Pharmacology

It’s now official: The investigational sodium-glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin is the first agent clearly shown in a prespecified analysis of randomized trials to improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFpEF).

Researchers who ran the SCORED and SOLOIST-WHF pivotal trials for sotagliflozin first made that claim in November 2020 when reporting top-line results from a prespecified meta-analysis of the two trials during the American Heart Association annual scientific sessions. A follow-up report during the annual scientific sessions of the American College of Cardiology fleshed out the evidence and firmed up their landmark conclusion.

The meta-analysis (Abstract 410-08) included 4,500 patients with type 2 diabetes and diagnosed heart failure at entry; its primary endpoint, which was the same in both trials, was the combined incidence of cardiovascular death and the total number of either hospitalization for heart failure or urgent outpatient visits for heart failure.

Compared with placebo, treatment with sotagliflozin for a median of about 15 months dropped this composite endpoint by a relative 33% among the 1,931 who began the study with a left ventricular ejection fraction (LVEF) of at least 50% (HFpEF), by a relative 22% in the 1,758 patients who entered with an LVEF of less than 40% (patients with heart failure with reduced ejection fraction), and by a relative 43% among the 811 patients who began with an LVEF of 40%-49% (patients with heart failure with mid-range ejection fraction). The relative risk reductions were significant for all three subgroups, Deepak L. Bhatt, MD, reported at the meeting.
 

Equally effective ‘across the full range of LVEFs.’

Perhaps as notable and unprecedented was the further finding that the clinical benefits seen with treatment of patients with type 2 diabetes with sotagliflozin was consistent regardless of the ejection fraction they had at entry. Enrolled patients with baseline LVEFs in the range of 25% received a relative benefit from sotagliflozin treatment that was statistically no different from the benefit seen in patients who entered with an LVEF in the neighborhood of 45%, 65%, or at any other level across the LVEF spectrum, a finding that Dr. Bhatt called “remarkable” during a press briefing. “The results show the benefit of sotagliflozin across the full range of LVEFs.”

“We are very excited in the heart failure world by the SGLT2 inhibitors; we’ve been impressed by their reduction in heart failure hospitalizations, but we wonder about the patients with HFpEF, where we haven’t had a blockbuster drug to give,” said Ileana L. Piña, MD, a heart failure specialist and medical officer with the Food and Drug Administration.

The new findings “look like they could pose a regulatory indication [for sotagliflozin] for patients with type 2 diabetes and heart failure across the entire spectrum of heart failure,” said Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart & Vascular institute in Falls Church, Va., and designated discussant for Dr. Bhatt’s report.

A significant on-treatment reduction in CV death

Other new, notable findings from the meta-analysis included the observation that while treatment with sotagliflozin failed to produce a significant reduction in cardiovascular death, compared with placebo, in the intent-to-treat analysis of all patients and of those with heart failure at baseline (it produced nonsignificant point-estimate reductions of 11% compared with placebo for all patients, and of 23% for patients who began the study with heart failure), it did result in a significant 23% relative risk reduction when the researchers focused on patients while they remained adherent to their sotagliflozin regimen (the on-treatment analysis). This 23% relative reduction appeared among all enrolled patients, as well as in the subgroup that started with diagnosed heart failure.

“Given the totality of data from the SGLT2 inhibitors, I think this is a real finding,” Dr. Bhatt said.

Additional analyses also showed that, among women, treatment with sotagliflozin was linked with significant relative reductions in the primary endpoint of roughly 30% compared with placebo among all patients, and also among those with heart failure at baseline. “HFpEF is a problem particularly in older women, and we showed that the benefit was consistent in men and women,” Dr. Bhatt said.

He acknowledged that results are expected soon from two pivotal trials that are examining two different SGLT2 inhibitors, dapagliflozin and empagliflozin, in patients with HFpEF. “I think there will be a class effect for both SGLT2 inhibitors and sotagliflozin for reducing heart failure events in patients with HFpEF, and I predict that the dapagliflozin and empagliflozin trials will have positive results,” Dr. Bhatt said.

Sotagliflozin differs from the SGLT2 inhibitors by also inhibiting SGLT1, an enzyme found in the gastrointestinal system that, when inhibited, results in increased glucose excretion from the gut and a cut in bloodstream levels of postprandial glucose levels. The Food and Drug Administration accepted data from SCORED and SOLOIST-WHF as part of the evidence the agency is now considering for granting a new drug approval to sotagliflozin.

SCORED and SOLOIST-WHF were initially sponsored by Sanofi, and later by Lexicon Pharmaceuticals. Dr. Bhatt’s institution, Brigham and Women’s Hospital, has received funding from Sanofi and Lexicon Pharmaceuticals. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an adviser to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies. Dr. Piña has no relevant disclosures. Dr. O’Connor has been a consultant to Arena, Bayer, Bristol-Myers Squibb, Merck, and Windtree, and he has an ownership interest in Biscardia.

mzoler@mdedge.com

It’s now official: The investigational sodium-glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin is the first agent clearly shown in a prespecified analysis of randomized trials to improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFpEF).

Researchers who ran the SCORED and SOLOIST-WHF pivotal trials for sotagliflozin first made that claim in November 2020 when reporting top-line results from a prespecified meta-analysis of the two trials during the American Heart Association annual scientific sessions. A follow-up report during the annual scientific sessions of the American College of Cardiology fleshed out the evidence and firmed up their landmark conclusion.

The meta-analysis (Abstract 410-08) included 4,500 patients with type 2 diabetes and diagnosed heart failure at entry; its primary endpoint, which was the same in both trials, was the combined incidence of cardiovascular death and the total number of either hospitalization for heart failure or urgent outpatient visits for heart failure.

Compared with placebo, treatment with sotagliflozin for a median of about 15 months dropped this composite endpoint by a relative 33% among the 1,931 who began the study with a left ventricular ejection fraction (LVEF) of at least 50% (HFpEF), by a relative 22% in the 1,758 patients who entered with an LVEF of less than 40% (patients with heart failure with reduced ejection fraction), and by a relative 43% among the 811 patients who began with an LVEF of 40%-49% (patients with heart failure with mid-range ejection fraction). The relative risk reductions were significant for all three subgroups, Deepak L. Bhatt, MD, reported at the meeting.
 

Equally effective ‘across the full range of LVEFs.’

Perhaps as notable and unprecedented was the further finding that the clinical benefits seen with treatment of patients with type 2 diabetes with sotagliflozin was consistent regardless of the ejection fraction they had at entry. Enrolled patients with baseline LVEFs in the range of 25% received a relative benefit from sotagliflozin treatment that was statistically no different from the benefit seen in patients who entered with an LVEF in the neighborhood of 45%, 65%, or at any other level across the LVEF spectrum, a finding that Dr. Bhatt called “remarkable” during a press briefing. “The results show the benefit of sotagliflozin across the full range of LVEFs.”

“We are very excited in the heart failure world by the SGLT2 inhibitors; we’ve been impressed by their reduction in heart failure hospitalizations, but we wonder about the patients with HFpEF, where we haven’t had a blockbuster drug to give,” said Ileana L. Piña, MD, a heart failure specialist and medical officer with the Food and Drug Administration.

The new findings “look like they could pose a regulatory indication [for sotagliflozin] for patients with type 2 diabetes and heart failure across the entire spectrum of heart failure,” said Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart & Vascular institute in Falls Church, Va., and designated discussant for Dr. Bhatt’s report.

A significant on-treatment reduction in CV death

Other new, notable findings from the meta-analysis included the observation that while treatment with sotagliflozin failed to produce a significant reduction in cardiovascular death, compared with placebo, in the intent-to-treat analysis of all patients and of those with heart failure at baseline (it produced nonsignificant point-estimate reductions of 11% compared with placebo for all patients, and of 23% for patients who began the study with heart failure), it did result in a significant 23% relative risk reduction when the researchers focused on patients while they remained adherent to their sotagliflozin regimen (the on-treatment analysis). This 23% relative reduction appeared among all enrolled patients, as well as in the subgroup that started with diagnosed heart failure.

“Given the totality of data from the SGLT2 inhibitors, I think this is a real finding,” Dr. Bhatt said.

Additional analyses also showed that, among women, treatment with sotagliflozin was linked with significant relative reductions in the primary endpoint of roughly 30% compared with placebo among all patients, and also among those with heart failure at baseline. “HFpEF is a problem particularly in older women, and we showed that the benefit was consistent in men and women,” Dr. Bhatt said.

He acknowledged that results are expected soon from two pivotal trials that are examining two different SGLT2 inhibitors, dapagliflozin and empagliflozin, in patients with HFpEF. “I think there will be a class effect for both SGLT2 inhibitors and sotagliflozin for reducing heart failure events in patients with HFpEF, and I predict that the dapagliflozin and empagliflozin trials will have positive results,” Dr. Bhatt said.

Sotagliflozin differs from the SGLT2 inhibitors by also inhibiting SGLT1, an enzyme found in the gastrointestinal system that, when inhibited, results in increased glucose excretion from the gut and a cut in bloodstream levels of postprandial glucose levels. The Food and Drug Administration accepted data from SCORED and SOLOIST-WHF as part of the evidence the agency is now considering for granting a new drug approval to sotagliflozin.

SCORED and SOLOIST-WHF were initially sponsored by Sanofi, and later by Lexicon Pharmaceuticals. Dr. Bhatt’s institution, Brigham and Women’s Hospital, has received funding from Sanofi and Lexicon Pharmaceuticals. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an adviser to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies. Dr. Piña has no relevant disclosures. Dr. O’Connor has been a consultant to Arena, Bayer, Bristol-Myers Squibb, Merck, and Windtree, and he has an ownership interest in Biscardia.

mzoler@mdedge.com

It’s now official: The investigational sodium-glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin is the first agent clearly shown in a prespecified analysis of randomized trials to improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFpEF).

Researchers who ran the SCORED and SOLOIST-WHF pivotal trials for sotagliflozin first made that claim in November 2020 when reporting top-line results from a prespecified meta-analysis of the two trials during the American Heart Association annual scientific sessions. A follow-up report during the annual scientific sessions of the American College of Cardiology fleshed out the evidence and firmed up their landmark conclusion.

The meta-analysis (Abstract 410-08) included 4,500 patients with type 2 diabetes and diagnosed heart failure at entry; its primary endpoint, which was the same in both trials, was the combined incidence of cardiovascular death and the total number of either hospitalization for heart failure or urgent outpatient visits for heart failure.

Compared with placebo, treatment with sotagliflozin for a median of about 15 months dropped this composite endpoint by a relative 33% among the 1,931 who began the study with a left ventricular ejection fraction (LVEF) of at least 50% (HFpEF), by a relative 22% in the 1,758 patients who entered with an LVEF of less than 40% (patients with heart failure with reduced ejection fraction), and by a relative 43% among the 811 patients who began with an LVEF of 40%-49% (patients with heart failure with mid-range ejection fraction). The relative risk reductions were significant for all three subgroups, Deepak L. Bhatt, MD, reported at the meeting.
 

Equally effective ‘across the full range of LVEFs.’

Perhaps as notable and unprecedented was the further finding that the clinical benefits seen with treatment of patients with type 2 diabetes with sotagliflozin was consistent regardless of the ejection fraction they had at entry. Enrolled patients with baseline LVEFs in the range of 25% received a relative benefit from sotagliflozin treatment that was statistically no different from the benefit seen in patients who entered with an LVEF in the neighborhood of 45%, 65%, or at any other level across the LVEF spectrum, a finding that Dr. Bhatt called “remarkable” during a press briefing. “The results show the benefit of sotagliflozin across the full range of LVEFs.”

“We are very excited in the heart failure world by the SGLT2 inhibitors; we’ve been impressed by their reduction in heart failure hospitalizations, but we wonder about the patients with HFpEF, where we haven’t had a blockbuster drug to give,” said Ileana L. Piña, MD, a heart failure specialist and medical officer with the Food and Drug Administration.

The new findings “look like they could pose a regulatory indication [for sotagliflozin] for patients with type 2 diabetes and heart failure across the entire spectrum of heart failure,” said Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart & Vascular institute in Falls Church, Va., and designated discussant for Dr. Bhatt’s report.

A significant on-treatment reduction in CV death

Other new, notable findings from the meta-analysis included the observation that while treatment with sotagliflozin failed to produce a significant reduction in cardiovascular death, compared with placebo, in the intent-to-treat analysis of all patients and of those with heart failure at baseline (it produced nonsignificant point-estimate reductions of 11% compared with placebo for all patients, and of 23% for patients who began the study with heart failure), it did result in a significant 23% relative risk reduction when the researchers focused on patients while they remained adherent to their sotagliflozin regimen (the on-treatment analysis). This 23% relative reduction appeared among all enrolled patients, as well as in the subgroup that started with diagnosed heart failure.

“Given the totality of data from the SGLT2 inhibitors, I think this is a real finding,” Dr. Bhatt said.

Additional analyses also showed that, among women, treatment with sotagliflozin was linked with significant relative reductions in the primary endpoint of roughly 30% compared with placebo among all patients, and also among those with heart failure at baseline. “HFpEF is a problem particularly in older women, and we showed that the benefit was consistent in men and women,” Dr. Bhatt said.

He acknowledged that results are expected soon from two pivotal trials that are examining two different SGLT2 inhibitors, dapagliflozin and empagliflozin, in patients with HFpEF. “I think there will be a class effect for both SGLT2 inhibitors and sotagliflozin for reducing heart failure events in patients with HFpEF, and I predict that the dapagliflozin and empagliflozin trials will have positive results,” Dr. Bhatt said.

Sotagliflozin differs from the SGLT2 inhibitors by also inhibiting SGLT1, an enzyme found in the gastrointestinal system that, when inhibited, results in increased glucose excretion from the gut and a cut in bloodstream levels of postprandial glucose levels. The Food and Drug Administration accepted data from SCORED and SOLOIST-WHF as part of the evidence the agency is now considering for granting a new drug approval to sotagliflozin.

SCORED and SOLOIST-WHF were initially sponsored by Sanofi, and later by Lexicon Pharmaceuticals. Dr. Bhatt’s institution, Brigham and Women’s Hospital, has received funding from Sanofi and Lexicon Pharmaceuticals. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an adviser to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies. Dr. Piña has no relevant disclosures. Dr. O’Connor has been a consultant to Arena, Bayer, Bristol-Myers Squibb, Merck, and Windtree, and he has an ownership interest in Biscardia.

mzoler@mdedge.com

Although use of some herbal and dietary supplements show statistically greater weight loss compared with placebo, it is not sufficient to benefit health, according to the joint findings of two systematic reviews, which are the first to comprehensively include all available herbal and dietary supplements for weight loss for over 15 years.

Sally Kubetin/MDedge News

“There is currently insufficient evidence to recommend any of the supplements we included in our reviews for weight loss,” stressed lead author Erica Bessell, a PhD candidate from the University of Sydney.

She added that some products with promising results warrant further investigation in well-conducted randomized controlled trials (RCTs) to determine their efficacy and safety.

But, overall, she would like to see a reduction in the number of products on the market without evidence to support their efficacy, “because, as we found, many of the products currently marketed for weight loss just do not work.

“Herbal and dietary supplements might seem like a quick-fix solution to weight problems, but people need to be aware of how little we actually know about them,” she said in an interview. “We would recommend that people trying to lose weight should save their money and seek out evidence-based care instead,” she emphasized.

The research was presented as two posters at this year’s online European Congress on Obesity (ECO). The meeting was presented by the European Association for the Study of Obesity.
 

Herbal and dietary supplement industry booming

Supplements for weight loss are growing in popularity, sustaining a rapidly expanding business sector globally. In the United States, the herbal and dietary supplements industry was estimated to be worth USD $41 billion in 2020, with 15% of Americans having tried a weight loss supplement in their efforts to shed pounds.

In light of this, Ms. Bessell said it is increasingly important to ensure supplements are efficacious and safe: “The popularity of these products underscores the urgency of conducting larger, more rigorous studies to have reasonable assurance of their safety and effectiveness for weight loss.”

Commenting on the study and the wider issues related to the surge in uptake of herbal and dietary supplements, Susan Arentz, PhD, said the evidence is similar to that for other complex interventions that people attempt for weight loss, including for example exercise, in that it is heterogeneous and low quality.

“One outstanding limitation for herbal medicine was the failure of trialists to validate the contents of interventions. Given the chemical variability of plants grown and harvested in different conditions, and the presence of pharmaceuticals and heavy metals found in some supplements ... future investigations of standardized herbal supplements and RCTs of higher methodological quality are needed,” remarked Dr. Arentz, a board member of the Australasian Integrative Medicine Association and researcher at Western Sydney University.

“Also, further RCTs are warranted due to the consumer preferences for natural treatments, especially in health settings with predominant use of traditional medicines and practices,” said Dr. Arentz.   
 

One review for herbal supplements, one for organic compounds

To accommodate the large number of trials investigating supplements for weight loss, the researchers conducted two systematic reviews, together representing 121 randomized placebo-controlled trials. One of the reviews investigated herbal supplements, and the other examined supplements with isolated organic compounds for example, specific fibers or lipids.  

Many of the included trials had been published in the last decade and had not been previously included in an up-to-date systematic review.

Ms. Bessell added that many studies often had a small sample size or were poorly designed, with insufficient information on the composition of supplements, and often featured little data on long-term effectiveness.

The two reviews primarily analyzed efficacy, not safety, because many of the studies did not report adverse effects.

The first review, published last year in Diabetes, Obesity and Metabolism, looked at 54 placebo-controlled randomized trials up to August 2018 on the effect of herbal supplements on weight loss . The study included 4,331 individuals aged 16 years or older who were overweight or obese. To be clinically meaningful, a weight loss of at least 2.5 kg was required over a period of, most often, 12 weeks or less.

Herbal supplements included in the analysis included green tea, Garcinia cambogia and mangosteen (tropical fruits), white kidney bean, ephedra (a stimulant that increases metabolism), African mango, yerba mate (herbal tea made from the leaves and twigs of the Ilex paraguariensis plant), veld grape (commonly used in Indian traditional medicine), licorice root, and East Indian Globe Thistle (used in Ayurvedic medicine).

The second review analyzed 67 randomized trials up to December 2019 that compared the effect of dietary supplements containing naturally occurring isolated organic compounds to placebo for weight loss in 5,194 individuals aged 16 years or older who were overweight or obese.

Meta-analyses were conducted for chitosan, glucomannan, conjugated linoleic acid, and fructans comparing the mean weight difference post intervention between participants receiving the dietary supplement and those on placebo.
 

No clinically significant results

Commenting on the overall results, Ms. Bessell said: “Though most supplements were safe for use in the short term, very few were found to produce clinically meaningful weight loss. Those that were found to result in clinically meaningful weight loss had only been investigated in one or two trials, so we need more research.”

The first review on herbal supplements found that only Phaseolus vulgaris (white kidney bean) resulted in significant weight loss compared with placebo, with an average weight difference of 1.61 kg (3.5 pounds). The result was not clinically meaningful, however.

For isolated organic compounds, significant weight differences compared with placebo were seen for chitosan, with a mean difference of 1.84 kg (4 pounds), glucomannan at 1.27 kg (2.8 pounds), and conjugated linoleic acid at 1.08 kg (2.4 pounds).

Again, none of these findings met the criteria for clinical significance (weight loss of 2.5 kg [5.5 pounds] or more).

In addition, some combination preparations containing African mango, veld grape, East Indian Globe Thistle, and mangosteen showed promising results with a mean weight difference of 1.85 kg (4 pounds), but were investigated in three or fewer trials, often with poor research methodology or reporting, and the findings should be interpreted with caution, the researchers noted.

Other dietary supplements, including modified cellulose – a plant fiber that expands in the stomach to induce a feeling of fullness – and blood orange juice extract, also showed encouraging results but were investigated in one trial and need more evidence before they can be recommended for weight loss, Ms. Bessell added.

She pointed out that some supplements are banned in some countries, such as ephedra (an extract from the plant Ephedra sinica). “This supplement is already banned in many countries because of the risk of serious adverse effects. The possibility of drug interactions may also be present with some other supplements, so health professionals and consumers should be aware of this.”

The isolated organic compounds supplements review was published in the International Journal of Obesity to coincide with the ECO 2021 conference.

Ms. Bessell has declared no relevant conflicts of interests. Dr. Arentz reviewed the systematic review of RCTs of herbal medicine supplements for weight loss published in Diabetes, Obesity and Metabolism.
 

A version of this article first appeared on Medscape.com.

Although use of some herbal and dietary supplements show statistically greater weight loss compared with placebo, it is not sufficient to benefit health, according to the joint findings of two systematic reviews, which are the first to comprehensively include all available herbal and dietary supplements for weight loss for over 15 years.

Sally Kubetin/MDedge News

“There is currently insufficient evidence to recommend any of the supplements we included in our reviews for weight loss,” stressed lead author Erica Bessell, a PhD candidate from the University of Sydney.

She added that some products with promising results warrant further investigation in well-conducted randomized controlled trials (RCTs) to determine their efficacy and safety.

But, overall, she would like to see a reduction in the number of products on the market without evidence to support their efficacy, “because, as we found, many of the products currently marketed for weight loss just do not work.

“Herbal and dietary supplements might seem like a quick-fix solution to weight problems, but people need to be aware of how little we actually know about them,” she said in an interview. “We would recommend that people trying to lose weight should save their money and seek out evidence-based care instead,” she emphasized.

The research was presented as two posters at this year’s online European Congress on Obesity (ECO). The meeting was presented by the European Association for the Study of Obesity.
 

Herbal and dietary supplement industry booming

Supplements for weight loss are growing in popularity, sustaining a rapidly expanding business sector globally. In the United States, the herbal and dietary supplements industry was estimated to be worth USD $41 billion in 2020, with 15% of Americans having tried a weight loss supplement in their efforts to shed pounds.

In light of this, Ms. Bessell said it is increasingly important to ensure supplements are efficacious and safe: “The popularity of these products underscores the urgency of conducting larger, more rigorous studies to have reasonable assurance of their safety and effectiveness for weight loss.”

Commenting on the study and the wider issues related to the surge in uptake of herbal and dietary supplements, Susan Arentz, PhD, said the evidence is similar to that for other complex interventions that people attempt for weight loss, including for example exercise, in that it is heterogeneous and low quality.

“One outstanding limitation for herbal medicine was the failure of trialists to validate the contents of interventions. Given the chemical variability of plants grown and harvested in different conditions, and the presence of pharmaceuticals and heavy metals found in some supplements ... future investigations of standardized herbal supplements and RCTs of higher methodological quality are needed,” remarked Dr. Arentz, a board member of the Australasian Integrative Medicine Association and researcher at Western Sydney University.

“Also, further RCTs are warranted due to the consumer preferences for natural treatments, especially in health settings with predominant use of traditional medicines and practices,” said Dr. Arentz.   
 

One review for herbal supplements, one for organic compounds

To accommodate the large number of trials investigating supplements for weight loss, the researchers conducted two systematic reviews, together representing 121 randomized placebo-controlled trials. One of the reviews investigated herbal supplements, and the other examined supplements with isolated organic compounds for example, specific fibers or lipids.  

Many of the included trials had been published in the last decade and had not been previously included in an up-to-date systematic review.

Ms. Bessell added that many studies often had a small sample size or were poorly designed, with insufficient information on the composition of supplements, and often featured little data on long-term effectiveness.

The two reviews primarily analyzed efficacy, not safety, because many of the studies did not report adverse effects.

The first review, published last year in Diabetes, Obesity and Metabolism, looked at 54 placebo-controlled randomized trials up to August 2018 on the effect of herbal supplements on weight loss . The study included 4,331 individuals aged 16 years or older who were overweight or obese. To be clinically meaningful, a weight loss of at least 2.5 kg was required over a period of, most often, 12 weeks or less.

Herbal supplements included in the analysis included green tea, Garcinia cambogia and mangosteen (tropical fruits), white kidney bean, ephedra (a stimulant that increases metabolism), African mango, yerba mate (herbal tea made from the leaves and twigs of the Ilex paraguariensis plant), veld grape (commonly used in Indian traditional medicine), licorice root, and East Indian Globe Thistle (used in Ayurvedic medicine).

The second review analyzed 67 randomized trials up to December 2019 that compared the effect of dietary supplements containing naturally occurring isolated organic compounds to placebo for weight loss in 5,194 individuals aged 16 years or older who were overweight or obese.

Meta-analyses were conducted for chitosan, glucomannan, conjugated linoleic acid, and fructans comparing the mean weight difference post intervention between participants receiving the dietary supplement and those on placebo.
 

No clinically significant results

Commenting on the overall results, Ms. Bessell said: “Though most supplements were safe for use in the short term, very few were found to produce clinically meaningful weight loss. Those that were found to result in clinically meaningful weight loss had only been investigated in one or two trials, so we need more research.”

The first review on herbal supplements found that only Phaseolus vulgaris (white kidney bean) resulted in significant weight loss compared with placebo, with an average weight difference of 1.61 kg (3.5 pounds). The result was not clinically meaningful, however.

For isolated organic compounds, significant weight differences compared with placebo were seen for chitosan, with a mean difference of 1.84 kg (4 pounds), glucomannan at 1.27 kg (2.8 pounds), and conjugated linoleic acid at 1.08 kg (2.4 pounds).

Again, none of these findings met the criteria for clinical significance (weight loss of 2.5 kg [5.5 pounds] or more).

In addition, some combination preparations containing African mango, veld grape, East Indian Globe Thistle, and mangosteen showed promising results with a mean weight difference of 1.85 kg (4 pounds), but were investigated in three or fewer trials, often with poor research methodology or reporting, and the findings should be interpreted with caution, the researchers noted.

Other dietary supplements, including modified cellulose – a plant fiber that expands in the stomach to induce a feeling of fullness – and blood orange juice extract, also showed encouraging results but were investigated in one trial and need more evidence before they can be recommended for weight loss, Ms. Bessell added.

She pointed out that some supplements are banned in some countries, such as ephedra (an extract from the plant Ephedra sinica). “This supplement is already banned in many countries because of the risk of serious adverse effects. The possibility of drug interactions may also be present with some other supplements, so health professionals and consumers should be aware of this.”

The isolated organic compounds supplements review was published in the International Journal of Obesity to coincide with the ECO 2021 conference.

