psychosocial intervention to enhance cognition and functionality," said Dr. Buchanan, professor of psychiatry at the University of Maryland, Baltimore.

First- and second-generation antipsychotics, although very effective in reducing hallucinations and delusions, have not demonstrated similar benefit in improving cognition. In a meta-analysis accounting for 208 effect sizes from 34 studies of first-generation antipsychotics, the overall effect size for nine cognitive measures was just 0.22. ("Small" was defined as 0.2, "moderate" was 0.5, and "large" was 0.7). Effect sizes for individual domains ranged from 0.13 (executive function) to 0.29 (automatic processing), to a negative effect of –0.11 for motor function (Biol. Psychiatry 2004;55:1013-22).

Initially, it had been hoped that through their unique pharmacologic profile, second-generation antipsychotics would be more beneficial than first-generation agents in improving cognition. But that was shown not to be the case in a substudy of 817 of the total 1,460 participants in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) project. At 2 months, patients who were randomized to the newer agents (olanzapine, quetiapine, risperidone, and ziprasidone) had similar, small neurocognitive improvements, compared with those taking the first-generation agent perphenazine (Arch. Gen. Psychiatry 2007;64:633-47).

"Second-generation antipsychotics offer little advantage vs. first-generation agents. Despite antipsychotic treatment, people with schizophrenia continue to exhibit marked cognitive impairments," Dr. Buchanan commented.

Indeed, it appears that there is a "cognitive cost" associated with medications – including antipsychotics – that raise serum anticholinergic activity. A study of 55 schizophrenia patients demonstrated a clear association between serum anticholinergic activity and impaired performance in verbal working memory and verbal learning and memory, independent of age, IQ, or symptom severity (Am. J. Psychiatry 2009;166:1055-62).

Various adjunctive pharmacologic approaches have been tried, with varying success. In a 12-week, double-blind, placebo-controlled, randomized trial, the acetylcholinesterase inhibitor galantamine had an insignificant overall effect on a composite of neuropsychological outcomes among 44 patients who received it, compared with 42 who got placebo. However, those taking galantamine did show significant improvements in certain measures, particularly processing speed and verbal memory (Am. J. Psychiatry 2008;165:82-9).

And in several small studies, galantamine appeared superior to placebo in improving attention, delayed memory, visual recognition, and emotional acuity.

The clinical observation that people with schizophrenia often appear to be self-medicating by cigarette smoking – as well as experimental findings of deficient expression of alpha(7)-nicotinic receptors in people with schizophrenia – led to interest in nicotinic acetylcholine receptors as possible therapeutic targets. In a 4-week, double-blind, crossover study of 31 nonsmoking people with schizophrenia, significant improvements over placebo were seen with a higher dose (150 mg twice daily) of the agent DMXBA (3-[2,4-dimethoxybenzylidene]-anabaseine) on SANS (Scale for the Assessment of Negative Symptoms) and BPRS (Brief Psychiatric Rating Scale) scores (Am. J. Psychiatry 2008;165:1040-7).

However, trials looking at other nicotinic receptor agonists, particularly the alpha4beta2 agent varenicline, have been uniformly negative, noted Dr. Buchanan, who was one of the authors of the DMXBA study.

Glutamatergic agents also have been studied. CONSIST (Cognitive and Negative Symptoms in Schizophrenia Trial), led by Dr. Buchanan, was a 16-week, double-blind, double-dummy, parallel group study of 157 patients who were randomized to adjunctive glycine, d-cycloserine, or placebo. There were no significant differences in the SANS scores or on a composite neuropsychological measure, suggesting that neither glycine nor d-cycloserine is effective for treating negative symptoms or cognitive impairments (Am. J. Psychiatry 2007;164:1593-602).

GABA (gamma aminobutyric acid) also has been looked at as a potential drug target. In another study led by Dr. Buchanan, the GABAA alpha2/alpha3 partial agonist MK-0777 was studied in 60 people in a 4-week, multicenter, double-blind, placebo-controlled randomized clinical trial. Again, results were negative: No significant group differences were found on the primary outcome measure, which was the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) consensus cognitive battery composite score. Moreover, secondary analysis suggested that patients who received placebo actually performed better on visual memory and reasoning/problem-solving tests than did those assigned to either of two MK-0777 doses (Biol. Psychiatry 2011;69:442-9).

Why so many negative studies? It might be that the best targets have not yet been identified. Alternative agents might include allosteric modulators, reuptake inhibitors, or enzyme inhibitors. Perhaps the problem has been in the choice of dose or dosing schedule, as there are data suggesting that intermittent or once-weekly dosing might better hit the "sweet spot" of drug efficacy, Dr. Buchanan postulated.

Or, it’s possible that drugs require "practice," in the form of cognitive remediation, to be effective. "Rather than continue to search for the miracle drug that will single-handedly reverse the various cognitive impairments, should we be examining the extent to which pharmacological agents can enhance the therapeutic effects of nonpharmacological approaches for the enhancement of cognition?" he asked.

Such interventions might include cognitive remediation such as PositScience (www.positscience.com), cognitive enhancement therapy, cognitive-behavioral therapy (CBT), and even exercise.

In an interview, Dr. Buchanan said that studies are underway using d-cycloserine to enhance CBT and cognitive remediation, and his own group has proposed a study using nicotine to enhance cognitive remediation. Another potential agent that could be used with psychosocial treatment is oxytocin, a naturally occurring hormone, which might facilitate social interactions.

Dr. Buchanan has received grant/research support from Janssen and is a consultant to Abbott Laboratories, GlaxoSmithKline, Sanofi-Aventis, Schering-Plough, and Takeda. He serves on advisory boards for Abbott, Astellas Pharma, AstraZeneca, Cypress Bioscience, Merck, Pfizer, Roche, Solvay Pharmaceuticals, and Wyeth. He also is a data and safety monitoring board member for Cephalon, Otsuka, and Pfizer.

PITTSBURGH – Effective treatment of cognitive impairments in people with schizophrenia probably will require a combination of pharmacologic and psychosocial interventions, said Dr. Robert W. Buchanan.

His conclusion was based on data from a large body of previous studies that looked at potential cognitive-enhancing drugs with a variety of mechanisms.

"Given the pattern of observed effects of drugs on various cognitive processes to date, it seems unlikely to me that we’re going to find a drug that has broad spectrum effects. ... I think the best that we can hope for is to find a drug with a pronounced effect on a particular component of cognition. We’d then want to use that drug in combination with a psychosocial intervention to enhance cognition and functionality," said Dr. Buchanan, professor of psychiatry at the University of Maryland, Baltimore.

First- and second-generation antipsychotics, although very effective in reducing hallucinations and delusions, have not demonstrated similar benefit in improving cognition. In a meta-analysis accounting for 208 effect sizes from 34 studies of first-generation antipsychotics, the overall effect size for nine cognitive measures was just 0.22. ("Small" was defined as 0.2, "moderate" was 0.5, and "large" was 0.7). Effect sizes for individual domains ranged from 0.13 (executive function) to 0.29 (automatic processing), to a negative effect of –0.11 for motor function (Biol. Psychiatry 2004;55:1013-22).

Initially, it had been hoped that through their unique pharmacologic profile, second-generation antipsychotics would be more beneficial than first-generation agents in improving cognition. But that was shown not to be the case in a substudy of 817 of the total 1,460 participants in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) project. At 2 months, patients who were randomized to the newer agents (olanzapine, quetiapine, risperidone, and ziprasidone) had similar, small neurocognitive improvements, compared with those taking the first-generation agent perphenazine (Arch. Gen. Psychiatry 2007;64:633-47).

"Second-generation antipsychotics offer little advantage vs. first-generation agents. Despite antipsychotic treatment, people with schizophrenia continue to exhibit marked cognitive impairments," Dr. Buchanan commented.

Indeed, it appears that there is a "cognitive cost" associated with medications – including antipsychotics – that raise serum anticholinergic activity. A study of 55 schizophrenia patients demonstrated a clear association between serum anticholinergic activity and impaired performance in verbal working memory and verbal learning and memory, independent of age, IQ, or symptom severity (Am. J. Psychiatry 2009;166:1055-62).

Various adjunctive pharmacologic approaches have been tried, with varying success. In a 12-week, double-blind, placebo-controlled, randomized trial, the acetylcholinesterase inhibitor galantamine had an insignificant overall effect on a composite of neuropsychological outcomes among 44 patients who received it, compared with 42 who got placebo. However, those taking galantamine did show significant improvements in certain measures, particularly processing speed and verbal memory (Am. J. Psychiatry 2008;165:82-9).

And in several small studies, galantamine appeared superior to placebo in improving attention, delayed memory, visual recognition, and emotional acuity.

The clinical observation that people with schizophrenia often appear to be self-medicating by cigarette smoking – as well as experimental findings of deficient expression of alpha(7)-nicotinic receptors in people with schizophrenia – led to interest in nicotinic acetylcholine receptors as possible therapeutic targets. In a 4-week, double-blind, crossover study of 31 nonsmoking people with schizophrenia, significant improvements over placebo were seen with a higher dose (150 mg twice daily) of the agent DMXBA (3-[2,4-dimethoxybenzylidene]-anabaseine) on SANS (Scale for the Assessment of Negative Symptoms) and BPRS (Brief Psychiatric Rating Scale) scores (Am. J. Psychiatry 2008;165:1040-7).

However, trials looking at other nicotinic receptor agonists, particularly the alpha4beta2 agent varenicline, have been uniformly negative, noted Dr. Buchanan, who was one of the authors of the DMXBA study.

Glutamatergic agents also have been studied. CONSIST (Cognitive and Negative Symptoms in Schizophrenia Trial), led by Dr. Buchanan, was a 16-week, double-blind, double-dummy, parallel group study of 157 patients who were randomized to adjunctive glycine, d-cycloserine, or placebo. There were no significant differences in the SANS scores or on a composite neuropsychological measure, suggesting that neither glycine nor d-cycloserine is effective for treating negative symptoms or cognitive impairments (Am. J. Psychiatry 2007;164:1593-602).

GABA (gamma aminobutyric acid) also has been looked at as a potential drug target. In another study led by Dr. Buchanan, the GABAA alpha2/alpha3 partial agonist MK-0777 was studied in 60 people in a 4-week, multicenter, double-blind, placebo-controlled randomized clinical trial. Again, results were negative: No significant group differences were found on the primary outcome measure, which was the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) consensus cognitive battery composite score. Moreover, secondary analysis suggested that patients who received placebo actually performed better on visual memory and reasoning/problem-solving tests than did those assigned to either of two MK-0777 doses (Biol. Psychiatry 2011;69:442-9).

Why so many negative studies? It might be that the best targets have not yet been identified. Alternative agents might include allosteric modulators, reuptake inhibitors, or enzyme inhibitors. Perhaps the problem has been in the choice of dose or dosing schedule, as there are data suggesting that intermittent or once-weekly dosing might better hit the "sweet spot" of drug efficacy, Dr. Buchanan postulated.

Or, it’s possible that drugs require "practice," in the form of cognitive remediation, to be effective. "Rather than continue to search for the miracle drug that will single-handedly reverse the various cognitive impairments, should we be examining the extent to which pharmacological agents can enhance the therapeutic effects of nonpharmacological approaches for the enhancement of cognition?" he asked.

Such interventions might include cognitive remediation such as PositScience (www.positscience.com), cognitive enhancement therapy, cognitive-behavioral therapy (CBT), and even exercise.

In an interview, Dr. Buchanan said that studies are underway using d-cycloserine to enhance CBT and cognitive remediation, and his own group has proposed a study using nicotine to enhance cognitive remediation. Another potential agent that could be used with psychosocial treatment is oxytocin, a naturally occurring hormone, which might facilitate social interactions.

Dr. Buchanan has received grant/research support from Janssen and is a consultant to Abbott Laboratories, GlaxoSmithKline, Sanofi-Aventis, Schering-Plough, and Takeda. He serves on advisory boards for Abbott, Astellas Pharma, AstraZeneca, Cypress Bioscience, Merck, Pfizer, Roche, Solvay Pharmaceuticals, and Wyeth. He also is a data and safety monitoring board member for Cephalon, Otsuka, and Pfizer.

PITTSBURGH – Effective treatment of cognitive impairments in people with schizophrenia probably will require a combination of pharmacologic and psychosocial interventions, said Dr. Robert W. Buchanan.

His conclusion was based on data from a large body of previous studies that looked at potential cognitive-enhancing drugs with a variety of mechanisms.

"Given the pattern of observed effects of drugs on various cognitive processes to date, it seems unlikely to me that we’re going to find a drug that has broad spectrum effects. ... I think the best that we can hope for is to find a drug with a pronounced effect on a particular component of cognition. We’d then want to use that drug in combination with a psychosocial intervention to enhance cognition and functionality," said Dr. Buchanan, professor of psychiatry at the University of Maryland, Baltimore.

First- and second-generation antipsychotics, although very effective in reducing hallucinations and delusions, have not demonstrated similar benefit in improving cognition. In a meta-analysis accounting for 208 effect sizes from 34 studies of first-generation antipsychotics, the overall effect size for nine cognitive measures was just 0.22. ("Small" was defined as 0.2, "moderate" was 0.5, and "large" was 0.7). Effect sizes for individual domains ranged from 0.13 (executive function) to 0.29 (automatic processing), to a negative effect of –0.11 for motor function (Biol. Psychiatry 2004;55:1013-22).

Initially, it had been hoped that through their unique pharmacologic profile, second-generation antipsychotics would be more beneficial than first-generation agents in improving cognition. But that was shown not to be the case in a substudy of 817 of the total 1,460 participants in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) project. At 2 months, patients who were randomized to the newer agents (olanzapine, quetiapine, risperidone, and ziprasidone) had similar, small neurocognitive improvements, compared with those taking the first-generation agent perphenazine (Arch. Gen. Psychiatry 2007;64:633-47).

"Second-generation antipsychotics offer little advantage vs. first-generation agents. Despite antipsychotic treatment, people with schizophrenia continue to exhibit marked cognitive impairments," Dr. Buchanan commented.

Indeed, it appears that there is a "cognitive cost" associated with medications – including antipsychotics – that raise serum anticholinergic activity. A study of 55 schizophrenia patients demonstrated a clear association between serum anticholinergic activity and impaired performance in verbal working memory and verbal learning and memory, independent of age, IQ, or symptom severity (Am. J. Psychiatry 2009;166:1055-62).

Various adjunctive pharmacologic approaches have been tried, with varying success. In a 12-week, double-blind, placebo-controlled, randomized trial, the acetylcholinesterase inhibitor galantamine had an insignificant overall effect on a composite of neuropsychological outcomes among 44 patients who received it, compared with 42 who got placebo. However, those taking galantamine did show significant improvements in certain measures, particularly processing speed and verbal memory (Am. J. Psychiatry 2008;165:82-9).

And in several small studies, galantamine appeared superior to placebo in improving attention, delayed memory, visual recognition, and emotional acuity.

The clinical observation that people with schizophrenia often appear to be self-medicating by cigarette smoking – as well as experimental findings of deficient expression of alpha(7)-nicotinic receptors in people with schizophrenia – led to interest in nicotinic acetylcholine receptors as possible therapeutic targets. In a 4-week, double-blind, crossover study of 31 nonsmoking people with schizophrenia, significant improvements over placebo were seen with a higher dose (150 mg twice daily) of the agent DMXBA (3-[2,4-dimethoxybenzylidene]-anabaseine) on SANS (Scale for the Assessment of Negative Symptoms) and BPRS (Brief Psychiatric Rating Scale) scores (Am. J. Psychiatry 2008;165:1040-7).

However, trials looking at other nicotinic receptor agonists, particularly the alpha4beta2 agent varenicline, have been uniformly negative, noted Dr. Buchanan, who was one of the authors of the DMXBA study.

Glutamatergic agents also have been studied. CONSIST (Cognitive and Negative Symptoms in Schizophrenia Trial), led by Dr. Buchanan, was a 16-week, double-blind, double-dummy, parallel group study of 157 patients who were randomized to adjunctive glycine, d-cycloserine, or placebo. There were no significant differences in the SANS scores or on a composite neuropsychological measure, suggesting that neither glycine nor d-cycloserine is effective for treating negative symptoms or cognitive impairments (Am. J. Psychiatry 2007;164:1593-602).

