Mixed Topics

Neuropathy is the result of damage to the nervous system. This dysfunction generally occurs in peripheral nerves, which are the circuits that transmit signals to the brain and spinal cord. The peripheral nervous system is responsible for controlling motor and autonomic nerves and conduction of sensory information. Injury to the nervous system can lead to changes in nerve fiber sensitivity and malfunctioning of nerve stimuli pathways. Neuropathy may be a sequela of a wide variety of diseases, including diabetes mellitus (DM), autoimmune disorders, infections, and cancer. Also, neuropathy can be caused by medications, trauma, exposure to toxins, classified idiopathic.^1-5

Peripheral neuropathy is a common condition with an estimated incidence of > 3 million cases in the United States per year.⁴ The burden of neuropathy may be greater among veterans, due to a higher prevalence of type 2 DM (T2DM) and an aging population. Manifestations of neuropathy include weakness, numbness, burning or tingling sensations, and lingering pain.^3,5 This can lead to limited mobility and decreased quality of life. Neuropathy can be debilitating, but several medications can be used to alleviate symptoms—including duloxetine and pregabalin. The American Diabetes Association recommends either agent as initial treatment for neuropathic pain in patients with DM.² As with all medication use, the benefits and risks of treatment must be assessed prior to initiation of therapy.

The Centers for Disease Control and Prevention estimates > 70% of adults in the United States are overweight or obese.⁶ Excessive weight gain causes a higher risk of developing certain comorbidities, such as coronary artery disease, cerebrovascular accident, T2DM, and cancer, and all can lead to premature death. It is important to avoid excessive weight gain whenever possible, especially in patients already at a high risk for developing these diseases.

The correlation of weight gain in patients taking duloxetine, pregabalin, or both is not well studied. Duloxetine has the potential to cause weight gain or weight loss, with reports of > 1% incidence for either effect.⁷ Clinical significance of weight changes caused by duloxetine is uncertain.Pregabalin is more likely to cause weight gain, with a reported incidence between 2 and 14%.⁸ Weight gain may be associated with dose and duration; 1 study demonstrated an average weight gain of about 11 lb after 2 years of pregabalin treatment.⁸ The medical literature lacks information regarding weight gain associated with combination therapy of duloxetine and pregabalin. The objective of this study was to investigate the association of weight gain in veterans taking duloxetine, pregabalin, or both for the treatment of neuropathy.

Methods 

A retrospective, single-center, chart review was conducted at the Sioux Falls Veterans Affairs Health Care System (SFVAHCS). Data were collected through manual chart review of US Department of Veterans Affairs (VA) electronic health records (EHRs). Patients included were veterans aged 18 to 89 years who were initiated on duloxetine and/or pregabalin between October 2015 and September 2018. The monotherapy groups were made equal by randomization based on whichever group had the lesser number of participants. The indication of neuropathy was determined by the presence of neuropathic pain, neuropathy, nerve pain, or otherwise similar terminology in the prescription directions for use in the EHR. Patients were excluded if they did not have an active prescription of the study agent(s) for ≥ 12 months or if there was a lack of documented body weight(s) at baseline and/or at follow-up outpatient visit(s) occurring 12 to 18 months after initiation of therapy. Additional exclusion criteria were health conditions, including active cancer; pregnancy; history of bariatric surgery; if the patient received hospice care; was morbidly obese (body mass index [BMI] > 40; or if estimated glomerular filtration rate (eGFR) was < 30 mL/min/1.83m². Patients also were excluded if they were concurrently taking any of the following medications: antipsychotics, tricyclic antidepressants, venlafaxine, divalproex/valproic acid, lithium, mirtazapine, weight loss medications (orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion, liraglutide), chronic corticosteroids, or chronic opioids; chronic being defined as receiving more than a 30-day supply.

The primary end point of this study was the change in body weight, expressed in pounds, after 12 to 18 months of treatment. If multiple weights were obtained during the 12- to 18-month period, the weight recorded closest to 12 months was used. The secondary end points included the percent change in body weight and dose effect, which evaluated change in weight at doses of duloxetine > 60 mg/d, and pregabalin at doses > 300 mg/d. Duration of effect was evaluated as a secondary end point; contrary to the primary end point, the weight furthest from 12 months was recorded. The change in hemoglobin A_1c (HbA_1c) in patients with prediabetes and DM also was investigated as a secondary end point. Last, involvement in the Managing Overweight Veterans Everywhere (MOVE!) weight management program at SFVAHCS and its effect on weight gain was reviewed.