Ms. Bessell has declared no relevant conflicts of interests. Dr. Arentz reviewed the systematic review of RCTs of herbal medicine supplements for weight loss published in Diabetes, Obesity and Metabolism.
 

A version of this article first appeared on Medscape.com.

Although use of some herbal and dietary supplements show statistically greater weight loss compared with placebo, it is not sufficient to benefit health, according to the joint findings of two systematic reviews, which are the first to comprehensively include all available herbal and dietary supplements for weight loss for over 15 years.

Sally Kubetin/MDedge News

“There is currently insufficient evidence to recommend any of the supplements we included in our reviews for weight loss,” stressed lead author Erica Bessell, a PhD candidate from the University of Sydney.

She added that some products with promising results warrant further investigation in well-conducted randomized controlled trials (RCTs) to determine their efficacy and safety.

But, overall, she would like to see a reduction in the number of products on the market without evidence to support their efficacy, “because, as we found, many of the products currently marketed for weight loss just do not work.

“Herbal and dietary supplements might seem like a quick-fix solution to weight problems, but people need to be aware of how little we actually know about them,” she said in an interview. “We would recommend that people trying to lose weight should save their money and seek out evidence-based care instead,” she emphasized.

The research was presented as two posters at this year’s online European Congress on Obesity (ECO). The meeting was presented by the European Association for the Study of Obesity.
 

Herbal and dietary supplement industry booming

Supplements for weight loss are growing in popularity, sustaining a rapidly expanding business sector globally. In the United States, the herbal and dietary supplements industry was estimated to be worth USD $41 billion in 2020, with 15% of Americans having tried a weight loss supplement in their efforts to shed pounds.

In light of this, Ms. Bessell said it is increasingly important to ensure supplements are efficacious and safe: “The popularity of these products underscores the urgency of conducting larger, more rigorous studies to have reasonable assurance of their safety and effectiveness for weight loss.”

Commenting on the study and the wider issues related to the surge in uptake of herbal and dietary supplements, Susan Arentz, PhD, said the evidence is similar to that for other complex interventions that people attempt for weight loss, including for example exercise, in that it is heterogeneous and low quality.

“One outstanding limitation for herbal medicine was the failure of trialists to validate the contents of interventions. Given the chemical variability of plants grown and harvested in different conditions, and the presence of pharmaceuticals and heavy metals found in some supplements ... future investigations of standardized herbal supplements and RCTs of higher methodological quality are needed,” remarked Dr. Arentz, a board member of the Australasian Integrative Medicine Association and researcher at Western Sydney University.

“Also, further RCTs are warranted due to the consumer preferences for natural treatments, especially in health settings with predominant use of traditional medicines and practices,” said Dr. Arentz.   
 

One review for herbal supplements, one for organic compounds

To accommodate the large number of trials investigating supplements for weight loss, the researchers conducted two systematic reviews, together representing 121 randomized placebo-controlled trials. One of the reviews investigated herbal supplements, and the other examined supplements with isolated organic compounds for example, specific fibers or lipids.  

Many of the included trials had been published in the last decade and had not been previously included in an up-to-date systematic review.

Ms. Bessell added that many studies often had a small sample size or were poorly designed, with insufficient information on the composition of supplements, and often featured little data on long-term effectiveness.

The two reviews primarily analyzed efficacy, not safety, because many of the studies did not report adverse effects.

The first review, published last year in Diabetes, Obesity and Metabolism, looked at 54 placebo-controlled randomized trials up to August 2018 on the effect of herbal supplements on weight loss . The study included 4,331 individuals aged 16 years or older who were overweight or obese. To be clinically meaningful, a weight loss of at least 2.5 kg was required over a period of, most often, 12 weeks or less.

Herbal supplements included in the analysis included green tea, Garcinia cambogia and mangosteen (tropical fruits), white kidney bean, ephedra (a stimulant that increases metabolism), African mango, yerba mate (herbal tea made from the leaves and twigs of the Ilex paraguariensis plant), veld grape (commonly used in Indian traditional medicine), licorice root, and East Indian Globe Thistle (used in Ayurvedic medicine).

The second review analyzed 67 randomized trials up to December 2019 that compared the effect of dietary supplements containing naturally occurring isolated organic compounds to placebo for weight loss in 5,194 individuals aged 16 years or older who were overweight or obese.

Meta-analyses were conducted for chitosan, glucomannan, conjugated linoleic acid, and fructans comparing the mean weight difference post intervention between participants receiving the dietary supplement and those on placebo.
 

No clinically significant results

Commenting on the overall results, Ms. Bessell said: “Though most supplements were safe for use in the short term, very few were found to produce clinically meaningful weight loss. Those that were found to result in clinically meaningful weight loss had only been investigated in one or two trials, so we need more research.”

The first review on herbal supplements found that only Phaseolus vulgaris (white kidney bean) resulted in significant weight loss compared with placebo, with an average weight difference of 1.61 kg (3.5 pounds). The result was not clinically meaningful, however.

For isolated organic compounds, significant weight differences compared with placebo were seen for chitosan, with a mean difference of 1.84 kg (4 pounds), glucomannan at 1.27 kg (2.8 pounds), and conjugated linoleic acid at 1.08 kg (2.4 pounds).

Again, none of these findings met the criteria for clinical significance (weight loss of 2.5 kg [5.5 pounds] or more).

In addition, some combination preparations containing African mango, veld grape, East Indian Globe Thistle, and mangosteen showed promising results with a mean weight difference of 1.85 kg (4 pounds), but were investigated in three or fewer trials, often with poor research methodology or reporting, and the findings should be interpreted with caution, the researchers noted.

Other dietary supplements, including modified cellulose – a plant fiber that expands in the stomach to induce a feeling of fullness – and blood orange juice extract, also showed encouraging results but were investigated in one trial and need more evidence before they can be recommended for weight loss, Ms. Bessell added.

She pointed out that some supplements are banned in some countries, such as ephedra (an extract from the plant Ephedra sinica). “This supplement is already banned in many countries because of the risk of serious adverse effects. The possibility of drug interactions may also be present with some other supplements, so health professionals and consumers should be aware of this.”

The isolated organic compounds supplements review was published in the International Journal of Obesity to coincide with the ECO 2021 conference.

Ms. Bessell has declared no relevant conflicts of interests. Dr. Arentz reviewed the systematic review of RCTs of herbal medicine supplements for weight loss published in Diabetes, Obesity and Metabolism.
 

A version of this article first appeared on Medscape.com.

Adults in treatment for opioid dependence report high satisfaction with buprenorphine injections, in new findings that researchers say could help improve treatment and management of patients with opioid dependence.

In the DEBUT trial, patients who received weekly or monthly depot buprenorphine had significantly higher overall treatment satisfaction, reduced treatment burden, and higher quality-of-life ratings than peers who received daily treatment with sublingual buprenorphine.

“The study’s focus on patient-reported outcomes (PROs) can help to better inform patients and clinicians when selecting treatment options than the clinical traditional outcomes of opioid dependence treatment studies,” lead investigator Fredrik Tiberg, PhD, president and CEO of Camurus, a pharmaceutical company in Lund, Sweden, said in an interview.

“The positive patient experiences with the depot buprenorphine injection reported in the DEBUT study indicate that long-acting treatments could contribute to advancing the quality of care and access to treatment for patients with opioid dependence/use disorder,” said Dr. Tiberg.

The study was published online May 10 in JAMA Network Open.
 

Novel study

The study was an open-label, parallel-group randomized controlled trial that included 119 patients from six outpatient clinics in Australia; 60 received weekly or monthly depot buprenorphine and 59 received sublingual buprenorphine for 24 weeks.

The primary outcome was global treatment satisfaction, as measured by the 14-question Treatment Satisfaction Questionnaire for Medication (TSQM) at the end of the study at week 24.

The study met its primary endpoint with a significantly higher TSQM global satisfaction score among adults who received depot injections, compared with those who received sublingual buprenorphine (mean score 82.5 vs. 74.3; difference, 8.2; 95% confidence interval, 1.7-14.6; P = .01).

Improvement was also observed for several secondary outcomes, including decreased treatment burden and higher quality of life.

The safety profile was consistent with the known safety profile of buprenorphine, aside from transient, mild-to-moderate injection site reactions.

“To our knowledge, this is the first randomized study that has used a range of PROs to compare outcomes between a long-acting injection and daily dosing of buprenorphine in the treatment of opioid dependence,” the investigators note.

“The study highlights the application of PROs as alternate endpoints to traditional markers of substance use in addiction treatment outcome studies,” they conclude.
 

Giving patients a voice

In an invited commentary, Nora D. Volkow, MD, director of the National Institute on Drug Abuse, and Wilson M. Compton, MD, deputy director of NIDA, note that the “voice of the patient” has been missing from most of the work in medication development, including for opioid use disorder.

The current study addresses this very issue in a “well designed and executed” fashion and the results “consistently demonstrated” the superiority of injectable buprenorphine across many outcomes.

The study highlights the importance of considering PRO measures in clinical trials, Dr. Volkow and Dr. Compton say.

“Even if efficacy is no different for various formulations, PROs may provide an important reason to select a new formulation. Patient preferences and apparently improved function may prove to be useful secondary outcomes in medication trials, and the measures used in this new study deserve consideration,” they write.

In addition, the greater treatment satisfaction by patients receiving extended-release buprenorphine suggests that these formulations “might help to improve long-term retention and, as such, be a valuable tool to help combat the current opioid epidemic and reduce its associated mortality,” they conclude.

This study was supported by Camurus AB. Dr. Tiberg is president and CEO of Camurus AB. A complete list of author disclosures is with the original article. Dr. Volkow and Dr. Compton have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Adults in treatment for opioid dependence report high satisfaction with buprenorphine injections, in new findings that researchers say could help improve treatment and management of patients with opioid dependence.

In the DEBUT trial, patients who received weekly or monthly depot buprenorphine had significantly higher overall treatment satisfaction, reduced treatment burden, and higher quality-of-life ratings than peers who received daily treatment with sublingual buprenorphine.

“The study’s focus on patient-reported outcomes (PROs) can help to better inform patients and clinicians when selecting treatment options than the clinical traditional outcomes of opioid dependence treatment studies,” lead investigator Fredrik Tiberg, PhD, president and CEO of Camurus, a pharmaceutical company in Lund, Sweden, said in an interview.

“The positive patient experiences with the depot buprenorphine injection reported in the DEBUT study indicate that long-acting treatments could contribute to advancing the quality of care and access to treatment for patients with opioid dependence/use disorder,” said Dr. Tiberg.

The study was published online May 10 in JAMA Network Open.
 

Novel study

The study was an open-label, parallel-group randomized controlled trial that included 119 patients from six outpatient clinics in Australia; 60 received weekly or monthly depot buprenorphine and 59 received sublingual buprenorphine for 24 weeks.

The primary outcome was global treatment satisfaction, as measured by the 14-question Treatment Satisfaction Questionnaire for Medication (TSQM) at the end of the study at week 24.

The study met its primary endpoint with a significantly higher TSQM global satisfaction score among adults who received depot injections, compared with those who received sublingual buprenorphine (mean score 82.5 vs. 74.3; difference, 8.2; 95% confidence interval, 1.7-14.6; P = .01).

Improvement was also observed for several secondary outcomes, including decreased treatment burden and higher quality of life.

The safety profile was consistent with the known safety profile of buprenorphine, aside from transient, mild-to-moderate injection site reactions.

“To our knowledge, this is the first randomized study that has used a range of PROs to compare outcomes between a long-acting injection and daily dosing of buprenorphine in the treatment of opioid dependence,” the investigators note.

“The study highlights the application of PROs as alternate endpoints to traditional markers of substance use in addiction treatment outcome studies,” they conclude.
 

Giving patients a voice

In an invited commentary, Nora D. Volkow, MD, director of the National Institute on Drug Abuse, and Wilson M. Compton, MD, deputy director of NIDA, note that the “voice of the patient” has been missing from most of the work in medication development, including for opioid use disorder.

The current study addresses this very issue in a “well designed and executed” fashion and the results “consistently demonstrated” the superiority of injectable buprenorphine across many outcomes.

The study highlights the importance of considering PRO measures in clinical trials, Dr. Volkow and Dr. Compton say.

“Even if efficacy is no different for various formulations, PROs may provide an important reason to select a new formulation. Patient preferences and apparently improved function may prove to be useful secondary outcomes in medication trials, and the measures used in this new study deserve consideration,” they write.

In addition, the greater treatment satisfaction by patients receiving extended-release buprenorphine suggests that these formulations “might help to improve long-term retention and, as such, be a valuable tool to help combat the current opioid epidemic and reduce its associated mortality,” they conclude.

This study was supported by Camurus AB. Dr. Tiberg is president and CEO of Camurus AB. A complete list of author disclosures is with the original article. Dr. Volkow and Dr. Compton have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Adults in treatment for opioid dependence report high satisfaction with buprenorphine injections, in new findings that researchers say could help improve treatment and management of patients with opioid dependence.

In the DEBUT trial, patients who received weekly or monthly depot buprenorphine had significantly higher overall treatment satisfaction, reduced treatment burden, and higher quality-of-life ratings than peers who received daily treatment with sublingual buprenorphine.

“The study’s focus on patient-reported outcomes (PROs) can help to better inform patients and clinicians when selecting treatment options than the clinical traditional outcomes of opioid dependence treatment studies,” lead investigator Fredrik Tiberg, PhD, president and CEO of Camurus, a pharmaceutical company in Lund, Sweden, said in an interview.

“The positive patient experiences with the depot buprenorphine injection reported in the DEBUT study indicate that long-acting treatments could contribute to advancing the quality of care and access to treatment for patients with opioid dependence/use disorder,” said Dr. Tiberg.

The study was published online May 10 in JAMA Network Open.
 

Novel study

The study was an open-label, parallel-group randomized controlled trial that included 119 patients from six outpatient clinics in Australia; 60 received weekly or monthly depot buprenorphine and 59 received sublingual buprenorphine for 24 weeks.

The primary outcome was global treatment satisfaction, as measured by the 14-question Treatment Satisfaction Questionnaire for Medication (TSQM) at the end of the study at week 24.

The study met its primary endpoint with a significantly higher TSQM global satisfaction score among adults who received depot injections, compared with those who received sublingual buprenorphine (mean score 82.5 vs. 74.3; difference, 8.2; 95% confidence interval, 1.7-14.6; P = .01).

Improvement was also observed for several secondary outcomes, including decreased treatment burden and higher quality of life.

The safety profile was consistent with the known safety profile of buprenorphine, aside from transient, mild-to-moderate injection site reactions.

“To our knowledge, this is the first randomized study that has used a range of PROs to compare outcomes between a long-acting injection and daily dosing of buprenorphine in the treatment of opioid dependence,” the investigators note.

“The study highlights the application of PROs as alternate endpoints to traditional markers of substance use in addiction treatment outcome studies,” they conclude.
 

Giving patients a voice

In an invited commentary, Nora D. Volkow, MD, director of the National Institute on Drug Abuse, and Wilson M. Compton, MD, deputy director of NIDA, note that the “voice of the patient” has been missing from most of the work in medication development, including for opioid use disorder.

The current study addresses this very issue in a “well designed and executed” fashion and the results “consistently demonstrated” the superiority of injectable buprenorphine across many outcomes.

The study highlights the importance of considering PRO measures in clinical trials, Dr. Volkow and Dr. Compton say.

“Even if efficacy is no different for various formulations, PROs may provide an important reason to select a new formulation. Patient preferences and apparently improved function may prove to be useful secondary outcomes in medication trials, and the measures used in this new study deserve consideration,” they write.

In addition, the greater treatment satisfaction by patients receiving extended-release buprenorphine suggests that these formulations “might help to improve long-term retention and, as such, be a valuable tool to help combat the current opioid epidemic and reduce its associated mortality,” they conclude.

This study was supported by Camurus AB. Dr. Tiberg is president and CEO of Camurus AB. A complete list of author disclosures is with the original article. Dr. Volkow and Dr. Compton have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Perimenopausal women are using prescription sleep medications for long periods of time despite no evidence of efficacy, a new study shows.

“While there are good data from [randomized, controlled trials] that these medications improve sleep disturbances in the short term,” few studies have examined whether they provide long-term benefits, stated the authors of the paper, which was published in BMJ Open.

“The current observational study does not support use of sleep medications over the long term, as there were no self-reported differences at 1 or 2 years of follow-up comparing sleep medication users with nonusers,” author Daniel H. Solomon, MD, MPH, from Brigham and Women’s Hospital, Boston, and colleagues wrote.

Women included in the analysis were drawn from the Study of Women’s Health Across the Nation (SWAN), an ongoing multicenter, longitudinal study examining women during the menopausal transition. The average age of the women included in the cohort was 49.5 years and approximately half were White. All women reported a sleep disturbance on at least 3 nights per week during a 2-week interval. At follow up, women were asked to use a Likert scale to rate three aspects of sleep: difficulty initiating sleep, frequent awakening, and waking up early. On the scale, 1 represented having no difficulties on any nights, 3 represented having difficulties 1-2 nights per week, and 5 represented having difficulty 5-7 nights per week.

Women already using prescription sleep medication at their baseline visit were excluded from the study. Medications used included benzodiazepines, selective BZD receptor agonists, and other hypnotics.

Over the 21 years of follow-up in the SWAN study (1995-2016), Dr. Solomon and colleagues identified 238 women using sleep medication and these were compared with a cohort of 447 propensity score–matched non–sleep medication uses. Overall, the 685 women included were similar in characteristics to each other as well as to the other potentially eligible women not included in the analysis.
 

Sleep disturbance patterns compared

At baseline, sleep disturbance patterns were similar between the two groups. Among medication users, the mean score for difficulty initiating sleep was 2.7 (95% confidence interval, 2.5-2.9), waking frequently 3.8 (95% CI, 3.6-3.9), and waking early 2.9 (95% CI, 2.7-3.1). Among the nonusers, the baseline scores were 2.6 (95% CI, 2.5-2.7), 3.7 (95% CI, 3.6-3.8), and 2.7 (95% CI, 2.5-2.8), respectively. After 1 year, there was no statistically significant difference in scores between the two groups. The average ratings for medication users were 2.6 (95% CI, 2.3-2.8) for difficulty initiating sleep, 3.8 (95% CI, 3.6-4.0) for waking frequently, and 2.8 (95% CI, 2.6-3.0) for waking early.

Average ratings among nonusers were 2.3 (95% CI, 2.2-2.4), 3.5 (95% CI, 3.3-3.6), and 2.5 (95% CI, 2.3-2.6), respectively.

After 2 years, there were still no statistically significant reductions in sleep disturbances among those taking prescription sleep medications, compared with those not taking medication.

The researchers noted that approximately half of the women in this cohort were current or past tobacco users and that 20% were moderate to heavy alcohol users.
 

More work-up, not more medication, needed

The study authors acknowledged the limitations of an observational study and noted that, since participants only reported medication use and sleep disturbances at annual visits, they did not know whether patients’ medication use was intermittent or of any interim outcomes. Additionally, the authors pointed out that those classified as “nonusers” may have been using over-the-counter medication.

“Investigations should look at detailed-use patterns, on a daily or weekly basis, with frequent outcomes data,” Dr. Solomon said in an interview. “While our data shed new light on chronic use, we only had data collected on an annual basis; daily or weekly data would provide more granular information.”

Regarding clinician prescribing practices, Dr. Solomon said, “short-term, intermittent use can be helpful, but use these agents sparingly” and “educate patients that chronic regular use of medications for sleep is not associated with improvement in sleep disturbances.”

Commenting on the study, Andrea Matsumura, MD, a sleep specialist at the Oregon Clinic in Portland, echoed this sentiment: “When someone says they are having trouble sleeping this is the tip of the iceberg and it warrants an evaluation to determine if someone has a breathing disorder, a circadian disorder, a life situation, or a type of insomnia that is driving the sleeplessness.”

“I think this study supports what we all should know,” Dr. Matsumura concluded. “Sleep aids are not meant to be used long term” and should not be used for longer than 2 weeks without further work-up.

Funding for this study was provided through a grant from the National Institutes of Health. Dr. Solomon has received salary support from research grants to Brigham and Women’s Hospital for unrelated work from AbbVie, Amgen, Corrona, Genentech and Pfizer. The other authors and Dr. Matsumura have reported no relevant financial relationships.

Perimenopausal women are using prescription sleep medications for long periods of time despite no evidence of efficacy, a new study shows.

“While there are good data from [randomized, controlled trials] that these medications improve sleep disturbances in the short term,” few studies have examined whether they provide long-term benefits, stated the authors of the paper, which was published in BMJ Open.

“The current observational study does not support use of sleep medications over the long term, as there were no self-reported differences at 1 or 2 years of follow-up comparing sleep medication users with nonusers,” author Daniel H. Solomon, MD, MPH, from Brigham and Women’s Hospital, Boston, and colleagues wrote.

Women included in the analysis were drawn from the Study of Women’s Health Across the Nation (SWAN), an ongoing multicenter, longitudinal study examining women during the menopausal transition. The average age of the women included in the cohort was 49.5 years and approximately half were White. All women reported a sleep disturbance on at least 3 nights per week during a 2-week interval. At follow up, women were asked to use a Likert scale to rate three aspects of sleep: difficulty initiating sleep, frequent awakening, and waking up early. On the scale, 1 represented having no difficulties on any nights, 3 represented having difficulties 1-2 nights per week, and 5 represented having difficulty 5-7 nights per week.

Women already using prescription sleep medication at their baseline visit were excluded from the study. Medications used included benzodiazepines, selective BZD receptor agonists, and other hypnotics.

Over the 21 years of follow-up in the SWAN study (1995-2016), Dr. Solomon and colleagues identified 238 women using sleep medication and these were compared with a cohort of 447 propensity score–matched non–sleep medication uses. Overall, the 685 women included were similar in characteristics to each other as well as to the other potentially eligible women not included in the analysis.
 

Sleep disturbance patterns compared

At baseline, sleep disturbance patterns were similar between the two groups. Among medication users, the mean score for difficulty initiating sleep was 2.7 (95% confidence interval, 2.5-2.9), waking frequently 3.8 (95% CI, 3.6-3.9), and waking early 2.9 (95% CI, 2.7-3.1). Among the nonusers, the baseline scores were 2.6 (95% CI, 2.5-2.7), 3.7 (95% CI, 3.6-3.8), and 2.7 (95% CI, 2.5-2.8), respectively. After 1 year, there was no statistically significant difference in scores between the two groups. The average ratings for medication users were 2.6 (95% CI, 2.3-2.8) for difficulty initiating sleep, 3.8 (95% CI, 3.6-4.0) for waking frequently, and 2.8 (95% CI, 2.6-3.0) for waking early.

Average ratings among nonusers were 2.3 (95% CI, 2.2-2.4), 3.5 (95% CI, 3.3-3.6), and 2.5 (95% CI, 2.3-2.6), respectively.

After 2 years, there were still no statistically significant reductions in sleep disturbances among those taking prescription sleep medications, compared with those not taking medication.

The researchers noted that approximately half of the women in this cohort were current or past tobacco users and that 20% were moderate to heavy alcohol users.
 

More work-up, not more medication, needed

The study authors acknowledged the limitations of an observational study and noted that, since participants only reported medication use and sleep disturbances at annual visits, they did not know whether patients’ medication use was intermittent or of any interim outcomes. Additionally, the authors pointed out that those classified as “nonusers” may have been using over-the-counter medication.

“Investigations should look at detailed-use patterns, on a daily or weekly basis, with frequent outcomes data,” Dr. Solomon said in an interview. “While our data shed new light on chronic use, we only had data collected on an annual basis; daily or weekly data would provide more granular information.”

Regarding clinician prescribing practices, Dr. Solomon said, “short-term, intermittent use can be helpful, but use these agents sparingly” and “educate patients that chronic regular use of medications for sleep is not associated with improvement in sleep disturbances.”

Commenting on the study, Andrea Matsumura, MD, a sleep specialist at the Oregon Clinic in Portland, echoed this sentiment: “When someone says they are having trouble sleeping this is the tip of the iceberg and it warrants an evaluation to determine if someone has a breathing disorder, a circadian disorder, a life situation, or a type of insomnia that is driving the sleeplessness.”

“I think this study supports what we all should know,” Dr. Matsumura concluded. “Sleep aids are not meant to be used long term” and should not be used for longer than 2 weeks without further work-up.

Funding for this study was provided through a grant from the National Institutes of Health. Dr. Solomon has received salary support from research grants to Brigham and Women’s Hospital for unrelated work from AbbVie, Amgen, Corrona, Genentech and Pfizer. The other authors and Dr. Matsumura have reported no relevant financial relationships.

Perimenopausal women are using prescription sleep medications for long periods of time despite no evidence of efficacy, a new study shows.

“While there are good data from [randomized, controlled trials] that these medications improve sleep disturbances in the short term,” few studies have examined whether they provide long-term benefits, stated the authors of the paper, which was published in BMJ Open.

“The current observational study does not support use of sleep medications over the long term, as there were no self-reported differences at 1 or 2 years of follow-up comparing sleep medication users with nonusers,” author Daniel H. Solomon, MD, MPH, from Brigham and Women’s Hospital, Boston, and colleagues wrote.

Women included in the analysis were drawn from the Study of Women’s Health Across the Nation (SWAN), an ongoing multicenter, longitudinal study examining women during the menopausal transition. The average age of the women included in the cohort was 49.5 years and approximately half were White. All women reported a sleep disturbance on at least 3 nights per week during a 2-week interval. At follow up, women were asked to use a Likert scale to rate three aspects of sleep: difficulty initiating sleep, frequent awakening, and waking up early. On the scale, 1 represented having no difficulties on any nights, 3 represented having difficulties 1-2 nights per week, and 5 represented having difficulty 5-7 nights per week.

Women already using prescription sleep medication at their baseline visit were excluded from the study. Medications used included benzodiazepines, selective BZD receptor agonists, and other hypnotics.

Over the 21 years of follow-up in the SWAN study (1995-2016), Dr. Solomon and colleagues identified 238 women using sleep medication and these were compared with a cohort of 447 propensity score–matched non–sleep medication uses. Overall, the 685 women included were similar in characteristics to each other as well as to the other potentially eligible women not included in the analysis.
 