GABA (gamma aminobutyric acid) also has been looked at as a potential drug target. In another study led by Dr. Buchanan, the GABAA alpha2/alpha3 partial agonist MK-0777 was studied in 60 people in a 4-week, multicenter, double-blind, placebo-controlled randomized clinical trial. Again, results were negative: No significant group differences were found on the primary outcome measure, which was the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) consensus cognitive battery composite score. Moreover, secondary analysis suggested that patients who received placebo actually performed better on visual memory and reasoning/problem-solving tests than did those assigned to either of two MK-0777 doses (Biol. Psychiatry 2011;69:442-9).

Why so many negative studies? It might be that the best targets have not yet been identified. Alternative agents might include allosteric modulators, reuptake inhibitors, or enzyme inhibitors. Perhaps the problem has been in the choice of dose or dosing schedule, as there are data suggesting that intermittent or once-weekly dosing might better hit the "sweet spot" of drug efficacy, Dr. Buchanan postulated.

Or, it’s possible that drugs require "practice," in the form of cognitive remediation, to be effective. "Rather than continue to search for the miracle drug that will single-handedly reverse the various cognitive impairments, should we be examining the extent to which pharmacological agents can enhance the therapeutic effects of nonpharmacological approaches for the enhancement of cognition?" he asked.

Such interventions might include cognitive remediation such as PositScience (www.positscience.com), cognitive enhancement therapy, cognitive-behavioral therapy (CBT), and even exercise.

In an interview, Dr. Buchanan said that studies are underway using d-cycloserine to enhance CBT and cognitive remediation, and his own group has proposed a study using nicotine to enhance cognitive remediation. Another potential agent that could be used with psychosocial treatment is oxytocin, a naturally occurring hormone, which might facilitate social interactions.

Dr. Buchanan has received grant/research support from Janssen and is a consultant to Abbott Laboratories, GlaxoSmithKline, Sanofi-Aventis, Schering-Plough, and Takeda. He serves on advisory boards for Abbott, Astellas Pharma, AstraZeneca, Cypress Bioscience, Merck, Pfizer, Roche, Solvay Pharmaceuticals, and Wyeth. He also is a data and safety monitoring board member for Cephalon, Otsuka, and Pfizer.

PITTSBURGH – Effective treatment of cognitive impairments in people with schizophrenia probably will require a combination of pharmacologic and psychosocial interventions, said Dr. Robert W. Buchanan.

His conclusion was based on data from a large body of previous studies that looked at potential cognitive-enhancing drugs with a variety of mechanisms.

"Given the pattern of observed effects of drugs on various cognitive processes to date, it seems unlikely to me that we’re going to find a drug that has broad spectrum effects. ... I think the best that we can hope for is to find a drug with a pronounced effect on a particular component of cognition. We’d then want to use that drug in combination with a psychosocial intervention to enhance cognition and functionality," said Dr. Buchanan, professor of psychiatry at the University of Maryland, Baltimore.

First- and second-generation antipsychotics, although very effective in reducing hallucinations and delusions, have not demonstrated similar benefit in improving cognition. In a meta-analysis accounting for 208 effect sizes from 34 studies of first-generation antipsychotics, the overall effect size for nine cognitive measures was just 0.22. ("Small" was defined as 0.2, "moderate" was 0.5, and "large" was 0.7). Effect sizes for individual domains ranged from 0.13 (executive function) to 0.29 (automatic processing), to a negative effect of –0.11 for motor function (Biol. Psychiatry 2004;55:1013-22).

Initially, it had been hoped that through their unique pharmacologic profile, second-generation antipsychotics would be more beneficial than first-generation agents in improving cognition. But that was shown not to be the case in a substudy of 817 of the total 1,460 participants in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) project. At 2 months, patients who were randomized to the newer agents (olanzapine, quetiapine, risperidone, and ziprasidone) had similar, small neurocognitive improvements, compared with those taking the first-generation agent perphenazine (Arch. Gen. Psychiatry 2007;64:633-47).

"Second-generation antipsychotics offer little advantage vs. first-generation agents. Despite antipsychotic treatment, people with schizophrenia continue to exhibit marked cognitive impairments," Dr. Buchanan commented.

Indeed, it appears that there is a "cognitive cost" associated with medications – including antipsychotics – that raise serum anticholinergic activity. A study of 55 schizophrenia patients demonstrated a clear association between serum anticholinergic activity and impaired performance in verbal working memory and verbal learning and memory, independent of age, IQ, or symptom severity (Am. J. Psychiatry 2009;166:1055-62).

Various adjunctive pharmacologic approaches have been tried, with varying success. In a 12-week, double-blind, placebo-controlled, randomized trial, the acetylcholinesterase inhibitor galantamine had an insignificant overall effect on a composite of neuropsychological outcomes among 44 patients who received it, compared with 42 who got placebo. However, those taking galantamine did show significant improvements in certain measures, particularly processing speed and verbal memory (Am. J. Psychiatry 2008;165:82-9).

And in several small studies, galantamine appeared superior to placebo in improving attention, delayed memory, visual recognition, and emotional acuity.

The clinical observation that people with schizophrenia often appear to be self-medicating by cigarette smoking – as well as experimental findings of deficient expression of alpha(7)-nicotinic receptors in people with schizophrenia – led to interest in nicotinic acetylcholine receptors as possible therapeutic targets. In a 4-week, double-blind, crossover study of 31 nonsmoking people with schizophrenia, significant improvements over placebo were seen with a higher dose (150 mg twice daily) of the agent DMXBA (3-[2,4-dimethoxybenzylidene]-anabaseine) on SANS (Scale for the Assessment of Negative Symptoms) and BPRS (Brief Psychiatric Rating Scale) scores (Am. J. Psychiatry 2008;165:1040-7).

However, trials looking at other nicotinic receptor agonists, particularly the alpha4beta2 agent varenicline, have been uniformly negative, noted Dr. Buchanan, who was one of the authors of the DMXBA study.

Glutamatergic agents also have been studied. CONSIST (Cognitive and Negative Symptoms in Schizophrenia Trial), led by Dr. Buchanan, was a 16-week, double-blind, double-dummy, parallel group study of 157 patients who were randomized to adjunctive glycine, d-cycloserine, or placebo. There were no significant differences in the SANS scores or on a composite neuropsychological measure, suggesting that neither glycine nor d-cycloserine is effective for treating negative symptoms or cognitive impairments (Am. J. Psychiatry 2007;164:1593-602).

GABA (gamma aminobutyric acid) also has been looked at as a potential drug target. In another study led by Dr. Buchanan, the GABAA alpha2/alpha3 partial agonist MK-0777 was studied in 60 people in a 4-week, multicenter, double-blind, placebo-controlled randomized clinical trial. Again, results were negative: No significant group differences were found on the primary outcome measure, which was the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) consensus cognitive battery composite score. Moreover, secondary analysis suggested that patients who received placebo actually performed better on visual memory and reasoning/problem-solving tests than did those assigned to either of two MK-0777 doses (Biol. Psychiatry 2011;69:442-9).

Why so many negative studies? It might be that the best targets have not yet been identified. Alternative agents might include allosteric modulators, reuptake inhibitors, or enzyme inhibitors. Perhaps the problem has been in the choice of dose or dosing schedule, as there are data suggesting that intermittent or once-weekly dosing might better hit the "sweet spot" of drug efficacy, Dr. Buchanan postulated.

Or, it’s possible that drugs require "practice," in the form of cognitive remediation, to be effective. "Rather than continue to search for the miracle drug that will single-handedly reverse the various cognitive impairments, should we be examining the extent to which pharmacological agents can enhance the therapeutic effects of nonpharmacological approaches for the enhancement of cognition?" he asked.

Such interventions might include cognitive remediation such as PositScience (www.positscience.com), cognitive enhancement therapy, cognitive-behavioral therapy (CBT), and even exercise.

In an interview, Dr. Buchanan said that studies are underway using d-cycloserine to enhance CBT and cognitive remediation, and his own group has proposed a study using nicotine to enhance cognitive remediation. Another potential agent that could be used with psychosocial treatment is oxytocin, a naturally occurring hormone, which might facilitate social interactions.

Dr. Buchanan has received grant/research support from Janssen and is a consultant to Abbott Laboratories, GlaxoSmithKline, Sanofi-Aventis, Schering-Plough, and Takeda. He serves on advisory boards for Abbott, Astellas Pharma, AstraZeneca, Cypress Bioscience, Merck, Pfizer, Roche, Solvay Pharmaceuticals, and Wyeth. He also is a data and safety monitoring board member for Cephalon, Otsuka, and Pfizer.

Each year, the Advisory Committee on Immunization Practices (ACIP) publishes immunization schedules for persons aged 0 through 18 years. For 2011, most of the changes from 2010 are in the footnotes, with only small changes to the grid itself.

Among the new items:

• Hepatitis B vaccine. Guidance has been added to the hepatitis B vaccine schedule for children who did not receive the recommended birth dose. They should receive three doses on a schedule of 0, 1, and 6 months, with the final dose in the series administered no earlier than age 24 weeks.

• 13-valent pneumococcal conjugate vaccine. Information on use of the new 13-valent pneumococcal conjugate vaccine (PCV13) has been added. Prevnar-13 was licensed in February 2010 and recommended by ACIP to replace the old 7-valent version for routine childhood immunization. Children who began the series with PCV7 should receive the rest of the doses in the series as PCV13. Children aged 14-59 months and those aged 60-71 months with underlying medical conditions who received the entire age-appropriate series of PCV7 should receive one supplemental dose of PCV13. That dose should be given at least 8 weeks after the previous PCV7 dose.

• Influenza vaccine. Guidance has been added for administration of one or two doses of seasonal influenza vaccine based upon the child’s history of monovalent 2009 H1N1 vaccination. Two doses – separated by at least 4 weeks – should be given to children aged 6 months through 8 years who are receiving seasonal influenza vaccine for the first time or who were vaccinated for the first time during the previous influenza season but received only one dose. Children aged 6 months through 8 years who received no doses of monovalent 2009 H1N1 vaccine should receive two doses of 2010-2011 seasonal influenza vaccine, which contains H1N1.

• Tetanus and diphtheria toxoids and acellular pertussis (Tdap) vaccine. Use of Tdap among children aged 7-10 years who are incompletely vaccinated against pertussis – either never vaccinated or with unknown status – is now addressed, with a recommendation that those children receive a single dose of Tdap. Reference to a specified interval between tetanus and between tetanus and diphtheria toxoids (Td) and Tdap vaccination has been removed, so Tdap can be administered without regard for the interval since the last dose of Td (or T).

• Meningococcal conjugate vaccine, quadrivalent (MCV4). For MCV4, recommendations for a routine two-dose schedule have been added for certain individuals at high risk of meningococcal disease, including children aged 2-10 years with persistent complement-component deficiency and anatomic or functional asplenia (who should also receive one dose every 5 years thereafter) and those with HIV infection. A new recommendation for a booster dose of MCV4 at age 16 years also has been added.

• Human papillomavirus vaccine (HPV) and Haemophilus influenzae type b (Hib). Footnote sections on use of the HPV vaccine and use of the Hib vaccine in persons aged 5 years and older in the catch-up schedule have been condensed.

Detailed recommendations for using vaccines are available from ACIP statements and the 2009 Red Book. Guidance regarding the Vaccine Adverse Event Reporting System form is available online or by telephone (800-822-7967).

Each year, the Advisory Committee on Immunization Practices (ACIP) publishes immunization schedules for persons aged 0 through 18 years. For 2011, most of the changes from 2010 are in the footnotes, with only small changes to the grid itself.

Among the new items:

• Hepatitis B vaccine. Guidance has been added to the hepatitis B vaccine schedule for children who did not receive the recommended birth dose. They should receive three doses on a schedule of 0, 1, and 6 months, with the final dose in the series administered no earlier than age 24 weeks.

• 13-valent pneumococcal conjugate vaccine. Information on use of the new 13-valent pneumococcal conjugate vaccine (PCV13) has been added. Prevnar-13 was licensed in February 2010 and recommended by ACIP to replace the old 7-valent version for routine childhood immunization. Children who began the series with PCV7 should receive the rest of the doses in the series as PCV13. Children aged 14-59 months and those aged 60-71 months with underlying medical conditions who received the entire age-appropriate series of PCV7 should receive one supplemental dose of PCV13. That dose should be given at least 8 weeks after the previous PCV7 dose.

• Influenza vaccine. Guidance has been added for administration of one or two doses of seasonal influenza vaccine based upon the child’s history of monovalent 2009 H1N1 vaccination. Two doses – separated by at least 4 weeks – should be given to children aged 6 months through 8 years who are receiving seasonal influenza vaccine for the first time or who were vaccinated for the first time during the previous influenza season but received only one dose. Children aged 6 months through 8 years who received no doses of monovalent 2009 H1N1 vaccine should receive two doses of 2010-2011 seasonal influenza vaccine, which contains H1N1.

• Tetanus and diphtheria toxoids and acellular pertussis (Tdap) vaccine. Use of Tdap among children aged 7-10 years who are incompletely vaccinated against pertussis – either never vaccinated or with unknown status – is now addressed, with a recommendation that those children receive a single dose of Tdap. Reference to a specified interval between tetanus and between tetanus and diphtheria toxoids (Td) and Tdap vaccination has been removed, so Tdap can be administered without regard for the interval since the last dose of Td (or T).

• Meningococcal conjugate vaccine, quadrivalent (MCV4). For MCV4, recommendations for a routine two-dose schedule have been added for certain individuals at high risk of meningococcal disease, including children aged 2-10 years with persistent complement-component deficiency and anatomic or functional asplenia (who should also receive one dose every 5 years thereafter) and those with HIV infection. A new recommendation for a booster dose of MCV4 at age 16 years also has been added.

• Human papillomavirus vaccine (HPV) and Haemophilus influenzae type b (Hib). Footnote sections on use of the HPV vaccine and use of the Hib vaccine in persons aged 5 years and older in the catch-up schedule have been condensed.

Detailed recommendations for using vaccines are available from ACIP statements and the 2009 Red Book. Guidance regarding the Vaccine Adverse Event Reporting System form is available online or by telephone (800-822-7967).

Each year, the Advisory Committee on Immunization Practices (ACIP) publishes immunization schedules for persons aged 0 through 18 years. For 2011, most of the changes from 2010 are in the footnotes, with only small changes to the grid itself.

Among the new items:

• Hepatitis B vaccine. Guidance has been added to the hepatitis B vaccine schedule for children who did not receive the recommended birth dose. They should receive three doses on a schedule of 0, 1, and 6 months, with the final dose in the series administered no earlier than age 24 weeks.

• 13-valent pneumococcal conjugate vaccine. Information on use of the new 13-valent pneumococcal conjugate vaccine (PCV13) has been added. Prevnar-13 was licensed in February 2010 and recommended by ACIP to replace the old 7-valent version for routine childhood immunization. Children who began the series with PCV7 should receive the rest of the doses in the series as PCV13. Children aged 14-59 months and those aged 60-71 months with underlying medical conditions who received the entire age-appropriate series of PCV7 should receive one supplemental dose of PCV13. That dose should be given at least 8 weeks after the previous PCV7 dose.

• Influenza vaccine. Guidance has been added for administration of one or two doses of seasonal influenza vaccine based upon the child’s history of monovalent 2009 H1N1 vaccination. Two doses – separated by at least 4 weeks – should be given to children aged 6 months through 8 years who are receiving seasonal influenza vaccine for the first time or who were vaccinated for the first time during the previous influenza season but received only one dose. Children aged 6 months through 8 years who received no doses of monovalent 2009 H1N1 vaccine should receive two doses of 2010-2011 seasonal influenza vaccine, which contains H1N1.

• Tetanus and diphtheria toxoids and acellular pertussis (Tdap) vaccine. Use of Tdap among children aged 7-10 years who are incompletely vaccinated against pertussis – either never vaccinated or with unknown status – is now addressed, with a recommendation that those children receive a single dose of Tdap. Reference to a specified interval between tetanus and between tetanus and diphtheria toxoids (Td) and Tdap vaccination has been removed, so Tdap can be administered without regard for the interval since the last dose of Td (or T).

• Meningococcal conjugate vaccine, quadrivalent (MCV4). For MCV4, recommendations for a routine two-dose schedule have been added for certain individuals at high risk of meningococcal disease, including children aged 2-10 years with persistent complement-component deficiency and anatomic or functional asplenia (who should also receive one dose every 5 years thereafter) and those with HIV infection. A new recommendation for a booster dose of MCV4 at age 16 years also has been added.