Baseline characteristics were collected to determine the variability between each study group. Data collected during the study included age, sex, race, weight, BMI, HbA_1c, eGFR, DM diagnosis, insulin therapy prescription, duration of use, and MOVE! program participation.

Statistical Analysis

The primary and secondary end points were analyzed using an analysis of variance statistical test. Results were considered statistically significant at P < .05.

Results

A total of 174 participants were included in this study, with 77 in each monotherapy group, and 22 in the combination therapy group. More than 300 patients were excluded from the study due to prespecified inclusion and exclusion criteria. Baseline characteristics were similar among the 3 groups, with no statistically significant differences identified (Table 1).

Primary End Point

The change in body weight after 12 to 18 months of treatment was –0.8 lb in the duloxetine group, +2.9 lb in the pregabalin group, and +5.5 lb in the pregabalin plus duloxetine group (P = .12) (Figure).

Secondary End Points

The percent change in body weight after 12 to 18 months of treatment was −0.3% in the duloxetine group, +1.5% in the pregabalin group, and +2.0% in the duloxetine plus pregabalin group (P = .18). The change in body weight beyond 12 months of treatment was −0.9 lb in the duloxetine group, +3.6 lb in the pregabalin group, and +8.5 lb in the duloxetine plus pregabalin group (P = .05). The change in HbA_1c in patients with DM and pre-DM was −0.1% in the duloxetine group, +0.3% in the pregabalin group, and −0.3% in the duloxetine plus pregabalin group (P = .14). The change in body weight in patients who received increased doses of the study agents was −2.8 lb in the duloxetine group and +6.5 lb in the pregabalin group (P = .05). Among veterans who participated in MOVE!, change in body weight after 12 to 18 months of treatment was +1.5 lb in the duloxetine group, +4.9 lb in the pregabalin group, and +3.4 lb in the pregabalin plus duloxetine group (P = .91)(Table 2).

Discussion

The purpose of this retrospective chart review was to evaluate the association of weight gain in veterans taking duloxetine and/or pregabalin for the treatment of neuropathy. Although the primary end point, weight gain after 12 to 18 months of therapy, was not statistically significant, we found notable trends and associations worthy of discussion.

The secondary end point of the difference in weight gain in veterans taking duloxetine, pregabalin, or both for a treatment duration > 12 months was statistically significant. For this secondary end point, the weight recorded was when the study agent(s) were discontinued or the most recent weight obtained if participants still had an active prescription; the average duration of treatment in the 3 study groups was about 24 months. These weights differed from the primary end point, in which weight closest to 12 months of therapy was recorded.

The other secondary end point that was statistically significant was the difference in weight gain in patients who were on higher doses of duloxetine or pregabalin. This specifically examined participants who were on doses of duloxetine > 60 mg/d and pregabalin > 300 mg/d. Duloxetine was associated with weight loss, whereas pregabalin was associated with weight gain, with a difference of about 10 lb between the groups. The significance of this secondary end point demonstrates that increased doses of duloxetine and pregabalin are more associated with changes in weight compared with standard doses.

The secondary end points of percent change in body weight, change in HBA_1c in patients with DM and prediabetes, and weight gain in patients who participated in the MOVE! weight management program were not statistically significant among the 3 study groups. Given the relatively small sample sizes, more significant differences in the evaluation of the primary and secondary end points may have been observed with a larger patient population.

Study investigators made additional observations beyond the primary and secondary end points. Most notably, > 300 patients were excluded from this study because they did not continue treatment beyond 12 months. The investigators found this number staggering, as it may imply that veterans were not satisfied with treatment agent(s) within 1 year of initiation, which could be due to lack of efficacy or intolerable adverse effects.

The mechanism of why combination therapy of duloxetine and pregabalin may be more associated with weight gain compared with either agent alone is unknown. Since this study found duloxetine to be more associated with weight loss, the mechanism does not seem to be an additive effect. The alternative hypothesis proposed prior to the completion of this study stemmed from an observation seen by health care providers at SFVAHCS.

Limitations

The retrospective nature of the study does not provide proof of causation but does demonstrate association. There was no control group, and the study design did not allow for randomization of participants. Additionally, since the study was completed at a single center, there was potential for selection bias. Future studies could benefit from pursuing a multicenter study design, which may provide a higher level of external validity. There are several confounding factors that have the potential to influence changes in weight, all of which cannot feasibly be accounted for. Since participants were ambulatory veterans, medication adherence could not be confirmed.