Sleep disturbance patterns compared

At baseline, sleep disturbance patterns were similar between the two groups. Among medication users, the mean score for difficulty initiating sleep was 2.7 (95% confidence interval, 2.5-2.9), waking frequently 3.8 (95% CI, 3.6-3.9), and waking early 2.9 (95% CI, 2.7-3.1). Among the nonusers, the baseline scores were 2.6 (95% CI, 2.5-2.7), 3.7 (95% CI, 3.6-3.8), and 2.7 (95% CI, 2.5-2.8), respectively. After 1 year, there was no statistically significant difference in scores between the two groups. The average ratings for medication users were 2.6 (95% CI, 2.3-2.8) for difficulty initiating sleep, 3.8 (95% CI, 3.6-4.0) for waking frequently, and 2.8 (95% CI, 2.6-3.0) for waking early.

Average ratings among nonusers were 2.3 (95% CI, 2.2-2.4), 3.5 (95% CI, 3.3-3.6), and 2.5 (95% CI, 2.3-2.6), respectively.

After 2 years, there were still no statistically significant reductions in sleep disturbances among those taking prescription sleep medications, compared with those not taking medication.

The researchers noted that approximately half of the women in this cohort were current or past tobacco users and that 20% were moderate to heavy alcohol users.
 

More work-up, not more medication, needed

The study authors acknowledged the limitations of an observational study and noted that, since participants only reported medication use and sleep disturbances at annual visits, they did not know whether patients’ medication use was intermittent or of any interim outcomes. Additionally, the authors pointed out that those classified as “nonusers” may have been using over-the-counter medication.

“Investigations should look at detailed-use patterns, on a daily or weekly basis, with frequent outcomes data,” Dr. Solomon said in an interview. “While our data shed new light on chronic use, we only had data collected on an annual basis; daily or weekly data would provide more granular information.”

Regarding clinician prescribing practices, Dr. Solomon said, “short-term, intermittent use can be helpful, but use these agents sparingly” and “educate patients that chronic regular use of medications for sleep is not associated with improvement in sleep disturbances.”

Commenting on the study, Andrea Matsumura, MD, a sleep specialist at the Oregon Clinic in Portland, echoed this sentiment: “When someone says they are having trouble sleeping this is the tip of the iceberg and it warrants an evaluation to determine if someone has a breathing disorder, a circadian disorder, a life situation, or a type of insomnia that is driving the sleeplessness.”

“I think this study supports what we all should know,” Dr. Matsumura concluded. “Sleep aids are not meant to be used long term” and should not be used for longer than 2 weeks without further work-up.

Funding for this study was provided through a grant from the National Institutes of Health. Dr. Solomon has received salary support from research grants to Brigham and Women’s Hospital for unrelated work from AbbVie, Amgen, Corrona, Genentech and Pfizer. The other authors and Dr. Matsumura have reported no relevant financial relationships.

Psychotherapy and pharmacotherapy appear to be similarly effective for the treatment of depression, and a combination of both treatments might pack the biggest punch, according to a network meta-analysis (NMA) comparing either and both approaches with control conditions in the primary care setting.

The findings are important, since the majority of depressed patients are treated by primary care physicians, yet relatively few randomized trials of treatment have focused on this setting, noted senior study author Pim Cuijpers, PhD, from Vrije Universiteit Amsterdam, and colleagues, in the paper, which was published in Annals of Family Medicine.

“The main message is that clinicians should certainly consider psychotherapy instead of pharmacotherapy, because this is preferred by most patients, and when possible, combined treatments should be the preferred choice because the outcomes are considerably better,” he said in an interview. Either way, he emphasized that “preference of patients is very important and all three treatments are better than usual care.”

The NMA included studies comparing psychotherapy, antidepressant medication, or a combination of both, with control conditions (defined as usual care, wait list, or pill placebo) in adult primary care patients with depression.

Patients could have major depression, persistent mood disorders (dysthymia), both, or high scores on self-rating depression scales. The primary outcome of the NMA was response, defined as a 50% improvement in the Hamilton Depression Rating scores (HAM-D).

A total of 58 studies met inclusion criteria, involving 9,301 patients.
 

Treatment options compared

Compared with usual care, both psychotherapy alone and pharmacotherapy alone had significantly better response rates, with no significant difference between them (relative risk, 1.60 and RR, 1.65, respectively). The combination of psychotherapy and pharmacotherapy was even better (RR, 2.15), whereas the wait list was less effective (RR, 0.68).

When comparing combined therapy with psychotherapy or pharmacotherapy, the superiority of combination therapy over psychotherapy was only slightly statistically significant (RR, 1.35; 95% confidence interval, 1.00-1.81), while pharmacotherapy was only slightly inferior (RR, 1.30; 95% CI, 0.98-1.73).

“The significance level is not very high, which is related to statistical power,” said Dr. Cuijpers. “But the mean benefit is quite substantial in my opinion, with a 35% higher chance of response in the combined treatment, compared to psychotherapy alone.”

Looking at the outcome of remission, (normally defined as a score of 7 or less on the HAM-D), the outcomes were “comparable to those for response, with the exception that combined treatment was not significantly different from psychotherapy,” they wrote.

One important caveat is that several studies included in the NMA included patients with moderate to severe depression, a population that is different from the usual primary care population of depressed patients who have mild to moderate symptoms. Antidepressant medications are also assumed to work better against more severe symptoms, added the authors. “The inclusion of these studies might therefore have resulted in an overestimation of the effects of pharmacotherapy in the present NMA.”

Among other limitations, the authors noted that studies included mixed populations of patients with dysthymia and major depression; they also made no distinction between different types of antidepressants.
 

Psychotherapies unknown, but meta-analysis is still useful

Commenting on these findings, Neil Skolnik, MD, professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, said this is “an important study, confirming and extending the conclusions” of a systematic review published in 2016 as a Clinical Practice Guideline from the American College of Physicians.

“Unfortunately, the authors did not specify what type of psychotherapy was studied in the meta-analysis, so we have to look elsewhere if we want to advise our patients on what type of psychotherapy to seek, since there are important differences between different types of therapy,” he said.

Still, he described the study as providing “helpful information for the practicing clinician, as it gives us solid information with which to engage and advise patients in a shared decision-making process for effective treatment of depression.”

“Some patients will choose psychotherapy, some will choose medications. They can make either choice with the confidence that both approaches are effective,” Dr. Skolnik elaborated. “In addition, if psychotherapy does not seem to be sufficiently helping we are on solid ground adding an antidepressant medication to psychotherapy, with this data showing that the combined treatment works better than psychotherapy alone.”

Dr. Cuijpers receives allowances for his memberships on the board of directors of Mind, Fonds Psychische Gezondheid, and Korrelatie, and for being chair of the PACO committee of the Raad voor Civiel-militaire Zorg en Onderzoek of the Dutch Ministry of Defense. He also serves as deputy editor of Depression and Anxiety and associate editor of Psychological Bulletin, and he receives royalties for books he has authored or coauthored. He received grants from the European Union, ZonMw, and PFGV. Another study author reported receiving personal fees from Mitsubishi-Tanabe, MSD, and Shionogi and a grant from Mitsubishi-Tanabe outside the submitted work. One author has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation, and Angelini Pharmam, while another reported receiving personal fees from Boehringer Ingelheim, Kyowa Kirin, ASKA Pharmaceutical, and Toyota Motor Corporation outside the submitted work. The other authors and Dr. Skolnik reported no conflicts.

Psychotherapy and pharmacotherapy appear to be similarly effective for the treatment of depression, and a combination of both treatments might pack the biggest punch, according to a network meta-analysis (NMA) comparing either and both approaches with control conditions in the primary care setting.

The findings are important, since the majority of depressed patients are treated by primary care physicians, yet relatively few randomized trials of treatment have focused on this setting, noted senior study author Pim Cuijpers, PhD, from Vrije Universiteit Amsterdam, and colleagues, in the paper, which was published in Annals of Family Medicine.

“The main message is that clinicians should certainly consider psychotherapy instead of pharmacotherapy, because this is preferred by most patients, and when possible, combined treatments should be the preferred choice because the outcomes are considerably better,” he said in an interview. Either way, he emphasized that “preference of patients is very important and all three treatments are better than usual care.”

The NMA included studies comparing psychotherapy, antidepressant medication, or a combination of both, with control conditions (defined as usual care, wait list, or pill placebo) in adult primary care patients with depression.

Patients could have major depression, persistent mood disorders (dysthymia), both, or high scores on self-rating depression scales. The primary outcome of the NMA was response, defined as a 50% improvement in the Hamilton Depression Rating scores (HAM-D).

A total of 58 studies met inclusion criteria, involving 9,301 patients.
 

Treatment options compared

Compared with usual care, both psychotherapy alone and pharmacotherapy alone had significantly better response rates, with no significant difference between them (relative risk, 1.60 and RR, 1.65, respectively). The combination of psychotherapy and pharmacotherapy was even better (RR, 2.15), whereas the wait list was less effective (RR, 0.68).

When comparing combined therapy with psychotherapy or pharmacotherapy, the superiority of combination therapy over psychotherapy was only slightly statistically significant (RR, 1.35; 95% confidence interval, 1.00-1.81), while pharmacotherapy was only slightly inferior (RR, 1.30; 95% CI, 0.98-1.73).

“The significance level is not very high, which is related to statistical power,” said Dr. Cuijpers. “But the mean benefit is quite substantial in my opinion, with a 35% higher chance of response in the combined treatment, compared to psychotherapy alone.”

Looking at the outcome of remission, (normally defined as a score of 7 or less on the HAM-D), the outcomes were “comparable to those for response, with the exception that combined treatment was not significantly different from psychotherapy,” they wrote.

One important caveat is that several studies included in the NMA included patients with moderate to severe depression, a population that is different from the usual primary care population of depressed patients who have mild to moderate symptoms. Antidepressant medications are also assumed to work better against more severe symptoms, added the authors. “The inclusion of these studies might therefore have resulted in an overestimation of the effects of pharmacotherapy in the present NMA.”

Among other limitations, the authors noted that studies included mixed populations of patients with dysthymia and major depression; they also made no distinction between different types of antidepressants.
 

Psychotherapies unknown, but meta-analysis is still useful

Commenting on these findings, Neil Skolnik, MD, professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, said this is “an important study, confirming and extending the conclusions” of a systematic review published in 2016 as a Clinical Practice Guideline from the American College of Physicians.

“Unfortunately, the authors did not specify what type of psychotherapy was studied in the meta-analysis, so we have to look elsewhere if we want to advise our patients on what type of psychotherapy to seek, since there are important differences between different types of therapy,” he said.

Still, he described the study as providing “helpful information for the practicing clinician, as it gives us solid information with which to engage and advise patients in a shared decision-making process for effective treatment of depression.”

“Some patients will choose psychotherapy, some will choose medications. They can make either choice with the confidence that both approaches are effective,” Dr. Skolnik elaborated. “In addition, if psychotherapy does not seem to be sufficiently helping we are on solid ground adding an antidepressant medication to psychotherapy, with this data showing that the combined treatment works better than psychotherapy alone.”

Dr. Cuijpers receives allowances for his memberships on the board of directors of Mind, Fonds Psychische Gezondheid, and Korrelatie, and for being chair of the PACO committee of the Raad voor Civiel-militaire Zorg en Onderzoek of the Dutch Ministry of Defense. He also serves as deputy editor of Depression and Anxiety and associate editor of Psychological Bulletin, and he receives royalties for books he has authored or coauthored. He received grants from the European Union, ZonMw, and PFGV. Another study author reported receiving personal fees from Mitsubishi-Tanabe, MSD, and Shionogi and a grant from Mitsubishi-Tanabe outside the submitted work. One author has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation, and Angelini Pharmam, while another reported receiving personal fees from Boehringer Ingelheim, Kyowa Kirin, ASKA Pharmaceutical, and Toyota Motor Corporation outside the submitted work. The other authors and Dr. Skolnik reported no conflicts.

Psychotherapy and pharmacotherapy appear to be similarly effective for the treatment of depression, and a combination of both treatments might pack the biggest punch, according to a network meta-analysis (NMA) comparing either and both approaches with control conditions in the primary care setting.

The findings are important, since the majority of depressed patients are treated by primary care physicians, yet relatively few randomized trials of treatment have focused on this setting, noted senior study author Pim Cuijpers, PhD, from Vrije Universiteit Amsterdam, and colleagues, in the paper, which was published in Annals of Family Medicine.

“The main message is that clinicians should certainly consider psychotherapy instead of pharmacotherapy, because this is preferred by most patients, and when possible, combined treatments should be the preferred choice because the outcomes are considerably better,” he said in an interview. Either way, he emphasized that “preference of patients is very important and all three treatments are better than usual care.”

The NMA included studies comparing psychotherapy, antidepressant medication, or a combination of both, with control conditions (defined as usual care, wait list, or pill placebo) in adult primary care patients with depression.

Patients could have major depression, persistent mood disorders (dysthymia), both, or high scores on self-rating depression scales. The primary outcome of the NMA was response, defined as a 50% improvement in the Hamilton Depression Rating scores (HAM-D).

A total of 58 studies met inclusion criteria, involving 9,301 patients.
 

Treatment options compared

Compared with usual care, both psychotherapy alone and pharmacotherapy alone had significantly better response rates, with no significant difference between them (relative risk, 1.60 and RR, 1.65, respectively). The combination of psychotherapy and pharmacotherapy was even better (RR, 2.15), whereas the wait list was less effective (RR, 0.68).

When comparing combined therapy with psychotherapy or pharmacotherapy, the superiority of combination therapy over psychotherapy was only slightly statistically significant (RR, 1.35; 95% confidence interval, 1.00-1.81), while pharmacotherapy was only slightly inferior (RR, 1.30; 95% CI, 0.98-1.73).

“The significance level is not very high, which is related to statistical power,” said Dr. Cuijpers. “But the mean benefit is quite substantial in my opinion, with a 35% higher chance of response in the combined treatment, compared to psychotherapy alone.”

Looking at the outcome of remission, (normally defined as a score of 7 or less on the HAM-D), the outcomes were “comparable to those for response, with the exception that combined treatment was not significantly different from psychotherapy,” they wrote.

One important caveat is that several studies included in the NMA included patients with moderate to severe depression, a population that is different from the usual primary care population of depressed patients who have mild to moderate symptoms. Antidepressant medications are also assumed to work better against more severe symptoms, added the authors. “The inclusion of these studies might therefore have resulted in an overestimation of the effects of pharmacotherapy in the present NMA.”

Among other limitations, the authors noted that studies included mixed populations of patients with dysthymia and major depression; they also made no distinction between different types of antidepressants.
 

Psychotherapies unknown, but meta-analysis is still useful

Commenting on these findings, Neil Skolnik, MD, professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, said this is “an important study, confirming and extending the conclusions” of a systematic review published in 2016 as a Clinical Practice Guideline from the American College of Physicians.

“Unfortunately, the authors did not specify what type of psychotherapy was studied in the meta-analysis, so we have to look elsewhere if we want to advise our patients on what type of psychotherapy to seek, since there are important differences between different types of therapy,” he said.

Still, he described the study as providing “helpful information for the practicing clinician, as it gives us solid information with which to engage and advise patients in a shared decision-making process for effective treatment of depression.”

“Some patients will choose psychotherapy, some will choose medications. They can make either choice with the confidence that both approaches are effective,” Dr. Skolnik elaborated. “In addition, if psychotherapy does not seem to be sufficiently helping we are on solid ground adding an antidepressant medication to psychotherapy, with this data showing that the combined treatment works better than psychotherapy alone.”

Dr. Cuijpers receives allowances for his memberships on the board of directors of Mind, Fonds Psychische Gezondheid, and Korrelatie, and for being chair of the PACO committee of the Raad voor Civiel-militaire Zorg en Onderzoek of the Dutch Ministry of Defense. He also serves as deputy editor of Depression and Anxiety and associate editor of Psychological Bulletin, and he receives royalties for books he has authored or coauthored. He received grants from the European Union, ZonMw, and PFGV. Another study author reported receiving personal fees from Mitsubishi-Tanabe, MSD, and Shionogi and a grant from Mitsubishi-Tanabe outside the submitted work. One author has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation, and Angelini Pharmam, while another reported receiving personal fees from Boehringer Ingelheim, Kyowa Kirin, ASKA Pharmaceutical, and Toyota Motor Corporation outside the submitted work. The other authors and Dr. Skolnik reported no conflicts.

In the late 1980s and early 1990s, an emphasis on better pain management led health care professionals (HCPs) to increase prescribing of opioids to better manage patient’s pain. In 1991, 76 million prescriptions were written for opioids in the United States, and by 2011, the number had nearly tripled to 219 million.¹ Overdose rates increased as well, nearly tripling from 1999 to 2014.² Of the 52,404 US deaths from drug overdoses in the in 2015, 63% involved an opioid.²

Opioid Safety Initiative

In response to the growing opioid epidemic, the US Department of Veterans Affairs (VA) created the Opioid Safety Initiative in 2014.³ This comprehensive, multifaceted initiative was designed to improve the care and safety of veterans managed with opioid therapy and promote rational opioid prescribing and monitoring. In 2016 the Centers for Disease Control and Prevention (CDC) issued guidelines for opioid prescriptions, and the following year the VA and the US Department of Defense (DoD) updated the VA/DoD Clinical Practice Guidelines for Opioid Therapy for Chronic Pain (VA/DoD guidelines).^4,5 After the release of these guidelines, the use of opioid tapers expanded. However, due to public outcry of forced opioid tapering in 2019, the US Food and Drug Administration updated its opioid labeling requirements to provide clearer guidance on opioid tapers for tolerant patients.^6,7

As a result, HCPs began to develop various strategies to balance the safety and efficacy of opioid use in patients with chronic pain. The West Palm Beach VA Medical Center (WPBVAMC) in Florida has a Pain Clinic that includes 2 pain management clinical pharmacy specialists (CPSs) with specialized training in pain management, who are uniquely qualified to assess and evaluate medication therapy in complex pain patient cases. These CPSs were involved in the face-to-face management of patients requiring specialized pain care and participated in a pain pharmacy electronic consult (eConsult) service to document pain management consultative recommendations for patients appropriate for management at the primary care level. This formalized process increased specialty pain care access for veterans whose pain was managed by primary care providers (PCPs).

The pain pharmacy eConsult service was initiated at the WPBVAMC in June 2013 to assist PCPs in the management of outpatients with chronic pain. The eConsult service includes evaluation of a patient’s electronic health records (EHRs) by CPSs. The eConsult service also provided PCPs with the option to engage a pharmacist who could provide recommendations for opioid dosing conversion, opioid tapering, pain pharmacotherapy, or drug screen interpretation, without the necessity for an additional patient visit.

Subsequent to the release of the 2016 CDC (and later the 2017 VA/DoD) guidelines recommending reducing morphine equivalent daily dose (MEDD) levels, the WPBVAMC had a large increase in pain eConsult requests for opioid tapering and opioid pharmacotherapy. A 3.4-fold increase in requests occurred in March, April, and May vs the following 9 months, and a nearly 4-fold increase in requests for opioid tapers during the same period. However, the impact of the completed eConsults was unclear. Therefore, the primary objective of this study was to assess the effect of CPS services for opioid tapering and opioid pharmacotherapy by quantifying the number of recommendations accepted/implemented by PCPs. The secondary objectives included evaluating harms associated with the recommendations (eg, increase in visits to the emergency department [ED], hospitalizations, suicide attempts, or PCP visits) and provider satisfaction.

Methods

A retrospective chart review was completed to assess data of patients from the WPBVAMC and its associated community-based outpatient clinics (CBOCs). The project was approved by the WPBVAMC Scientific Advisory Committee as part of the facility’s performance improvement efforts.

Included patients had a pain pharmacy eConsult placed between April 1, 2016 and March 31, 2017. EHRs were reviewed and only eConsults for opioid pharmacotherapy recommendation or opioid tapers were evaluated. eConsults were excluded if the request was discontinued, completed by a HCP other than the pain CPS, or placed for an opioid dose conversion, nonopioid pharmacotherapy, or drug screen interpretation.

Data for analyses were entered into Microsoft Excel 2016 and were securely saved and accessible to relevant researchers. Patient protected health information used during patient care remained confidential.

Demographic data were collected, including age, gender, race, pertinent medical comorbidities (eg, diabetes mellitus, sleep apnea), and mental health comorbidities. Pain scores were collected at baseline and 6-months postconsult. Pain medications used by patients were noted at baseline and 6 months postconsult, including concomitant opioid and benzodiazepine use, MEDD, and other pain medication. The duration of time needed by pain CPS to complete each eConsult and total time from eConsult entered to HCP implementation of the initial recommendation was collected. The number of actionable recommendations (eg, changes in drug therapy, urine drug screens [UDSs], and referrals to other services also were recorded and reviewed 6 months postconsult to determine the number and percentage of recommendations implemented by the HCP. The EHR was examined to determine adverse events (AEs) (eg, any documentation of suicide attempt, calls to the Veterans Crisis Line, or death 6 month postconsult). Collected data also included new eConsults, the reason for opioid tapering either by HCP or patient, and assessment of economic harms (count of the number of visits to ED, hospitalizations, or unscheduled PCP visits with uncontrolled pain as chief reason within 6 months postconsult). Last, PCPs were sent a survey to assess their satisfaction with the pain eConsult service.

Results

Of 517 eConsults received from April 1, 2016 to March 31, 2017, 285 (55.1%) met inclusion criteria (Figure). Using a random number generator, 100 eConsults were further reviewed for outcomes of interest.

In this cohort, the mean age was 61 years, 87% were male, and 80% were White individuals. Most patients (83%) had ≥ 1 mental health comorbidity, and 53% had ≥ 2, with depressive symptoms, tobacco use, and/or posttraumatic stress disorder the most common diagnoses (Table 1). Eighty-seven percent of eConsults were for opioid tapers and the remaining 13% were for opioid pharmacotherapy.

The median pain score at time of consult was 6 on a 10-point scale, with no change at 6 months postconsult. However, 41% of patients overall had a median 3.3-point drop in pain score, 17% had no change in pain score, and 42% had a median 2.6-point increase in pain score.

Electronic Consults

Table 2 describes the reasons eConsults were requested. The most common reason was to taper the dose to be in compliance with the CDC 2016 guideline recommendation of MEDD < 90 mg, which was later increased to 100 mg by the VA/DoD guideline.

On average, eConsults were completed within a mean of 11.5 days of the PCP request, including nights and weekends. The CPS spent a mean 66.8 minutes to complete each eConsult. Once the eConsult was completed, PCPs took a mean of 9 days to initiate the primary recommendation. This 9-day average does not include 11 eConsults with no accepted recommendations and 11 eConsults for which the PCP implemented the primary recommendation before the CPS completed the consult, most likely due to a phone call or direct contact with the CPS at the time the eConsult was ordered.

A mean 3.5 actionable recommendations were made by the CPS and a mean 1.6 recommendations were implemented within 6 months by the PCP. At least 1 recommendation was accepted/implemented for 89% of patients, with a mean 55% recommendations that were accepted/implemented. Eleven percent of the eConsult final recommendations were not accepted by PCPs and clear documentation of the reasons were not provided.

In the 6 months postconsult, 11 patients (7 men and 4 women) experienced 32 AEs (Table 3). Eight patients had 15 ED visits, with 3 of the visits resulting in hospitalizations, 8 patients had 9 unscheduled PCP visits, 1 patient reported suicidal ideation and 2 patients made a total of 4 calls to the Veterans Crisis Line. There were also 2 deaths; however, both were due to end-stage disease (cirrhosis and amyotrophic lateral sclerosis) and not believed to be related to eConsult recommendations.

Eight patients had a history of substance use disorders (SUDs) and 8 had a history of a mood disorder or psychosis. One patient had both SUD and a mood/psychosis-related mental health disorder, including a reported suicidal attempt/ideation at an ED visit and a subsequent hospitalization. A similar number of AEs occurred in patients with decreases in MEDD of 0 to 24% compared with those that received more aggressive tapers of 75 to 100% (Table 4).

Primary Care Providers

Nine patients were reconsulted, with only 1 secondary to the PCP not implementing recommendations from the initial consult. No factors were found that correlated with likelihood of a patient being reconsulted.

Surveys on PCP satisfaction with the eConsult service were completed by 29 of the 55 PCPs. PCP feedback was generally positive with nearly 90% of PCPs planning to use the service in the future as well as recommending use to other providers.

Discussion

Most (89%) PCPs accepted at least 1 recommendation from the completed eConsult, and MEDDs decreased by 60%, likely reducing the patient’s risk of overdose or other AEs from opioids. There also was a slight reduction in patient’s mean pain scores; however, 41% had a decrease and 42% had an increase in pain scores. There was no clear relationship when pain scores were compared with MEDDs, likely giving credence to the idea that pain scores are largely subjective and an unreliable surrogate marker for assessing effectiveness of analgesic regimens.

Eleven patients experienced AEs, including 1 patient for whom the recommendations were not implemented by the PCP. Eight of the 11 had multiple AEs. One interesting finding was that 7 of the 11 patients with an AE tested positive for unexpected substances on routine UDS or were arrested for driving while intoxicated (DWI). However, only 3 of the 7 had an active SUD diagnosis. With 25% of the AEs coming from patients with a history of SUD, it is important that any history of SUD be documented in the EHR. Maintaining this documentation can be especially difficult if patients switch VA medical centers or receive services outside the VA. Thorough and accurate history and chart review should ideally be completed before prescribing opioids.

Guidelines

While the PCPs were following VA/DoD and CDC recommendations for opioid tapering to < 100 or 90 mg MEDD, respectively, there is weak evidence in these guidelines to support specific MEDD cutoffs. The CDC guidelines even state, “a single dosage threshold for safe opioid use could not be identified.”⁵ One of the largest issues when using MEDD as a cutoff is the lack of agreement on its calculation. In 2014, Nuckols and colleagues al conducted a study to compare the existing guidelines on the use of opioids for chronic pain. While 13 guidelines were considered eligible, most recommendations were supported only by observational data or expert recommendations, and there was no consensus on what constitutes a “morphine equivalent.”⁸ Currently there is no universally accepted opioid-conversion method, resulting in a substantial problem when calculating a MEDD.⁹ A survey of 8 online opioid dose conversion tools found a -55% to +242% variation.¹⁰ As Fudin and colleagues concluded in response to the large variations found in these various analyses, the studies “unequivocally disqualify the validity of embracing MEDD to assess risk in any meaningful statistical way.”¹¹ Pharmacogenetics, drug tolerance, drug-drug interactions, body surface area, and organ function are patient- specific factors that are not taken into consideration when relying solely on a MEDD calculation. Tapering to lowest functional dose rather than a specific number or cutoff may be a more effective way to treat patients, and providers should use the guidelines as recommendations and not a hardline mandate.