• Human papillomavirus vaccine (HPV) and Haemophilus influenzae type b (Hib). Footnote sections on use of the HPV vaccine and use of the Hib vaccine in persons aged 5 years and older in the catch-up schedule have been condensed.

Detailed recommendations for using vaccines are available from ACIP statements and the 2009 Red Book. Guidance regarding the Vaccine Adverse Event Reporting System form is available online or by telephone (800-822-7967).

PITTSBURGH – Emerging evidence is leading to optimism that early interventions could prevent the onset of schizophrenia or reduce its impact on cognitive function.

Among psychiatric disorders, schizophrenia tends to manifest later in life than most, typically not until late adolescence or early adulthood. Yet, evidence suggests that brain changes actually occur much earlier in life among those destined to develop the disease, said Dr. Matcheri S. Keshavan, the Stanley Cobb Professor of Psychiatry at Harvard Medical School and vice-chair of public psychiatry at Beth Israel Deaconess Medical Center and the Massachusetts Mental Health Center, all in Boston.

Indeed, schizophrenia is increasingly being viewed as a neurodevelopmental disorder with psychosis as a late and potentially preventable stage of the illness (Nature 2010;468:187-93). Research is now investigating whether it is possible to detect these early signs and intervene before the onset of psychosis to minimize the impact of the disease, said Dr. Keshavan, who is also professor of psychiatry at the University of Pittsburgh.

The emergence of cognitive control and emotion regulation during adolescence are related to expansion of connectivity and fine-tuning of both excitatory and inhibitory neurotransmitter systems. At the same time, abstract thinking and executive function arise from increased efficiency at the expense of brain plasticity, or the ability of the brain to rewire itself in response to change. These processes might go haywire in those at risk for schizophrenia, and a combination of genetic and environmental factors could lead to a failure of inhibitory processes resulting in psychosis, he explained.

"Psychosis begins in adolescence, but schizophrenia really begins in childhood or even earlier. ... The risk-plasticity model of development of schizophrenia suggests several windows of opportunity for primary, secondary, and tertiary prevention," he said.

Several signs mark the early stages of disease. In one recent meta-analysis of 18 studies, individuals with schizophrenia demonstrated mean IQ scores of approximately half a standard deviation below those of healthy comparison subjects, years before the onset of psychotic symptoms (Am. J. Psychiatry 2008;165:579-87).

Certain biomarkers might help to identify those at risk. In a study from Dr. Keshavan’s work in Pittsburgh, at-risk relatives of schizophrenia patients who themselves had schizotypy performed less well on the Wisconsin Card Sort task, which assesses executive function, and showed age-related deficits on the oculomotor delayed response task, compared with non-schizotypal relatives and healthy controls (Prog. Neuropsychopharmacol. Biol. Psychiatry 2006;30:230-8).

Two follow-up studies showed gray matter losses evolving during the premorbid phase among high-risk relatives, compared with control relatives, in areas mediating social cognition and overlapping with cognitive deficits (Neuroimage 2011;54S1:S272-9 and Neuroimage 2011;54S1:S287-92).

Other data from Dr. Keshavan’s group at the University of Pittsburgh indirectly suggest that neurons do not appear to be lost in schizophrenia, but that a reduction in synaptic connectivity occurs leading to reduced brain plasticity (Schizophr. Res. 2010;119:47-51). Such a process might be reversible, he noted.

A variety of environmental factors have been implicated in triggering schizophrenia among individuals who already are genetically predisposed. These include obstetric complications (Ann. NY Acad. Sci. 2003;1008:269-75), exposure to the herpes simplex virus (Mol. Psychiatry 2007;12:105-13), and cannabis use (Schizophr. Res. 2008;99:1-6).

In a longitudinal study of 291 prodromal individuals who sought treatment, the risk of conversion to psychosis was 35% over 2.5 years. Five baseline features independently predicted conversion risk: A genetic risk for schizophrenia with recent deterioration in functioning, higher levels of unusual thought content, higher levels of suspicion/paranoia, greater social impairment, and a history of substance abuse. Algorithms combining two or three of these variables resulted in positive predictive power of 68%-80%, significantly greater than using prodromal criteria alone (Arch. Gen. Psychiatry 2008;65:28-37).

For individuals identified as being at high risk for progression to psychosis, studies are suggesting that use of a variety of pharmacologic and nonpharmacologic preventive interventions during the prodrome might be of benefit.

In a small randomized trial, 31 outpatients with prodromal symptoms of schizophrenia received 5-15 mg/day of olanzapine and 29 took placebo during a 1-year double-blind treatment period. No treatment was given in the subsequent year of follow-up. Although the difference in the rate of conversion during the treatment year was statistically insignificant, it was more than double in the placebo group – 38% vs. 16% with olanzapine (Am. J. Psychiatry 2006;163:790-9).

However, the olanzapine patients did gain significantly more weight (8.8 vs. 0.30kg), Dr. Keshavan noted.

Cognitive therapy (CT) is another potential approach. A randomized controlled trial compared CT over 6 months with monthly monitoring in 58 patients who met criteria for ultrahigh risk of developing a first episode of psychosis. Those receiving CT were less likely to be prescribed an antipsychotic medication over the subsequent 3 years. While CT did not affect transition to psychosis using two different measures, it did significantly reduce the likelihood of progression to psychosis after controlling for baseline cognitive factors (Schizophr. Bull. 2007;33:682-7).

Omega-3 fatty acids also have been investigated, based on evidence that their levels might be deficient in schizophrenia patients, leading to alterations in neurotransmission among other processes.

In a randomized, double-blind placebo-controlled trial, 81 adolescents and young adults with subthreshold psychosis received 1.2 g/d of omega-3 polyunsaturated fatty acids (PUFAs) for 12 weeks, followed by a 40-week monitoring period. At 12 months, 2 of 41 in the omega-3 group (4.9%) and 11 of 40 (27.5%) in the placebo group had transitioned to psychotic disorder, a significant difference (Arch. Gen. Psychiatry 2010;67:146-54).

The omega-3s also significantly reduced positive symptoms, negative symptoms, general symptoms, and improved functioning, compared with placebo, with no difference in the incidence of adverse effects between the treatment groups. "This finding suggests that the omega-3s prevented the transition to psychosis. If this is the case, it would be significant for young people at high risk of developing schizophrenia or other psychotic disorders," Dr. Keshavan said.

Antiviral agents also might have prevention potential. In an unpublished study by Dr. Konasale M. Prasad in Dr. Keshavan’s Pittsburgh group, valacyclovir in patients with schizophrenia produced a trend toward improvement in working memory.

And finally, evidence suggests that an integrated neurocognitive and social-cognitive rehabilitation program using cognitive enhancement therapy (CET) can positively affect cognitive and functional outcomes. A total of 58 early-course outpatients with schizophrenia or schizoaffective disorder were randomly assigned to CET or enriched supportive therapy, an illness management intervention using psychoeducation and applied coping strategies. After 2 years, CET moderately enhanced neurocognitive function. Strong differential effects on social cognition, cognitive style, and social adjustment composites remained at year 2 and also extended to measures of symptomatology, particularly negative symptoms (Psychiatr. Serv. 2009;60:1468-76).

The University of Pittsburgh authors, of whom Dr. Keshavan was again the principal investigator, concluded "CET appears to be an effective approach to the remediation of cognitive deficits in early schizophrenia that may help reduce disability in this population. The remediation of such deficits should be an integral component of early intervention programs treating psychiatrically stable schizophrenia outpatients."

Another study, currently in press, showed that gray matter density increased with CET compared to enriched supportive therapy at 1 year, Dr. Keshavan said.

"The summary is that there are many promising hypotheses and more research is needed to develop proof of concept," he concluded.

Dr. Keshavan disclosed that he receives grant/research support from GlaxoSmithKline.

PITTSBURGH – Emerging evidence is leading to optimism that early interventions could prevent the onset of schizophrenia or reduce its impact on cognitive function.

Among psychiatric disorders, schizophrenia tends to manifest later in life than most, typically not until late adolescence or early adulthood. Yet, evidence suggests that brain changes actually occur much earlier in life among those destined to develop the disease, said Dr. Matcheri S. Keshavan, the Stanley Cobb Professor of Psychiatry at Harvard Medical School and vice-chair of public psychiatry at Beth Israel Deaconess Medical Center and the Massachusetts Mental Health Center, all in Boston.

Indeed, schizophrenia is increasingly being viewed as a neurodevelopmental disorder with psychosis as a late and potentially preventable stage of the illness (Nature 2010;468:187-93). Research is now investigating whether it is possible to detect these early signs and intervene before the onset of psychosis to minimize the impact of the disease, said Dr. Keshavan, who is also professor of psychiatry at the University of Pittsburgh.

The emergence of cognitive control and emotion regulation during adolescence are related to expansion of connectivity and fine-tuning of both excitatory and inhibitory neurotransmitter systems. At the same time, abstract thinking and executive function arise from increased efficiency at the expense of brain plasticity, or the ability of the brain to rewire itself in response to change. These processes might go haywire in those at risk for schizophrenia, and a combination of genetic and environmental factors could lead to a failure of inhibitory processes resulting in psychosis, he explained.

"Psychosis begins in adolescence, but schizophrenia really begins in childhood or even earlier. ... The risk-plasticity model of development of schizophrenia suggests several windows of opportunity for primary, secondary, and tertiary prevention," he said.

Several signs mark the early stages of disease. In one recent meta-analysis of 18 studies, individuals with schizophrenia demonstrated mean IQ scores of approximately half a standard deviation below those of healthy comparison subjects, years before the onset of psychotic symptoms (Am. J. Psychiatry 2008;165:579-87).

Certain biomarkers might help to identify those at risk. In a study from Dr. Keshavan’s work in Pittsburgh, at-risk relatives of schizophrenia patients who themselves had schizotypy performed less well on the Wisconsin Card Sort task, which assesses executive function, and showed age-related deficits on the oculomotor delayed response task, compared with non-schizotypal relatives and healthy controls (Prog. Neuropsychopharmacol. Biol. Psychiatry 2006;30:230-8).

Two follow-up studies showed gray matter losses evolving during the premorbid phase among high-risk relatives, compared with control relatives, in areas mediating social cognition and overlapping with cognitive deficits (Neuroimage 2011;54S1:S272-9 and Neuroimage 2011;54S1:S287-92).

Other data from Dr. Keshavan’s group at the University of Pittsburgh indirectly suggest that neurons do not appear to be lost in schizophrenia, but that a reduction in synaptic connectivity occurs leading to reduced brain plasticity (Schizophr. Res. 2010;119:47-51). Such a process might be reversible, he noted.

A variety of environmental factors have been implicated in triggering schizophrenia among individuals who already are genetically predisposed. These include obstetric complications (Ann. NY Acad. Sci. 2003;1008:269-75), exposure to the herpes simplex virus (Mol. Psychiatry 2007;12:105-13), and cannabis use (Schizophr. Res. 2008;99:1-6).

In a longitudinal study of 291 prodromal individuals who sought treatment, the risk of conversion to psychosis was 35% over 2.5 years. Five baseline features independently predicted conversion risk: A genetic risk for schizophrenia with recent deterioration in functioning, higher levels of unusual thought content, higher levels of suspicion/paranoia, greater social impairment, and a history of substance abuse. Algorithms combining two or three of these variables resulted in positive predictive power of 68%-80%, significantly greater than using prodromal criteria alone (Arch. Gen. Psychiatry 2008;65:28-37).

For individuals identified as being at high risk for progression to psychosis, studies are suggesting that use of a variety of pharmacologic and nonpharmacologic preventive interventions during the prodrome might be of benefit.

In a small randomized trial, 31 outpatients with prodromal symptoms of schizophrenia received 5-15 mg/day of olanzapine and 29 took placebo during a 1-year double-blind treatment period. No treatment was given in the subsequent year of follow-up. Although the difference in the rate of conversion during the treatment year was statistically insignificant, it was more than double in the placebo group – 38% vs. 16% with olanzapine (Am. J. Psychiatry 2006;163:790-9).

However, the olanzapine patients did gain significantly more weight (8.8 vs. 0.30kg), Dr. Keshavan noted.

Cognitive therapy (CT) is another potential approach. A randomized controlled trial compared CT over 6 months with monthly monitoring in 58 patients who met criteria for ultrahigh risk of developing a first episode of psychosis. Those receiving CT were less likely to be prescribed an antipsychotic medication over the subsequent 3 years. While CT did not affect transition to psychosis using two different measures, it did significantly reduce the likelihood of progression to psychosis after controlling for baseline cognitive factors (Schizophr. Bull. 2007;33:682-7).

Omega-3 fatty acids also have been investigated, based on evidence that their levels might be deficient in schizophrenia patients, leading to alterations in neurotransmission among other processes.

In a randomized, double-blind placebo-controlled trial, 81 adolescents and young adults with subthreshold psychosis received 1.2 g/d of omega-3 polyunsaturated fatty acids (PUFAs) for 12 weeks, followed by a 40-week monitoring period. At 12 months, 2 of 41 in the omega-3 group (4.9%) and 11 of 40 (27.5%) in the placebo group had transitioned to psychotic disorder, a significant difference (Arch. Gen. Psychiatry 2010;67:146-54).

The omega-3s also significantly reduced positive symptoms, negative symptoms, general symptoms, and improved functioning, compared with placebo, with no difference in the incidence of adverse effects between the treatment groups. "This finding suggests that the omega-3s prevented the transition to psychosis. If this is the case, it would be significant for young people at high risk of developing schizophrenia or other psychotic disorders," Dr. Keshavan said.

Antiviral agents also might have prevention potential. In an unpublished study by Dr. Konasale M. Prasad in Dr. Keshavan’s Pittsburgh group, valacyclovir in patients with schizophrenia produced a trend toward improvement in working memory.

And finally, evidence suggests that an integrated neurocognitive and social-cognitive rehabilitation program using cognitive enhancement therapy (CET) can positively affect cognitive and functional outcomes. A total of 58 early-course outpatients with schizophrenia or schizoaffective disorder were randomly assigned to CET or enriched supportive therapy, an illness management intervention using psychoeducation and applied coping strategies. After 2 years, CET moderately enhanced neurocognitive function. Strong differential effects on social cognition, cognitive style, and social adjustment composites remained at year 2 and also extended to measures of symptomatology, particularly negative symptoms (Psychiatr. Serv. 2009;60:1468-76).

The University of Pittsburgh authors, of whom Dr. Keshavan was again the principal investigator, concluded "CET appears to be an effective approach to the remediation of cognitive deficits in early schizophrenia that may help reduce disability in this population. The remediation of such deficits should be an integral component of early intervention programs treating psychiatrically stable schizophrenia outpatients."

Another study, currently in press, showed that gray matter density increased with CET compared to enriched supportive therapy at 1 year, Dr. Keshavan said.

"The summary is that there are many promising hypotheses and more research is needed to develop proof of concept," he concluded.

Dr. Keshavan disclosed that he receives grant/research support from GlaxoSmithKline.

PITTSBURGH – Emerging evidence is leading to optimism that early interventions could prevent the onset of schizophrenia or reduce its impact on cognitive function.

Among psychiatric disorders, schizophrenia tends to manifest later in life than most, typically not until late adolescence or early adulthood. Yet, evidence suggests that brain changes actually occur much earlier in life among those destined to develop the disease, said Dr. Matcheri S. Keshavan, the Stanley Cobb Professor of Psychiatry at Harvard Medical School and vice-chair of public psychiatry at Beth Israel Deaconess Medical Center and the Massachusetts Mental Health Center, all in Boston.

Indeed, schizophrenia is increasingly being viewed as a neurodevelopmental disorder with psychosis as a late and potentially preventable stage of the illness (Nature 2010;468:187-93). Research is now investigating whether it is possible to detect these early signs and intervene before the onset of psychosis to minimize the impact of the disease, said Dr. Keshavan, who is also professor of psychiatry at the University of Pittsburgh.

The emergence of cognitive control and emotion regulation during adolescence are related to expansion of connectivity and fine-tuning of both excitatory and inhibitory neurotransmitter systems. At the same time, abstract thinking and executive function arise from increased efficiency at the expense of brain plasticity, or the ability of the brain to rewire itself in response to change. These processes might go haywire in those at risk for schizophrenia, and a combination of genetic and environmental factors could lead to a failure of inhibitory processes resulting in psychosis, he explained.

"Psychosis begins in adolescence, but schizophrenia really begins in childhood or even earlier. ... The risk-plasticity model of development of schizophrenia suggests several windows of opportunity for primary, secondary, and tertiary prevention," he said.