Conclusions

There was no difference in weight gain in veterans who took duloxetine, pregabalin, or both for treatment of neuropathy after 12 to 18 months of therapy. However, there was a difference in weight gain between the 3 groups when therapy lasted > 12 months. The combination therapy of pregabalin and duloxetine was associated with the most amount of weight gain, followed by pregabalin alone. Duloxetine monotherapy had minimal impact on weight.

In veterans who took increased doses of duloxetine or pregabalin, there was a statistically significant difference in weight between the monotherapy groups, with pregabalin associated with weight gain and duloxetine associated with weight loss.

For patients in which weight gain may be a concern, it would be reasonable to prefer duloxetine rather than pregabalin for initial treatment of neuropathy. Pregabalin should be used at the lowest effective dose to minimize risk of weight gain. Combination therapy of duloxetine and pregabalin for the treatment of neuropathy seems to be associated with the most amount of weight gain compared with either therapy alone. Association of changes in weight is greater as treatment duration lasts beyond 12 months.

Neuropathy is the result of damage to the nervous system. This dysfunction generally occurs in peripheral nerves, which are the circuits that transmit signals to the brain and spinal cord. The peripheral nervous system is responsible for controlling motor and autonomic nerves and conduction of sensory information. Injury to the nervous system can lead to changes in nerve fiber sensitivity and malfunctioning of nerve stimuli pathways. Neuropathy may be a sequela of a wide variety of diseases, including diabetes mellitus (DM), autoimmune disorders, infections, and cancer. Also, neuropathy can be caused by medications, trauma, exposure to toxins, classified idiopathic.^1-5

Peripheral neuropathy is a common condition with an estimated incidence of > 3 million cases in the United States per year.⁴ The burden of neuropathy may be greater among veterans, due to a higher prevalence of type 2 DM (T2DM) and an aging population. Manifestations of neuropathy include weakness, numbness, burning or tingling sensations, and lingering pain.^3,5 This can lead to limited mobility and decreased quality of life. Neuropathy can be debilitating, but several medications can be used to alleviate symptoms—including duloxetine and pregabalin. The American Diabetes Association recommends either agent as initial treatment for neuropathic pain in patients with DM.² As with all medication use, the benefits and risks of treatment must be assessed prior to initiation of therapy.

The Centers for Disease Control and Prevention estimates > 70% of adults in the United States are overweight or obese.⁶ Excessive weight gain causes a higher risk of developing certain comorbidities, such as coronary artery disease, cerebrovascular accident, T2DM, and cancer, and all can lead to premature death. It is important to avoid excessive weight gain whenever possible, especially in patients already at a high risk for developing these diseases.

The correlation of weight gain in patients taking duloxetine, pregabalin, or both is not well studied. Duloxetine has the potential to cause weight gain or weight loss, with reports of > 1% incidence for either effect.⁷ Clinical significance of weight changes caused by duloxetine is uncertain.Pregabalin is more likely to cause weight gain, with a reported incidence between 2 and 14%.⁸ Weight gain may be associated with dose and duration; 1 study demonstrated an average weight gain of about 11 lb after 2 years of pregabalin treatment.⁸ The medical literature lacks information regarding weight gain associated with combination therapy of duloxetine and pregabalin. The objective of this study was to investigate the association of weight gain in veterans taking duloxetine, pregabalin, or both for the treatment of neuropathy.

Methods 

A retrospective, single-center, chart review was conducted at the Sioux Falls Veterans Affairs Health Care System (SFVAHCS). Data were collected through manual chart review of US Department of Veterans Affairs (VA) electronic health records (EHRs). Patients included were veterans aged 18 to 89 years who were initiated on duloxetine and/or pregabalin between October 2015 and September 2018. The monotherapy groups were made equal by randomization based on whichever group had the lesser number of participants. The indication of neuropathy was determined by the presence of neuropathic pain, neuropathy, nerve pain, or otherwise similar terminology in the prescription directions for use in the EHR. Patients were excluded if they did not have an active prescription of the study agent(s) for ≥ 12 months or if there was a lack of documented body weight(s) at baseline and/or at follow-up outpatient visit(s) occurring 12 to 18 months after initiation of therapy. Additional exclusion criteria were health conditions, including active cancer; pregnancy; history of bariatric surgery; if the patient received hospice care; was morbidly obese (body mass index [BMI] > 40; or if estimated glomerular filtration rate (eGFR) was < 30 mL/min/1.83m². Patients also were excluded if they were concurrently taking any of the following medications: antipsychotics, tricyclic antidepressants, venlafaxine, divalproex/valproic acid, lithium, mirtazapine, weight loss medications (orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion, liraglutide), chronic corticosteroids, or chronic opioids; chronic being defined as receiving more than a 30-day supply.