At 6 months, 6 patients were receiving no pain medications from the VA, and 24 of the patients were tapered from their opiate to discontinuation. It is unclear whether patients are no longer taking opioids or switched their care to non-VA providers to receive medications, including opioids, privately. This is difficult to verify, though a prescription drug monitoring program (PDMP) could be used to assess patient adherence. As many of the patients that were tapered due to identification of aberrant behaviors, lack of continuity of care across health care systems may result in future patient harm.

The results of this analysis highlight the importance of checking PDMP databases and routine UDSs when prescribing opioids—there can be serious safety concerns if patients are taking other prescribed or illicit medications. However, care must be taken; there were 2 instances of patients’ chronic opioid prescriptions discontinued by their VA provider after a review of the PDMP showed they had received non-VA opioids. In both cases, the quantity and doses received were small (counts of ≤ 12) and were received more than 6 months prior to the check of the PDMP. While this constitutes a breach of the Informed Consent for long-term opioid use, if there are no other concerning behaviors, it may be more prudent to review the informed consent with the patient and discuss why the behavior is a breach to ensure that patients and PCPs continue to work as a team to manage chronic pain.

Limitations

The study population was one limitation of this project. While data suggest that chronic pain affects women more than men, this study’s population was only 13% female. Thirty percent of the women in this study had an AE compared with only 8% of the men. Additional limitations included use of problem list for comorbidities, as lists may be inaccurate or outdated, and limiting the monitoring of AE to only 6 months. As some tapers were not initiated immediately and some taper schedules can last several months to years; therefor, outcomes may have been higher if patients were followed longer. Many of the patients with AEs had increased ED visits or unscheduled primary care visits as the tapers went on and their pain worsened, but the visits were outside the 6-month time frame for data collection. An additional weakness of this review included assessing a pain score, but not functional status, which may be a better predictor of the effectiveness of a patient’s pain management regimen. This assessment is needed in future studies for more reliable data. Finally, PCP survey results also should be viewed with caution. The current survey had only 29 respondents, and the 2014 survey had only 10 respondents and did not include CBOC providers.

Conclusion

A pain eConsult service managed by CPSs specializing in pain management can assist patients and PCPs with opioid therapy recommendations in a safe and timely manner, reducing risk of overdose secondary to high dose opioid therapy and with limited harm to patients.

In the late 1980s and early 1990s, an emphasis on better pain management led health care professionals (HCPs) to increase prescribing of opioids to better manage patient’s pain. In 1991, 76 million prescriptions were written for opioids in the United States, and by 2011, the number had nearly tripled to 219 million.¹ Overdose rates increased as well, nearly tripling from 1999 to 2014.² Of the 52,404 US deaths from drug overdoses in the in 2015, 63% involved an opioid.²

Opioid Safety Initiative

In response to the growing opioid epidemic, the US Department of Veterans Affairs (VA) created the Opioid Safety Initiative in 2014.³ This comprehensive, multifaceted initiative was designed to improve the care and safety of veterans managed with opioid therapy and promote rational opioid prescribing and monitoring. In 2016 the Centers for Disease Control and Prevention (CDC) issued guidelines for opioid prescriptions, and the following year the VA and the US Department of Defense (DoD) updated the VA/DoD Clinical Practice Guidelines for Opioid Therapy for Chronic Pain (VA/DoD guidelines).^4,5 After the release of these guidelines, the use of opioid tapers expanded. However, due to public outcry of forced opioid tapering in 2019, the US Food and Drug Administration updated its opioid labeling requirements to provide clearer guidance on opioid tapers for tolerant patients.^6,7

As a result, HCPs began to develop various strategies to balance the safety and efficacy of opioid use in patients with chronic pain. The West Palm Beach VA Medical Center (WPBVAMC) in Florida has a Pain Clinic that includes 2 pain management clinical pharmacy specialists (CPSs) with specialized training in pain management, who are uniquely qualified to assess and evaluate medication therapy in complex pain patient cases. These CPSs were involved in the face-to-face management of patients requiring specialized pain care and participated in a pain pharmacy electronic consult (eConsult) service to document pain management consultative recommendations for patients appropriate for management at the primary care level. This formalized process increased specialty pain care access for veterans whose pain was managed by primary care providers (PCPs).

The pain pharmacy eConsult service was initiated at the WPBVAMC in June 2013 to assist PCPs in the management of outpatients with chronic pain. The eConsult service includes evaluation of a patient’s electronic health records (EHRs) by CPSs. The eConsult service also provided PCPs with the option to engage a pharmacist who could provide recommendations for opioid dosing conversion, opioid tapering, pain pharmacotherapy, or drug screen interpretation, without the necessity for an additional patient visit.

Subsequent to the release of the 2016 CDC (and later the 2017 VA/DoD) guidelines recommending reducing morphine equivalent daily dose (MEDD) levels, the WPBVAMC had a large increase in pain eConsult requests for opioid tapering and opioid pharmacotherapy. A 3.4-fold increase in requests occurred in March, April, and May vs the following 9 months, and a nearly 4-fold increase in requests for opioid tapers during the same period. However, the impact of the completed eConsults was unclear. Therefore, the primary objective of this study was to assess the effect of CPS services for opioid tapering and opioid pharmacotherapy by quantifying the number of recommendations accepted/implemented by PCPs. The secondary objectives included evaluating harms associated with the recommendations (eg, increase in visits to the emergency department [ED], hospitalizations, suicide attempts, or PCP visits) and provider satisfaction.

Methods

A retrospective chart review was completed to assess data of patients from the WPBVAMC and its associated community-based outpatient clinics (CBOCs). The project was approved by the WPBVAMC Scientific Advisory Committee as part of the facility’s performance improvement efforts.

Included patients had a pain pharmacy eConsult placed between April 1, 2016 and March 31, 2017. EHRs were reviewed and only eConsults for opioid pharmacotherapy recommendation or opioid tapers were evaluated. eConsults were excluded if the request was discontinued, completed by a HCP other than the pain CPS, or placed for an opioid dose conversion, nonopioid pharmacotherapy, or drug screen interpretation.

Data for analyses were entered into Microsoft Excel 2016 and were securely saved and accessible to relevant researchers. Patient protected health information used during patient care remained confidential.

Demographic data were collected, including age, gender, race, pertinent medical comorbidities (eg, diabetes mellitus, sleep apnea), and mental health comorbidities. Pain scores were collected at baseline and 6-months postconsult. Pain medications used by patients were noted at baseline and 6 months postconsult, including concomitant opioid and benzodiazepine use, MEDD, and other pain medication. The duration of time needed by pain CPS to complete each eConsult and total time from eConsult entered to HCP implementation of the initial recommendation was collected. The number of actionable recommendations (eg, changes in drug therapy, urine drug screens [UDSs], and referrals to other services also were recorded and reviewed 6 months postconsult to determine the number and percentage of recommendations implemented by the HCP. The EHR was examined to determine adverse events (AEs) (eg, any documentation of suicide attempt, calls to the Veterans Crisis Line, or death 6 month postconsult). Collected data also included new eConsults, the reason for opioid tapering either by HCP or patient, and assessment of economic harms (count of the number of visits to ED, hospitalizations, or unscheduled PCP visits with uncontrolled pain as chief reason within 6 months postconsult). Last, PCPs were sent a survey to assess their satisfaction with the pain eConsult service.

Results

Of 517 eConsults received from April 1, 2016 to March 31, 2017, 285 (55.1%) met inclusion criteria (Figure). Using a random number generator, 100 eConsults were further reviewed for outcomes of interest.

In this cohort, the mean age was 61 years, 87% were male, and 80% were White individuals. Most patients (83%) had ≥ 1 mental health comorbidity, and 53% had ≥ 2, with depressive symptoms, tobacco use, and/or posttraumatic stress disorder the most common diagnoses (Table 1). Eighty-seven percent of eConsults were for opioid tapers and the remaining 13% were for opioid pharmacotherapy.

The median pain score at time of consult was 6 on a 10-point scale, with no change at 6 months postconsult. However, 41% of patients overall had a median 3.3-point drop in pain score, 17% had no change in pain score, and 42% had a median 2.6-point increase in pain score.

Electronic Consults

Table 2 describes the reasons eConsults were requested. The most common reason was to taper the dose to be in compliance with the CDC 2016 guideline recommendation of MEDD < 90 mg, which was later increased to 100 mg by the VA/DoD guideline.

On average, eConsults were completed within a mean of 11.5 days of the PCP request, including nights and weekends. The CPS spent a mean 66.8 minutes to complete each eConsult. Once the eConsult was completed, PCPs took a mean of 9 days to initiate the primary recommendation. This 9-day average does not include 11 eConsults with no accepted recommendations and 11 eConsults for which the PCP implemented the primary recommendation before the CPS completed the consult, most likely due to a phone call or direct contact with the CPS at the time the eConsult was ordered.

A mean 3.5 actionable recommendations were made by the CPS and a mean 1.6 recommendations were implemented within 6 months by the PCP. At least 1 recommendation was accepted/implemented for 89% of patients, with a mean 55% recommendations that were accepted/implemented. Eleven percent of the eConsult final recommendations were not accepted by PCPs and clear documentation of the reasons were not provided.

In the 6 months postconsult, 11 patients (7 men and 4 women) experienced 32 AEs (Table 3). Eight patients had 15 ED visits, with 3 of the visits resulting in hospitalizations, 8 patients had 9 unscheduled PCP visits, 1 patient reported suicidal ideation and 2 patients made a total of 4 calls to the Veterans Crisis Line. There were also 2 deaths; however, both were due to end-stage disease (cirrhosis and amyotrophic lateral sclerosis) and not believed to be related to eConsult recommendations.

Eight patients had a history of substance use disorders (SUDs) and 8 had a history of a mood disorder or psychosis. One patient had both SUD and a mood/psychosis-related mental health disorder, including a reported suicidal attempt/ideation at an ED visit and a subsequent hospitalization. A similar number of AEs occurred in patients with decreases in MEDD of 0 to 24% compared with those that received more aggressive tapers of 75 to 100% (Table 4).

Primary Care Providers

Nine patients were reconsulted, with only 1 secondary to the PCP not implementing recommendations from the initial consult. No factors were found that correlated with likelihood of a patient being reconsulted.

Surveys on PCP satisfaction with the eConsult service were completed by 29 of the 55 PCPs. PCP feedback was generally positive with nearly 90% of PCPs planning to use the service in the future as well as recommending use to other providers.

Discussion

Most (89%) PCPs accepted at least 1 recommendation from the completed eConsult, and MEDDs decreased by 60%, likely reducing the patient’s risk of overdose or other AEs from opioids. There also was a slight reduction in patient’s mean pain scores; however, 41% had a decrease and 42% had an increase in pain scores. There was no clear relationship when pain scores were compared with MEDDs, likely giving credence to the idea that pain scores are largely subjective and an unreliable surrogate marker for assessing effectiveness of analgesic regimens.

Eleven patients experienced AEs, including 1 patient for whom the recommendations were not implemented by the PCP. Eight of the 11 had multiple AEs. One interesting finding was that 7 of the 11 patients with an AE tested positive for unexpected substances on routine UDS or were arrested for driving while intoxicated (DWI). However, only 3 of the 7 had an active SUD diagnosis. With 25% of the AEs coming from patients with a history of SUD, it is important that any history of SUD be documented in the EHR. Maintaining this documentation can be especially difficult if patients switch VA medical centers or receive services outside the VA. Thorough and accurate history and chart review should ideally be completed before prescribing opioids.

Guidelines

While the PCPs were following VA/DoD and CDC recommendations for opioid tapering to < 100 or 90 mg MEDD, respectively, there is weak evidence in these guidelines to support specific MEDD cutoffs. The CDC guidelines even state, “a single dosage threshold for safe opioid use could not be identified.”⁵ One of the largest issues when using MEDD as a cutoff is the lack of agreement on its calculation. In 2014, Nuckols and colleagues al conducted a study to compare the existing guidelines on the use of opioids for chronic pain. While 13 guidelines were considered eligible, most recommendations were supported only by observational data or expert recommendations, and there was no consensus on what constitutes a “morphine equivalent.”⁸ Currently there is no universally accepted opioid-conversion method, resulting in a substantial problem when calculating a MEDD.⁹ A survey of 8 online opioid dose conversion tools found a -55% to +242% variation.¹⁰ As Fudin and colleagues concluded in response to the large variations found in these various analyses, the studies “unequivocally disqualify the validity of embracing MEDD to assess risk in any meaningful statistical way.”¹¹ Pharmacogenetics, drug tolerance, drug-drug interactions, body surface area, and organ function are patient- specific factors that are not taken into consideration when relying solely on a MEDD calculation. Tapering to lowest functional dose rather than a specific number or cutoff may be a more effective way to treat patients, and providers should use the guidelines as recommendations and not a hardline mandate.

At 6 months, 6 patients were receiving no pain medications from the VA, and 24 of the patients were tapered from their opiate to discontinuation. It is unclear whether patients are no longer taking opioids or switched their care to non-VA providers to receive medications, including opioids, privately. This is difficult to verify, though a prescription drug monitoring program (PDMP) could be used to assess patient adherence. As many of the patients that were tapered due to identification of aberrant behaviors, lack of continuity of care across health care systems may result in future patient harm.

The results of this analysis highlight the importance of checking PDMP databases and routine UDSs when prescribing opioids—there can be serious safety concerns if patients are taking other prescribed or illicit medications. However, care must be taken; there were 2 instances of patients’ chronic opioid prescriptions discontinued by their VA provider after a review of the PDMP showed they had received non-VA opioids. In both cases, the quantity and doses received were small (counts of ≤ 12) and were received more than 6 months prior to the check of the PDMP. While this constitutes a breach of the Informed Consent for long-term opioid use, if there are no other concerning behaviors, it may be more prudent to review the informed consent with the patient and discuss why the behavior is a breach to ensure that patients and PCPs continue to work as a team to manage chronic pain.

Limitations

The study population was one limitation of this project. While data suggest that chronic pain affects women more than men, this study’s population was only 13% female. Thirty percent of the women in this study had an AE compared with only 8% of the men. Additional limitations included use of problem list for comorbidities, as lists may be inaccurate or outdated, and limiting the monitoring of AE to only 6 months. As some tapers were not initiated immediately and some taper schedules can last several months to years; therefor, outcomes may have been higher if patients were followed longer. Many of the patients with AEs had increased ED visits or unscheduled primary care visits as the tapers went on and their pain worsened, but the visits were outside the 6-month time frame for data collection. An additional weakness of this review included assessing a pain score, but not functional status, which may be a better predictor of the effectiveness of a patient’s pain management regimen. This assessment is needed in future studies for more reliable data. Finally, PCP survey results also should be viewed with caution. The current survey had only 29 respondents, and the 2014 survey had only 10 respondents and did not include CBOC providers.

Conclusion

A pain eConsult service managed by CPSs specializing in pain management can assist patients and PCPs with opioid therapy recommendations in a safe and timely manner, reducing risk of overdose secondary to high dose opioid therapy and with limited harm to patients.

In the late 1980s and early 1990s, an emphasis on better pain management led health care professionals (HCPs) to increase prescribing of opioids to better manage patient’s pain. In 1991, 76 million prescriptions were written for opioids in the United States, and by 2011, the number had nearly tripled to 219 million.¹ Overdose rates increased as well, nearly tripling from 1999 to 2014.² Of the 52,404 US deaths from drug overdoses in the in 2015, 63% involved an opioid.²

Opioid Safety Initiative

In response to the growing opioid epidemic, the US Department of Veterans Affairs (VA) created the Opioid Safety Initiative in 2014.³ This comprehensive, multifaceted initiative was designed to improve the care and safety of veterans managed with opioid therapy and promote rational opioid prescribing and monitoring. In 2016 the Centers for Disease Control and Prevention (CDC) issued guidelines for opioid prescriptions, and the following year the VA and the US Department of Defense (DoD) updated the VA/DoD Clinical Practice Guidelines for Opioid Therapy for Chronic Pain (VA/DoD guidelines).^4,5 After the release of these guidelines, the use of opioid tapers expanded. However, due to public outcry of forced opioid tapering in 2019, the US Food and Drug Administration updated its opioid labeling requirements to provide clearer guidance on opioid tapers for tolerant patients.^6,7

As a result, HCPs began to develop various strategies to balance the safety and efficacy of opioid use in patients with chronic pain. The West Palm Beach VA Medical Center (WPBVAMC) in Florida has a Pain Clinic that includes 2 pain management clinical pharmacy specialists (CPSs) with specialized training in pain management, who are uniquely qualified to assess and evaluate medication therapy in complex pain patient cases. These CPSs were involved in the face-to-face management of patients requiring specialized pain care and participated in a pain pharmacy electronic consult (eConsult) service to document pain management consultative recommendations for patients appropriate for management at the primary care level. This formalized process increased specialty pain care access for veterans whose pain was managed by primary care providers (PCPs).

The pain pharmacy eConsult service was initiated at the WPBVAMC in June 2013 to assist PCPs in the management of outpatients with chronic pain. The eConsult service includes evaluation of a patient’s electronic health records (EHRs) by CPSs. The eConsult service also provided PCPs with the option to engage a pharmacist who could provide recommendations for opioid dosing conversion, opioid tapering, pain pharmacotherapy, or drug screen interpretation, without the necessity for an additional patient visit.

Subsequent to the release of the 2016 CDC (and later the 2017 VA/DoD) guidelines recommending reducing morphine equivalent daily dose (MEDD) levels, the WPBVAMC had a large increase in pain eConsult requests for opioid tapering and opioid pharmacotherapy. A 3.4-fold increase in requests occurred in March, April, and May vs the following 9 months, and a nearly 4-fold increase in requests for opioid tapers during the same period. However, the impact of the completed eConsults was unclear. Therefore, the primary objective of this study was to assess the effect of CPS services for opioid tapering and opioid pharmacotherapy by quantifying the number of recommendations accepted/implemented by PCPs. The secondary objectives included evaluating harms associated with the recommendations (eg, increase in visits to the emergency department [ED], hospitalizations, suicide attempts, or PCP visits) and provider satisfaction.

Methods

A retrospective chart review was completed to assess data of patients from the WPBVAMC and its associated community-based outpatient clinics (CBOCs). The project was approved by the WPBVAMC Scientific Advisory Committee as part of the facility’s performance improvement efforts.

Included patients had a pain pharmacy eConsult placed between April 1, 2016 and March 31, 2017. EHRs were reviewed and only eConsults for opioid pharmacotherapy recommendation or opioid tapers were evaluated. eConsults were excluded if the request was discontinued, completed by a HCP other than the pain CPS, or placed for an opioid dose conversion, nonopioid pharmacotherapy, or drug screen interpretation.

Data for analyses were entered into Microsoft Excel 2016 and were securely saved and accessible to relevant researchers. Patient protected health information used during patient care remained confidential.

Demographic data were collected, including age, gender, race, pertinent medical comorbidities (eg, diabetes mellitus, sleep apnea), and mental health comorbidities. Pain scores were collected at baseline and 6-months postconsult. Pain medications used by patients were noted at baseline and 6 months postconsult, including concomitant opioid and benzodiazepine use, MEDD, and other pain medication. The duration of time needed by pain CPS to complete each eConsult and total time from eConsult entered to HCP implementation of the initial recommendation was collected. The number of actionable recommendations (eg, changes in drug therapy, urine drug screens [UDSs], and referrals to other services also were recorded and reviewed 6 months postconsult to determine the number and percentage of recommendations implemented by the HCP. The EHR was examined to determine adverse events (AEs) (eg, any documentation of suicide attempt, calls to the Veterans Crisis Line, or death 6 month postconsult). Collected data also included new eConsults, the reason for opioid tapering either by HCP or patient, and assessment of economic harms (count of the number of visits to ED, hospitalizations, or unscheduled PCP visits with uncontrolled pain as chief reason within 6 months postconsult). Last, PCPs were sent a survey to assess their satisfaction with the pain eConsult service.

Results

Of 517 eConsults received from April 1, 2016 to March 31, 2017, 285 (55.1%) met inclusion criteria (Figure). Using a random number generator, 100 eConsults were further reviewed for outcomes of interest.

In this cohort, the mean age was 61 years, 87% were male, and 80% were White individuals. Most patients (83%) had ≥ 1 mental health comorbidity, and 53% had ≥ 2, with depressive symptoms, tobacco use, and/or posttraumatic stress disorder the most common diagnoses (Table 1). Eighty-seven percent of eConsults were for opioid tapers and the remaining 13% were for opioid pharmacotherapy.

The median pain score at time of consult was 6 on a 10-point scale, with no change at 6 months postconsult. However, 41% of patients overall had a median 3.3-point drop in pain score, 17% had no change in pain score, and 42% had a median 2.6-point increase in pain score.

Electronic Consults

Table 2 describes the reasons eConsults were requested. The most common reason was to taper the dose to be in compliance with the CDC 2016 guideline recommendation of MEDD < 90 mg, which was later increased to 100 mg by the VA/DoD guideline.

On average, eConsults were completed within a mean of 11.5 days of the PCP request, including nights and weekends. The CPS spent a mean 66.8 minutes to complete each eConsult. Once the eConsult was completed, PCPs took a mean of 9 days to initiate the primary recommendation. This 9-day average does not include 11 eConsults with no accepted recommendations and 11 eConsults for which the PCP implemented the primary recommendation before the CPS completed the consult, most likely due to a phone call or direct contact with the CPS at the time the eConsult was ordered.

A mean 3.5 actionable recommendations were made by the CPS and a mean 1.6 recommendations were implemented within 6 months by the PCP. At least 1 recommendation was accepted/implemented for 89% of patients, with a mean 55% recommendations that were accepted/implemented. Eleven percent of the eConsult final recommendations were not accepted by PCPs and clear documentation of the reasons were not provided.

In the 6 months postconsult, 11 patients (7 men and 4 women) experienced 32 AEs (Table 3). Eight patients had 15 ED visits, with 3 of the visits resulting in hospitalizations, 8 patients had 9 unscheduled PCP visits, 1 patient reported suicidal ideation and 2 patients made a total of 4 calls to the Veterans Crisis Line. There were also 2 deaths; however, both were due to end-stage disease (cirrhosis and amyotrophic lateral sclerosis) and not believed to be related to eConsult recommendations.

Eight patients had a history of substance use disorders (SUDs) and 8 had a history of a mood disorder or psychosis. One patient had both SUD and a mood/psychosis-related mental health disorder, including a reported suicidal attempt/ideation at an ED visit and a subsequent hospitalization. A similar number of AEs occurred in patients with decreases in MEDD of 0 to 24% compared with those that received more aggressive tapers of 75 to 100% (Table 4).

Primary Care Providers

Nine patients were reconsulted, with only 1 secondary to the PCP not implementing recommendations from the initial consult. No factors were found that correlated with likelihood of a patient being reconsulted.

Surveys on PCP satisfaction with the eConsult service were completed by 29 of the 55 PCPs. PCP feedback was generally positive with nearly 90% of PCPs planning to use the service in the future as well as recommending use to other providers.

Discussion

Most (89%) PCPs accepted at least 1 recommendation from the completed eConsult, and MEDDs decreased by 60%, likely reducing the patient’s risk of overdose or other AEs from opioids. There also was a slight reduction in patient’s mean pain scores; however, 41% had a decrease and 42% had an increase in pain scores. There was no clear relationship when pain scores were compared with MEDDs, likely giving credence to the idea that pain scores are largely subjective and an unreliable surrogate marker for assessing effectiveness of analgesic regimens.

Eleven patients experienced AEs, including 1 patient for whom the recommendations were not implemented by the PCP. Eight of the 11 had multiple AEs. One interesting finding was that 7 of the 11 patients with an AE tested positive for unexpected substances on routine UDS or were arrested for driving while intoxicated (DWI). However, only 3 of the 7 had an active SUD diagnosis. With 25% of the AEs coming from patients with a history of SUD, it is important that any history of SUD be documented in the EHR. Maintaining this documentation can be especially difficult if patients switch VA medical centers or receive services outside the VA. Thorough and accurate history and chart review should ideally be completed before prescribing opioids.

Guidelines

While the PCPs were following VA/DoD and CDC recommendations for opioid tapering to < 100 or 90 mg MEDD, respectively, there is weak evidence in these guidelines to support specific MEDD cutoffs. The CDC guidelines even state, “a single dosage threshold for safe opioid use could not be identified.”⁵ One of the largest issues when using MEDD as a cutoff is the lack of agreement on its calculation. In 2014, Nuckols and colleagues al conducted a study to compare the existing guidelines on the use of opioids for chronic pain. While 13 guidelines were considered eligible, most recommendations were supported only by observational data or expert recommendations, and there was no consensus on what constitutes a “morphine equivalent.”⁸ Currently there is no universally accepted opioid-conversion method, resulting in a substantial problem when calculating a MEDD.⁹ A survey of 8 online opioid dose conversion tools found a -55% to +242% variation.¹⁰ As Fudin and colleagues concluded in response to the large variations found in these various analyses, the studies “unequivocally disqualify the validity of embracing MEDD to assess risk in any meaningful statistical way.”¹¹ Pharmacogenetics, drug tolerance, drug-drug interactions, body surface area, and organ function are patient- specific factors that are not taken into consideration when relying solely on a MEDD calculation. Tapering to lowest functional dose rather than a specific number or cutoff may be a more effective way to treat patients, and providers should use the guidelines as recommendations and not a hardline mandate.

At 6 months, 6 patients were receiving no pain medications from the VA, and 24 of the patients were tapered from their opiate to discontinuation. It is unclear whether patients are no longer taking opioids or switched their care to non-VA providers to receive medications, including opioids, privately. This is difficult to verify, though a prescription drug monitoring program (PDMP) could be used to assess patient adherence. As many of the patients that were tapered due to identification of aberrant behaviors, lack of continuity of care across health care systems may result in future patient harm.