Several signs mark the early stages of disease. In one recent meta-analysis of 18 studies, individuals with schizophrenia demonstrated mean IQ scores of approximately half a standard deviation below those of healthy comparison subjects, years before the onset of psychotic symptoms (Am. J. Psychiatry 2008;165:579-87).

Certain biomarkers might help to identify those at risk. In a study from Dr. Keshavan’s work in Pittsburgh, at-risk relatives of schizophrenia patients who themselves had schizotypy performed less well on the Wisconsin Card Sort task, which assesses executive function, and showed age-related deficits on the oculomotor delayed response task, compared with non-schizotypal relatives and healthy controls (Prog. Neuropsychopharmacol. Biol. Psychiatry 2006;30:230-8).

Two follow-up studies showed gray matter losses evolving during the premorbid phase among high-risk relatives, compared with control relatives, in areas mediating social cognition and overlapping with cognitive deficits (Neuroimage 2011;54S1:S272-9 and Neuroimage 2011;54S1:S287-92).

Other data from Dr. Keshavan’s group at the University of Pittsburgh indirectly suggest that neurons do not appear to be lost in schizophrenia, but that a reduction in synaptic connectivity occurs leading to reduced brain plasticity (Schizophr. Res. 2010;119:47-51). Such a process might be reversible, he noted.

A variety of environmental factors have been implicated in triggering schizophrenia among individuals who already are genetically predisposed. These include obstetric complications (Ann. NY Acad. Sci. 2003;1008:269-75), exposure to the herpes simplex virus (Mol. Psychiatry 2007;12:105-13), and cannabis use (Schizophr. Res. 2008;99:1-6).

In a longitudinal study of 291 prodromal individuals who sought treatment, the risk of conversion to psychosis was 35% over 2.5 years. Five baseline features independently predicted conversion risk: A genetic risk for schizophrenia with recent deterioration in functioning, higher levels of unusual thought content, higher levels of suspicion/paranoia, greater social impairment, and a history of substance abuse. Algorithms combining two or three of these variables resulted in positive predictive power of 68%-80%, significantly greater than using prodromal criteria alone (Arch. Gen. Psychiatry 2008;65:28-37).

For individuals identified as being at high risk for progression to psychosis, studies are suggesting that use of a variety of pharmacologic and nonpharmacologic preventive interventions during the prodrome might be of benefit.

In a small randomized trial, 31 outpatients with prodromal symptoms of schizophrenia received 5-15 mg/day of olanzapine and 29 took placebo during a 1-year double-blind treatment period. No treatment was given in the subsequent year of follow-up. Although the difference in the rate of conversion during the treatment year was statistically insignificant, it was more than double in the placebo group – 38% vs. 16% with olanzapine (Am. J. Psychiatry 2006;163:790-9).

However, the olanzapine patients did gain significantly more weight (8.8 vs. 0.30kg), Dr. Keshavan noted.

Cognitive therapy (CT) is another potential approach. A randomized controlled trial compared CT over 6 months with monthly monitoring in 58 patients who met criteria for ultrahigh risk of developing a first episode of psychosis. Those receiving CT were less likely to be prescribed an antipsychotic medication over the subsequent 3 years. While CT did not affect transition to psychosis using two different measures, it did significantly reduce the likelihood of progression to psychosis after controlling for baseline cognitive factors (Schizophr. Bull. 2007;33:682-7).

Omega-3 fatty acids also have been investigated, based on evidence that their levels might be deficient in schizophrenia patients, leading to alterations in neurotransmission among other processes.

In a randomized, double-blind placebo-controlled trial, 81 adolescents and young adults with subthreshold psychosis received 1.2 g/d of omega-3 polyunsaturated fatty acids (PUFAs) for 12 weeks, followed by a 40-week monitoring period. At 12 months, 2 of 41 in the omega-3 group (4.9%) and 11 of 40 (27.5%) in the placebo group had transitioned to psychotic disorder, a significant difference (Arch. Gen. Psychiatry 2010;67:146-54).

The omega-3s also significantly reduced positive symptoms, negative symptoms, general symptoms, and improved functioning, compared with placebo, with no difference in the incidence of adverse effects between the treatment groups. "This finding suggests that the omega-3s prevented the transition to psychosis. If this is the case, it would be significant for young people at high risk of developing schizophrenia or other psychotic disorders," Dr. Keshavan said.

Antiviral agents also might have prevention potential. In an unpublished study by Dr. Konasale M. Prasad in Dr. Keshavan’s Pittsburgh group, valacyclovir in patients with schizophrenia produced a trend toward improvement in working memory.

And finally, evidence suggests that an integrated neurocognitive and social-cognitive rehabilitation program using cognitive enhancement therapy (CET) can positively affect cognitive and functional outcomes. A total of 58 early-course outpatients with schizophrenia or schizoaffective disorder were randomly assigned to CET or enriched supportive therapy, an illness management intervention using psychoeducation and applied coping strategies. After 2 years, CET moderately enhanced neurocognitive function. Strong differential effects on social cognition, cognitive style, and social adjustment composites remained at year 2 and also extended to measures of symptomatology, particularly negative symptoms (Psychiatr. Serv. 2009;60:1468-76).

The University of Pittsburgh authors, of whom Dr. Keshavan was again the principal investigator, concluded "CET appears to be an effective approach to the remediation of cognitive deficits in early schizophrenia that may help reduce disability in this population. The remediation of such deficits should be an integral component of early intervention programs treating psychiatrically stable schizophrenia outpatients."

Another study, currently in press, showed that gray matter density increased with CET compared to enriched supportive therapy at 1 year, Dr. Keshavan said.

"The summary is that there are many promising hypotheses and more research is needed to develop proof of concept," he concluded.

Dr. Keshavan disclosed that he receives grant/research support from GlaxoSmithKline.

The number of people in the United States with diabetes has now risen to nearly 26 million, while another 79 million have prediabetes, according to data released Jan. 26 by the Centers for Disease Control and Prevention.

Diabetes is present in 8.3% of all Americans and 11.3% of those aged 20 years and older, according to the CDC’s 2011 National Diabetes Fact Sheet. More than a third (35%) of those aged 20 and older have prediabetes. Over a quarter of Americans aged 65 years and older have diabetes, and half have prediabetes.

Among those with diabetes, about 27% (or 7 million people) are undiagnosed.

"Although consecutive fact sheets aren’t meant to determine trends, it’s discouraging that the proportion of people undiagnosed has remained at about one in four since the last fact sheet [was published in 2008]. This is after falling from one in two and then one in three over the decade prior to 2007," said Dr. Sue Kirkman, senior vice president of medical affairs and community information for the American Diabetes Association, in an interview.

"The take-home message is what ADA has been recommending all along: Health care professionals need to assess patients for risk factors and test those who are at risk, including those who are overweight; have a family history of diabetes or gestational diabetes, high-risk ethnicity, hypertension, [or] dyslipidemia; or are [older than age 45]," Dr. Kirkman said.

In 2008, the CDC estimated that 23.6 million Americans (or 7.8% of the population) had diabetes, and another 57 million adults had prediabetes. The rise in diabetes prevalence seen in the 2011 data results from both the fact that more people are developing the disease and the fact that people are living longer with it, thanks to better management of cardiovascular risk factors and a reduction in complications such as renal failure and amputations. These new estimates of national prevalence are the first to include cases diagnosed using hemoglobin A1c, which means that the estimates of prediabetes and diabetes may not be directly comparable to previous estimates, the agency noted.

Dr. Kirkman said she believes that the impact of this change is greater for prediabetes than for diabetes. "The incorporation of A1C into the diagnosis of diabetes didn’t make a significant difference in the prevalence of diabetes, so the 25.8 million estimate reflects a true increase in prevalence. In contrast, adding the A1C does increase the number estimated to have prediabetes a lot, although there is also an underlying true increase in prevalence there as well," she noted.

She advised that people with prediabetes be referred to programs that can support them in losing weight and exercising. "With the roll-out of the National Diabetes Prevention programs in the community, such as through YMCAs, the hope is that in the next few years there will be more and more programs to refer people to."

Dr. Kirkman stated that she has no financial disclosures.

The number of people in the United States with diabetes has now risen to nearly 26 million, while another 79 million have prediabetes, according to data released Jan. 26 by the Centers for Disease Control and Prevention.

Diabetes is present in 8.3% of all Americans and 11.3% of those aged 20 years and older, according to the CDC’s 2011 National Diabetes Fact Sheet. More than a third (35%) of those aged 20 and older have prediabetes. Over a quarter of Americans aged 65 years and older have diabetes, and half have prediabetes.

Among those with diabetes, about 27% (or 7 million people) are undiagnosed.

"Although consecutive fact sheets aren’t meant to determine trends, it’s discouraging that the proportion of people undiagnosed has remained at about one in four since the last fact sheet [was published in 2008]. This is after falling from one in two and then one in three over the decade prior to 2007," said Dr. Sue Kirkman, senior vice president of medical affairs and community information for the American Diabetes Association, in an interview.

"The take-home message is what ADA has been recommending all along: Health care professionals need to assess patients for risk factors and test those who are at risk, including those who are overweight; have a family history of diabetes or gestational diabetes, high-risk ethnicity, hypertension, [or] dyslipidemia; or are [older than age 45]," Dr. Kirkman said.

In 2008, the CDC estimated that 23.6 million Americans (or 7.8% of the population) had diabetes, and another 57 million adults had prediabetes. The rise in diabetes prevalence seen in the 2011 data results from both the fact that more people are developing the disease and the fact that people are living longer with it, thanks to better management of cardiovascular risk factors and a reduction in complications such as renal failure and amputations. These new estimates of national prevalence are the first to include cases diagnosed using hemoglobin A1c, which means that the estimates of prediabetes and diabetes may not be directly comparable to previous estimates, the agency noted.

Dr. Kirkman said she believes that the impact of this change is greater for prediabetes than for diabetes. "The incorporation of A1C into the diagnosis of diabetes didn’t make a significant difference in the prevalence of diabetes, so the 25.8 million estimate reflects a true increase in prevalence. In contrast, adding the A1C does increase the number estimated to have prediabetes a lot, although there is also an underlying true increase in prevalence there as well," she noted.

She advised that people with prediabetes be referred to programs that can support them in losing weight and exercising. "With the roll-out of the National Diabetes Prevention programs in the community, such as through YMCAs, the hope is that in the next few years there will be more and more programs to refer people to."

Dr. Kirkman stated that she has no financial disclosures.

The number of people in the United States with diabetes has now risen to nearly 26 million, while another 79 million have prediabetes, according to data released Jan. 26 by the Centers for Disease Control and Prevention.

Diabetes is present in 8.3% of all Americans and 11.3% of those aged 20 years and older, according to the CDC’s 2011 National Diabetes Fact Sheet. More than a third (35%) of those aged 20 and older have prediabetes. Over a quarter of Americans aged 65 years and older have diabetes, and half have prediabetes.

Among those with diabetes, about 27% (or 7 million people) are undiagnosed.

"Although consecutive fact sheets aren’t meant to determine trends, it’s discouraging that the proportion of people undiagnosed has remained at about one in four since the last fact sheet [was published in 2008]. This is after falling from one in two and then one in three over the decade prior to 2007," said Dr. Sue Kirkman, senior vice president of medical affairs and community information for the American Diabetes Association, in an interview.

"The take-home message is what ADA has been recommending all along: Health care professionals need to assess patients for risk factors and test those who are at risk, including those who are overweight; have a family history of diabetes or gestational diabetes, high-risk ethnicity, hypertension, [or] dyslipidemia; or are [older than age 45]," Dr. Kirkman said.

In 2008, the CDC estimated that 23.6 million Americans (or 7.8% of the population) had diabetes, and another 57 million adults had prediabetes. The rise in diabetes prevalence seen in the 2011 data results from both the fact that more people are developing the disease and the fact that people are living longer with it, thanks to better management of cardiovascular risk factors and a reduction in complications such as renal failure and amputations. These new estimates of national prevalence are the first to include cases diagnosed using hemoglobin A1c, which means that the estimates of prediabetes and diabetes may not be directly comparable to previous estimates, the agency noted.

Dr. Kirkman said she believes that the impact of this change is greater for prediabetes than for diabetes. "The incorporation of A1C into the diagnosis of diabetes didn’t make a significant difference in the prevalence of diabetes, so the 25.8 million estimate reflects a true increase in prevalence. In contrast, adding the A1C does increase the number estimated to have prediabetes a lot, although there is also an underlying true increase in prevalence there as well," she noted.

She advised that people with prediabetes be referred to programs that can support them in losing weight and exercising. "With the roll-out of the National Diabetes Prevention programs in the community, such as through YMCAs, the hope is that in the next few years there will be more and more programs to refer people to."

Dr. Kirkman stated that she has no financial disclosures.

BETHESDA, MD. – When it comes to managing chronic pain, Dr. Daniel J. Clauw said physicians have been looking in the wrong places.

"There is no chronic pain state where degree of damage or inflammation in the periphery correlates well with level of pain. Yet, the diagnostic algorithms or paradigms that everyone uses for treating chronic pain still assume that all pain is nociceptive. What we see in the peripheral tissues is not necessarily what our patients are experiencing," said Dr. Clauw, director of the chronic pain and fatigue research center at the University of Michigan, Ann Arbor.

Historically, it has been assumed that when there was a disparity between peripheral findings and pain, psychological factors were at work. But the current view of chronic pain is that while it may originate from peripheral nociceptive input or nerve damage, central neuronal factors – at least some of them genetically determined – are nearly always playing a role in leading to interindividual differences in pain sensitivity, which are in turn closely associated with clinical outcomes.

For instance, population-based studies have shown that 30%-40% of individuals with radiographic evidence of severe damage from osteoarthritis are pain free, while 10% of those with normal radiographs have severe pain (Br. J. Rheumatol. 1997;36:726-8). Psychological factors explain very little of the variance between symptoms and structure (Arthritis Care Res. 1998;11:60-5), suggesting that central mechanisms involved in pain processing are at work, Dr. Clauw said at the workshop, sponsored by the University of Michigan and the National Institutes of Health.

Of course, individuals with osteoarthritis and rheumatoid arthritis will often have evidence of nociceptive input, while those with fibromyalgia have more prominent central factors. But no chronic pain state is solely due to any one of these mechanisms, he said.

"The scientific paradigm shift requires that we rethink everything from diagnostics and treatment approaches – which currently place an unjustified importance on treating peripheral factors," he said.

The new paradigm suggests that, regardless of the specific diagnosis, "central pain states" including fibromyalgia, rheumatoid arthritis, osteoarthritis, lupus, and low back pain all tend to share certain characteristics that can be better assessed by asking questions than by physical examination.

Showing patients a body diagram and asking them to label all the areas where they have pain is a simple assessment tool for multifocal pain. Also, ask about previous pain and other somatic symptoms such as fatigue, memory difficulty, mood disorders, and sleep disturbances, all common in the context of central pain but not with pain that is solely peripheral.

Is the pain triggered or exacerbated by stressors, such as psychological stress, infections, or physical trauma? Was there a salient stressor in the patient’s early life, such as an auto accident or the death of a loved one? All are common among patients with central pain, said Dr. Clauw, professor of anesthesiology and medicine (rheumatology) at the university.

Because these patients tend to have global sensory processing problems, asking about hypersensitivity to bright lights, odors, or noises will also help confirm the "central" diagnosis. Take a family history of pain as well, as there are strong familial and genetic linkages among the chronic pain syndromes, at least among women (Psychol. Med. 2009;39:497-505).

Physical examination is likely to be normal except for diffuse tenderness and nonspecific neurologic signs (Arthritis Rheum. 2009;60:2839-44). "This is why, historically, patients with fibromyalgia haven’t been believed," Dr. Clauw commented.

As for treatment, it is becoming increasingly clear that peripherally-acting pharmacologic agents such as opioids, corticosteroids, and nonsteroidal anti-inflammatory drugs simply do not work in central pain states.

Far more effective for fibromyalgia – and most likely other central pain states as well – are dual reuptake inhibitors such as tricyclic compounds (amitriptyline, cyclobenzaprine), serotonin-norepinephrine reuptake inhibitors (milnacipran, duloxetine), gamma hydroxybutyrate, and gabapentin. There is also modest evidence supporting the use of tramadol, selective serotonin reuptake inhibitors, and dopamine agonists (JAMA 2004;292:2388-95).

Nonpharmacologic therapies are also beneficial, including cognitive-behavioral therapy, exercise, and sleep hygiene (Best Pract. Res. Clin. Rheumatol. 2003;17:685-701).