The primary end point of this study was the change in body weight, expressed in pounds, after 12 to 18 months of treatment. If multiple weights were obtained during the 12- to 18-month period, the weight recorded closest to 12 months was used. The secondary end points included the percent change in body weight and dose effect, which evaluated change in weight at doses of duloxetine > 60 mg/d, and pregabalin at doses > 300 mg/d. Duration of effect was evaluated as a secondary end point; contrary to the primary end point, the weight furthest from 12 months was recorded. The change in hemoglobin A_1c (HbA_1c) in patients with prediabetes and DM also was investigated as a secondary end point. Last, involvement in the Managing Overweight Veterans Everywhere (MOVE!) weight management program at SFVAHCS and its effect on weight gain was reviewed.

Baseline characteristics were collected to determine the variability between each study group. Data collected during the study included age, sex, race, weight, BMI, HbA_1c, eGFR, DM diagnosis, insulin therapy prescription, duration of use, and MOVE! program participation.

Statistical Analysis

The primary and secondary end points were analyzed using an analysis of variance statistical test. Results were considered statistically significant at P < .05.

Results

A total of 174 participants were included in this study, with 77 in each monotherapy group, and 22 in the combination therapy group. More than 300 patients were excluded from the study due to prespecified inclusion and exclusion criteria. Baseline characteristics were similar among the 3 groups, with no statistically significant differences identified (Table 1).

Primary End Point

The change in body weight after 12 to 18 months of treatment was –0.8 lb in the duloxetine group, +2.9 lb in the pregabalin group, and +5.5 lb in the pregabalin plus duloxetine group (P = .12) (Figure).

Secondary End Points

The percent change in body weight after 12 to 18 months of treatment was −0.3% in the duloxetine group, +1.5% in the pregabalin group, and +2.0% in the duloxetine plus pregabalin group (P = .18). The change in body weight beyond 12 months of treatment was −0.9 lb in the duloxetine group, +3.6 lb in the pregabalin group, and +8.5 lb in the duloxetine plus pregabalin group (P = .05). The change in HbA_1c in patients with DM and pre-DM was −0.1% in the duloxetine group, +0.3% in the pregabalin group, and −0.3% in the duloxetine plus pregabalin group (P = .14). The change in body weight in patients who received increased doses of the study agents was −2.8 lb in the duloxetine group and +6.5 lb in the pregabalin group (P = .05). Among veterans who participated in MOVE!, change in body weight after 12 to 18 months of treatment was +1.5 lb in the duloxetine group, +4.9 lb in the pregabalin group, and +3.4 lb in the pregabalin plus duloxetine group (P = .91)(Table 2).

Discussion

The purpose of this retrospective chart review was to evaluate the association of weight gain in veterans taking duloxetine and/or pregabalin for the treatment of neuropathy. Although the primary end point, weight gain after 12 to 18 months of therapy, was not statistically significant, we found notable trends and associations worthy of discussion.

The secondary end point of the difference in weight gain in veterans taking duloxetine, pregabalin, or both for a treatment duration > 12 months was statistically significant. For this secondary end point, the weight recorded was when the study agent(s) were discontinued or the most recent weight obtained if participants still had an active prescription; the average duration of treatment in the 3 study groups was about 24 months. These weights differed from the primary end point, in which weight closest to 12 months of therapy was recorded.

The other secondary end point that was statistically significant was the difference in weight gain in patients who were on higher doses of duloxetine or pregabalin. This specifically examined participants who were on doses of duloxetine > 60 mg/d and pregabalin > 300 mg/d. Duloxetine was associated with weight loss, whereas pregabalin was associated with weight gain, with a difference of about 10 lb between the groups. The significance of this secondary end point demonstrates that increased doses of duloxetine and pregabalin are more associated with changes in weight compared with standard doses.