The results of this analysis highlight the importance of checking PDMP databases and routine UDSs when prescribing opioids—there can be serious safety concerns if patients are taking other prescribed or illicit medications. However, care must be taken; there were 2 instances of patients’ chronic opioid prescriptions discontinued by their VA provider after a review of the PDMP showed they had received non-VA opioids. In both cases, the quantity and doses received were small (counts of ≤ 12) and were received more than 6 months prior to the check of the PDMP. While this constitutes a breach of the Informed Consent for long-term opioid use, if there are no other concerning behaviors, it may be more prudent to review the informed consent with the patient and discuss why the behavior is a breach to ensure that patients and PCPs continue to work as a team to manage chronic pain.

Limitations

The study population was one limitation of this project. While data suggest that chronic pain affects women more than men, this study’s population was only 13% female. Thirty percent of the women in this study had an AE compared with only 8% of the men. Additional limitations included use of problem list for comorbidities, as lists may be inaccurate or outdated, and limiting the monitoring of AE to only 6 months. As some tapers were not initiated immediately and some taper schedules can last several months to years; therefor, outcomes may have been higher if patients were followed longer. Many of the patients with AEs had increased ED visits or unscheduled primary care visits as the tapers went on and their pain worsened, but the visits were outside the 6-month time frame for data collection. An additional weakness of this review included assessing a pain score, but not functional status, which may be a better predictor of the effectiveness of a patient’s pain management regimen. This assessment is needed in future studies for more reliable data. Finally, PCP survey results also should be viewed with caution. The current survey had only 29 respondents, and the 2014 survey had only 10 respondents and did not include CBOC providers.

Conclusion

A pain eConsult service managed by CPSs specializing in pain management can assist patients and PCPs with opioid therapy recommendations in a safe and timely manner, reducing risk of overdose secondary to high dose opioid therapy and with limited harm to patients.

Evaluation of oral antineoplastic agent (OAN) adherence patterns have identified correlations between nonadherence or over-adherence and poorer disease-related outcomes. Multiple studies have focused on imatinib use in chronic myeloid leukemia (CML) due to its continuous, long-term use. A study by Ganesan and colleagues found that nonadherence to imatinib showed a significant decrease in 5-year event-free survival between 76.7% of adherent participants compared with 59.8% of nonadherent participants.¹ This study found that 44% of patients who were adherent to imatinib achieved complete cytogenetic response vs only 26% of patients who were nonadherent. In another study of imatinib for CML, major molecular response (MMR) was strongly correlated with adherence and no patients with adherence < 80% were able to achieve MMR.² Similarly, in studies of tamoxifen for breast cancer, < 80% adherence resulted in a 10% decrease in survival when compared to those who were more adherent.^3,4

In addition to the clinical implications of nonadherence, there can be a significant cost associated with suboptimal use of these medications. The price of a single dose of OAN medication may cost as much as $440.⁵

The benefits of multidisciplinary care teams have been identified in many studies.^6,7 While studies are limited in oncology, pharmacists provide vital contributions to the oncology multidisciplinary team when managing OANs as these health care professionals have expert knowledge of the medications, potential adverse events (AEs), and necessary monitoring parameters.⁸ In one study, patients seen by the pharmacist-led oral chemotherapy management program experienced improved clinical outcomes and response to therapy when compared with preintervention patients (early molecular response, 88.9% vs 54.8%, P = .01; major molecular response, 83.3% vs 57.6%, P = .06).⁹ During the study, 318 AEs were reported, leading to 235 pharmacist interventions to ameliorate AEs and improve adherence.

The primary objective of this study was to measure the impact of a pharmacist-driven OAN renewal clinic on medication adherence. The secondary objective was to estimate cost-savings of this new service.

Methods 

Prior to July 2014, several limitations were identified related to OAN prescribing and monitoring at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, Indiana (RLRVAMC). The prescription ordering process relied primarily on the patient to initiate refills, rather than the prescriber OAN prescriptions also lacked consistency for number of refills or quantities dispensed. Furthermore, ordering of antineoplastic products was not limited to hematology/oncology providers. Patients were identified with significant supply on hand at the time of medication discontinuation, creating concerns for medication waste, tolerability, and nonadherence.

As a result, opportunities were identified to improve the prescribing process, recommended monitoring, toxicity and tolerability evaluation, medication reconciliation, and medication adherence. In July of 2014, the RLRVAMC adopted a new chemotherapy order entry system capable of restricting prescriptions to hematology/oncology providers and limiting dispensed quantities and refill amounts. A comprehensive pharmacist driven OAN renewal clinic was implemented on September 1, 2014 with the goal of improving long-term adherence and tolerability, in addition to minimizing medication waste.

Study Design and Setting

This was a pre/post retrospective cohort, quality improvement study of patients enrolled in the RLRVAMC OAN pharmacist renewal clinic. The study was deemed exempt from institutional review board (IRB) by the US Department of Veterans Affairs (VA) Research and Development Department.

Study Population

Patients were included in the preimplementation group if they had received at least 2 prescriptions of an eligible OAN. Therapy for the preimplementation group was required to be a monthly duration > 21 days and between the dates of September 1, 2013 and August 31, 2014. Patients were included in the postimplementation group if they had received at least 2 prescriptions of the studied OANs between September 1, 2014 and January 31, 2015. Patients were excluded if they had filled < 2 prescriptions of OAN; were managed by a non-VA oncologist or hematologist; or received an OAN other than those listed in Table 1.

Data Collection

For all patients in both the pre- and postimplementation cohorts, a standardized data collection tool was used to collect the following via electronic health record review by a PGY2 oncology resident: age, race, gender, oral antineoplastic agent, refill dates, days’ supply, estimated unit cost per dose cancer diagnosis, distance from the RLRVAMC, copay status, presence of hospitalizations/ED visits/dosage reductions, discontinuation rates, reasons for discontinuation, and total number of current prescriptions. The presence or absence of dosage reductions were collected to identify concerns for tolerability, but only the original dose for the preimplementation group and dosage at time of clinic enrollment for the postimplementation group was included in the analysis.

Outcomes and Statistical Analyses

The primary outcome was medication adherence defined as the median medication possession ratio (MPR) before and after implementation of the clinic. Secondary outcomes included the proportion of patients who were adherent from before implementation to after implementation and estimated cost-savings of this clinic after implementation. MPR was used to estimate medication adherence by taking the cumulative day supply of medication on hand divided by the number of days on therapy.¹² Number of days on therapy was determined by taking the difference on the start date of the new medication regimen and the discontinuation date of the same regimen. Patients were grouped by adherence into one of the following categories: < 0.8, 0.8 to 0.89, 0.9 to 1, and > 1.1. Patients were considered adherent if they reported taking ≥ 90% (MPR ≥ 0.9) of prescribed doses, adopted from the study by Anderson and colleagues.¹² A patient with an MPR > 1, likely due to filling prior to the anticipated refill date, was considered 100% adherent (MPR = 1). If a patient switched OAN during the study, both agents were included as separate entities.

A conservative estimate of cost-savings was made by multiplying the RLRVAMC cost per unit of medication at time of initial prescription fill by the number of units taken each day multiplied by the total days’ supply on hand at time of therapy discontinuation. Patients with an MPR < 1 at time of therapy discontinuation were assumed to have zero remaining units on hand and zero cost savings was estimated. Waste, for purposes of cost-savings, was calculated for all MPR values > 1. Additional supply anticipated to be on hand from dose reductions was not included in the estimated cost of unused medication.

Descriptive statistics compared demographic characteristics between the pre- and postimplementation groups. MPR data were not normally distributed, which required the use of nonparametric Mann-Whitney U tests to compare pre- and postMPRs. Pearson χ² compared the proportion of adherent patients between groups while descriptive statistics were used to estimate cost savings. Significance was determined based on a P value < .05. IBM SPSS Statistics software was used for all statistical analyses. As this was a complete sample of all eligible subjects, no sample size calculation was performed.

Results

In the preimplementation period, 246 patients received an OAN and 61 patients received an OAN in the postimplementation period (Figure 1). Of the 246 patients in the preimplementation period, 98 were eligible and included in the preimplementation group. Similarly, of the 61 patients in the postimplementation period, 35 patients met inclusion criteria for the postimplementation group. The study population was predominantly male with an average age of approximately 70 years in both groups (Table 3). More than 70% of the population in each group was White. No statistically significant differences between groups were identified. The most commonly prescribed OAN in the preimplementation group were abiraterone, imatinib, and enzalutamide (Table 3). In the postimplementation group, the most commonly prescribed agents were abiraterone, imatinib, pazopanib, and dasatinib. No significant differences were observed in prescribing of individual agents between the pre- and postimplementation groups or other characteristics that may affect adherence including patient copay status, number of concomitant medications, and driving distance from the RLRVAMC.

Thirty-six (36.7%) patients in the preimplementation group were considered nonadherent (MPR < 0.9) and 18 (18.4%) had an MPR < 0.8. Fifteen (15.3%) patients in the preimplementation clinic were considered overadherent (MPR > 1.1). Forty-seven (47.9%) patients in the preimplementation group were considered adherent (MPR 0.9 - 1.1) while all 35 (100%) patients in the postimplementation group were considered adherent (MPR 0.9 - 1.1). No non- or overadherent patients were identified in the postimplementation group (Figure 2). The median MPR for all patients in the preimplementation group was 0.94 compared with 1.06 (P < .001) in the postimplementation group.

Discussion

OANs are widely used therapies, with more than 25 million doses administered per year in the United States alone.¹² The use of these agents will continue to grow as more targeted agents become available and patients request more convenient treatment options. The role for hematology/oncology clinical pharmacy services must adapt to this increased usage of OANs, including increasing pharmacist involvement in medication education, adherence and tolerability assessments, and proactive drug interaction monitoring.However, additional research is needed to determine optimal management strategies.

Our study aimed to compare OAN adherence among patients at a tertiary care VA hospital before and after implementation of a renewal clinic. The preimplementation population had a median MPR of 0.94 compared with 1.06 in the postimplementation group (P < .001). Although an ideal MPR is 1.0, we aimed for a slightly higher MPR to allow a supply buffer in the event of prescription delivery delays, as more than 90% of prescriptions are mailed to patients from a regional mail-order pharmacy. Importantly, the median MPRs do not adequately convey the impact from this clinic. The proportion of patients who were considered adherent to OANs increased from 47.9% in the preimplementation to 100% in the postimplementation period. These finding suggest that the clinical pharmacist role to assess and encourage adherence through monitoring tolerability of these OANs improved the overall medication taking experience of these patients.

Upon initial evaluation of adherence pre- and postimplementation, median adherence rates in both groups appeared to be above goal at 0.94 and 1.06 respectively. Patients in the postimplementation group intentionally received a 5- to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer. After correcting for patients with confounding reasons for excess (dose reductions, breaks in treatment, etc.), the median MPR in the prerefill clinic group decreased to 0.9 and the MPR in the postrefill clinic group increased slightly to 1.08. Although the median adherence rate in both the pre- and postimplementation groups were above goal of 0.90, 36% of the patients in the preimplementation group were considered nonadherent (MPR < 0.9) compared with no patients in the postimplementation group. Therefore, our intervention to improve patient adherence appeared to be beneficial at our institution.

In addition to improving adherence, one of the goals of the renewal clinic was to minimize excess supply at the time of therapy discontinuation. This was accomplished by aligning medication fills with medical visits and objective monitoring, as well as limiting supply to no more than 30 days. Of the patients in the postimplementation group, only 1 patient had remaining medication at the time of therapy discontinuation compared with 14 patients in the preimplementation group. The estimated cost savings from excess supply was $36,335. Limiting the amount of unused supply not only saves money for the patient and the institution, but also decreases opportunity for improper hazardous waste disposal and unnecessary exposure of hazardous materials to others.

Our results show the pharmacist intervention in the coordination of renewals improved adherence, minimized medication waste, and saved money. The cost of pharmacist time participating in the refill clinic was not calculated. Each visit was completed in approximately 5 minutes, with subsequent documentation and coordination taking an additional 5 to 10 minutes. During the launch of this service, the oncology pharmacy resident provided all coverage of the clinic. Oversite of the resident was provided by hematology/oncology clinical pharmacy specialists. We have continued to utilize pharmacy resident coverage since that time to meet education needs and keep the estimated cost per visit low. Another option in the case that pharmacy residents are not available would be utilization of a pharmacy technician, intern, or professional student to conduct the adherence and tolerability phone assessments. Our escalation protocol allows intervention by clinical pharmacy specialist and/or other health care providers when necessary. Trainees have only required basic training on how to use the protocol.

Limitations

Due to this study’s retrospective design, an inherent limitation is dependence on prescriber and refill records for documentation of initiation and discontinuation dates. Therefore, only the association of impact of pharmacist intervention on medication adherence can be determined as opposed to causation. We did not take into account discrepancies in day supply secondary to ‘held’ therapies, dose reductions, or doses supplied during an inpatient admission, which may alter estimates of MPR and cost-savings data. Patients in the postimplementation group intentionally received a 5 to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer, thereby skewing MPR values. This study did not account for cost avoidance resulting from early identification and management of toxicity. Finally, the postimplementation data only spans 4 months and a longer duration of time is needed to more accurately determine sustainability of renewal clinic interventions and provide comprehensive evaluation of cost-avoidance.

Conclusion

Implementation of an OAN renewal clinic was associated with an increase in MPR, improved proportion of patients considered adherent, and an estimated $36,335 cost-savings. However, prospective evaluation and a longer study duration are needed to determine causality of improved adherence and cost-savings associated with a pharmacist-driven OAN renewal clinic.

Evaluation of oral antineoplastic agent (OAN) adherence patterns have identified correlations between nonadherence or over-adherence and poorer disease-related outcomes. Multiple studies have focused on imatinib use in chronic myeloid leukemia (CML) due to its continuous, long-term use. A study by Ganesan and colleagues found that nonadherence to imatinib showed a significant decrease in 5-year event-free survival between 76.7% of adherent participants compared with 59.8% of nonadherent participants.¹ This study found that 44% of patients who were adherent to imatinib achieved complete cytogenetic response vs only 26% of patients who were nonadherent. In another study of imatinib for CML, major molecular response (MMR) was strongly correlated with adherence and no patients with adherence < 80% were able to achieve MMR.² Similarly, in studies of tamoxifen for breast cancer, < 80% adherence resulted in a 10% decrease in survival when compared to those who were more adherent.^3,4

In addition to the clinical implications of nonadherence, there can be a significant cost associated with suboptimal use of these medications. The price of a single dose of OAN medication may cost as much as $440.⁵

The benefits of multidisciplinary care teams have been identified in many studies.^6,7 While studies are limited in oncology, pharmacists provide vital contributions to the oncology multidisciplinary team when managing OANs as these health care professionals have expert knowledge of the medications, potential adverse events (AEs), and necessary monitoring parameters.⁸ In one study, patients seen by the pharmacist-led oral chemotherapy management program experienced improved clinical outcomes and response to therapy when compared with preintervention patients (early molecular response, 88.9% vs 54.8%, P = .01; major molecular response, 83.3% vs 57.6%, P = .06).⁹ During the study, 318 AEs were reported, leading to 235 pharmacist interventions to ameliorate AEs and improve adherence.

The primary objective of this study was to measure the impact of a pharmacist-driven OAN renewal clinic on medication adherence. The secondary objective was to estimate cost-savings of this new service.

Methods 

Prior to July 2014, several limitations were identified related to OAN prescribing and monitoring at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, Indiana (RLRVAMC). The prescription ordering process relied primarily on the patient to initiate refills, rather than the prescriber OAN prescriptions also lacked consistency for number of refills or quantities dispensed. Furthermore, ordering of antineoplastic products was not limited to hematology/oncology providers. Patients were identified with significant supply on hand at the time of medication discontinuation, creating concerns for medication waste, tolerability, and nonadherence.

As a result, opportunities were identified to improve the prescribing process, recommended monitoring, toxicity and tolerability evaluation, medication reconciliation, and medication adherence. In July of 2014, the RLRVAMC adopted a new chemotherapy order entry system capable of restricting prescriptions to hematology/oncology providers and limiting dispensed quantities and refill amounts. A comprehensive pharmacist driven OAN renewal clinic was implemented on September 1, 2014 with the goal of improving long-term adherence and tolerability, in addition to minimizing medication waste.

Study Design and Setting

This was a pre/post retrospective cohort, quality improvement study of patients enrolled in the RLRVAMC OAN pharmacist renewal clinic. The study was deemed exempt from institutional review board (IRB) by the US Department of Veterans Affairs (VA) Research and Development Department.

Study Population

Patients were included in the preimplementation group if they had received at least 2 prescriptions of an eligible OAN. Therapy for the preimplementation group was required to be a monthly duration > 21 days and between the dates of September 1, 2013 and August 31, 2014. Patients were included in the postimplementation group if they had received at least 2 prescriptions of the studied OANs between September 1, 2014 and January 31, 2015. Patients were excluded if they had filled < 2 prescriptions of OAN; were managed by a non-VA oncologist or hematologist; or received an OAN other than those listed in Table 1.

Data Collection

For all patients in both the pre- and postimplementation cohorts, a standardized data collection tool was used to collect the following via electronic health record review by a PGY2 oncology resident: age, race, gender, oral antineoplastic agent, refill dates, days’ supply, estimated unit cost per dose cancer diagnosis, distance from the RLRVAMC, copay status, presence of hospitalizations/ED visits/dosage reductions, discontinuation rates, reasons for discontinuation, and total number of current prescriptions. The presence or absence of dosage reductions were collected to identify concerns for tolerability, but only the original dose for the preimplementation group and dosage at time of clinic enrollment for the postimplementation group was included in the analysis.

Outcomes and Statistical Analyses

The primary outcome was medication adherence defined as the median medication possession ratio (MPR) before and after implementation of the clinic. Secondary outcomes included the proportion of patients who were adherent from before implementation to after implementation and estimated cost-savings of this clinic after implementation. MPR was used to estimate medication adherence by taking the cumulative day supply of medication on hand divided by the number of days on therapy.¹² Number of days on therapy was determined by taking the difference on the start date of the new medication regimen and the discontinuation date of the same regimen. Patients were grouped by adherence into one of the following categories: < 0.8, 0.8 to 0.89, 0.9 to 1, and > 1.1. Patients were considered adherent if they reported taking ≥ 90% (MPR ≥ 0.9) of prescribed doses, adopted from the study by Anderson and colleagues.¹² A patient with an MPR > 1, likely due to filling prior to the anticipated refill date, was considered 100% adherent (MPR = 1). If a patient switched OAN during the study, both agents were included as separate entities.

A conservative estimate of cost-savings was made by multiplying the RLRVAMC cost per unit of medication at time of initial prescription fill by the number of units taken each day multiplied by the total days’ supply on hand at time of therapy discontinuation. Patients with an MPR < 1 at time of therapy discontinuation were assumed to have zero remaining units on hand and zero cost savings was estimated. Waste, for purposes of cost-savings, was calculated for all MPR values > 1. Additional supply anticipated to be on hand from dose reductions was not included in the estimated cost of unused medication.

Descriptive statistics compared demographic characteristics between the pre- and postimplementation groups. MPR data were not normally distributed, which required the use of nonparametric Mann-Whitney U tests to compare pre- and postMPRs. Pearson χ² compared the proportion of adherent patients between groups while descriptive statistics were used to estimate cost savings. Significance was determined based on a P value < .05. IBM SPSS Statistics software was used for all statistical analyses. As this was a complete sample of all eligible subjects, no sample size calculation was performed.

Results

In the preimplementation period, 246 patients received an OAN and 61 patients received an OAN in the postimplementation period (Figure 1). Of the 246 patients in the preimplementation period, 98 were eligible and included in the preimplementation group. Similarly, of the 61 patients in the postimplementation period, 35 patients met inclusion criteria for the postimplementation group. The study population was predominantly male with an average age of approximately 70 years in both groups (Table 3). More than 70% of the population in each group was White. No statistically significant differences between groups were identified. The most commonly prescribed OAN in the preimplementation group were abiraterone, imatinib, and enzalutamide (Table 3). In the postimplementation group, the most commonly prescribed agents were abiraterone, imatinib, pazopanib, and dasatinib. No significant differences were observed in prescribing of individual agents between the pre- and postimplementation groups or other characteristics that may affect adherence including patient copay status, number of concomitant medications, and driving distance from the RLRVAMC.

Thirty-six (36.7%) patients in the preimplementation group were considered nonadherent (MPR < 0.9) and 18 (18.4%) had an MPR < 0.8. Fifteen (15.3%) patients in the preimplementation clinic were considered overadherent (MPR > 1.1). Forty-seven (47.9%) patients in the preimplementation group were considered adherent (MPR 0.9 - 1.1) while all 35 (100%) patients in the postimplementation group were considered adherent (MPR 0.9 - 1.1). No non- or overadherent patients were identified in the postimplementation group (Figure 2). The median MPR for all patients in the preimplementation group was 0.94 compared with 1.06 (P < .001) in the postimplementation group.

Discussion

OANs are widely used therapies, with more than 25 million doses administered per year in the United States alone.¹² The use of these agents will continue to grow as more targeted agents become available and patients request more convenient treatment options. The role for hematology/oncology clinical pharmacy services must adapt to this increased usage of OANs, including increasing pharmacist involvement in medication education, adherence and tolerability assessments, and proactive drug interaction monitoring.However, additional research is needed to determine optimal management strategies.

Our study aimed to compare OAN adherence among patients at a tertiary care VA hospital before and after implementation of a renewal clinic. The preimplementation population had a median MPR of 0.94 compared with 1.06 in the postimplementation group (P < .001). Although an ideal MPR is 1.0, we aimed for a slightly higher MPR to allow a supply buffer in the event of prescription delivery delays, as more than 90% of prescriptions are mailed to patients from a regional mail-order pharmacy. Importantly, the median MPRs do not adequately convey the impact from this clinic. The proportion of patients who were considered adherent to OANs increased from 47.9% in the preimplementation to 100% in the postimplementation period. These finding suggest that the clinical pharmacist role to assess and encourage adherence through monitoring tolerability of these OANs improved the overall medication taking experience of these patients.

Upon initial evaluation of adherence pre- and postimplementation, median adherence rates in both groups appeared to be above goal at 0.94 and 1.06 respectively. Patients in the postimplementation group intentionally received a 5- to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer. After correcting for patients with confounding reasons for excess (dose reductions, breaks in treatment, etc.), the median MPR in the prerefill clinic group decreased to 0.9 and the MPR in the postrefill clinic group increased slightly to 1.08. Although the median adherence rate in both the pre- and postimplementation groups were above goal of 0.90, 36% of the patients in the preimplementation group were considered nonadherent (MPR < 0.9) compared with no patients in the postimplementation group. Therefore, our intervention to improve patient adherence appeared to be beneficial at our institution.

In addition to improving adherence, one of the goals of the renewal clinic was to minimize excess supply at the time of therapy discontinuation. This was accomplished by aligning medication fills with medical visits and objective monitoring, as well as limiting supply to no more than 30 days. Of the patients in the postimplementation group, only 1 patient had remaining medication at the time of therapy discontinuation compared with 14 patients in the preimplementation group. The estimated cost savings from excess supply was $36,335. Limiting the amount of unused supply not only saves money for the patient and the institution, but also decreases opportunity for improper hazardous waste disposal and unnecessary exposure of hazardous materials to others.

Our results show the pharmacist intervention in the coordination of renewals improved adherence, minimized medication waste, and saved money. The cost of pharmacist time participating in the refill clinic was not calculated. Each visit was completed in approximately 5 minutes, with subsequent documentation and coordination taking an additional 5 to 10 minutes. During the launch of this service, the oncology pharmacy resident provided all coverage of the clinic. Oversite of the resident was provided by hematology/oncology clinical pharmacy specialists. We have continued to utilize pharmacy resident coverage since that time to meet education needs and keep the estimated cost per visit low. Another option in the case that pharmacy residents are not available would be utilization of a pharmacy technician, intern, or professional student to conduct the adherence and tolerability phone assessments. Our escalation protocol allows intervention by clinical pharmacy specialist and/or other health care providers when necessary. Trainees have only required basic training on how to use the protocol.

Limitations

Due to this study’s retrospective design, an inherent limitation is dependence on prescriber and refill records for documentation of initiation and discontinuation dates. Therefore, only the association of impact of pharmacist intervention on medication adherence can be determined as opposed to causation. We did not take into account discrepancies in day supply secondary to ‘held’ therapies, dose reductions, or doses supplied during an inpatient admission, which may alter estimates of MPR and cost-savings data. Patients in the postimplementation group intentionally received a 5 to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer, thereby skewing MPR values. This study did not account for cost avoidance resulting from early identification and management of toxicity. Finally, the postimplementation data only spans 4 months and a longer duration of time is needed to more accurately determine sustainability of renewal clinic interventions and provide comprehensive evaluation of cost-avoidance.

Conclusion

Implementation of an OAN renewal clinic was associated with an increase in MPR, improved proportion of patients considered adherent, and an estimated $36,335 cost-savings. However, prospective evaluation and a longer study duration are needed to determine causality of improved adherence and cost-savings associated with a pharmacist-driven OAN renewal clinic.

Evaluation of oral antineoplastic agent (OAN) adherence patterns have identified correlations between nonadherence or over-adherence and poorer disease-related outcomes. Multiple studies have focused on imatinib use in chronic myeloid leukemia (CML) due to its continuous, long-term use. A study by Ganesan and colleagues found that nonadherence to imatinib showed a significant decrease in 5-year event-free survival between 76.7% of adherent participants compared with 59.8% of nonadherent participants.¹ This study found that 44% of patients who were adherent to imatinib achieved complete cytogenetic response vs only 26% of patients who were nonadherent. In another study of imatinib for CML, major molecular response (MMR) was strongly correlated with adherence and no patients with adherence < 80% were able to achieve MMR.² Similarly, in studies of tamoxifen for breast cancer, < 80% adherence resulted in a 10% decrease in survival when compared to those who were more adherent.^3,4

In addition to the clinical implications of nonadherence, there can be a significant cost associated with suboptimal use of these medications. The price of a single dose of OAN medication may cost as much as $440.⁵

The benefits of multidisciplinary care teams have been identified in many studies.^6,7 While studies are limited in oncology, pharmacists provide vital contributions to the oncology multidisciplinary team when managing OANs as these health care professionals have expert knowledge of the medications, potential adverse events (AEs), and necessary monitoring parameters.⁸ In one study, patients seen by the pharmacist-led oral chemotherapy management program experienced improved clinical outcomes and response to therapy when compared with preintervention patients (early molecular response, 88.9% vs 54.8%, P = .01; major molecular response, 83.3% vs 57.6%, P = .06).⁹ During the study, 318 AEs were reported, leading to 235 pharmacist interventions to ameliorate AEs and improve adherence.