Despite an abundance of emerging data to support the new way of thinking about chronic pain, Dr. Clauw said he thinks that shifting to a new management strategy could be difficult. "It takes a long time for people trained in one way of thinking to think differently. This isn’t just a new drug or a new device. This is a major paradigm shift."

Dr. Clauw disclosed that he is a consultant for Pfizer, Forest, Eli Lilly, Pierre Fabre Laboratories, Cypress Biosciences, Wyeth, UCB, AstraZeneca, Merck, Johnson & Johnson, Nuvo, and Jazz. He said he has also received research support from Pfizer, Cypress, and Forest.

BETHESDA, MD. – When it comes to managing chronic pain, Dr. Daniel J. Clauw said physicians have been looking in the wrong places.

"There is no chronic pain state where degree of damage or inflammation in the periphery correlates well with level of pain. Yet, the diagnostic algorithms or paradigms that everyone uses for treating chronic pain still assume that all pain is nociceptive. What we see in the peripheral tissues is not necessarily what our patients are experiencing," said Dr. Clauw, director of the chronic pain and fatigue research center at the University of Michigan, Ann Arbor.

Historically, it has been assumed that when there was a disparity between peripheral findings and pain, psychological factors were at work. But the current view of chronic pain is that while it may originate from peripheral nociceptive input or nerve damage, central neuronal factors – at least some of them genetically determined – are nearly always playing a role in leading to interindividual differences in pain sensitivity, which are in turn closely associated with clinical outcomes.

For instance, population-based studies have shown that 30%-40% of individuals with radiographic evidence of severe damage from osteoarthritis are pain free, while 10% of those with normal radiographs have severe pain (Br. J. Rheumatol. 1997;36:726-8). Psychological factors explain very little of the variance between symptoms and structure (Arthritis Care Res. 1998;11:60-5), suggesting that central mechanisms involved in pain processing are at work, Dr. Clauw said at the workshop, sponsored by the University of Michigan and the National Institutes of Health.

Of course, individuals with osteoarthritis and rheumatoid arthritis will often have evidence of nociceptive input, while those with fibromyalgia have more prominent central factors. But no chronic pain state is solely due to any one of these mechanisms, he said.

"The scientific paradigm shift requires that we rethink everything from diagnostics and treatment approaches – which currently place an unjustified importance on treating peripheral factors," he said.

The new paradigm suggests that, regardless of the specific diagnosis, "central pain states" including fibromyalgia, rheumatoid arthritis, osteoarthritis, lupus, and low back pain all tend to share certain characteristics that can be better assessed by asking questions than by physical examination.

Showing patients a body diagram and asking them to label all the areas where they have pain is a simple assessment tool for multifocal pain. Also, ask about previous pain and other somatic symptoms such as fatigue, memory difficulty, mood disorders, and sleep disturbances, all common in the context of central pain but not with pain that is solely peripheral.

Is the pain triggered or exacerbated by stressors, such as psychological stress, infections, or physical trauma? Was there a salient stressor in the patient’s early life, such as an auto accident or the death of a loved one? All are common among patients with central pain, said Dr. Clauw, professor of anesthesiology and medicine (rheumatology) at the university.

Because these patients tend to have global sensory processing problems, asking about hypersensitivity to bright lights, odors, or noises will also help confirm the "central" diagnosis. Take a family history of pain as well, as there are strong familial and genetic linkages among the chronic pain syndromes, at least among women (Psychol. Med. 2009;39:497-505).

Physical examination is likely to be normal except for diffuse tenderness and nonspecific neurologic signs (Arthritis Rheum. 2009;60:2839-44). "This is why, historically, patients with fibromyalgia haven’t been believed," Dr. Clauw commented.

As for treatment, it is becoming increasingly clear that peripherally-acting pharmacologic agents such as opioids, corticosteroids, and nonsteroidal anti-inflammatory drugs simply do not work in central pain states.

Far more effective for fibromyalgia – and most likely other central pain states as well – are dual reuptake inhibitors such as tricyclic compounds (amitriptyline, cyclobenzaprine), serotonin-norepinephrine reuptake inhibitors (milnacipran, duloxetine), gamma hydroxybutyrate, and gabapentin. There is also modest evidence supporting the use of tramadol, selective serotonin reuptake inhibitors, and dopamine agonists (JAMA 2004;292:2388-95).

Nonpharmacologic therapies are also beneficial, including cognitive-behavioral therapy, exercise, and sleep hygiene (Best Pract. Res. Clin. Rheumatol. 2003;17:685-701).

Despite an abundance of emerging data to support the new way of thinking about chronic pain, Dr. Clauw said he thinks that shifting to a new management strategy could be difficult. "It takes a long time for people trained in one way of thinking to think differently. This isn’t just a new drug or a new device. This is a major paradigm shift."

Dr. Clauw disclosed that he is a consultant for Pfizer, Forest, Eli Lilly, Pierre Fabre Laboratories, Cypress Biosciences, Wyeth, UCB, AstraZeneca, Merck, Johnson & Johnson, Nuvo, and Jazz. He said he has also received research support from Pfizer, Cypress, and Forest.

BETHESDA, MD. – When it comes to managing chronic pain, Dr. Daniel J. Clauw said physicians have been looking in the wrong places.

"There is no chronic pain state where degree of damage or inflammation in the periphery correlates well with level of pain. Yet, the diagnostic algorithms or paradigms that everyone uses for treating chronic pain still assume that all pain is nociceptive. What we see in the peripheral tissues is not necessarily what our patients are experiencing," said Dr. Clauw, director of the chronic pain and fatigue research center at the University of Michigan, Ann Arbor.

Historically, it has been assumed that when there was a disparity between peripheral findings and pain, psychological factors were at work. But the current view of chronic pain is that while it may originate from peripheral nociceptive input or nerve damage, central neuronal factors – at least some of them genetically determined – are nearly always playing a role in leading to interindividual differences in pain sensitivity, which are in turn closely associated with clinical outcomes.

For instance, population-based studies have shown that 30%-40% of individuals with radiographic evidence of severe damage from osteoarthritis are pain free, while 10% of those with normal radiographs have severe pain (Br. J. Rheumatol. 1997;36:726-8). Psychological factors explain very little of the variance between symptoms and structure (Arthritis Care Res. 1998;11:60-5), suggesting that central mechanisms involved in pain processing are at work, Dr. Clauw said at the workshop, sponsored by the University of Michigan and the National Institutes of Health.

Of course, individuals with osteoarthritis and rheumatoid arthritis will often have evidence of nociceptive input, while those with fibromyalgia have more prominent central factors. But no chronic pain state is solely due to any one of these mechanisms, he said.

"The scientific paradigm shift requires that we rethink everything from diagnostics and treatment approaches – which currently place an unjustified importance on treating peripheral factors," he said.

The new paradigm suggests that, regardless of the specific diagnosis, "central pain states" including fibromyalgia, rheumatoid arthritis, osteoarthritis, lupus, and low back pain all tend to share certain characteristics that can be better assessed by asking questions than by physical examination.

Showing patients a body diagram and asking them to label all the areas where they have pain is a simple assessment tool for multifocal pain. Also, ask about previous pain and other somatic symptoms such as fatigue, memory difficulty, mood disorders, and sleep disturbances, all common in the context of central pain but not with pain that is solely peripheral.

Is the pain triggered or exacerbated by stressors, such as psychological stress, infections, or physical trauma? Was there a salient stressor in the patient’s early life, such as an auto accident or the death of a loved one? All are common among patients with central pain, said Dr. Clauw, professor of anesthesiology and medicine (rheumatology) at the university.

Because these patients tend to have global sensory processing problems, asking about hypersensitivity to bright lights, odors, or noises will also help confirm the "central" diagnosis. Take a family history of pain as well, as there are strong familial and genetic linkages among the chronic pain syndromes, at least among women (Psychol. Med. 2009;39:497-505).

Physical examination is likely to be normal except for diffuse tenderness and nonspecific neurologic signs (Arthritis Rheum. 2009;60:2839-44). "This is why, historically, patients with fibromyalgia haven’t been believed," Dr. Clauw commented.

As for treatment, it is becoming increasingly clear that peripherally-acting pharmacologic agents such as opioids, corticosteroids, and nonsteroidal anti-inflammatory drugs simply do not work in central pain states.

Far more effective for fibromyalgia – and most likely other central pain states as well – are dual reuptake inhibitors such as tricyclic compounds (amitriptyline, cyclobenzaprine), serotonin-norepinephrine reuptake inhibitors (milnacipran, duloxetine), gamma hydroxybutyrate, and gabapentin. There is also modest evidence supporting the use of tramadol, selective serotonin reuptake inhibitors, and dopamine agonists (JAMA 2004;292:2388-95).

Nonpharmacologic therapies are also beneficial, including cognitive-behavioral therapy, exercise, and sleep hygiene (Best Pract. Res. Clin. Rheumatol. 2003;17:685-701).

Despite an abundance of emerging data to support the new way of thinking about chronic pain, Dr. Clauw said he thinks that shifting to a new management strategy could be difficult. "It takes a long time for people trained in one way of thinking to think differently. This isn’t just a new drug or a new device. This is a major paradigm shift."

Dr. Clauw disclosed that he is a consultant for Pfizer, Forest, Eli Lilly, Pierre Fabre Laboratories, Cypress Biosciences, Wyeth, UCB, AstraZeneca, Merck, Johnson & Johnson, Nuvo, and Jazz. He said he has also received research support from Pfizer, Cypress, and Forest.

BETHESDA, MD.  – Gene therapy is showing promise in early trials as a novel targeted approach to alleviating chronic pain while avoiding the off-target side effects common to most oral analgesics.

The genetic therapy approach is potentially appropriate for patients with focal musculoskeletal pain. "We are only just now starting the phase II trial, but in principle the approach could be applied to intractable joint pain in a patient in whom joint replacement is not an option," Dr. David J. Fink said in an interview.

However, gene therapy would not be applicable to a problem of diffuse multifocal pain such as that seen in fibromyalgia, he added.

Clinical research, funded by Diamyd Inc., is now entering phase II human trials, said Dr. Fink, the Robert Brear Professor and chair of the department of neurology at the University of Michigan, Ann Arbor.

The use of most standard oral analgesics to treat long-term chronic pain is severely limited because of their effects on neural pathways unrelated to the pain or on organs outside the nervous system, leading to side effects such as lethargy, confusion, and respiratory suppression. And, in the case of opiates, there is the added potential for addiction and abuse.

To overcome this problem, Dr. Fink and his associates have constructed a series of nonreplicating herpes simplex virus (HSV)–based vectors that target gene delivery to the dorsal root ganglion via skin inoculation. HSV was chosen as a vector because it is a naturally neurotropic virus, he said.

In preclinical research supported by the National Institutes of Health and the Department of Veterans Affairs, Dr. Fink and his colleagues demonstrated that an HSV vector that produces the opioid peptide enkephalin reduces pain-related behavior in animal models of inflammatory pain, neuropathic pain, and pain caused by cancer (Pain Medicine 2009;10:1325-30).

A phase I human trial of a human-grade nonreplicating HSV vector expressing preproenkephalin has now been completed. Safety was the primary outcome, with secondary outcomes including evaluation of pain and performance status using the numeric rating scale (NRS) for evaluation of pain, along with other measures of pain and general health and function and concurrent analgesic drug utilization.

No serious vector-related adverse events were observed in the study, which enrolled 10 patients who had intractable localized cancer pain rated greater than 4 of 10 on a visual analog scale, despite taking at least 200 mg/day of oral morphine or the equivalent. Three patients received a dose of 107 plaque-forming units (pfu) of vector, another three received 108 pfu, and four were given 109.

No effect was seen with the lowest dose, but patients in the two higher-dose groups reported subjective improvements in pain, averaging an 80% reduction in the NRS score at 7 and 14 days after the injection. The average NRS score fell from 7.5 at baseline to below 2, Dr. Fink reported at the meeting sponsored by the University of Michigan.

While this study did not have placebo controls, the dose-response result prompted Diamyd to move to a phase I/II clinical trial that will include a placebo group. For this, they are currently constructing a human-grade glutamic acid decarboxylase–expressing vector that will release gamma-aminobutyric acid into the dorsal horn.

This trial will enroll 60 patients with painful diabetic neuropathy of at least 6 months’ duration, rated consistently at 4 or above on the 10-point pain scale. They will randomly be assigned to receive vector or placebo in a 2:1 ratio, injected into the distal lower extremity. Safety will be the primary outcome of the phase I trial, while the phase II primary outcome will be efficacy, as determined by electronic pain diary recording of 24-hour average pain intensity at 2, 4, and 6 weeks after vector inoculation.

Dr. Fink cautioned that the data are preliminary. "I’m very excited to see the preclinical data appear to be holding up in phase I, but we’ll see."

Dr. Fink disclosed that he is the inventor on patents that have been licensed by Diamyd, but said he has no direct financial relationship with the company.

BETHESDA, MD.  – Gene therapy is showing promise in early trials as a novel targeted approach to alleviating chronic pain while avoiding the off-target side effects common to most oral analgesics.

The genetic therapy approach is potentially appropriate for patients with focal musculoskeletal pain. "We are only just now starting the phase II trial, but in principle the approach could be applied to intractable joint pain in a patient in whom joint replacement is not an option," Dr. David J. Fink said in an interview.

However, gene therapy would not be applicable to a problem of diffuse multifocal pain such as that seen in fibromyalgia, he added.

Clinical research, funded by Diamyd Inc., is now entering phase II human trials, said Dr. Fink, the Robert Brear Professor and chair of the department of neurology at the University of Michigan, Ann Arbor.

The use of most standard oral analgesics to treat long-term chronic pain is severely limited because of their effects on neural pathways unrelated to the pain or on organs outside the nervous system, leading to side effects such as lethargy, confusion, and respiratory suppression. And, in the case of opiates, there is the added potential for addiction and abuse.

To overcome this problem, Dr. Fink and his associates have constructed a series of nonreplicating herpes simplex virus (HSV)–based vectors that target gene delivery to the dorsal root ganglion via skin inoculation. HSV was chosen as a vector because it is a naturally neurotropic virus, he said.

In preclinical research supported by the National Institutes of Health and the Department of Veterans Affairs, Dr. Fink and his colleagues demonstrated that an HSV vector that produces the opioid peptide enkephalin reduces pain-related behavior in animal models of inflammatory pain, neuropathic pain, and pain caused by cancer (Pain Medicine 2009;10:1325-30).

A phase I human trial of a human-grade nonreplicating HSV vector expressing preproenkephalin has now been completed. Safety was the primary outcome, with secondary outcomes including evaluation of pain and performance status using the numeric rating scale (NRS) for evaluation of pain, along with other measures of pain and general health and function and concurrent analgesic drug utilization.

No serious vector-related adverse events were observed in the study, which enrolled 10 patients who had intractable localized cancer pain rated greater than 4 of 10 on a visual analog scale, despite taking at least 200 mg/day of oral morphine or the equivalent. Three patients received a dose of 107 plaque-forming units (pfu) of vector, another three received 108 pfu, and four were given 109.

No effect was seen with the lowest dose, but patients in the two higher-dose groups reported subjective improvements in pain, averaging an 80% reduction in the NRS score at 7 and 14 days after the injection. The average NRS score fell from 7.5 at baseline to below 2, Dr. Fink reported at the meeting sponsored by the University of Michigan.

While this study did not have placebo controls, the dose-response result prompted Diamyd to move to a phase I/II clinical trial that will include a placebo group. For this, they are currently constructing a human-grade glutamic acid decarboxylase–expressing vector that will release gamma-aminobutyric acid into the dorsal horn.

This trial will enroll 60 patients with painful diabetic neuropathy of at least 6 months’ duration, rated consistently at 4 or above on the 10-point pain scale. They will randomly be assigned to receive vector or placebo in a 2:1 ratio, injected into the distal lower extremity. Safety will be the primary outcome of the phase I trial, while the phase II primary outcome will be efficacy, as determined by electronic pain diary recording of 24-hour average pain intensity at 2, 4, and 6 weeks after vector inoculation.

Dr. Fink cautioned that the data are preliminary. "I’m very excited to see the preclinical data appear to be holding up in phase I, but we’ll see."

Dr. Fink disclosed that he is the inventor on patents that have been licensed by Diamyd, but said he has no direct financial relationship with the company.