The secondary end points of percent change in body weight, change in HBA_1c in patients with DM and prediabetes, and weight gain in patients who participated in the MOVE! weight management program were not statistically significant among the 3 study groups. Given the relatively small sample sizes, more significant differences in the evaluation of the primary and secondary end points may have been observed with a larger patient population.

Study investigators made additional observations beyond the primary and secondary end points. Most notably, > 300 patients were excluded from this study because they did not continue treatment beyond 12 months. The investigators found this number staggering, as it may imply that veterans were not satisfied with treatment agent(s) within 1 year of initiation, which could be due to lack of efficacy or intolerable adverse effects.

The mechanism of why combination therapy of duloxetine and pregabalin may be more associated with weight gain compared with either agent alone is unknown. Since this study found duloxetine to be more associated with weight loss, the mechanism does not seem to be an additive effect. The alternative hypothesis proposed prior to the completion of this study stemmed from an observation seen by health care providers at SFVAHCS.

Limitations

The retrospective nature of the study does not provide proof of causation but does demonstrate association. There was no control group, and the study design did not allow for randomization of participants. Additionally, since the study was completed at a single center, there was potential for selection bias. Future studies could benefit from pursuing a multicenter study design, which may provide a higher level of external validity. There are several confounding factors that have the potential to influence changes in weight, all of which cannot feasibly be accounted for. Since participants were ambulatory veterans, medication adherence could not be confirmed.

Conclusions

There was no difference in weight gain in veterans who took duloxetine, pregabalin, or both for treatment of neuropathy after 12 to 18 months of therapy. However, there was a difference in weight gain between the 3 groups when therapy lasted > 12 months. The combination therapy of pregabalin and duloxetine was associated with the most amount of weight gain, followed by pregabalin alone. Duloxetine monotherapy had minimal impact on weight.

In veterans who took increased doses of duloxetine or pregabalin, there was a statistically significant difference in weight between the monotherapy groups, with pregabalin associated with weight gain and duloxetine associated with weight loss.

For patients in which weight gain may be a concern, it would be reasonable to prefer duloxetine rather than pregabalin for initial treatment of neuropathy. Pregabalin should be used at the lowest effective dose to minimize risk of weight gain. Combination therapy of duloxetine and pregabalin for the treatment of neuropathy seems to be associated with the most amount of weight gain compared with either therapy alone. Association of changes in weight is greater as treatment duration lasts beyond 12 months.

Neuropathy is the result of damage to the nervous system. This dysfunction generally occurs in peripheral nerves, which are the circuits that transmit signals to the brain and spinal cord. The peripheral nervous system is responsible for controlling motor and autonomic nerves and conduction of sensory information. Injury to the nervous system can lead to changes in nerve fiber sensitivity and malfunctioning of nerve stimuli pathways. Neuropathy may be a sequela of a wide variety of diseases, including diabetes mellitus (DM), autoimmune disorders, infections, and cancer. Also, neuropathy can be caused by medications, trauma, exposure to toxins, classified idiopathic.^1-5

Peripheral neuropathy is a common condition with an estimated incidence of > 3 million cases in the United States per year.⁴ The burden of neuropathy may be greater among veterans, due to a higher prevalence of type 2 DM (T2DM) and an aging population. Manifestations of neuropathy include weakness, numbness, burning or tingling sensations, and lingering pain.^3,5 This can lead to limited mobility and decreased quality of life. Neuropathy can be debilitating, but several medications can be used to alleviate symptoms—including duloxetine and pregabalin. The American Diabetes Association recommends either agent as initial treatment for neuropathic pain in patients with DM.² As with all medication use, the benefits and risks of treatment must be assessed prior to initiation of therapy.

The Centers for Disease Control and Prevention estimates > 70% of adults in the United States are overweight or obese.⁶ Excessive weight gain causes a higher risk of developing certain comorbidities, such as coronary artery disease, cerebrovascular accident, T2DM, and cancer, and all can lead to premature death. It is important to avoid excessive weight gain whenever possible, especially in patients already at a high risk for developing these diseases.

The correlation of weight gain in patients taking duloxetine, pregabalin, or both is not well studied. Duloxetine has the potential to cause weight gain or weight loss, with reports of > 1% incidence for either effect.⁷ Clinical significance of weight changes caused by duloxetine is uncertain.Pregabalin is more likely to cause weight gain, with a reported incidence between 2 and 14%.⁸ Weight gain may be associated with dose and duration; 1 study demonstrated an average weight gain of about 11 lb after 2 years of pregabalin treatment.⁸ The medical literature lacks information regarding weight gain associated with combination therapy of duloxetine and pregabalin. The objective of this study was to investigate the association of weight gain in veterans taking duloxetine, pregabalin, or both for the treatment of neuropathy.