The primary objective of this study was to measure the impact of a pharmacist-driven OAN renewal clinic on medication adherence. The secondary objective was to estimate cost-savings of this new service.

Methods 

Prior to July 2014, several limitations were identified related to OAN prescribing and monitoring at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, Indiana (RLRVAMC). The prescription ordering process relied primarily on the patient to initiate refills, rather than the prescriber OAN prescriptions also lacked consistency for number of refills or quantities dispensed. Furthermore, ordering of antineoplastic products was not limited to hematology/oncology providers. Patients were identified with significant supply on hand at the time of medication discontinuation, creating concerns for medication waste, tolerability, and nonadherence.

As a result, opportunities were identified to improve the prescribing process, recommended monitoring, toxicity and tolerability evaluation, medication reconciliation, and medication adherence. In July of 2014, the RLRVAMC adopted a new chemotherapy order entry system capable of restricting prescriptions to hematology/oncology providers and limiting dispensed quantities and refill amounts. A comprehensive pharmacist driven OAN renewal clinic was implemented on September 1, 2014 with the goal of improving long-term adherence and tolerability, in addition to minimizing medication waste.

Study Design and Setting

This was a pre/post retrospective cohort, quality improvement study of patients enrolled in the RLRVAMC OAN pharmacist renewal clinic. The study was deemed exempt from institutional review board (IRB) by the US Department of Veterans Affairs (VA) Research and Development Department.

Study Population

Patients were included in the preimplementation group if they had received at least 2 prescriptions of an eligible OAN. Therapy for the preimplementation group was required to be a monthly duration > 21 days and between the dates of September 1, 2013 and August 31, 2014. Patients were included in the postimplementation group if they had received at least 2 prescriptions of the studied OANs between September 1, 2014 and January 31, 2015. Patients were excluded if they had filled < 2 prescriptions of OAN; were managed by a non-VA oncologist or hematologist; or received an OAN other than those listed in Table 1.

Data Collection

For all patients in both the pre- and postimplementation cohorts, a standardized data collection tool was used to collect the following via electronic health record review by a PGY2 oncology resident: age, race, gender, oral antineoplastic agent, refill dates, days’ supply, estimated unit cost per dose cancer diagnosis, distance from the RLRVAMC, copay status, presence of hospitalizations/ED visits/dosage reductions, discontinuation rates, reasons for discontinuation, and total number of current prescriptions. The presence or absence of dosage reductions were collected to identify concerns for tolerability, but only the original dose for the preimplementation group and dosage at time of clinic enrollment for the postimplementation group was included in the analysis.

Outcomes and Statistical Analyses

The primary outcome was medication adherence defined as the median medication possession ratio (MPR) before and after implementation of the clinic. Secondary outcomes included the proportion of patients who were adherent from before implementation to after implementation and estimated cost-savings of this clinic after implementation. MPR was used to estimate medication adherence by taking the cumulative day supply of medication on hand divided by the number of days on therapy.¹² Number of days on therapy was determined by taking the difference on the start date of the new medication regimen and the discontinuation date of the same regimen. Patients were grouped by adherence into one of the following categories: < 0.8, 0.8 to 0.89, 0.9 to 1, and > 1.1. Patients were considered adherent if they reported taking ≥ 90% (MPR ≥ 0.9) of prescribed doses, adopted from the study by Anderson and colleagues.¹² A patient with an MPR > 1, likely due to filling prior to the anticipated refill date, was considered 100% adherent (MPR = 1). If a patient switched OAN during the study, both agents were included as separate entities.

A conservative estimate of cost-savings was made by multiplying the RLRVAMC cost per unit of medication at time of initial prescription fill by the number of units taken each day multiplied by the total days’ supply on hand at time of therapy discontinuation. Patients with an MPR < 1 at time of therapy discontinuation were assumed to have zero remaining units on hand and zero cost savings was estimated. Waste, for purposes of cost-savings, was calculated for all MPR values > 1. Additional supply anticipated to be on hand from dose reductions was not included in the estimated cost of unused medication.

Descriptive statistics compared demographic characteristics between the pre- and postimplementation groups. MPR data were not normally distributed, which required the use of nonparametric Mann-Whitney U tests to compare pre- and postMPRs. Pearson χ² compared the proportion of adherent patients between groups while descriptive statistics were used to estimate cost savings. Significance was determined based on a P value < .05. IBM SPSS Statistics software was used for all statistical analyses. As this was a complete sample of all eligible subjects, no sample size calculation was performed.

Results

In the preimplementation period, 246 patients received an OAN and 61 patients received an OAN in the postimplementation period (Figure 1). Of the 246 patients in the preimplementation period, 98 were eligible and included in the preimplementation group. Similarly, of the 61 patients in the postimplementation period, 35 patients met inclusion criteria for the postimplementation group. The study population was predominantly male with an average age of approximately 70 years in both groups (Table 3). More than 70% of the population in each group was White. No statistically significant differences between groups were identified. The most commonly prescribed OAN in the preimplementation group were abiraterone, imatinib, and enzalutamide (Table 3). In the postimplementation group, the most commonly prescribed agents were abiraterone, imatinib, pazopanib, and dasatinib. No significant differences were observed in prescribing of individual agents between the pre- and postimplementation groups or other characteristics that may affect adherence including patient copay status, number of concomitant medications, and driving distance from the RLRVAMC.

Thirty-six (36.7%) patients in the preimplementation group were considered nonadherent (MPR < 0.9) and 18 (18.4%) had an MPR < 0.8. Fifteen (15.3%) patients in the preimplementation clinic were considered overadherent (MPR > 1.1). Forty-seven (47.9%) patients in the preimplementation group were considered adherent (MPR 0.9 - 1.1) while all 35 (100%) patients in the postimplementation group were considered adherent (MPR 0.9 - 1.1). No non- or overadherent patients were identified in the postimplementation group (Figure 2). The median MPR for all patients in the preimplementation group was 0.94 compared with 1.06 (P < .001) in the postimplementation group.

Discussion

OANs are widely used therapies, with more than 25 million doses administered per year in the United States alone.¹² The use of these agents will continue to grow as more targeted agents become available and patients request more convenient treatment options. The role for hematology/oncology clinical pharmacy services must adapt to this increased usage of OANs, including increasing pharmacist involvement in medication education, adherence and tolerability assessments, and proactive drug interaction monitoring.However, additional research is needed to determine optimal management strategies.

Our study aimed to compare OAN adherence among patients at a tertiary care VA hospital before and after implementation of a renewal clinic. The preimplementation population had a median MPR of 0.94 compared with 1.06 in the postimplementation group (P < .001). Although an ideal MPR is 1.0, we aimed for a slightly higher MPR to allow a supply buffer in the event of prescription delivery delays, as more than 90% of prescriptions are mailed to patients from a regional mail-order pharmacy. Importantly, the median MPRs do not adequately convey the impact from this clinic. The proportion of patients who were considered adherent to OANs increased from 47.9% in the preimplementation to 100% in the postimplementation period. These finding suggest that the clinical pharmacist role to assess and encourage adherence through monitoring tolerability of these OANs improved the overall medication taking experience of these patients.

Upon initial evaluation of adherence pre- and postimplementation, median adherence rates in both groups appeared to be above goal at 0.94 and 1.06 respectively. Patients in the postimplementation group intentionally received a 5- to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer. After correcting for patients with confounding reasons for excess (dose reductions, breaks in treatment, etc.), the median MPR in the prerefill clinic group decreased to 0.9 and the MPR in the postrefill clinic group increased slightly to 1.08. Although the median adherence rate in both the pre- and postimplementation groups were above goal of 0.90, 36% of the patients in the preimplementation group were considered nonadherent (MPR < 0.9) compared with no patients in the postimplementation group. Therefore, our intervention to improve patient adherence appeared to be beneficial at our institution.

In addition to improving adherence, one of the goals of the renewal clinic was to minimize excess supply at the time of therapy discontinuation. This was accomplished by aligning medication fills with medical visits and objective monitoring, as well as limiting supply to no more than 30 days. Of the patients in the postimplementation group, only 1 patient had remaining medication at the time of therapy discontinuation compared with 14 patients in the preimplementation group. The estimated cost savings from excess supply was $36,335. Limiting the amount of unused supply not only saves money for the patient and the institution, but also decreases opportunity for improper hazardous waste disposal and unnecessary exposure of hazardous materials to others.

Our results show the pharmacist intervention in the coordination of renewals improved adherence, minimized medication waste, and saved money. The cost of pharmacist time participating in the refill clinic was not calculated. Each visit was completed in approximately 5 minutes, with subsequent documentation and coordination taking an additional 5 to 10 minutes. During the launch of this service, the oncology pharmacy resident provided all coverage of the clinic. Oversite of the resident was provided by hematology/oncology clinical pharmacy specialists. We have continued to utilize pharmacy resident coverage since that time to meet education needs and keep the estimated cost per visit low. Another option in the case that pharmacy residents are not available would be utilization of a pharmacy technician, intern, or professional student to conduct the adherence and tolerability phone assessments. Our escalation protocol allows intervention by clinical pharmacy specialist and/or other health care providers when necessary. Trainees have only required basic training on how to use the protocol.

Limitations

Due to this study’s retrospective design, an inherent limitation is dependence on prescriber and refill records for documentation of initiation and discontinuation dates. Therefore, only the association of impact of pharmacist intervention on medication adherence can be determined as opposed to causation. We did not take into account discrepancies in day supply secondary to ‘held’ therapies, dose reductions, or doses supplied during an inpatient admission, which may alter estimates of MPR and cost-savings data. Patients in the postimplementation group intentionally received a 5 to 7-day supply buffer to account for potential prescription delivery delays due to holidays and inclement weather. This would indicate that the patients in the postimplementation group would have 15% oversupply due to the 5-day supply buffer, thereby skewing MPR values. This study did not account for cost avoidance resulting from early identification and management of toxicity. Finally, the postimplementation data only spans 4 months and a longer duration of time is needed to more accurately determine sustainability of renewal clinic interventions and provide comprehensive evaluation of cost-avoidance.

Conclusion

Implementation of an OAN renewal clinic was associated with an increase in MPR, improved proportion of patients considered adherent, and an estimated $36,335 cost-savings. However, prospective evaluation and a longer study duration are needed to determine causality of improved adherence and cost-savings associated with a pharmacist-driven OAN renewal clinic.

Total knee arthroplasty (TKA) is one of the most common surgical procedures in the United States. The volume of TKAs is projected to substantially increase over the next 30 years.¹ Adequate pain control after TKA is critically important to achieve early mobilization, shorten the length of hospital stay, and reduce postoperative complications. The evolution and inclusion of multimodal pain-management protocols have had a major impact on the clinical outcomes for TKA patients.^2,3

Pain-management protocols typically use several modalities to control pain throughout the perioperative period. Multimodal opioid and nonopioid oral medications are administered during the pre- and postoperative periods and often involve a combination of acetaminophen, gabapentinoids, and cyclooxygenase-2 inhibitors.⁴ Peripheral nerve blocks and central neuraxial blockades are widely used and have been shown to be effective in reducing postoperative pain as well as overall opioid consumption.^5,6 Finally, intraoperative periarticular injections have been shown to reduce postoperative pain and opioid consumption as well as improve patient satisfaction scores.^7-9 These strategies are routinely used in TKA with the goal of minimizing overall opioid consumption and adverse events, reducing perioperative complications, and improving patient satisfaction.

Periarticular injections during surgery are an integral part of the multimodal pain-management protocols, though no consensus has been reached on proper injection formulation or technique. Liposomal bupivacaine is a local anesthetic depot formulation approved by the US Food and Drug Administration for surgical patients. The reported results have been discrepant regarding the efficacy of using liposomal bupivacaine injection in patients with TKA. Several studies have reported no added benefit of liposomal bupivacaine in contrast to a mixture of local anesthetics.^10,11 Other studies have demonstrated superior pain relief.¹² Many factors may contribute to the discrepant data, such as injection techniques, infiltration volume, and the assessment tools used to measure efficacy and safety.¹³

The US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) provides care to a large patient population. Many of the patients in that system have high-risk profiles, including medical comorbidities; exposure to chronic pain and opioid use; and psychological and central nervous system injuries, including posttraumatic stress disorder and traumatic brain injury. Hadlandsmyth and colleagues reported increased risk of prolonged opioid use in VA patients after TKA surgery.¹⁴ They found that 20% of the patients were still on long-term opioids more than 90 days after TKA.

The purpose of this study was to evaluate the efficacy of the implementation of a comprehensive enhanced recovery after surgery (ERAS) protocol at a regional VA medical center. We hypothesize that the addition of liposomal bupivacaine in a multidisciplinary ERAS protocol would reduce the length of hospital stay and opioid consumption without any deleterious effects on postoperative outcomes.

Methods

A postoperative recovery protocol was implemented in 2013 at VA North Texas Health Care System (VANTHCS) in Dallas, and many of the patients continued to have issues with satisfactory pain control, prolonged length of stay, and extended opioid consumption postoperatively. A multimodal pain-management protocol and multidisciplinary perioperative case-management protocol were implemented in 2016 to further improve the clinical outcomes of patients undergoing TKA surgery. The senior surgeon (JM) organized a multidisciplinary team of health care providers to identify and implement potential solutions. This task force met weekly and consisted of surgeons, anesthesiologists, certified registered nurse anesthetists, orthopedic physician assistants, a nurse coordinator, a physical therapist, and an occupational therapist, as well as operating room, postanesthesia care unit (PACU), and surgical ward nurses. In addition, the staff from the home health agencies and social services attended the weekly meetings.

We conducted a retrospective review of all patients who had undergone unilateral TKA from 2013 to 2018 at VANTHCS. This was a consecutive, unselected cohort. All patients were under the care of a single surgeon using identical implant systems and identical surgical techniques. This study was approved by the institutional review board at VANTHCS. Patients were divided into 2 distinct and consecutive cohorts. The standard of care (SOC) group included all patients from 2013 to 2016. The ERAS group included all patients after the institution of the standardized protocol until the end of the study period.

Data on patient demographics, the American Society of Anesthesiologists risk classification, and preoperative functional status were extracted. Anesthesia techniques included either general endotracheal anesthesia or subarachnoid block with monitored anesthesia care. The quantity of the opioids given during surgery, in the PACU, during the inpatient stay, as discharge prescriptions, and as refills of the narcotic prescriptions up to 3 months postsurgery were recorded. All opioids were converted into morphine equivalent dosages (MED) in order to be properly analyzed using the statistical methodologies described in the statistical section.¹⁵ The VHA is a closed health care delivery system; therefore, all of the prescriptions ordered by surgery providers were recorded in the electronic health record.

ERAS Protocol

The SOC cohort was predominantly managed with general endotracheal anesthesia. The ERAS group was predominantly managed with subarachnoid blocks (Table 1). For the ERAS protocol preoperatively, the patients were administered oral gabapentin 300 mg, acetaminophen 650 mg, and oxycodone 20 mg, and IV ondansetron 4 mg. Intraoperatively, minimal opioids were used. In the PACU, the patients received dilaudid 0.25 mg IV as needed every 15 minutes for up to 1 mg/h. The nursing staff was trained to use the visual analog pain scale scores to titrate the medication. During the inpatient stay, patients received 1 g IV acetaminophen every 6 hours for 3 doses. The patients thereafter received oral acetaminophen as needed. Other medications in the multimodal pain-management protocol included gabapentin 300 mg twice daily, meloxicam 15 mg daily, and oxycodone 10 mg every 4 hours as needed. Rescue medication for insufficient pain relief was dilaudid 0.25 mg IV every 15 minutes for visual analog pain scale > 8. On discharge, the patients received a prescription of 30 tablets of hydrocodone 10 mg.

Periarticular Injections

Intraoperatively, all patients in the SOC and ERAS groups received periarticular injections. The liposomal bupivacaine injection was added to the standard injection mixture for the ERAS group. For the SOC group, the total volume of 100 ml was divided into 10 separate 10 cc syringes, and for the ERAS group, the total volume of 140 ml was divided into 14 separate 10 cc syringes. The SOC group injections were performed with an 18-gauge needle and the periarticular soft tissues grossly infiltrated. The ERAS group injections were done with more attention to anatomical detail. Injection sites for the ERAS group included the posterior joint capsule, the medial compartment, the lateral compartment, the tibial fat pad, the quadriceps and the patellar tendon, the femoral and tibial periosteum circumferentially, and the anterior joint capsule. Each needle-stick in the ERAS group delivered 1 to 1.5 ml through a 22-gauge needle to each compartment of the knee.

Outcome Variable

The primary outcome measure was total oral MED intraoperatively, in the PACU, during the hospital inpatient stay, in the hospital discharge prescription, and during the 3-month period after hospital discharge. Incidence of nausea and vomiting during the inpatient stay and any narcotic use at 6 months postsurgery were secondary binary outcomes.

Statistical Analysis

Demographic data and the clinical characteristics for the entire group were described using the sample mean and SD for continuous variables and the frequency and percentage for categorical variables. Differences between the 2 cohorts were analyzed using a 2-independent-sample t test and Fisher exact test.

The estimation of the total oral MED throughout all phases of care was done using a separate Poisson model due to the data being not normally distributed. A log-linear regression model was used to evaluate the main effect of ERAS vs the SOC cohort on the total oral MED used. Finally, a separate multiple logistic regression model was used to estimate the odds of postoperative nausea and vomiting and narcotic use at 6 months postsurgery between the cohorts. The adjusted odds ratio (OR) was estimated from the logistic model. Age, sex, body mass index, preoperative functional independence score, narcotic use within 3 months prior to surgery, anesthesia type used (subarachnoid block with monitored anesthesia care vs general endotracheal anesthesia), and postoperative complications (yes/no) were included as covariates in each model. The length of hospital stay and the above-mentioned factors were also included as covariates in the model estimating the total oral MED during the hospital stay, on hospital discharge, during the 3-month period after hospital discharge, and at 6 months following hospital discharge.

Results

Two hundred forty-nine patients had 296 elective unilateral TKAs in this study from 2013 through 2018. Thirty-one patients had both unilateral TKAs under the SOC protocol; 5 patients had both unilateral TKAs under the ERAS protocol. Eleven of the patients who eventually had both knees replaced had 1 operation under each protocol The SOC group included 196 TKAs and the ERAS group included 100 TKAs. Of the 196 SOC patients, 94% were male. The mean age was 68.2 years (range, 48-86). The length of hospital stay ranged from 36.6 to 664.3 hours. Of the 100 ERAS patients, 96% were male (Table 2). The mean age was 66.7 years (range, 48-85). The length of hospital stay ranged from 12.5 to 45 hours.

Perioperative Opioid Use

Of the SOC patients, 99.0% received narcotics intraoperatively (range, 0-198 mg MED), and 74.5% received narcotics during PACU recovery (range, 0-141 mg MED). The total oral MED during the hospital stay for the SOC patients ranged from 10 to 2,946 mg. Of the ERAS patients, 86% received no narcotics during surgery (range, 0-110 mg MED), and 98% received no narcotics during PACU recovery (range, 0-65 mg MED). The total oral MED during the hospital stay for the ERAS patients ranged from 10 to 240 mg.

The MED used was significantly lower for the ERAS patients than it was for the SOC patients during surgery (10.5 mg vs 57.4 mg, P = .0001, FDR = .0002) and in the PACU (1.3 mg vs 13.6 mg, P = .0002, FDR = .0004), during the inpatient stay (66.7 mg vs 169.5 mg, P = .0001, FDR = .0002), and on hospital discharge (419.3 mg vs 776.7 mg, P = .0001, FDR = .0002). However, there was no significant difference in the total MED prescriptions filled between patients on the ERAS protocol vs those who received SOC during the 3-month period after hospital discharge (858.3 mg vs 1126.1 mg, P = .29, FDR = .29)(Table 3).

Discussion

Orthopedic surgery has been associated with long-term opioid use and misuse. Orthopedic surgeons are frequently among the highest prescribers of narcotics. According to Volkow and colleagues, orthopedic surgeons were the fourth largest prescribers of opioids in 2009, behind primary care physicians, internists, and dentists.¹⁷ The opioid crisis in the United States is well recognized. In 2017, > 70,000 deaths occurred due to drug overdoses, with 68% involving a prescription or illicit opioid. The Centers for Disease Control and Prevention has estimated a total economic burden of $78.5 billion per year as a direct result of misused prescribed opioids.¹⁸ This includes the cost of health care, lost productivity, addiction treatment, and the impact on the criminal justice system.

The current opioid crisis places further emphasis on opioid-reducing or sparing techniques in patients undergoing TKA. The use of liposomal bupivacaine for intraoperative periarticular injection is debated in the literature regarding its efficacy and whether it should be included in multimodal protocols. Researchers have argued that liposomal bupivacaine is not superior to regular bupivacaine and because of its increased cost is not justified.^19,20 A meta-analysis from Zhao and colleagues showed no difference in pain control and functional recovery when comparing liposomal bupivacaine and control.²¹ In a randomized clinical trial, Schroer and colleagues matched liposomal bupivacaine against regular bupivacaine and found no difference in pain scores and similar narcotic use during hospitalization.²²

Studies evaluating liposomal bupivacaine have demonstrated postoperative benefits in pain relief and potential opioid consumption.²³ In a multicenter randomized controlled trial, Barrington and colleagues noted improved pain control at 6 and 12 hours after surgery with liposomal bupivacaine as a periarticular injection vs ropivacaine, though results were similar when compared with intrathecal morphine.²⁴ Snyder and colleagues reported higher patient satisfaction in pain control and overall experience as well as decreased MED consumption in the PACU and on postoperative days 0 to 2 when using liposomal bupivacaine vs a multidrug cocktail for periarticular injection.²⁵

The PILLAR trial, an industry-sponsored study, was designed to compare the effects of local infiltration anesthesia with and without liposomal bupivacaine with emphasis on a meticulous standardized infiltration technique. In our study, we used a similar technique with an expanded volume of injection solution to 140 ml that was delivered throughout the knee in a series of 14 syringes. Each needle-stick delivered 1 to 1.5 ml through a 22-gauge needle to each compartment of the knee. Infiltration technique has varied among the literature focused on periarticular injections.

In our experience, a standard infiltration technique is critical to the effective delivery of liposomal bupivacaine throughout all compartments of the knee and to obtaining reproducible pain control. The importance of injection technique cannot be overemphasized, and variations can be seen in studies published to date.²⁶ Well-designed trials are needed to address this key component.

There have been limited data focused on the veteran population regarding postoperative pain-management strategies and recovery pathways either with or without liposomal bupivacaine. In a retrospective review, Sakamoto and colleagues found VA patients undergoing TKA had reduced opioid use in the first 24 hours after primary TKA with the use of intraoperative liposomal bupivacaine.²⁷ The VA population has been shown to be at high risk for opioid misuse. The prevalence of comorbidities such as traumatic brain injury, posttraumatic stress disorder, and depression in the VA population also places them at risk for polypharmacy of central nervous system–acting medications.²⁸ This emphasizes the importance of multimodal strategies, which can limit or eliminate narcotics in the perioperative period. The implementation of our ERAS protocol reduced opioid use during intraoperative, PACU, and inpatient hospital stay.

While the financial implications of our recovery protocol were not a primary focus of this study, there are many notable benefits on the overall inpatient cost to the VHA. According to the Health Economics Resource Center, the average daily cost of stay while under VA care for an inpatient surgical bed increased from $4,831 in 2013 to $6,220 in 2018.²⁹ Our reduction in length of stay between our cohorts is 44.5 hours, which translates to a substantial financial savings per patient after protocol implementation. A more detailed look at the financial aspect of our protocol would need to be performed to evaluate the financial impact of other aspects of our protocol, such as the elimination of patient-controlled anesthesia and the reduction in total narcotics prescribed in the postoperative global period.

Limitations

The limitations of this study include its retrospective study design. With the VHA patient population, it may be subject to selection bias, as the population is mostly older and predominantly male compared with that of the general population. This could potentially influence the efficacy of our protocol on a population of patients with more women. In a recent study by Perruccio and colleagues, sex was found to moderate the effects of comorbidities, low back pain, and depressive symptoms on postoperative pain in patients undergoing TKA.³⁰

With regard to outpatient narcotic prescriptions, although we cannot fully know whether these filled prescriptions were used for pain control, it is a reasonable assumption that patients who are dealing with continued postoperative or chronic pain issues will fill these prescriptions or seek refills. It is important to note that the data on prescriptions and refills in the 3-month postoperative period include all narcotic prescriptions filled by any VHA prescriber and are not specifically limited to our orthopedic team. For outpatient narcotic use, we were not able to access accurate pill counts for any discharge prescriptions or subsequent refills that were given throughout the VA system. We were able to report on total prescriptions filled in the first 3 months following TKA.

We calculated total oral MEDs to better understand the amount of narcotics being distributed throughout our population of patients. We believe this provides important information about the overall narcotic burden in the veteran population. There was no significant difference between the SOC and ERAS groups regarding oral MED prescribed in the 3-month postoperative period; however, at the 6-month follow-up visit, only 16% of patients in the ERAS group were taking any type of narcotic vs 37.2% in the SOC group (P = .0002).

Conclusions

A multidisciplinary ERAS protocol implemented at VANTHCS was effective in reducing length of stay and opioid burden throughout all phases of surgical care in our patients undergoing primary TKA. Patient and nursing education seem to be critical components to the implementation of a successful multimodal pain protocol. Reducing the narcotic burden has valuable financial and medical benefits in this at-risk population.

Total knee arthroplasty (TKA) is one of the most common surgical procedures in the United States. The volume of TKAs is projected to substantially increase over the next 30 years.¹ Adequate pain control after TKA is critically important to achieve early mobilization, shorten the length of hospital stay, and reduce postoperative complications. The evolution and inclusion of multimodal pain-management protocols have had a major impact on the clinical outcomes for TKA patients.^2,3

Pain-management protocols typically use several modalities to control pain throughout the perioperative period. Multimodal opioid and nonopioid oral medications are administered during the pre- and postoperative periods and often involve a combination of acetaminophen, gabapentinoids, and cyclooxygenase-2 inhibitors.⁴ Peripheral nerve blocks and central neuraxial blockades are widely used and have been shown to be effective in reducing postoperative pain as well as overall opioid consumption.^5,6 Finally, intraoperative periarticular injections have been shown to reduce postoperative pain and opioid consumption as well as improve patient satisfaction scores.^7-9 These strategies are routinely used in TKA with the goal of minimizing overall opioid consumption and adverse events, reducing perioperative complications, and improving patient satisfaction.