BETHESDA, MD.  – Gene therapy is showing promise in early trials as a novel targeted approach to alleviating chronic pain while avoiding the off-target side effects common to most oral analgesics.

The genetic therapy approach is potentially appropriate for patients with focal musculoskeletal pain. "We are only just now starting the phase II trial, but in principle the approach could be applied to intractable joint pain in a patient in whom joint replacement is not an option," Dr. David J. Fink said in an interview.

However, gene therapy would not be applicable to a problem of diffuse multifocal pain such as that seen in fibromyalgia, he added.

Clinical research, funded by Diamyd Inc., is now entering phase II human trials, said Dr. Fink, the Robert Brear Professor and chair of the department of neurology at the University of Michigan, Ann Arbor.

The use of most standard oral analgesics to treat long-term chronic pain is severely limited because of their effects on neural pathways unrelated to the pain or on organs outside the nervous system, leading to side effects such as lethargy, confusion, and respiratory suppression. And, in the case of opiates, there is the added potential for addiction and abuse.

To overcome this problem, Dr. Fink and his associates have constructed a series of nonreplicating herpes simplex virus (HSV)–based vectors that target gene delivery to the dorsal root ganglion via skin inoculation. HSV was chosen as a vector because it is a naturally neurotropic virus, he said.

In preclinical research supported by the National Institutes of Health and the Department of Veterans Affairs, Dr. Fink and his colleagues demonstrated that an HSV vector that produces the opioid peptide enkephalin reduces pain-related behavior in animal models of inflammatory pain, neuropathic pain, and pain caused by cancer (Pain Medicine 2009;10:1325-30).

A phase I human trial of a human-grade nonreplicating HSV vector expressing preproenkephalin has now been completed. Safety was the primary outcome, with secondary outcomes including evaluation of pain and performance status using the numeric rating scale (NRS) for evaluation of pain, along with other measures of pain and general health and function and concurrent analgesic drug utilization.

No serious vector-related adverse events were observed in the study, which enrolled 10 patients who had intractable localized cancer pain rated greater than 4 of 10 on a visual analog scale, despite taking at least 200 mg/day of oral morphine or the equivalent. Three patients received a dose of 107 plaque-forming units (pfu) of vector, another three received 108 pfu, and four were given 109.

No effect was seen with the lowest dose, but patients in the two higher-dose groups reported subjective improvements in pain, averaging an 80% reduction in the NRS score at 7 and 14 days after the injection. The average NRS score fell from 7.5 at baseline to below 2, Dr. Fink reported at the meeting sponsored by the University of Michigan.

While this study did not have placebo controls, the dose-response result prompted Diamyd to move to a phase I/II clinical trial that will include a placebo group. For this, they are currently constructing a human-grade glutamic acid decarboxylase–expressing vector that will release gamma-aminobutyric acid into the dorsal horn.

This trial will enroll 60 patients with painful diabetic neuropathy of at least 6 months’ duration, rated consistently at 4 or above on the 10-point pain scale. They will randomly be assigned to receive vector or placebo in a 2:1 ratio, injected into the distal lower extremity. Safety will be the primary outcome of the phase I trial, while the phase II primary outcome will be efficacy, as determined by electronic pain diary recording of 24-hour average pain intensity at 2, 4, and 6 weeks after vector inoculation.

Dr. Fink cautioned that the data are preliminary. "I’m very excited to see the preclinical data appear to be holding up in phase I, but we’ll see."

Dr. Fink disclosed that he is the inventor on patents that have been licensed by Diamyd, but said he has no direct financial relationship with the company.

BETHESDA, Md. – Evidence-based nonpharmacologic therapies may be at least as effective as medications in treating chronic pain, and the Internet could prove to be a valuable method for delivering these interventions.

Although pharmacologic agents alone are of only modest benefit and rarely lead to clinically meaningful functional improvement among patients with chronic pain, there is strong evidence for nonpharmacologic therapies such as cognitive-behavioral therapy in improving functional status and mood, as well as pain itself, Dr. David A. Williams, Ph.D., said at a conference on pain and musculoskeletal disorders, sponsored by the University of Michigan and the National Institutes of Health.

A meta-analysis of 25 papers found that active psychological treatments based on the principle of cognitive-behavioral therapy (CBT) produced significantly greater improvements in pain experience, cognitive coping, appraisal, and behavioral expressions of pain, compared with other active treatments, in patients with a variety of chronic pain problems, excluding headache (Pain 1999;80:1-13).

Another meta-analysis, this one including 22 studies of adults with noncancerous chronic low back pain, found that psychological interventions – particularly CBT and self-regulatory treatments – significantly reduced pain intensity, pain-related interference, and depression while significantly improving health-related quality of life. Multidisciplinary approaches that included psychological interventions also had positive effects (Health Psychology 2007;26:1-9).

And two more meta-analyses – one of 49 studies, the other of 23 – have demonstrated an equal or greater effect for nonpharmacologic therapies compared with pharmacologic treatment for fibromyalgia (Ann. Behav. Med.1999;21:180-91; Pain 2010;151:280-95).

"There is a 30-year history of nonpharmacologic interventions that have rival effect sizes to some pharmacologic approaches and even surpass some. The problem is, [nonpharmacologic interventions are] rarely used in clinical practice," said Dr. Williams, professor of anesthesiology, medicine (rheumatology), psychiatry, and psychology and associate director of the chronic pain and fatigue research center at the University of Michigan, Ann Arbor.

The use of nonpharmacologic treatment has been limited for a variety of reasons. Medical schools don’t spend much time teaching it, insurance companies often don’t adequately cover it, patients often can’t access it, it lacks the million dollar marketing campaigns that pharmaceutical companies devote to their drugs, and it carries a stigma, he noted.

Delivering such evidence-based interventions via the Internet potentially sidesteps several of the barriers that prevent their wider use, including those of access, cost, convenience, and privacy. Numerous pilot or small-scale studies have supported the efficacy and utility of this approach, with outcomes that are often consistent with or even greater than those identified when using traditional face-to-face modalities, Dr. Williams said.

The following are studies of Web-based interventions with evidence to support their efficacy. Some of the sites are now online, while others were developed in the context of academic research and are currently not available to the public:

• E-mail discussion groups. These early e-health efforts demonstrated significant benefit in a randomized controlled trial of 580 individuals with chronic low back pain, from 49 states. The intervention included a moderated e-mail discussion group combined with a workbook and videotape about back pain. Controls received a subscription to a nonhealth magazine of their choice. At 1 year, the e-mail group had significant improvements in pain, disability, role function, distress, and health care utilization (Arch. Intern. Med. 2002;162:792-6).

• Swedish Study. In this controlled trial, 56 patients with chronic low back pain were randomized to 8 weeks of either Internet-based CBT with telephone support or to a waiting list. Treatment included CBT modules involving relaxation, exercise and stretching, cognitive restructuring, activity pacing, and relapse prevention. Weekly telephone contact with a therapist related to the goals of the program and homework.

At 3 months, those who had treatment showed statistically significant improvements, compared with those on a waiting list, in control over pain, ability to decrease pain, and catastrophizing (Pain 2004;111:368-77).

• WEBMAP. This one delivered CBT to the young. In a randomized controlled trial, 48 children aged 11-17 years who had chronic headache, abdominal, or musculoskeletal pain and associated functional disability were assigned with their parents to either an Internet treatment group or to a waiting list. The Internet treatment group completed 8 weeks of online modules including relaxation training, cognitive strategies, parent operant techniques, communication strategies, and sleep and activity interventions, in separate sites for patients and parents. Controls had only current medical care (Pain 2009;146:205-13).

There was a significantly greater reduction in activity limitations and pain intensity at post treatment for the Internet treatment group, which were maintained at a 3-month follow-up. Clinically significant lessening of pain was also greater for the Internet treatment group than for the waiting-list control group.

• Teens Taking Charge. Another CBT-based site for young people, "Teens Taking Charge: Managing Arthritis Online" focuses specifically on those with juvenile idiopathic arthritis and their parents. In a 12-week nonblinded, randomized controlled trial done at four centers in Canada, 46 adolescents aged 12-18 with JIA plus one parent each were randomized to the Internet intervention or control arm (J. Rheumatol. 2010;37:1944-52).

The CBT-based self-management modules, written specifically for teens, provide education about arthritis and symptom management, and also address areas such as relaxation, medications, distraction, and managing thoughts. A journal page allows the teen to track progress. Two modules for parents focus on arthritis impact and "letting go." Multimedia components include more than 300 pages of content, including flash animation, video, forums for teens and parents, surveys, and weekly quizzes. The online "coach" has a BA degree in psychology.

At posttreatment, the intervention group had significantly better knowledge and lower average weekly pain intensity.

•painAction. This interactive self-management Web site for people with chronic back pain was evaluated in a pretest-posttest controlled trial in which 209 patients were randomized to either the site for 4 weeks plus monthly boosters or text-based material (Pain Med. 2010;11:1044-58).

The site was based on CBT and self-management principles, including collaborative decision making, goal setting, problem solving, relapse prevention, nutrition, stress management, and exercise. As with many of the other sites, this one included interactive tools, personalized assessments, and a library of articles.

At 6 months, clinically significant changes were seen in pain, depression, anxiety, and global ratings of improvement among those randomized to the site, which is supported by Endo Pharmaceuticals Inc. and King Pharmaceuticals Inc.

Living Well With Fibromyalgia. From Dr. Williams’ group at the University of Michigan, this Internet-based exercise and behavioral self-management program for fibromyalgia was designed for use in the context of clinical care. A total of 118 patients were randomized to the program plus standard care, or standard care alone (Pain 2010;151:694-702).

Among the site’s features are CBT modules including educational material about fibromyalgia and its treatment; symptom management with modalities including medications, exercise, sleep, and relaxation; and lifestyle changes including goal setting, problem solving, and graded activation. Multimedia tools include video lectures by professionals, downloadable worksheets, self-monitoring forms, and audio-recorded exercises.

At 6 months, overall improvement was seen in 57% with the Web program vs. 21% with standard care alone. The proportion experiencing 30% pain improvement or greater (pain responders) was 29% vs. 8% with standard care alone, and functional improvement, defined as an improvement of 0.5 standard deviations, was seen in 31% vs. 6%. All differences were statistically significant, and the number needed to treat for both outcomes was 5, better than the typical 7-19 seen in pharmaceutical trials, Dr. Williams noted.

In a recent meta-analysis of 11 studies of Web-based interventions for chronic pain that used pain scale scores as the main outcome, the standardized mean difference between intervention and waiting-list group means was 0.285, favoring the Web interventions but with a small effect size (J. Pain 2010;11:917-29).

"Broader adoption of this method of delivering care for pain needs to be moved to the next level in terms of both infrastructure and practitioner consensus," Dr. Williams said in an interview.

"Hopes of expanding Internet-based behavioral treatment for pain would need to contain content reflecting a broader consensus of experts from the various disciplines associated with pain management," he said. "Currently there is great interest in developing such resources both in the public and private sectors. This appears to be a valuable approach to supplying individuals with an aspect of effective pain management that is often missing."

Dr. Williams is a consultant for Eli Lilly & Co., Forest Pharmaceuticals, and Bristol-Myers Squibb.

BETHESDA, Md. – Evidence-based nonpharmacologic therapies may be at least as effective as medications in treating chronic pain, and the Internet could prove to be a valuable method for delivering these interventions.

Although pharmacologic agents alone are of only modest benefit and rarely lead to clinically meaningful functional improvement among patients with chronic pain, there is strong evidence for nonpharmacologic therapies such as cognitive-behavioral therapy in improving functional status and mood, as well as pain itself, Dr. David A. Williams, Ph.D., said at a conference on pain and musculoskeletal disorders, sponsored by the University of Michigan and the National Institutes of Health.

A meta-analysis of 25 papers found that active psychological treatments based on the principle of cognitive-behavioral therapy (CBT) produced significantly greater improvements in pain experience, cognitive coping, appraisal, and behavioral expressions of pain, compared with other active treatments, in patients with a variety of chronic pain problems, excluding headache (Pain 1999;80:1-13).

Another meta-analysis, this one including 22 studies of adults with noncancerous chronic low back pain, found that psychological interventions – particularly CBT and self-regulatory treatments – significantly reduced pain intensity, pain-related interference, and depression while significantly improving health-related quality of life. Multidisciplinary approaches that included psychological interventions also had positive effects (Health Psychology 2007;26:1-9).

And two more meta-analyses – one of 49 studies, the other of 23 – have demonstrated an equal or greater effect for nonpharmacologic therapies compared with pharmacologic treatment for fibromyalgia (Ann. Behav. Med.1999;21:180-91; Pain 2010;151:280-95).

"There is a 30-year history of nonpharmacologic interventions that have rival effect sizes to some pharmacologic approaches and even surpass some. The problem is, [nonpharmacologic interventions are] rarely used in clinical practice," said Dr. Williams, professor of anesthesiology, medicine (rheumatology), psychiatry, and psychology and associate director of the chronic pain and fatigue research center at the University of Michigan, Ann Arbor.

The use of nonpharmacologic treatment has been limited for a variety of reasons. Medical schools don’t spend much time teaching it, insurance companies often don’t adequately cover it, patients often can’t access it, it lacks the million dollar marketing campaigns that pharmaceutical companies devote to their drugs, and it carries a stigma, he noted.

Delivering such evidence-based interventions via the Internet potentially sidesteps several of the barriers that prevent their wider use, including those of access, cost, convenience, and privacy. Numerous pilot or small-scale studies have supported the efficacy and utility of this approach, with outcomes that are often consistent with or even greater than those identified when using traditional face-to-face modalities, Dr. Williams said.

The following are studies of Web-based interventions with evidence to support their efficacy. Some of the sites are now online, while others were developed in the context of academic research and are currently not available to the public:

• E-mail discussion groups. These early e-health efforts demonstrated significant benefit in a randomized controlled trial of 580 individuals with chronic low back pain, from 49 states. The intervention included a moderated e-mail discussion group combined with a workbook and videotape about back pain. Controls received a subscription to a nonhealth magazine of their choice. At 1 year, the e-mail group had significant improvements in pain, disability, role function, distress, and health care utilization (Arch. Intern. Med. 2002;162:792-6).

• Swedish Study. In this controlled trial, 56 patients with chronic low back pain were randomized to 8 weeks of either Internet-based CBT with telephone support or to a waiting list. Treatment included CBT modules involving relaxation, exercise and stretching, cognitive restructuring, activity pacing, and relapse prevention. Weekly telephone contact with a therapist related to the goals of the program and homework.

At 3 months, those who had treatment showed statistically significant improvements, compared with those on a waiting list, in control over pain, ability to decrease pain, and catastrophizing (Pain 2004;111:368-77).

• WEBMAP. This one delivered CBT to the young. In a randomized controlled trial, 48 children aged 11-17 years who had chronic headache, abdominal, or musculoskeletal pain and associated functional disability were assigned with their parents to either an Internet treatment group or to a waiting list. The Internet treatment group completed 8 weeks of online modules including relaxation training, cognitive strategies, parent operant techniques, communication strategies, and sleep and activity interventions, in separate sites for patients and parents. Controls had only current medical care (Pain 2009;146:205-13).

There was a significantly greater reduction in activity limitations and pain intensity at post treatment for the Internet treatment group, which were maintained at a 3-month follow-up. Clinically significant lessening of pain was also greater for the Internet treatment group than for the waiting-list control group.

• Teens Taking Charge. Another CBT-based site for young people, "Teens Taking Charge: Managing Arthritis Online" focuses specifically on those with juvenile idiopathic arthritis and their parents. In a 12-week nonblinded, randomized controlled trial done at four centers in Canada, 46 adolescents aged 12-18 with JIA plus one parent each were randomized to the Internet intervention or control arm (J. Rheumatol. 2010;37:1944-52).

The CBT-based self-management modules, written specifically for teens, provide education about arthritis and symptom management, and also address areas such as relaxation, medications, distraction, and managing thoughts. A journal page allows the teen to track progress. Two modules for parents focus on arthritis impact and "letting go." Multimedia components include more than 300 pages of content, including flash animation, video, forums for teens and parents, surveys, and weekly quizzes. The online "coach" has a BA degree in psychology.

At posttreatment, the intervention group had significantly better knowledge and lower average weekly pain intensity.

•painAction. This interactive self-management Web site for people with chronic back pain was evaluated in a pretest-posttest controlled trial in which 209 patients were randomized to either the site for 4 weeks plus monthly boosters or text-based material (Pain Med. 2010;11:1044-58).