Methods 

A retrospective, single-center, chart review was conducted at the Sioux Falls Veterans Affairs Health Care System (SFVAHCS). Data were collected through manual chart review of US Department of Veterans Affairs (VA) electronic health records (EHRs). Patients included were veterans aged 18 to 89 years who were initiated on duloxetine and/or pregabalin between October 2015 and September 2018. The monotherapy groups were made equal by randomization based on whichever group had the lesser number of participants. The indication of neuropathy was determined by the presence of neuropathic pain, neuropathy, nerve pain, or otherwise similar terminology in the prescription directions for use in the EHR. Patients were excluded if they did not have an active prescription of the study agent(s) for ≥ 12 months or if there was a lack of documented body weight(s) at baseline and/or at follow-up outpatient visit(s) occurring 12 to 18 months after initiation of therapy. Additional exclusion criteria were health conditions, including active cancer; pregnancy; history of bariatric surgery; if the patient received hospice care; was morbidly obese (body mass index [BMI] > 40; or if estimated glomerular filtration rate (eGFR) was < 30 mL/min/1.83m². Patients also were excluded if they were concurrently taking any of the following medications: antipsychotics, tricyclic antidepressants, venlafaxine, divalproex/valproic acid, lithium, mirtazapine, weight loss medications (orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion, liraglutide), chronic corticosteroids, or chronic opioids; chronic being defined as receiving more than a 30-day supply.

The primary end point of this study was the change in body weight, expressed in pounds, after 12 to 18 months of treatment. If multiple weights were obtained during the 12- to 18-month period, the weight recorded closest to 12 months was used. The secondary end points included the percent change in body weight and dose effect, which evaluated change in weight at doses of duloxetine > 60 mg/d, and pregabalin at doses > 300 mg/d. Duration of effect was evaluated as a secondary end point; contrary to the primary end point, the weight furthest from 12 months was recorded. The change in hemoglobin A_1c (HbA_1c) in patients with prediabetes and DM also was investigated as a secondary end point. Last, involvement in the Managing Overweight Veterans Everywhere (MOVE!) weight management program at SFVAHCS and its effect on weight gain was reviewed.

Baseline characteristics were collected to determine the variability between each study group. Data collected during the study included age, sex, race, weight, BMI, HbA_1c, eGFR, DM diagnosis, insulin therapy prescription, duration of use, and MOVE! program participation.

Statistical Analysis

The primary and secondary end points were analyzed using an analysis of variance statistical test. Results were considered statistically significant at P < .05.

Results

A total of 174 participants were included in this study, with 77 in each monotherapy group, and 22 in the combination therapy group. More than 300 patients were excluded from the study due to prespecified inclusion and exclusion criteria. Baseline characteristics were similar among the 3 groups, with no statistically significant differences identified (Table 1).

Primary End Point

The change in body weight after 12 to 18 months of treatment was –0.8 lb in the duloxetine group, +2.9 lb in the pregabalin group, and +5.5 lb in the pregabalin plus duloxetine group (P = .12) (Figure).

Secondary End Points

The percent change in body weight after 12 to 18 months of treatment was −0.3% in the duloxetine group, +1.5% in the pregabalin group, and +2.0% in the duloxetine plus pregabalin group (P = .18). The change in body weight beyond 12 months of treatment was −0.9 lb in the duloxetine group, +3.6 lb in the pregabalin group, and +8.5 lb in the duloxetine plus pregabalin group (P = .05). The change in HbA_1c in patients with DM and pre-DM was −0.1% in the duloxetine group, +0.3% in the pregabalin group, and −0.3% in the duloxetine plus pregabalin group (P = .14). The change in body weight in patients who received increased doses of the study agents was −2.8 lb in the duloxetine group and +6.5 lb in the pregabalin group (P = .05). Among veterans who participated in MOVE!, change in body weight after 12 to 18 months of treatment was +1.5 lb in the duloxetine group, +4.9 lb in the pregabalin group, and +3.4 lb in the pregabalin plus duloxetine group (P = .91)(Table 2).