Periarticular injections during surgery are an integral part of the multimodal pain-management protocols, though no consensus has been reached on proper injection formulation or technique. Liposomal bupivacaine is a local anesthetic depot formulation approved by the US Food and Drug Administration for surgical patients. The reported results have been discrepant regarding the efficacy of using liposomal bupivacaine injection in patients with TKA. Several studies have reported no added benefit of liposomal bupivacaine in contrast to a mixture of local anesthetics.^10,11 Other studies have demonstrated superior pain relief.¹² Many factors may contribute to the discrepant data, such as injection techniques, infiltration volume, and the assessment tools used to measure efficacy and safety.¹³

The US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) provides care to a large patient population. Many of the patients in that system have high-risk profiles, including medical comorbidities; exposure to chronic pain and opioid use; and psychological and central nervous system injuries, including posttraumatic stress disorder and traumatic brain injury. Hadlandsmyth and colleagues reported increased risk of prolonged opioid use in VA patients after TKA surgery.¹⁴ They found that 20% of the patients were still on long-term opioids more than 90 days after TKA.

The purpose of this study was to evaluate the efficacy of the implementation of a comprehensive enhanced recovery after surgery (ERAS) protocol at a regional VA medical center. We hypothesize that the addition of liposomal bupivacaine in a multidisciplinary ERAS protocol would reduce the length of hospital stay and opioid consumption without any deleterious effects on postoperative outcomes.

Methods

A postoperative recovery protocol was implemented in 2013 at VA North Texas Health Care System (VANTHCS) in Dallas, and many of the patients continued to have issues with satisfactory pain control, prolonged length of stay, and extended opioid consumption postoperatively. A multimodal pain-management protocol and multidisciplinary perioperative case-management protocol were implemented in 2016 to further improve the clinical outcomes of patients undergoing TKA surgery. The senior surgeon (JM) organized a multidisciplinary team of health care providers to identify and implement potential solutions. This task force met weekly and consisted of surgeons, anesthesiologists, certified registered nurse anesthetists, orthopedic physician assistants, a nurse coordinator, a physical therapist, and an occupational therapist, as well as operating room, postanesthesia care unit (PACU), and surgical ward nurses. In addition, the staff from the home health agencies and social services attended the weekly meetings.

We conducted a retrospective review of all patients who had undergone unilateral TKA from 2013 to 2018 at VANTHCS. This was a consecutive, unselected cohort. All patients were under the care of a single surgeon using identical implant systems and identical surgical techniques. This study was approved by the institutional review board at VANTHCS. Patients were divided into 2 distinct and consecutive cohorts. The standard of care (SOC) group included all patients from 2013 to 2016. The ERAS group included all patients after the institution of the standardized protocol until the end of the study period.

Data on patient demographics, the American Society of Anesthesiologists risk classification, and preoperative functional status were extracted. Anesthesia techniques included either general endotracheal anesthesia or subarachnoid block with monitored anesthesia care. The quantity of the opioids given during surgery, in the PACU, during the inpatient stay, as discharge prescriptions, and as refills of the narcotic prescriptions up to 3 months postsurgery were recorded. All opioids were converted into morphine equivalent dosages (MED) in order to be properly analyzed using the statistical methodologies described in the statistical section.¹⁵ The VHA is a closed health care delivery system; therefore, all of the prescriptions ordered by surgery providers were recorded in the electronic health record.

ERAS Protocol

The SOC cohort was predominantly managed with general endotracheal anesthesia. The ERAS group was predominantly managed with subarachnoid blocks (Table 1). For the ERAS protocol preoperatively, the patients were administered oral gabapentin 300 mg, acetaminophen 650 mg, and oxycodone 20 mg, and IV ondansetron 4 mg. Intraoperatively, minimal opioids were used. In the PACU, the patients received dilaudid 0.25 mg IV as needed every 15 minutes for up to 1 mg/h. The nursing staff was trained to use the visual analog pain scale scores to titrate the medication. During the inpatient stay, patients received 1 g IV acetaminophen every 6 hours for 3 doses. The patients thereafter received oral acetaminophen as needed. Other medications in the multimodal pain-management protocol included gabapentin 300 mg twice daily, meloxicam 15 mg daily, and oxycodone 10 mg every 4 hours as needed. Rescue medication for insufficient pain relief was dilaudid 0.25 mg IV every 15 minutes for visual analog pain scale > 8. On discharge, the patients received a prescription of 30 tablets of hydrocodone 10 mg.

Periarticular Injections

Intraoperatively, all patients in the SOC and ERAS groups received periarticular injections. The liposomal bupivacaine injection was added to the standard injection mixture for the ERAS group. For the SOC group, the total volume of 100 ml was divided into 10 separate 10 cc syringes, and for the ERAS group, the total volume of 140 ml was divided into 14 separate 10 cc syringes. The SOC group injections were performed with an 18-gauge needle and the periarticular soft tissues grossly infiltrated. The ERAS group injections were done with more attention to anatomical detail. Injection sites for the ERAS group included the posterior joint capsule, the medial compartment, the lateral compartment, the tibial fat pad, the quadriceps and the patellar tendon, the femoral and tibial periosteum circumferentially, and the anterior joint capsule. Each needle-stick in the ERAS group delivered 1 to 1.5 ml through a 22-gauge needle to each compartment of the knee.

Outcome Variable

The primary outcome measure was total oral MED intraoperatively, in the PACU, during the hospital inpatient stay, in the hospital discharge prescription, and during the 3-month period after hospital discharge. Incidence of nausea and vomiting during the inpatient stay and any narcotic use at 6 months postsurgery were secondary binary outcomes.

Statistical Analysis

Demographic data and the clinical characteristics for the entire group were described using the sample mean and SD for continuous variables and the frequency and percentage for categorical variables. Differences between the 2 cohorts were analyzed using a 2-independent-sample t test and Fisher exact test.

The estimation of the total oral MED throughout all phases of care was done using a separate Poisson model due to the data being not normally distributed. A log-linear regression model was used to evaluate the main effect of ERAS vs the SOC cohort on the total oral MED used. Finally, a separate multiple logistic regression model was used to estimate the odds of postoperative nausea and vomiting and narcotic use at 6 months postsurgery between the cohorts. The adjusted odds ratio (OR) was estimated from the logistic model. Age, sex, body mass index, preoperative functional independence score, narcotic use within 3 months prior to surgery, anesthesia type used (subarachnoid block with monitored anesthesia care vs general endotracheal anesthesia), and postoperative complications (yes/no) were included as covariates in each model. The length of hospital stay and the above-mentioned factors were also included as covariates in the model estimating the total oral MED during the hospital stay, on hospital discharge, during the 3-month period after hospital discharge, and at 6 months following hospital discharge.

Results

Two hundred forty-nine patients had 296 elective unilateral TKAs in this study from 2013 through 2018. Thirty-one patients had both unilateral TKAs under the SOC protocol; 5 patients had both unilateral TKAs under the ERAS protocol. Eleven of the patients who eventually had both knees replaced had 1 operation under each protocol The SOC group included 196 TKAs and the ERAS group included 100 TKAs. Of the 196 SOC patients, 94% were male. The mean age was 68.2 years (range, 48-86). The length of hospital stay ranged from 36.6 to 664.3 hours. Of the 100 ERAS patients, 96% were male (Table 2). The mean age was 66.7 years (range, 48-85). The length of hospital stay ranged from 12.5 to 45 hours.

Perioperative Opioid Use

Of the SOC patients, 99.0% received narcotics intraoperatively (range, 0-198 mg MED), and 74.5% received narcotics during PACU recovery (range, 0-141 mg MED). The total oral MED during the hospital stay for the SOC patients ranged from 10 to 2,946 mg. Of the ERAS patients, 86% received no narcotics during surgery (range, 0-110 mg MED), and 98% received no narcotics during PACU recovery (range, 0-65 mg MED). The total oral MED during the hospital stay for the ERAS patients ranged from 10 to 240 mg.

The MED used was significantly lower for the ERAS patients than it was for the SOC patients during surgery (10.5 mg vs 57.4 mg, P = .0001, FDR = .0002) and in the PACU (1.3 mg vs 13.6 mg, P = .0002, FDR = .0004), during the inpatient stay (66.7 mg vs 169.5 mg, P = .0001, FDR = .0002), and on hospital discharge (419.3 mg vs 776.7 mg, P = .0001, FDR = .0002). However, there was no significant difference in the total MED prescriptions filled between patients on the ERAS protocol vs those who received SOC during the 3-month period after hospital discharge (858.3 mg vs 1126.1 mg, P = .29, FDR = .29)(Table 3).

Discussion

Orthopedic surgery has been associated with long-term opioid use and misuse. Orthopedic surgeons are frequently among the highest prescribers of narcotics. According to Volkow and colleagues, orthopedic surgeons were the fourth largest prescribers of opioids in 2009, behind primary care physicians, internists, and dentists.¹⁷ The opioid crisis in the United States is well recognized. In 2017, > 70,000 deaths occurred due to drug overdoses, with 68% involving a prescription or illicit opioid. The Centers for Disease Control and Prevention has estimated a total economic burden of $78.5 billion per year as a direct result of misused prescribed opioids.¹⁸ This includes the cost of health care, lost productivity, addiction treatment, and the impact on the criminal justice system.

The current opioid crisis places further emphasis on opioid-reducing or sparing techniques in patients undergoing TKA. The use of liposomal bupivacaine for intraoperative periarticular injection is debated in the literature regarding its efficacy and whether it should be included in multimodal protocols. Researchers have argued that liposomal bupivacaine is not superior to regular bupivacaine and because of its increased cost is not justified.^19,20 A meta-analysis from Zhao and colleagues showed no difference in pain control and functional recovery when comparing liposomal bupivacaine and control.²¹ In a randomized clinical trial, Schroer and colleagues matched liposomal bupivacaine against regular bupivacaine and found no difference in pain scores and similar narcotic use during hospitalization.²²

Studies evaluating liposomal bupivacaine have demonstrated postoperative benefits in pain relief and potential opioid consumption.²³ In a multicenter randomized controlled trial, Barrington and colleagues noted improved pain control at 6 and 12 hours after surgery with liposomal bupivacaine as a periarticular injection vs ropivacaine, though results were similar when compared with intrathecal morphine.²⁴ Snyder and colleagues reported higher patient satisfaction in pain control and overall experience as well as decreased MED consumption in the PACU and on postoperative days 0 to 2 when using liposomal bupivacaine vs a multidrug cocktail for periarticular injection.²⁵

The PILLAR trial, an industry-sponsored study, was designed to compare the effects of local infiltration anesthesia with and without liposomal bupivacaine with emphasis on a meticulous standardized infiltration technique. In our study, we used a similar technique with an expanded volume of injection solution to 140 ml that was delivered throughout the knee in a series of 14 syringes. Each needle-stick delivered 1 to 1.5 ml through a 22-gauge needle to each compartment of the knee. Infiltration technique has varied among the literature focused on periarticular injections.

In our experience, a standard infiltration technique is critical to the effective delivery of liposomal bupivacaine throughout all compartments of the knee and to obtaining reproducible pain control. The importance of injection technique cannot be overemphasized, and variations can be seen in studies published to date.²⁶ Well-designed trials are needed to address this key component.

There have been limited data focused on the veteran population regarding postoperative pain-management strategies and recovery pathways either with or without liposomal bupivacaine. In a retrospective review, Sakamoto and colleagues found VA patients undergoing TKA had reduced opioid use in the first 24 hours after primary TKA with the use of intraoperative liposomal bupivacaine.²⁷ The VA population has been shown to be at high risk for opioid misuse. The prevalence of comorbidities such as traumatic brain injury, posttraumatic stress disorder, and depression in the VA population also places them at risk for polypharmacy of central nervous system–acting medications.²⁸ This emphasizes the importance of multimodal strategies, which can limit or eliminate narcotics in the perioperative period. The implementation of our ERAS protocol reduced opioid use during intraoperative, PACU, and inpatient hospital stay.

While the financial implications of our recovery protocol were not a primary focus of this study, there are many notable benefits on the overall inpatient cost to the VHA. According to the Health Economics Resource Center, the average daily cost of stay while under VA care for an inpatient surgical bed increased from $4,831 in 2013 to $6,220 in 2018.²⁹ Our reduction in length of stay between our cohorts is 44.5 hours, which translates to a substantial financial savings per patient after protocol implementation. A more detailed look at the financial aspect of our protocol would need to be performed to evaluate the financial impact of other aspects of our protocol, such as the elimination of patient-controlled anesthesia and the reduction in total narcotics prescribed in the postoperative global period.

Limitations

The limitations of this study include its retrospective study design. With the VHA patient population, it may be subject to selection bias, as the population is mostly older and predominantly male compared with that of the general population. This could potentially influence the efficacy of our protocol on a population of patients with more women. In a recent study by Perruccio and colleagues, sex was found to moderate the effects of comorbidities, low back pain, and depressive symptoms on postoperative pain in patients undergoing TKA.³⁰

With regard to outpatient narcotic prescriptions, although we cannot fully know whether these filled prescriptions were used for pain control, it is a reasonable assumption that patients who are dealing with continued postoperative or chronic pain issues will fill these prescriptions or seek refills. It is important to note that the data on prescriptions and refills in the 3-month postoperative period include all narcotic prescriptions filled by any VHA prescriber and are not specifically limited to our orthopedic team. For outpatient narcotic use, we were not able to access accurate pill counts for any discharge prescriptions or subsequent refills that were given throughout the VA system. We were able to report on total prescriptions filled in the first 3 months following TKA.

We calculated total oral MEDs to better understand the amount of narcotics being distributed throughout our population of patients. We believe this provides important information about the overall narcotic burden in the veteran population. There was no significant difference between the SOC and ERAS groups regarding oral MED prescribed in the 3-month postoperative period; however, at the 6-month follow-up visit, only 16% of patients in the ERAS group were taking any type of narcotic vs 37.2% in the SOC group (P = .0002).

Conclusions

A multidisciplinary ERAS protocol implemented at VANTHCS was effective in reducing length of stay and opioid burden throughout all phases of surgical care in our patients undergoing primary TKA. Patient and nursing education seem to be critical components to the implementation of a successful multimodal pain protocol. Reducing the narcotic burden has valuable financial and medical benefits in this at-risk population.

Total knee arthroplasty (TKA) is one of the most common surgical procedures in the United States. The volume of TKAs is projected to substantially increase over the next 30 years.¹ Adequate pain control after TKA is critically important to achieve early mobilization, shorten the length of hospital stay, and reduce postoperative complications. The evolution and inclusion of multimodal pain-management protocols have had a major impact on the clinical outcomes for TKA patients.^2,3

Pain-management protocols typically use several modalities to control pain throughout the perioperative period. Multimodal opioid and nonopioid oral medications are administered during the pre- and postoperative periods and often involve a combination of acetaminophen, gabapentinoids, and cyclooxygenase-2 inhibitors.⁴ Peripheral nerve blocks and central neuraxial blockades are widely used and have been shown to be effective in reducing postoperative pain as well as overall opioid consumption.^5,6 Finally, intraoperative periarticular injections have been shown to reduce postoperative pain and opioid consumption as well as improve patient satisfaction scores.^7-9 These strategies are routinely used in TKA with the goal of minimizing overall opioid consumption and adverse events, reducing perioperative complications, and improving patient satisfaction.

Periarticular injections during surgery are an integral part of the multimodal pain-management protocols, though no consensus has been reached on proper injection formulation or technique. Liposomal bupivacaine is a local anesthetic depot formulation approved by the US Food and Drug Administration for surgical patients. The reported results have been discrepant regarding the efficacy of using liposomal bupivacaine injection in patients with TKA. Several studies have reported no added benefit of liposomal bupivacaine in contrast to a mixture of local anesthetics.^10,11 Other studies have demonstrated superior pain relief.¹² Many factors may contribute to the discrepant data, such as injection techniques, infiltration volume, and the assessment tools used to measure efficacy and safety.¹³

The US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) provides care to a large patient population. Many of the patients in that system have high-risk profiles, including medical comorbidities; exposure to chronic pain and opioid use; and psychological and central nervous system injuries, including posttraumatic stress disorder and traumatic brain injury. Hadlandsmyth and colleagues reported increased risk of prolonged opioid use in VA patients after TKA surgery.¹⁴ They found that 20% of the patients were still on long-term opioids more than 90 days after TKA.

The purpose of this study was to evaluate the efficacy of the implementation of a comprehensive enhanced recovery after surgery (ERAS) protocol at a regional VA medical center. We hypothesize that the addition of liposomal bupivacaine in a multidisciplinary ERAS protocol would reduce the length of hospital stay and opioid consumption without any deleterious effects on postoperative outcomes.

Methods

A postoperative recovery protocol was implemented in 2013 at VA North Texas Health Care System (VANTHCS) in Dallas, and many of the patients continued to have issues with satisfactory pain control, prolonged length of stay, and extended opioid consumption postoperatively. A multimodal pain-management protocol and multidisciplinary perioperative case-management protocol were implemented in 2016 to further improve the clinical outcomes of patients undergoing TKA surgery. The senior surgeon (JM) organized a multidisciplinary team of health care providers to identify and implement potential solutions. This task force met weekly and consisted of surgeons, anesthesiologists, certified registered nurse anesthetists, orthopedic physician assistants, a nurse coordinator, a physical therapist, and an occupational therapist, as well as operating room, postanesthesia care unit (PACU), and surgical ward nurses. In addition, the staff from the home health agencies and social services attended the weekly meetings.

We conducted a retrospective review of all patients who had undergone unilateral TKA from 2013 to 2018 at VANTHCS. This was a consecutive, unselected cohort. All patients were under the care of a single surgeon using identical implant systems and identical surgical techniques. This study was approved by the institutional review board at VANTHCS. Patients were divided into 2 distinct and consecutive cohorts. The standard of care (SOC) group included all patients from 2013 to 2016. The ERAS group included all patients after the institution of the standardized protocol until the end of the study period.

Data on patient demographics, the American Society of Anesthesiologists risk classification, and preoperative functional status were extracted. Anesthesia techniques included either general endotracheal anesthesia or subarachnoid block with monitored anesthesia care. The quantity of the opioids given during surgery, in the PACU, during the inpatient stay, as discharge prescriptions, and as refills of the narcotic prescriptions up to 3 months postsurgery were recorded. All opioids were converted into morphine equivalent dosages (MED) in order to be properly analyzed using the statistical methodologies described in the statistical section.¹⁵ The VHA is a closed health care delivery system; therefore, all of the prescriptions ordered by surgery providers were recorded in the electronic health record.

ERAS Protocol

The SOC cohort was predominantly managed with general endotracheal anesthesia. The ERAS group was predominantly managed with subarachnoid blocks (Table 1). For the ERAS protocol preoperatively, the patients were administered oral gabapentin 300 mg, acetaminophen 650 mg, and oxycodone 20 mg, and IV ondansetron 4 mg. Intraoperatively, minimal opioids were used. In the PACU, the patients received dilaudid 0.25 mg IV as needed every 15 minutes for up to 1 mg/h. The nursing staff was trained to use the visual analog pain scale scores to titrate the medication. During the inpatient stay, patients received 1 g IV acetaminophen every 6 hours for 3 doses. The patients thereafter received oral acetaminophen as needed. Other medications in the multimodal pain-management protocol included gabapentin 300 mg twice daily, meloxicam 15 mg daily, and oxycodone 10 mg every 4 hours as needed. Rescue medication for insufficient pain relief was dilaudid 0.25 mg IV every 15 minutes for visual analog pain scale > 8. On discharge, the patients received a prescription of 30 tablets of hydrocodone 10 mg.

Periarticular Injections

Intraoperatively, all patients in the SOC and ERAS groups received periarticular injections. The liposomal bupivacaine injection was added to the standard injection mixture for the ERAS group. For the SOC group, the total volume of 100 ml was divided into 10 separate 10 cc syringes, and for the ERAS group, the total volume of 140 ml was divided into 14 separate 10 cc syringes. The SOC group injections were performed with an 18-gauge needle and the periarticular soft tissues grossly infiltrated. The ERAS group injections were done with more attention to anatomical detail. Injection sites for the ERAS group included the posterior joint capsule, the medial compartment, the lateral compartment, the tibial fat pad, the quadriceps and the patellar tendon, the femoral and tibial periosteum circumferentially, and the anterior joint capsule. Each needle-stick in the ERAS group delivered 1 to 1.5 ml through a 22-gauge needle to each compartment of the knee.

Outcome Variable

The primary outcome measure was total oral MED intraoperatively, in the PACU, during the hospital inpatient stay, in the hospital discharge prescription, and during the 3-month period after hospital discharge. Incidence of nausea and vomiting during the inpatient stay and any narcotic use at 6 months postsurgery were secondary binary outcomes.

Statistical Analysis

Demographic data and the clinical characteristics for the entire group were described using the sample mean and SD for continuous variables and the frequency and percentage for categorical variables. Differences between the 2 cohorts were analyzed using a 2-independent-sample t test and Fisher exact test.

The estimation of the total oral MED throughout all phases of care was done using a separate Poisson model due to the data being not normally distributed. A log-linear regression model was used to evaluate the main effect of ERAS vs the SOC cohort on the total oral MED used. Finally, a separate multiple logistic regression model was used to estimate the odds of postoperative nausea and vomiting and narcotic use at 6 months postsurgery between the cohorts. The adjusted odds ratio (OR) was estimated from the logistic model. Age, sex, body mass index, preoperative functional independence score, narcotic use within 3 months prior to surgery, anesthesia type used (subarachnoid block with monitored anesthesia care vs general endotracheal anesthesia), and postoperative complications (yes/no) were included as covariates in each model. The length of hospital stay and the above-mentioned factors were also included as covariates in the model estimating the total oral MED during the hospital stay, on hospital discharge, during the 3-month period after hospital discharge, and at 6 months following hospital discharge.

Results

Two hundred forty-nine patients had 296 elective unilateral TKAs in this study from 2013 through 2018. Thirty-one patients had both unilateral TKAs under the SOC protocol; 5 patients had both unilateral TKAs under the ERAS protocol. Eleven of the patients who eventually had both knees replaced had 1 operation under each protocol The SOC group included 196 TKAs and the ERAS group included 100 TKAs. Of the 196 SOC patients, 94% were male. The mean age was 68.2 years (range, 48-86). The length of hospital stay ranged from 36.6 to 664.3 hours. Of the 100 ERAS patients, 96% were male (Table 2). The mean age was 66.7 years (range, 48-85). The length of hospital stay ranged from 12.5 to 45 hours.

Perioperative Opioid Use

Of the SOC patients, 99.0% received narcotics intraoperatively (range, 0-198 mg MED), and 74.5% received narcotics during PACU recovery (range, 0-141 mg MED). The total oral MED during the hospital stay for the SOC patients ranged from 10 to 2,946 mg. Of the ERAS patients, 86% received no narcotics during surgery (range, 0-110 mg MED), and 98% received no narcotics during PACU recovery (range, 0-65 mg MED). The total oral MED during the hospital stay for the ERAS patients ranged from 10 to 240 mg.

The MED used was significantly lower for the ERAS patients than it was for the SOC patients during surgery (10.5 mg vs 57.4 mg, P = .0001, FDR = .0002) and in the PACU (1.3 mg vs 13.6 mg, P = .0002, FDR = .0004), during the inpatient stay (66.7 mg vs 169.5 mg, P = .0001, FDR = .0002), and on hospital discharge (419.3 mg vs 776.7 mg, P = .0001, FDR = .0002). However, there was no significant difference in the total MED prescriptions filled between patients on the ERAS protocol vs those who received SOC during the 3-month period after hospital discharge (858.3 mg vs 1126.1 mg, P = .29, FDR = .29)(Table 3).

Discussion

Orthopedic surgery has been associated with long-term opioid use and misuse. Orthopedic surgeons are frequently among the highest prescribers of narcotics. According to Volkow and colleagues, orthopedic surgeons were the fourth largest prescribers of opioids in 2009, behind primary care physicians, internists, and dentists.¹⁷ The opioid crisis in the United States is well recognized. In 2017, > 70,000 deaths occurred due to drug overdoses, with 68% involving a prescription or illicit opioid. The Centers for Disease Control and Prevention has estimated a total economic burden of $78.5 billion per year as a direct result of misused prescribed opioids.¹⁸ This includes the cost of health care, lost productivity, addiction treatment, and the impact on the criminal justice system.

The current opioid crisis places further emphasis on opioid-reducing or sparing techniques in patients undergoing TKA. The use of liposomal bupivacaine for intraoperative periarticular injection is debated in the literature regarding its efficacy and whether it should be included in multimodal protocols. Researchers have argued that liposomal bupivacaine is not superior to regular bupivacaine and because of its increased cost is not justified.^19,20 A meta-analysis from Zhao and colleagues showed no difference in pain control and functional recovery when comparing liposomal bupivacaine and control.²¹ In a randomized clinical trial, Schroer and colleagues matched liposomal bupivacaine against regular bupivacaine and found no difference in pain scores and similar narcotic use during hospitalization.²²

Studies evaluating liposomal bupivacaine have demonstrated postoperative benefits in pain relief and potential opioid consumption.²³ In a multicenter randomized controlled trial, Barrington and colleagues noted improved pain control at 6 and 12 hours after surgery with liposomal bupivacaine as a periarticular injection vs ropivacaine, though results were similar when compared with intrathecal morphine.²⁴ Snyder and colleagues reported higher patient satisfaction in pain control and overall experience as well as decreased MED consumption in the PACU and on postoperative days 0 to 2 when using liposomal bupivacaine vs a multidrug cocktail for periarticular injection.²⁵

The PILLAR trial, an industry-sponsored study, was designed to compare the effects of local infiltration anesthesia with and without liposomal bupivacaine with emphasis on a meticulous standardized infiltration technique. In our study, we used a similar technique with an expanded volume of injection solution to 140 ml that was delivered throughout the knee in a series of 14 syringes. Each needle-stick delivered 1 to 1.5 ml through a 22-gauge needle to each compartment of the knee. Infiltration technique has varied among the literature focused on periarticular injections.