The site was based on CBT and self-management principles, including collaborative decision making, goal setting, problem solving, relapse prevention, nutrition, stress management, and exercise. As with many of the other sites, this one included interactive tools, personalized assessments, and a library of articles.

At 6 months, clinically significant changes were seen in pain, depression, anxiety, and global ratings of improvement among those randomized to the site, which is supported by Endo Pharmaceuticals Inc. and King Pharmaceuticals Inc.

Living Well With Fibromyalgia. From Dr. Williams’ group at the University of Michigan, this Internet-based exercise and behavioral self-management program for fibromyalgia was designed for use in the context of clinical care. A total of 118 patients were randomized to the program plus standard care, or standard care alone (Pain 2010;151:694-702).

Among the site’s features are CBT modules including educational material about fibromyalgia and its treatment; symptom management with modalities including medications, exercise, sleep, and relaxation; and lifestyle changes including goal setting, problem solving, and graded activation. Multimedia tools include video lectures by professionals, downloadable worksheets, self-monitoring forms, and audio-recorded exercises.

At 6 months, overall improvement was seen in 57% with the Web program vs. 21% with standard care alone. The proportion experiencing 30% pain improvement or greater (pain responders) was 29% vs. 8% with standard care alone, and functional improvement, defined as an improvement of 0.5 standard deviations, was seen in 31% vs. 6%. All differences were statistically significant, and the number needed to treat for both outcomes was 5, better than the typical 7-19 seen in pharmaceutical trials, Dr. Williams noted.

In a recent meta-analysis of 11 studies of Web-based interventions for chronic pain that used pain scale scores as the main outcome, the standardized mean difference between intervention and waiting-list group means was 0.285, favoring the Web interventions but with a small effect size (J. Pain 2010;11:917-29).

"Broader adoption of this method of delivering care for pain needs to be moved to the next level in terms of both infrastructure and practitioner consensus," Dr. Williams said in an interview.

"Hopes of expanding Internet-based behavioral treatment for pain would need to contain content reflecting a broader consensus of experts from the various disciplines associated with pain management," he said. "Currently there is great interest in developing such resources both in the public and private sectors. This appears to be a valuable approach to supplying individuals with an aspect of effective pain management that is often missing."

Dr. Williams is a consultant for Eli Lilly & Co., Forest Pharmaceuticals, and Bristol-Myers Squibb.

BETHESDA, Md. – Evidence-based nonpharmacologic therapies may be at least as effective as medications in treating chronic pain, and the Internet could prove to be a valuable method for delivering these interventions.

Although pharmacologic agents alone are of only modest benefit and rarely lead to clinically meaningful functional improvement among patients with chronic pain, there is strong evidence for nonpharmacologic therapies such as cognitive-behavioral therapy in improving functional status and mood, as well as pain itself, Dr. David A. Williams, Ph.D., said at a conference on pain and musculoskeletal disorders, sponsored by the University of Michigan and the National Institutes of Health.

A meta-analysis of 25 papers found that active psychological treatments based on the principle of cognitive-behavioral therapy (CBT) produced significantly greater improvements in pain experience, cognitive coping, appraisal, and behavioral expressions of pain, compared with other active treatments, in patients with a variety of chronic pain problems, excluding headache (Pain 1999;80:1-13).

Another meta-analysis, this one including 22 studies of adults with noncancerous chronic low back pain, found that psychological interventions – particularly CBT and self-regulatory treatments – significantly reduced pain intensity, pain-related interference, and depression while significantly improving health-related quality of life. Multidisciplinary approaches that included psychological interventions also had positive effects (Health Psychology 2007;26:1-9).

And two more meta-analyses – one of 49 studies, the other of 23 – have demonstrated an equal or greater effect for nonpharmacologic therapies compared with pharmacologic treatment for fibromyalgia (Ann. Behav. Med.1999;21:180-91; Pain 2010;151:280-95).

"There is a 30-year history of nonpharmacologic interventions that have rival effect sizes to some pharmacologic approaches and even surpass some. The problem is, [nonpharmacologic interventions are] rarely used in clinical practice," said Dr. Williams, professor of anesthesiology, medicine (rheumatology), psychiatry, and psychology and associate director of the chronic pain and fatigue research center at the University of Michigan, Ann Arbor.

The use of nonpharmacologic treatment has been limited for a variety of reasons. Medical schools don’t spend much time teaching it, insurance companies often don’t adequately cover it, patients often can’t access it, it lacks the million dollar marketing campaigns that pharmaceutical companies devote to their drugs, and it carries a stigma, he noted.

Delivering such evidence-based interventions via the Internet potentially sidesteps several of the barriers that prevent their wider use, including those of access, cost, convenience, and privacy. Numerous pilot or small-scale studies have supported the efficacy and utility of this approach, with outcomes that are often consistent with or even greater than those identified when using traditional face-to-face modalities, Dr. Williams said.

The following are studies of Web-based interventions with evidence to support their efficacy. Some of the sites are now online, while others were developed in the context of academic research and are currently not available to the public:

• E-mail discussion groups. These early e-health efforts demonstrated significant benefit in a randomized controlled trial of 580 individuals with chronic low back pain, from 49 states. The intervention included a moderated e-mail discussion group combined with a workbook and videotape about back pain. Controls received a subscription to a nonhealth magazine of their choice. At 1 year, the e-mail group had significant improvements in pain, disability, role function, distress, and health care utilization (Arch. Intern. Med. 2002;162:792-6).

• Swedish Study. In this controlled trial, 56 patients with chronic low back pain were randomized to 8 weeks of either Internet-based CBT with telephone support or to a waiting list. Treatment included CBT modules involving relaxation, exercise and stretching, cognitive restructuring, activity pacing, and relapse prevention. Weekly telephone contact with a therapist related to the goals of the program and homework.

At 3 months, those who had treatment showed statistically significant improvements, compared with those on a waiting list, in control over pain, ability to decrease pain, and catastrophizing (Pain 2004;111:368-77).

• WEBMAP. This one delivered CBT to the young. In a randomized controlled trial, 48 children aged 11-17 years who had chronic headache, abdominal, or musculoskeletal pain and associated functional disability were assigned with their parents to either an Internet treatment group or to a waiting list. The Internet treatment group completed 8 weeks of online modules including relaxation training, cognitive strategies, parent operant techniques, communication strategies, and sleep and activity interventions, in separate sites for patients and parents. Controls had only current medical care (Pain 2009;146:205-13).

There was a significantly greater reduction in activity limitations and pain intensity at post treatment for the Internet treatment group, which were maintained at a 3-month follow-up. Clinically significant lessening of pain was also greater for the Internet treatment group than for the waiting-list control group.

• Teens Taking Charge. Another CBT-based site for young people, "Teens Taking Charge: Managing Arthritis Online" focuses specifically on those with juvenile idiopathic arthritis and their parents. In a 12-week nonblinded, randomized controlled trial done at four centers in Canada, 46 adolescents aged 12-18 with JIA plus one parent each were randomized to the Internet intervention or control arm (J. Rheumatol. 2010;37:1944-52).

The CBT-based self-management modules, written specifically for teens, provide education about arthritis and symptom management, and also address areas such as relaxation, medications, distraction, and managing thoughts. A journal page allows the teen to track progress. Two modules for parents focus on arthritis impact and "letting go." Multimedia components include more than 300 pages of content, including flash animation, video, forums for teens and parents, surveys, and weekly quizzes. The online "coach" has a BA degree in psychology.

At posttreatment, the intervention group had significantly better knowledge and lower average weekly pain intensity.

•painAction. This interactive self-management Web site for people with chronic back pain was evaluated in a pretest-posttest controlled trial in which 209 patients were randomized to either the site for 4 weeks plus monthly boosters or text-based material (Pain Med. 2010;11:1044-58).

The site was based on CBT and self-management principles, including collaborative decision making, goal setting, problem solving, relapse prevention, nutrition, stress management, and exercise. As with many of the other sites, this one included interactive tools, personalized assessments, and a library of articles.

At 6 months, clinically significant changes were seen in pain, depression, anxiety, and global ratings of improvement among those randomized to the site, which is supported by Endo Pharmaceuticals Inc. and King Pharmaceuticals Inc.

Living Well With Fibromyalgia. From Dr. Williams’ group at the University of Michigan, this Internet-based exercise and behavioral self-management program for fibromyalgia was designed for use in the context of clinical care. A total of 118 patients were randomized to the program plus standard care, or standard care alone (Pain 2010;151:694-702).

Among the site’s features are CBT modules including educational material about fibromyalgia and its treatment; symptom management with modalities including medications, exercise, sleep, and relaxation; and lifestyle changes including goal setting, problem solving, and graded activation. Multimedia tools include video lectures by professionals, downloadable worksheets, self-monitoring forms, and audio-recorded exercises.

At 6 months, overall improvement was seen in 57% with the Web program vs. 21% with standard care alone. The proportion experiencing 30% pain improvement or greater (pain responders) was 29% vs. 8% with standard care alone, and functional improvement, defined as an improvement of 0.5 standard deviations, was seen in 31% vs. 6%. All differences were statistically significant, and the number needed to treat for both outcomes was 5, better than the typical 7-19 seen in pharmaceutical trials, Dr. Williams noted.

In a recent meta-analysis of 11 studies of Web-based interventions for chronic pain that used pain scale scores as the main outcome, the standardized mean difference between intervention and waiting-list group means was 0.285, favoring the Web interventions but with a small effect size (J. Pain 2010;11:917-29).

"Broader adoption of this method of delivering care for pain needs to be moved to the next level in terms of both infrastructure and practitioner consensus," Dr. Williams said in an interview.

"Hopes of expanding Internet-based behavioral treatment for pain would need to contain content reflecting a broader consensus of experts from the various disciplines associated with pain management," he said. "Currently there is great interest in developing such resources both in the public and private sectors. This appears to be a valuable approach to supplying individuals with an aspect of effective pain management that is often missing."

Dr. Williams is a consultant for Eli Lilly & Co., Forest Pharmaceuticals, and Bristol-Myers Squibb.

BETHESDA, Md. – Evidence-based nonpharmacologic therapies may be at least as effective as medications in treating chronic pain, and the Internet could prove to be a valuable method for delivering these interventions.

Although pharmacologic agents alone are of only modest benefit and rarely lead to clinically meaningful functional improvement among patients with chronic pain, there is strong evidence for nonpharmacologic therapies such as cognitive-behavioral therapy in improving functional status and mood, as well as pain itself, Dr. David A. Williams, Ph.D., said at a conference on pain and musculoskeletal disorders, sponsored by the University of Michigan and the National Institutes of Health.

A meta-analysis of 25 papers found that active psychological treatments based on the principle of cognitive-behavioral therapy (CBT) produced significantly greater improvements in pain experience, cognitive coping, appraisal, and behavioral expressions of pain, compared with other active treatments, in patients with a variety of chronic pain problems, excluding headache (Pain 1999;80:1-13).

Another meta-analysis, this one including 22 studies of adults with noncancerous chronic low back pain, found that psychological interventions – particularly CBT and self-regulatory treatments – significantly reduced pain intensity, pain-related interference, and depression while significantly improving health-related quality of life. Multidisciplinary approaches that included psychological interventions also had positive effects (Health Psychology 2007;26:1-9).

And two more meta-analyses – one of 49 studies, the other of 23 – have demonstrated an equal or greater effect for nonpharmacologic therapies compared with pharmacologic treatment for fibromyalgia (Ann. Behav. Med.1999;21:180-91; Pain 2010;151:280-95).

"There is a 30-year history of nonpharmacologic interventions that have rival effect sizes to some pharmacologic approaches and even surpass some. The problem is, [nonpharmacologic interventions are] rarely used in clinical practice," said Dr. Williams, professor of anesthesiology, medicine (rheumatology), psychiatry, and psychology and associate director of the chronic pain and fatigue research center at the University of Michigan, Ann Arbor.

The use of nonpharmacologic treatment has been limited for a variety of reasons. Medical schools don’t spend much time teaching it, insurance companies often don’t adequately cover it, patients often can’t access it, it lacks the million dollar marketing campaigns that pharmaceutical companies devote to their drugs, and it carries a stigma, he noted.

Delivering such evidence-based interventions via the Internet potentially sidesteps several of the barriers that prevent their wider use, including those of access, cost, convenience, and privacy. Numerous pilot or small-scale studies have supported the efficacy and utility of this approach, with outcomes that are often consistent with or even greater than those identified when using traditional face-to-face modalities, Dr. Williams said.

The following are studies of Web-based interventions with evidence to support their efficacy. Some of the sites are now online, while others were developed in the context of academic research and are currently not available to the public:

• E-mail discussion groups. These early e-health efforts demonstrated significant benefit in a randomized controlled trial of 580 individuals with chronic low back pain, from 49 states. The intervention included a moderated e-mail discussion group combined with a workbook and videotape about back pain. Controls received a subscription to a nonhealth magazine of their choice. At 1 year, the e-mail group had significant improvements in pain, disability, role function, distress, and health care utilization (Arch. Intern. Med. 2002;162:792-6).

• Swedish Study. In this controlled trial, 56 patients with chronic low back pain were randomized to 8 weeks of either Internet-based CBT with telephone support or to a waiting list. Treatment included CBT modules involving relaxation, exercise and stretching, cognitive restructuring, activity pacing, and relapse prevention. Weekly telephone contact with a therapist related to the goals of the program and homework.

At 3 months, those who had treatment showed statistically significant improvements, compared with those on a waiting list, in control over pain, ability to decrease pain, and catastrophizing (Pain 2004;111:368-77).

• WEBMAP. This one delivered CBT to the young. In a randomized controlled trial, 48 children aged 11-17 years who had chronic headache, abdominal, or musculoskeletal pain and associated functional disability were assigned with their parents to either an Internet treatment group or to a waiting list. The Internet treatment group completed 8 weeks of online modules including relaxation training, cognitive strategies, parent operant techniques, communication strategies, and sleep and activity interventions, in separate sites for patients and parents. Controls had only current medical care (Pain 2009;146:205-13).

There was a significantly greater reduction in activity limitations and pain intensity at post treatment for the Internet treatment group, which were maintained at a 3-month follow-up. Clinically significant lessening of pain was also greater for the Internet treatment group than for the waiting-list control group.

• Teens Taking Charge. Another CBT-based site for young people, "Teens Taking Charge: Managing Arthritis Online" focuses specifically on those with juvenile idiopathic arthritis and their parents. In a 12-week nonblinded, randomized controlled trial done at four centers in Canada, 46 adolescents aged 12-18 with JIA plus one parent each were randomized to the Internet intervention or control arm (J. Rheumatol. 2010;37:1944-52).

The CBT-based self-management modules, written specifically for teens, provide education about arthritis and symptom management, and also address areas such as relaxation, medications, distraction, and managing thoughts. A journal page allows the teen to track progress. Two modules for parents focus on arthritis impact and "letting go." Multimedia components include more than 300 pages of content, including flash animation, video, forums for teens and parents, surveys, and weekly quizzes. The online "coach" has a BA degree in psychology.

At posttreatment, the intervention group had significantly better knowledge and lower average weekly pain intensity.

•painAction. This interactive self-management Web site for people with chronic back pain was evaluated in a pretest-posttest controlled trial in which 209 patients were randomized to either the site for 4 weeks plus monthly boosters or text-based material (Pain Med. 2010;11:1044-58).

The site was based on CBT and self-management principles, including collaborative decision making, goal setting, problem solving, relapse prevention, nutrition, stress management, and exercise. As with many of the other sites, this one included interactive tools, personalized assessments, and a library of articles.

At 6 months, clinically significant changes were seen in pain, depression, anxiety, and global ratings of improvement among those randomized to the site, which is supported by Endo Pharmaceuticals Inc. and King Pharmaceuticals Inc.

Living Well With Fibromyalgia. From Dr. Williams’ group at the University of Michigan, this Internet-based exercise and behavioral self-management program for fibromyalgia was designed for use in the context of clinical care. A total of 118 patients were randomized to the program plus standard care, or standard care alone (Pain 2010;151:694-702).

Among the site’s features are CBT modules including educational material about fibromyalgia and its treatment; symptom management with modalities including medications, exercise, sleep, and relaxation; and lifestyle changes including goal setting, problem solving, and graded activation. Multimedia tools include video lectures by professionals, downloadable worksheets, self-monitoring forms, and audio-recorded exercises.