Discussion

The purpose of this retrospective chart review was to evaluate the association of weight gain in veterans taking duloxetine and/or pregabalin for the treatment of neuropathy. Although the primary end point, weight gain after 12 to 18 months of therapy, was not statistically significant, we found notable trends and associations worthy of discussion.

The secondary end point of the difference in weight gain in veterans taking duloxetine, pregabalin, or both for a treatment duration > 12 months was statistically significant. For this secondary end point, the weight recorded was when the study agent(s) were discontinued or the most recent weight obtained if participants still had an active prescription; the average duration of treatment in the 3 study groups was about 24 months. These weights differed from the primary end point, in which weight closest to 12 months of therapy was recorded.

The other secondary end point that was statistically significant was the difference in weight gain in patients who were on higher doses of duloxetine or pregabalin. This specifically examined participants who were on doses of duloxetine > 60 mg/d and pregabalin > 300 mg/d. Duloxetine was associated with weight loss, whereas pregabalin was associated with weight gain, with a difference of about 10 lb between the groups. The significance of this secondary end point demonstrates that increased doses of duloxetine and pregabalin are more associated with changes in weight compared with standard doses.

The secondary end points of percent change in body weight, change in HBA_1c in patients with DM and prediabetes, and weight gain in patients who participated in the MOVE! weight management program were not statistically significant among the 3 study groups. Given the relatively small sample sizes, more significant differences in the evaluation of the primary and secondary end points may have been observed with a larger patient population.

Study investigators made additional observations beyond the primary and secondary end points. Most notably, > 300 patients were excluded from this study because they did not continue treatment beyond 12 months. The investigators found this number staggering, as it may imply that veterans were not satisfied with treatment agent(s) within 1 year of initiation, which could be due to lack of efficacy or intolerable adverse effects.

The mechanism of why combination therapy of duloxetine and pregabalin may be more associated with weight gain compared with either agent alone is unknown. Since this study found duloxetine to be more associated with weight loss, the mechanism does not seem to be an additive effect. The alternative hypothesis proposed prior to the completion of this study stemmed from an observation seen by health care providers at SFVAHCS.

Limitations

The retrospective nature of the study does not provide proof of causation but does demonstrate association. There was no control group, and the study design did not allow for randomization of participants. Additionally, since the study was completed at a single center, there was potential for selection bias. Future studies could benefit from pursuing a multicenter study design, which may provide a higher level of external validity. There are several confounding factors that have the potential to influence changes in weight, all of which cannot feasibly be accounted for. Since participants were ambulatory veterans, medication adherence could not be confirmed.

Conclusions

There was no difference in weight gain in veterans who took duloxetine, pregabalin, or both for treatment of neuropathy after 12 to 18 months of therapy. However, there was a difference in weight gain between the 3 groups when therapy lasted > 12 months. The combination therapy of pregabalin and duloxetine was associated with the most amount of weight gain, followed by pregabalin alone. Duloxetine monotherapy had minimal impact on weight.

In veterans who took increased doses of duloxetine or pregabalin, there was a statistically significant difference in weight between the monotherapy groups, with pregabalin associated with weight gain and duloxetine associated with weight loss.

For patients in which weight gain may be a concern, it would be reasonable to prefer duloxetine rather than pregabalin for initial treatment of neuropathy. Pregabalin should be used at the lowest effective dose to minimize risk of weight gain. Combination therapy of duloxetine and pregabalin for the treatment of neuropathy seems to be associated with the most amount of weight gain compared with either therapy alone. Association of changes in weight is greater as treatment duration lasts beyond 12 months.

Meralgia paresthetica (MP) is a sensory mononeuropathy of the lateral femoral cutaneous nerve (LFCN), clinically characterized by numbness, pain, and paresthesias involving the anterolateral aspect of the thigh. Estimates of MP incidence are derived largely from observational studies and reported to be about 3.2 to 4.3 cases per 10,000 patient-years.^1,2 Although typically arising during midlife and especially in the context of comorbid obesity, diabetes mellitus (DM), and excessive alcohol consumption, MP may occur at any age, and bears a slight predilection for males.^2-4

MP may be divided etiologically into iatrogenic and spontaneous subtypes.⁵ Iatrogenic cases generally are attributable to nerve injury in the setting of direct or indirect trauma (such as with patient malpositioning) arising in the context of multiple forms of procedural or surgical intervention (Table). Spontaneous MP is primarily thought to occur as a result of LFCN compression at the level of the inguinal ligament, wherein internal or external pressures may promote LFCN entrapment and resultant functional disruption (Figure 1).^6,7