In our experience, a standard infiltration technique is critical to the effective delivery of liposomal bupivacaine throughout all compartments of the knee and to obtaining reproducible pain control. The importance of injection technique cannot be overemphasized, and variations can be seen in studies published to date.²⁶ Well-designed trials are needed to address this key component.

There have been limited data focused on the veteran population regarding postoperative pain-management strategies and recovery pathways either with or without liposomal bupivacaine. In a retrospective review, Sakamoto and colleagues found VA patients undergoing TKA had reduced opioid use in the first 24 hours after primary TKA with the use of intraoperative liposomal bupivacaine.²⁷ The VA population has been shown to be at high risk for opioid misuse. The prevalence of comorbidities such as traumatic brain injury, posttraumatic stress disorder, and depression in the VA population also places them at risk for polypharmacy of central nervous system–acting medications.²⁸ This emphasizes the importance of multimodal strategies, which can limit or eliminate narcotics in the perioperative period. The implementation of our ERAS protocol reduced opioid use during intraoperative, PACU, and inpatient hospital stay.

While the financial implications of our recovery protocol were not a primary focus of this study, there are many notable benefits on the overall inpatient cost to the VHA. According to the Health Economics Resource Center, the average daily cost of stay while under VA care for an inpatient surgical bed increased from $4,831 in 2013 to $6,220 in 2018.²⁹ Our reduction in length of stay between our cohorts is 44.5 hours, which translates to a substantial financial savings per patient after protocol implementation. A more detailed look at the financial aspect of our protocol would need to be performed to evaluate the financial impact of other aspects of our protocol, such as the elimination of patient-controlled anesthesia and the reduction in total narcotics prescribed in the postoperative global period.

Limitations

The limitations of this study include its retrospective study design. With the VHA patient population, it may be subject to selection bias, as the population is mostly older and predominantly male compared with that of the general population. This could potentially influence the efficacy of our protocol on a population of patients with more women. In a recent study by Perruccio and colleagues, sex was found to moderate the effects of comorbidities, low back pain, and depressive symptoms on postoperative pain in patients undergoing TKA.³⁰

With regard to outpatient narcotic prescriptions, although we cannot fully know whether these filled prescriptions were used for pain control, it is a reasonable assumption that patients who are dealing with continued postoperative or chronic pain issues will fill these prescriptions or seek refills. It is important to note that the data on prescriptions and refills in the 3-month postoperative period include all narcotic prescriptions filled by any VHA prescriber and are not specifically limited to our orthopedic team. For outpatient narcotic use, we were not able to access accurate pill counts for any discharge prescriptions or subsequent refills that were given throughout the VA system. We were able to report on total prescriptions filled in the first 3 months following TKA.

We calculated total oral MEDs to better understand the amount of narcotics being distributed throughout our population of patients. We believe this provides important information about the overall narcotic burden in the veteran population. There was no significant difference between the SOC and ERAS groups regarding oral MED prescribed in the 3-month postoperative period; however, at the 6-month follow-up visit, only 16% of patients in the ERAS group were taking any type of narcotic vs 37.2% in the SOC group (P = .0002).

Conclusions

A multidisciplinary ERAS protocol implemented at VANTHCS was effective in reducing length of stay and opioid burden throughout all phases of surgical care in our patients undergoing primary TKA. Patient and nursing education seem to be critical components to the implementation of a successful multimodal pain protocol. Reducing the narcotic burden has valuable financial and medical benefits in this at-risk population.

Changing the continuous antibiotic prophylactic agent had no significant effect on the risk of a second infection in children with breakthrough urinary tract infections (UTIs), based on data from 62 children treated at a single center.

Continuous antibiotic prophylaxis (CAP) is often used for UTI prevention in children with febrile UTIs or anomalies that predispose them to UTIs, such as vesicoureteral reflux (VUR) or bladder and bowel dysfunction, said Lane M. Shish, MPH, of the University of Washington, Bothell, and colleagues in a poster (#1245) presented at the Pediatric Academic Societies annual meeting.

CAP, once initiated, is used until a planned endpoint or a breakthrough UTI, at which point alternative treatments usually include surgical intervention or a CAP agent change, the researchers said. However, changing the CAP agent is based on consensus without evidence of benefit, they noted.

To evaluate the potential effect of switching or maintaining CAP in cases of breakthrough UTIs, the researchers conducted a retrospective cohort study of all patients younger than 18 years on CAP for UTI prevention enrolled in a pediatric urology registry between January 2013 and August 2020.

All patients experienced a breakthrough UTI while on CAP; CAP was changed for 24 patients and left unchanged for 38 patients.

The primary outcome of second-breakthrough infections occurred in 12 of the changed CAP group and 22 of the unchanged group, with a relative risk of 0.86. The percentage of second breakthrough UTIs resistant to the current CAP was not significantly different between the changed and unchanged CAP groups (75% vs. 77%; P = 0.88).

The researchers also identified a rate ratio of 0.67 for a second breakthrough UTI in the changed CAP group, and found that approximately one-third of these patients (33.3%) developed antibiotic resistance to their initial antibiotic agent and the changed antibiotic agent.

The study findings were limited by several factors, including the retrospective design and small sample size, the researchers noted.

However, the results suggest that changing the CAP after an initial breakthrough UTI in children did not increase the risk of a second breakthrough UTI, and that CAP changing did introduce a risk of developing a second UTI with increased CAP resistance, the researchers noted. The results support leaving a child’s CAP unchanged after an initial breakthrough UTI, although additional research is needed to verify the findings, including studies involving a larger cohort with a multi-institutional prospective evaluation, they concluded.

Manage UTIs to reduce recurrence and resistance

“As we know, avoiding recurrent UTIs is important in preserving renal function in pediatric patients,” said Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, in an interview.

“Avoiding recurrent UTIs is also important to avoid the development and spread of multidrug-resistant organisms,” he said.

Dr. Joos said he was surprised by some of the study findings. “I was surprised that, over the course of this 7-year retrospective review, overall only approximately 50% of patients with a first breakthrough UTI on CAP developed a second breakthrough UTI,” he noted. “Also, the relative risk of a second UTI was not significantly affected by whether the CAP antibiotic was changed after the first infection,” he said. “It would be interesting to see whether these results hold up in a randomized, prospective study,” he added.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose, but serves as a member of the Pediatric News Editorial Advisory Board.

Changing the continuous antibiotic prophylactic agent had no significant effect on the risk of a second infection in children with breakthrough urinary tract infections (UTIs), based on data from 62 children treated at a single center.

Continuous antibiotic prophylaxis (CAP) is often used for UTI prevention in children with febrile UTIs or anomalies that predispose them to UTIs, such as vesicoureteral reflux (VUR) or bladder and bowel dysfunction, said Lane M. Shish, MPH, of the University of Washington, Bothell, and colleagues in a poster (#1245) presented at the Pediatric Academic Societies annual meeting.

CAP, once initiated, is used until a planned endpoint or a breakthrough UTI, at which point alternative treatments usually include surgical intervention or a CAP agent change, the researchers said. However, changing the CAP agent is based on consensus without evidence of benefit, they noted.

To evaluate the potential effect of switching or maintaining CAP in cases of breakthrough UTIs, the researchers conducted a retrospective cohort study of all patients younger than 18 years on CAP for UTI prevention enrolled in a pediatric urology registry between January 2013 and August 2020.

All patients experienced a breakthrough UTI while on CAP; CAP was changed for 24 patients and left unchanged for 38 patients.

The primary outcome of second-breakthrough infections occurred in 12 of the changed CAP group and 22 of the unchanged group, with a relative risk of 0.86. The percentage of second breakthrough UTIs resistant to the current CAP was not significantly different between the changed and unchanged CAP groups (75% vs. 77%; P = 0.88).

The researchers also identified a rate ratio of 0.67 for a second breakthrough UTI in the changed CAP group, and found that approximately one-third of these patients (33.3%) developed antibiotic resistance to their initial antibiotic agent and the changed antibiotic agent.

The study findings were limited by several factors, including the retrospective design and small sample size, the researchers noted.

However, the results suggest that changing the CAP after an initial breakthrough UTI in children did not increase the risk of a second breakthrough UTI, and that CAP changing did introduce a risk of developing a second UTI with increased CAP resistance, the researchers noted. The results support leaving a child’s CAP unchanged after an initial breakthrough UTI, although additional research is needed to verify the findings, including studies involving a larger cohort with a multi-institutional prospective evaluation, they concluded.

Manage UTIs to reduce recurrence and resistance

“As we know, avoiding recurrent UTIs is important in preserving renal function in pediatric patients,” said Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, in an interview.

“Avoiding recurrent UTIs is also important to avoid the development and spread of multidrug-resistant organisms,” he said.

Dr. Joos said he was surprised by some of the study findings. “I was surprised that, over the course of this 7-year retrospective review, overall only approximately 50% of patients with a first breakthrough UTI on CAP developed a second breakthrough UTI,” he noted. “Also, the relative risk of a second UTI was not significantly affected by whether the CAP antibiotic was changed after the first infection,” he said. “It would be interesting to see whether these results hold up in a randomized, prospective study,” he added.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose, but serves as a member of the Pediatric News Editorial Advisory Board.

Changing the continuous antibiotic prophylactic agent had no significant effect on the risk of a second infection in children with breakthrough urinary tract infections (UTIs), based on data from 62 children treated at a single center.

Continuous antibiotic prophylaxis (CAP) is often used for UTI prevention in children with febrile UTIs or anomalies that predispose them to UTIs, such as vesicoureteral reflux (VUR) or bladder and bowel dysfunction, said Lane M. Shish, MPH, of the University of Washington, Bothell, and colleagues in a poster (#1245) presented at the Pediatric Academic Societies annual meeting.

CAP, once initiated, is used until a planned endpoint or a breakthrough UTI, at which point alternative treatments usually include surgical intervention or a CAP agent change, the researchers said. However, changing the CAP agent is based on consensus without evidence of benefit, they noted.

To evaluate the potential effect of switching or maintaining CAP in cases of breakthrough UTIs, the researchers conducted a retrospective cohort study of all patients younger than 18 years on CAP for UTI prevention enrolled in a pediatric urology registry between January 2013 and August 2020.

All patients experienced a breakthrough UTI while on CAP; CAP was changed for 24 patients and left unchanged for 38 patients.

The primary outcome of second-breakthrough infections occurred in 12 of the changed CAP group and 22 of the unchanged group, with a relative risk of 0.86. The percentage of second breakthrough UTIs resistant to the current CAP was not significantly different between the changed and unchanged CAP groups (75% vs. 77%; P = 0.88).

The researchers also identified a rate ratio of 0.67 for a second breakthrough UTI in the changed CAP group, and found that approximately one-third of these patients (33.3%) developed antibiotic resistance to their initial antibiotic agent and the changed antibiotic agent.

The study findings were limited by several factors, including the retrospective design and small sample size, the researchers noted.

However, the results suggest that changing the CAP after an initial breakthrough UTI in children did not increase the risk of a second breakthrough UTI, and that CAP changing did introduce a risk of developing a second UTI with increased CAP resistance, the researchers noted. The results support leaving a child’s CAP unchanged after an initial breakthrough UTI, although additional research is needed to verify the findings, including studies involving a larger cohort with a multi-institutional prospective evaluation, they concluded.

Manage UTIs to reduce recurrence and resistance

“As we know, avoiding recurrent UTIs is important in preserving renal function in pediatric patients,” said Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, in an interview.

“Avoiding recurrent UTIs is also important to avoid the development and spread of multidrug-resistant organisms,” he said.

Dr. Joos said he was surprised by some of the study findings. “I was surprised that, over the course of this 7-year retrospective review, overall only approximately 50% of patients with a first breakthrough UTI on CAP developed a second breakthrough UTI,” he noted. “Also, the relative risk of a second UTI was not significantly affected by whether the CAP antibiotic was changed after the first infection,” he said. “It would be interesting to see whether these results hold up in a randomized, prospective study,” he added.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose, but serves as a member of the Pediatric News Editorial Advisory Board.

Third-generation fluoroquinolones may not pose the same risk to tendon health as earlier-generation agents, the findings of a new study suggest.

If confirmed, this will be good news for patients who are allergic to beta-lactam antibiotics and others in whom fluoroquinolones are the antibiotics of choice because of their favorable pharmacokinetic properties and broad-spectrum activity, according to Dr. Takashi Chinen of Jichi Medical University in Tochigi, Japan, lead investigator of the new study, published in Annals of Family Medicine.

“This is especially notable for patients who are at increased risk for tendon disorders, such as athletes,” Dr. Chinen said in an interview.

To investigate the association between third-generation fluoroquinolones and tendinopathy, Dr. Chinen and colleagues conducted a self-controlled case series analysis using administrative claims data for a single prefecture in Japan, focusing specifically on the risk of Achilles tendon rupture.

From a database of 780,000 residents in the Kumamoto Prefecture enrolled in the country’s National Health Insurance and Elderly Health Insurance from April 2012 to March 2017, the investigators identified 504 patients who experienced Achilles tendon rupture during the 5-year period and were prescribed an antibiotic at some time during that period. They divided the observation period into antibiotic exposure (30 days from prescription) and nonexposure periods based on previous research linking this fluoroquinolone exposure window to an elevated risk of tendon injury. They classified antibiotics into fluoroquinolones and nonfluoroquinolones and further classified the fluoroquinolones by first, second, and third generation, including the following agents:

• First generation: Norfloxacin, nalidixic acid, pipemidic acid
• Second generation: Levofloxacin, tosufloxacin, ciprofloxacin, ofloxacin, lomefloxacin
• Third generation: Garenoxacin, sitafloxacin, prulifloxacin, moxifloxacin, pazufloxacin.

Tendon rupture risk varied based on fluoroquinolone class

Comparing the incidence of Achilles tendon rupture in the exposure period relative to the nonexposure period, the risk of rupture was not elevated during exposure to third-generation fluoroquinolones (incidence rate ratio, 1.05; 95% confidence interval, 0.33-3.37) and nonfluoroquinolones (IRR, 1.08; 95% CI, 0.80- 1.47). Contrasting with those findings, the researchers found that the risk of tendon rupture was significantly elevated during exposure to first- and second-generation fluoroquinolones (IRR, 2.94; 95% CI, 1.90-4.54). Similar findings were observed in subgroup analyses by gender and recent corticosteroid use, the authors wrote.

The increased risk associated with exposure to first- and second-generation fluoroquinolones is consistent with the elevated risk observed in previous studies, the majority of which focused on first- and second-generation agents, the authors noted.

“Our study is the first to investigate the risk of Achilles tendon rupture associated with third-generation fluoroquinolones by self-controlled case series analysis and using a large administrative claims database,” they said.

Because the study is based on administrative claims data, it does not support conclusions about differential risks.

“Some preclinical studies suggest that structural differences [in the drugs] may affect the risks,” Dr. Chinen said. In particular, one preclinical study linked methylpiperazinyl substituent with increased risk of tendon injury, and this substituent is more common in first- and second-generation fluoroquinolones.

Outside experts were unable to draw conclusions

The accuracy of the current study is “extremely limited” by its design, according to Dr. Karsten Knobloch, a sports medicine physician in private practice in Hanover, Germany, who has reported on the risk of drug-induced tendon disorders.

“This is a case series only, which is a very strict limitation; therefore, the ability to generalize the data is also very limited,” he said in an interview. “In my view, the study does not add substantial data to support that third-generation [fluoroquinolones] are safer than the prior ones.”

Thomas Lodise, PharmD, PhD, who is a professor at the Albany College of Pharmacy and Health Sciences in New York, pointed out another barrier to determining the value of the new research .

“Without knowing how many received moxifloxacin and descriptors of patients at baseline by each drug, it is hard to draw any definitive results from the paper,” Dr. Lodise noted.

Study design and execution had limitations

The authors acknowledged the limitations in the study design and execution. In particular, reliance on an administrative claims database means that the accuracy of diagnoses cannot be validated. Further, the study sample size may not have been sufficient to estimate the rupture risk for individual fluoroquinolones, they wrote.

Despite these and additional limitations, the findings have merit, according to the authors, who noted that the information may be useful in personalizing antibiotic therapy for individual patients.

“Fluoroquinolone-induced tendon injury is a rare event, and managing risk for even rare adverse events depends on each case,” Dr. Chinen explained. The findings of this study together with previous studies indicate that third-generation fluoroquinolones may be a safer option with respect to risk of Achilles tendon rupture for some patients who can’t be prescribed beta-lactam antibiotics and for some conditions, such as Legionella pneumophila, he said.

To increase internal and external validity of the results, further research including prospective cohort studies in broader populations are necessary, Dr. Chinen stressed.

The authors, Dr. Lodise, and Dr. Knobloch, who is owner of SportPraxis in Hanover, Germany, reported no conflicts.

Third-generation fluoroquinolones may not pose the same risk to tendon health as earlier-generation agents, the findings of a new study suggest.

If confirmed, this will be good news for patients who are allergic to beta-lactam antibiotics and others in whom fluoroquinolones are the antibiotics of choice because of their favorable pharmacokinetic properties and broad-spectrum activity, according to Dr. Takashi Chinen of Jichi Medical University in Tochigi, Japan, lead investigator of the new study, published in Annals of Family Medicine.

“This is especially notable for patients who are at increased risk for tendon disorders, such as athletes,” Dr. Chinen said in an interview.

To investigate the association between third-generation fluoroquinolones and tendinopathy, Dr. Chinen and colleagues conducted a self-controlled case series analysis using administrative claims data for a single prefecture in Japan, focusing specifically on the risk of Achilles tendon rupture.

From a database of 780,000 residents in the Kumamoto Prefecture enrolled in the country’s National Health Insurance and Elderly Health Insurance from April 2012 to March 2017, the investigators identified 504 patients who experienced Achilles tendon rupture during the 5-year period and were prescribed an antibiotic at some time during that period. They divided the observation period into antibiotic exposure (30 days from prescription) and nonexposure periods based on previous research linking this fluoroquinolone exposure window to an elevated risk of tendon injury. They classified antibiotics into fluoroquinolones and nonfluoroquinolones and further classified the fluoroquinolones by first, second, and third generation, including the following agents:

• First generation: Norfloxacin, nalidixic acid, pipemidic acid
• Second generation: Levofloxacin, tosufloxacin, ciprofloxacin, ofloxacin, lomefloxacin
• Third generation: Garenoxacin, sitafloxacin, prulifloxacin, moxifloxacin, pazufloxacin.

Tendon rupture risk varied based on fluoroquinolone class

Comparing the incidence of Achilles tendon rupture in the exposure period relative to the nonexposure period, the risk of rupture was not elevated during exposure to third-generation fluoroquinolones (incidence rate ratio, 1.05; 95% confidence interval, 0.33-3.37) and nonfluoroquinolones (IRR, 1.08; 95% CI, 0.80- 1.47). Contrasting with those findings, the researchers found that the risk of tendon rupture was significantly elevated during exposure to first- and second-generation fluoroquinolones (IRR, 2.94; 95% CI, 1.90-4.54). Similar findings were observed in subgroup analyses by gender and recent corticosteroid use, the authors wrote.

The increased risk associated with exposure to first- and second-generation fluoroquinolones is consistent with the elevated risk observed in previous studies, the majority of which focused on first- and second-generation agents, the authors noted.

“Our study is the first to investigate the risk of Achilles tendon rupture associated with third-generation fluoroquinolones by self-controlled case series analysis and using a large administrative claims database,” they said.

Because the study is based on administrative claims data, it does not support conclusions about differential risks.

“Some preclinical studies suggest that structural differences [in the drugs] may affect the risks,” Dr. Chinen said. In particular, one preclinical study linked methylpiperazinyl substituent with increased risk of tendon injury, and this substituent is more common in first- and second-generation fluoroquinolones.

Outside experts were unable to draw conclusions

The accuracy of the current study is “extremely limited” by its design, according to Dr. Karsten Knobloch, a sports medicine physician in private practice in Hanover, Germany, who has reported on the risk of drug-induced tendon disorders.

“This is a case series only, which is a very strict limitation; therefore, the ability to generalize the data is also very limited,” he said in an interview. “In my view, the study does not add substantial data to support that third-generation [fluoroquinolones] are safer than the prior ones.”

Thomas Lodise, PharmD, PhD, who is a professor at the Albany College of Pharmacy and Health Sciences in New York, pointed out another barrier to determining the value of the new research .

“Without knowing how many received moxifloxacin and descriptors of patients at baseline by each drug, it is hard to draw any definitive results from the paper,” Dr. Lodise noted.

Study design and execution had limitations

The authors acknowledged the limitations in the study design and execution. In particular, reliance on an administrative claims database means that the accuracy of diagnoses cannot be validated. Further, the study sample size may not have been sufficient to estimate the rupture risk for individual fluoroquinolones, they wrote.

Despite these and additional limitations, the findings have merit, according to the authors, who noted that the information may be useful in personalizing antibiotic therapy for individual patients.

“Fluoroquinolone-induced tendon injury is a rare event, and managing risk for even rare adverse events depends on each case,” Dr. Chinen explained. The findings of this study together with previous studies indicate that third-generation fluoroquinolones may be a safer option with respect to risk of Achilles tendon rupture for some patients who can’t be prescribed beta-lactam antibiotics and for some conditions, such as Legionella pneumophila, he said.

To increase internal and external validity of the results, further research including prospective cohort studies in broader populations are necessary, Dr. Chinen stressed.

The authors, Dr. Lodise, and Dr. Knobloch, who is owner of SportPraxis in Hanover, Germany, reported no conflicts.

Third-generation fluoroquinolones may not pose the same risk to tendon health as earlier-generation agents, the findings of a new study suggest.

If confirmed, this will be good news for patients who are allergic to beta-lactam antibiotics and others in whom fluoroquinolones are the antibiotics of choice because of their favorable pharmacokinetic properties and broad-spectrum activity, according to Dr. Takashi Chinen of Jichi Medical University in Tochigi, Japan, lead investigator of the new study, published in Annals of Family Medicine.

“This is especially notable for patients who are at increased risk for tendon disorders, such as athletes,” Dr. Chinen said in an interview.

To investigate the association between third-generation fluoroquinolones and tendinopathy, Dr. Chinen and colleagues conducted a self-controlled case series analysis using administrative claims data for a single prefecture in Japan, focusing specifically on the risk of Achilles tendon rupture.

From a database of 780,000 residents in the Kumamoto Prefecture enrolled in the country’s National Health Insurance and Elderly Health Insurance from April 2012 to March 2017, the investigators identified 504 patients who experienced Achilles tendon rupture during the 5-year period and were prescribed an antibiotic at some time during that period. They divided the observation period into antibiotic exposure (30 days from prescription) and nonexposure periods based on previous research linking this fluoroquinolone exposure window to an elevated risk of tendon injury. They classified antibiotics into fluoroquinolones and nonfluoroquinolones and further classified the fluoroquinolones by first, second, and third generation, including the following agents:

• First generation: Norfloxacin, nalidixic acid, pipemidic acid
• Second generation: Levofloxacin, tosufloxacin, ciprofloxacin, ofloxacin, lomefloxacin
• Third generation: Garenoxacin, sitafloxacin, prulifloxacin, moxifloxacin, pazufloxacin.

Tendon rupture risk varied based on fluoroquinolone class

Comparing the incidence of Achilles tendon rupture in the exposure period relative to the nonexposure period, the risk of rupture was not elevated during exposure to third-generation fluoroquinolones (incidence rate ratio, 1.05; 95% confidence interval, 0.33-3.37) and nonfluoroquinolones (IRR, 1.08; 95% CI, 0.80- 1.47). Contrasting with those findings, the researchers found that the risk of tendon rupture was significantly elevated during exposure to first- and second-generation fluoroquinolones (IRR, 2.94; 95% CI, 1.90-4.54). Similar findings were observed in subgroup analyses by gender and recent corticosteroid use, the authors wrote.

The increased risk associated with exposure to first- and second-generation fluoroquinolones is consistent with the elevated risk observed in previous studies, the majority of which focused on first- and second-generation agents, the authors noted.

“Our study is the first to investigate the risk of Achilles tendon rupture associated with third-generation fluoroquinolones by self-controlled case series analysis and using a large administrative claims database,” they said.

Because the study is based on administrative claims data, it does not support conclusions about differential risks.

“Some preclinical studies suggest that structural differences [in the drugs] may affect the risks,” Dr. Chinen said. In particular, one preclinical study linked methylpiperazinyl substituent with increased risk of tendon injury, and this substituent is more common in first- and second-generation fluoroquinolones.

Outside experts were unable to draw conclusions

The accuracy of the current study is “extremely limited” by its design, according to Dr. Karsten Knobloch, a sports medicine physician in private practice in Hanover, Germany, who has reported on the risk of drug-induced tendon disorders.

“This is a case series only, which is a very strict limitation; therefore, the ability to generalize the data is also very limited,” he said in an interview. “In my view, the study does not add substantial data to support that third-generation [fluoroquinolones] are safer than the prior ones.”

Thomas Lodise, PharmD, PhD, who is a professor at the Albany College of Pharmacy and Health Sciences in New York, pointed out another barrier to determining the value of the new research .

“Without knowing how many received moxifloxacin and descriptors of patients at baseline by each drug, it is hard to draw any definitive results from the paper,” Dr. Lodise noted.

Study design and execution had limitations

The authors acknowledged the limitations in the study design and execution. In particular, reliance on an administrative claims database means that the accuracy of diagnoses cannot be validated. Further, the study sample size may not have been sufficient to estimate the rupture risk for individual fluoroquinolones, they wrote.

Despite these and additional limitations, the findings have merit, according to the authors, who noted that the information may be useful in personalizing antibiotic therapy for individual patients.

“Fluoroquinolone-induced tendon injury is a rare event, and managing risk for even rare adverse events depends on each case,” Dr. Chinen explained. The findings of this study together with previous studies indicate that third-generation fluoroquinolones may be a safer option with respect to risk of Achilles tendon rupture for some patients who can’t be prescribed beta-lactam antibiotics and for some conditions, such as Legionella pneumophila, he said.

To increase internal and external validity of the results, further research including prospective cohort studies in broader populations are necessary, Dr. Chinen stressed.

The authors, Dr. Lodise, and Dr. Knobloch, who is owner of SportPraxis in Hanover, Germany, reported no conflicts.