At 6 months, overall improvement was seen in 57% with the Web program vs. 21% with standard care alone. The proportion experiencing 30% pain improvement or greater (pain responders) was 29% vs. 8% with standard care alone, and functional improvement, defined as an improvement of 0.5 standard deviations, was seen in 31% vs. 6%. All differences were statistically significant, and the number needed to treat for both outcomes was 5, better than the typical 7-19 seen in pharmaceutical trials, Dr. Williams noted.

In a recent meta-analysis of 11 studies of Web-based interventions for chronic pain that used pain scale scores as the main outcome, the standardized mean difference between intervention and waiting-list group means was 0.285, favoring the Web interventions but with a small effect size (J. Pain 2010;11:917-29).

"Broader adoption of this method of delivering care for pain needs to be moved to the next level in terms of both infrastructure and practitioner consensus," Dr. Williams said in an interview.

"Hopes of expanding Internet-based behavioral treatment for pain would need to contain content reflecting a broader consensus of experts from the various disciplines associated with pain management," he said. "Currently there is great interest in developing such resources both in the public and private sectors. This appears to be a valuable approach to supplying individuals with an aspect of effective pain management that is often missing."

Dr. Williams is a consultant for Eli Lilly & Co., Forest Pharmaceuticals, and Bristol-Myers Squibb.

BETHESDA, Md. – Evidence-based nonpharmacologic therapies may be at least as effective as medications in treating chronic pain, and the Internet could prove to be a valuable method for delivering these interventions.

Although pharmacologic agents alone are of only modest benefit and rarely lead to clinically meaningful functional improvement among patients with chronic pain, there is strong evidence for nonpharmacologic therapies such as cognitive-behavioral therapy in improving functional status and mood, as well as pain itself, Dr. David A. Williams, Ph.D., said at a conference on pain and musculoskeletal disorders, sponsored by the University of Michigan and the National Institutes of Health.

A meta-analysis of 25 papers found that active psychological treatments based on the principle of cognitive-behavioral therapy (CBT) produced significantly greater improvements in pain experience, cognitive coping, appraisal, and behavioral expressions of pain, compared with other active treatments, in patients with a variety of chronic pain problems, excluding headache (Pain 1999;80:1-13).

Another meta-analysis, this one including 22 studies of adults with noncancerous chronic low back pain, found that psychological interventions – particularly CBT and self-regulatory treatments – significantly reduced pain intensity, pain-related interference, and depression while significantly improving health-related quality of life. Multidisciplinary approaches that included psychological interventions also had positive effects (Health Psychology 2007;26:1-9).

And two more meta-analyses – one of 49 studies, the other of 23 – have demonstrated an equal or greater effect for nonpharmacologic therapies compared with pharmacologic treatment for fibromyalgia (Ann. Behav. Med.1999;21:180-91; Pain 2010;151:280-95).

"There is a 30-year history of nonpharmacologic interventions that have rival effect sizes to some pharmacologic approaches and even surpass some. The problem is, [nonpharmacologic interventions are] rarely used in clinical practice," said Dr. Williams, professor of anesthesiology, medicine (rheumatology), psychiatry, and psychology and associate director of the chronic pain and fatigue research center at the University of Michigan, Ann Arbor.

The use of nonpharmacologic treatment has been limited for a variety of reasons. Medical schools don’t spend much time teaching it, insurance companies often don’t adequately cover it, patients often can’t access it, it lacks the million dollar marketing campaigns that pharmaceutical companies devote to their drugs, and it carries a stigma, he noted.

Delivering such evidence-based interventions via the Internet potentially sidesteps several of the barriers that prevent their wider use, including those of access, cost, convenience, and privacy. Numerous pilot or small-scale studies have supported the efficacy and utility of this approach, with outcomes that are often consistent with or even greater than those identified when using traditional face-to-face modalities, Dr. Williams said.

The following are studies of Web-based interventions with evidence to support their efficacy. Some of the sites are now online, while others were developed in the context of academic research and are currently not available to the public:

• E-mail discussion groups. These early e-health efforts demonstrated significant benefit in a randomized controlled trial of 580 individuals with chronic low back pain, from 49 states. The intervention included a moderated e-mail discussion group combined with a workbook and videotape about back pain. Controls received a subscription to a nonhealth magazine of their choice. At 1 year, the e-mail group had significant improvements in pain, disability, role function, distress, and health care utilization (Arch. Intern. Med. 2002;162:792-6).

• Swedish Study. In this controlled trial, 56 patients with chronic low back pain were randomized to 8 weeks of either Internet-based CBT with telephone support or to a waiting list. Treatment included CBT modules involving relaxation, exercise and stretching, cognitive restructuring, activity pacing, and relapse prevention. Weekly telephone contact with a therapist related to the goals of the program and homework.

At 3 months, those who had treatment showed statistically significant improvements, compared with those on a waiting list, in control over pain, ability to decrease pain, and catastrophizing (Pain 2004;111:368-77).

• WEBMAP. This one delivered CBT to the young. In a randomized controlled trial, 48 children aged 11-17 years who had chronic headache, abdominal, or musculoskeletal pain and associated functional disability were assigned with their parents to either an Internet treatment group or to a waiting list. The Internet treatment group completed 8 weeks of online modules including relaxation training, cognitive strategies, parent operant techniques, communication strategies, and sleep and activity interventions, in separate sites for patients and parents. Controls had only current medical care (Pain 2009;146:205-13).

There was a significantly greater reduction in activity limitations and pain intensity at post treatment for the Internet treatment group, which were maintained at a 3-month follow-up. Clinically significant lessening of pain was also greater for the Internet treatment group than for the waiting-list control group.

• Teens Taking Charge. Another CBT-based site for young people, "Teens Taking Charge: Managing Arthritis Online" focuses specifically on those with juvenile idiopathic arthritis and their parents. In a 12-week nonblinded, randomized controlled trial done at four centers in Canada, 46 adolescents aged 12-18 with JIA plus one parent each were randomized to the Internet intervention or control arm (J. Rheumatol. 2010;37:1944-52).

The CBT-based self-management modules, written specifically for teens, provide education about arthritis and symptom management, and also address areas such as relaxation, medications, distraction, and managing thoughts. A journal page allows the teen to track progress. Two modules for parents focus on arthritis impact and "letting go." Multimedia components include more than 300 pages of content, including flash animation, video, forums for teens and parents, surveys, and weekly quizzes. The online "coach" has a BA degree in psychology.

At posttreatment, the intervention group had significantly better knowledge and lower average weekly pain intensity.

•painAction. This interactive self-management Web site for people with chronic back pain was evaluated in a pretest-posttest controlled trial in which 209 patients were randomized to either the site for 4 weeks plus monthly boosters or text-based material (Pain Med. 2010;11:1044-58).

The site was based on CBT and self-management principles, including collaborative decision making, goal setting, problem solving, relapse prevention, nutrition, stress management, and exercise. As with many of the other sites, this one included interactive tools, personalized assessments, and a library of articles.

At 6 months, clinically significant changes were seen in pain, depression, anxiety, and global ratings of improvement among those randomized to the site, which is supported by Endo Pharmaceuticals Inc. and King Pharmaceuticals Inc.

Living Well With Fibromyalgia. From Dr. Williams’ group at the University of Michigan, this Internet-based exercise and behavioral self-management program for fibromyalgia was designed for use in the context of clinical care. A total of 118 patients were randomized to the program plus standard care, or standard care alone (Pain 2010;151:694-702).

Among the site’s features are CBT modules including educational material about fibromyalgia and its treatment; symptom management with modalities including medications, exercise, sleep, and relaxation; and lifestyle changes including goal setting, problem solving, and graded activation. Multimedia tools include video lectures by professionals, downloadable worksheets, self-monitoring forms, and audio-recorded exercises.

At 6 months, overall improvement was seen in 57% with the Web program vs. 21% with standard care alone. The proportion experiencing 30% pain improvement or greater (pain responders) was 29% vs. 8% with standard care alone, and functional improvement, defined as an improvement of 0.5 standard deviations, was seen in 31% vs. 6%. All differences were statistically significant, and the number needed to treat for both outcomes was 5, better than the typical 7-19 seen in pharmaceutical trials, Dr. Williams noted.

In a recent meta-analysis of 11 studies of Web-based interventions for chronic pain that used pain scale scores as the main outcome, the standardized mean difference between intervention and waiting-list group means was 0.285, favoring the Web interventions but with a small effect size (J. Pain 2010;11:917-29).

"Broader adoption of this method of delivering care for pain needs to be moved to the next level in terms of both infrastructure and practitioner consensus," Dr. Williams said in an interview.

"Hopes of expanding Internet-based behavioral treatment for pain would need to contain content reflecting a broader consensus of experts from the various disciplines associated with pain management," he said. "Currently there is great interest in developing such resources both in the public and private sectors. This appears to be a valuable approach to supplying individuals with an aspect of effective pain management that is often missing."

Dr. Williams is a consultant for Eli Lilly & Co., Forest Pharmaceuticals, and Bristol-Myers Squibb.

BETHESDA, Md. – Evidence-based nonpharmacologic therapies may be at least as effective as medications in treating chronic pain, and the Internet could prove to be a valuable method for delivering these interventions.

Although pharmacologic agents alone are of only modest benefit and rarely lead to clinically meaningful functional improvement among patients with chronic pain, there is strong evidence for nonpharmacologic therapies such as cognitive-behavioral therapy in improving functional status and mood, as well as pain itself, Dr. David A. Williams, Ph.D., said at a conference on pain and musculoskeletal disorders, sponsored by the University of Michigan and the National Institutes of Health.

A meta-analysis of 25 papers found that active psychological treatments based on the principle of cognitive-behavioral therapy (CBT) produced significantly greater improvements in pain experience, cognitive coping, appraisal, and behavioral expressions of pain, compared with other active treatments, in patients with a variety of chronic pain problems, excluding headache (Pain 1999;80:1-13).

Another meta-analysis, this one including 22 studies of adults with noncancerous chronic low back pain, found that psychological interventions – particularly CBT and self-regulatory treatments – significantly reduced pain intensity, pain-related interference, and depression while significantly improving health-related quality of life. Multidisciplinary approaches that included psychological interventions also had positive effects (Health Psychology 2007;26:1-9).

And two more meta-analyses – one of 49 studies, the other of 23 – have demonstrated an equal or greater effect for nonpharmacologic therapies compared with pharmacologic treatment for fibromyalgia (Ann. Behav. Med.1999;21:180-91; Pain 2010;151:280-95).

"There is a 30-year history of nonpharmacologic interventions that have rival effect sizes to some pharmacologic approaches and even surpass some. The problem is, [nonpharmacologic interventions are] rarely used in clinical practice," said Dr. Williams, professor of anesthesiology, medicine (rheumatology), psychiatry, and psychology and associate director of the chronic pain and fatigue research center at the University of Michigan, Ann Arbor.

The use of nonpharmacologic treatment has been limited for a variety of reasons. Medical schools don’t spend much time teaching it, insurance companies often don’t adequately cover it, patients often can’t access it, it lacks the million dollar marketing campaigns that pharmaceutical companies devote to their drugs, and it carries a stigma, he noted.

Delivering such evidence-based interventions via the Internet potentially sidesteps several of the barriers that prevent their wider use, including those of access, cost, convenience, and privacy. Numerous pilot or small-scale studies have supported the efficacy and utility of this approach, with outcomes that are often consistent with or even greater than those identified when using traditional face-to-face modalities, Dr. Williams said.

The following are studies of Web-based interventions with evidence to support their efficacy. Some of the sites are now online, while others were developed in the context of academic research and are currently not available to the public:

• E-mail discussion groups. These early e-health efforts demonstrated significant benefit in a randomized controlled trial of 580 individuals with chronic low back pain, from 49 states. The intervention included a moderated e-mail discussion group combined with a workbook and videotape about back pain. Controls received a subscription to a nonhealth magazine of their choice. At 1 year, the e-mail group had significant improvements in pain, disability, role function, distress, and health care utilization (Arch. Intern. Med. 2002;162:792-6).

• Swedish Study. In this controlled trial, 56 patients with chronic low back pain were randomized to 8 weeks of either Internet-based CBT with telephone support or to a waiting list. Treatment included CBT modules involving relaxation, exercise and stretching, cognitive restructuring, activity pacing, and relapse prevention. Weekly telephone contact with a therapist related to the goals of the program and homework.

At 3 months, those who had treatment showed statistically significant improvements, compared with those on a waiting list, in control over pain, ability to decrease pain, and catastrophizing (Pain 2004;111:368-77).

• WEBMAP. This one delivered CBT to the young. In a randomized controlled trial, 48 children aged 11-17 years who had chronic headache, abdominal, or musculoskeletal pain and associated functional disability were assigned with their parents to either an Internet treatment group or to a waiting list. The Internet treatment group completed 8 weeks of online modules including relaxation training, cognitive strategies, parent operant techniques, communication strategies, and sleep and activity interventions, in separate sites for patients and parents. Controls had only current medical care (Pain 2009;146:205-13).

There was a significantly greater reduction in activity limitations and pain intensity at post treatment for the Internet treatment group, which were maintained at a 3-month follow-up. Clinically significant lessening of pain was also greater for the Internet treatment group than for the waiting-list control group.

• Teens Taking Charge. Another CBT-based site for young people, "Teens Taking Charge: Managing Arthritis Online" focuses specifically on those with juvenile idiopathic arthritis and their parents. In a 12-week nonblinded, randomized controlled trial done at four centers in Canada, 46 adolescents aged 12-18 with JIA plus one parent each were randomized to the Internet intervention or control arm (J. Rheumatol. 2010;37:1944-52).

The CBT-based self-management modules, written specifically for teens, provide education about arthritis and symptom management, and also address areas such as relaxation, medications, distraction, and managing thoughts. A journal page allows the teen to track progress. Two modules for parents focus on arthritis impact and "letting go." Multimedia components include more than 300 pages of content, including flash animation, video, forums for teens and parents, surveys, and weekly quizzes. The online "coach" has a BA degree in psychology.

At posttreatment, the intervention group had significantly better knowledge and lower average weekly pain intensity.

•painAction. This interactive self-management Web site for people with chronic back pain was evaluated in a pretest-posttest controlled trial in which 209 patients were randomized to either the site for 4 weeks plus monthly boosters or text-based material (Pain Med. 2010;11:1044-58).

The site was based on CBT and self-management principles, including collaborative decision making, goal setting, problem solving, relapse prevention, nutrition, stress management, and exercise. As with many of the other sites, this one included interactive tools, personalized assessments, and a library of articles.

At 6 months, clinically significant changes were seen in pain, depression, anxiety, and global ratings of improvement among those randomized to the site, which is supported by Endo Pharmaceuticals Inc. and King Pharmaceuticals Inc.

Living Well With Fibromyalgia. From Dr. Williams’ group at the University of Michigan, this Internet-based exercise and behavioral self-management program for fibromyalgia was designed for use in the context of clinical care. A total of 118 patients were randomized to the program plus standard care, or standard care alone (Pain 2010;151:694-702).

Among the site’s features are CBT modules including educational material about fibromyalgia and its treatment; symptom management with modalities including medications, exercise, sleep, and relaxation; and lifestyle changes including goal setting, problem solving, and graded activation. Multimedia tools include video lectures by professionals, downloadable worksheets, self-monitoring forms, and audio-recorded exercises.

At 6 months, overall improvement was seen in 57% with the Web program vs. 21% with standard care alone. The proportion experiencing 30% pain improvement or greater (pain responders) was 29% vs. 8% with standard care alone, and functional improvement, defined as an improvement of 0.5 standard deviations, was seen in 31% vs. 6%. All differences were statistically significant, and the number needed to treat for both outcomes was 5, better than the typical 7-19 seen in pharmaceutical trials, Dr. Williams noted.

In a recent meta-analysis of 11 studies of Web-based interventions for chronic pain that used pain scale scores as the main outcome, the standardized mean difference between intervention and waiting-list group means was 0.285, favoring the Web interventions but with a small effect size (J. Pain 2010;11:917-29).

"Broader adoption of this method of delivering care for pain needs to be moved to the next level in terms of both infrastructure and practitioner consensus," Dr. Williams said in an interview.

"Hopes of expanding Internet-based behavioral treatment for pain would need to contain content reflecting a broader consensus of experts from the various disciplines associated with pain management," he said. "Currently there is great interest in developing such resources both in the public and private sectors. This appears to be a valuable approach to supplying individuals with an aspect of effective pain management that is often missing."

Dr. Williams is a consultant for Eli Lilly & Co., Forest Pharmaceuticals, and Bristol-Myers Squibb.