Case Presentation

A male Vietnam War veteran aged 69 years presented to a primary care clinic at West Roxbury Veterans Affairs Medical Center (WRVAMC) in Massachusetts with progressive right lower extremity numbness. Three months prior to this visit, he was evaluated in an urgent care clinic at WRVAMC for 6 months of numbness and increasingly painful nocturnal paresthesias involving the same extremity. A targeted physical examination at that visit revealed an obese male wearing tight suspenders, as well as focally diminished sensation to light touch involving the anterolateral aspect of the thigh, extending from just below the right hip to above the knee. Sensation in the medial thigh was spared. Strength and reflexes were normal in the bilateral lower extremities. An abdominal examination was not performed. He received a diagnosis of MP and counseled regarding weight loss, glycemic control, garment optimization, and conservative analgesia with as-needed nonsteroidal anti-inflammatory drugs. He was instructed to follow-up closely with his primary care physician for further monitoring.

During the current visit, the patient reported 2 atraumatic falls the prior 2 months, attributed to escalating right leg weakness. The patient reported that ascending stairs had become difficult, and he was unable to cross his right leg over his left while in a seated position. The territory of numbness expanded to his front and inner thigh. Although previously he was able to hike 4 miles, he now was unable to walk more than half of a mile without developing shortness of breath. He reported frequent urination without hematuria and a recent weight gain of 8 pounds despite early satiety.

His medical history included hypertension, hypercholesterolemia, truncal obesity, noninsulin dependent DM, coronary artery disease, atrial flutter, transient ischemic attack, and benign positional paroxysmal vertigo. He was exposed to Agent Orange during his service in Vietnam. Family history was notable for breast cancer (mother), lung cancer (father), and an unspecified form of lymphoma (brother). He had smoked approximately 2 packs of cigarettes daily for 15 years but quit 38 years prior. He reported consuming on average 3 alcohol-containing drinks per week and no illicit drug use. He was adherent with all medications, including furosemide 40 mg daily, losartan 25 mg daily, metoprolol succinate 50 mg daily, atorvastatin 80 mg daily, metformin 500 mg twice daily, and rivaroxaban 20 mg daily with dinner.

His vital signs included a blood pressure of 123/58 mmHg, a pulse of 74 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 94% on ambient air. His temperature was recorded at 96.7°F, and his weight was 234 pounds with a body mass index (BMI) of 34. He was well groomed and in no acute distress. His cardiopulmonary examination was normal. Carotid, radial, and bilateral dorsalis pedis pulsations were 2+ bilaterally, and no jugular venous distension was observed at 30°. The abdomen was protuberant. Nonshifting dullness to percussion and firmness to palpation was observed throughout right upper and lower quadrants, with hyperactive bowel sounds primarily localized to the left upper and lower quadrants.

Neurologic examination revealed symmetric facies with normal phonation and diction. He was spontaneously moving all extremities, and his gait was normal. Sensation to light touch was severely diminished throughout the anterolateral and medial thigh, extending to the level of the knee, and otherwise reduced in a stocking-type pattern over the bilateral feet and toes. His right hip flexion, adduction, as well as internal and external rotation were focally diminished to 4- out of 5. Right knee extension was 4+ out of 5. Strength was otherwise 5 out of 5. The patient exhibited asymmetric Patellar reflexes—absent on the right and 2+ on the left. Achilles reflexes were absent bilaterally. Straight-leg raise test was negative bilaterally and did not clearly exacerbate his right leg numbness or paresthesias. There were no notable fasciculations. There was 2+ bilateral lower extremity pitting edema appreciated to the level of the midshin (right greater than left), without palpable cords or new skin lesions.

Upon referral to the neurology service, the patient underwent electromyography, which revealed complex repetitive discharges in the right tibialis anterior and pattern of reduced recruitment upon activation of the right vastus medialis, collectively suggestive of an L3-4 plexopathy. The patient was admitted for expedited workup.

A complete blood count and metabolic panel that were taken in the emergency department were normal, save for a serum bicarbonate of 30 mEq/L. His hemoglobin A_1c was 6.6%. Computed tomography (CT) of the abdomen and pelvis with IV contrast was obtained, and notable for a 30 cm fat-containing right-sided retroperitoneal mass with associated solid nodular components and calcification (Figure 2). No enhancement of the lesion was observed. There was significant associated mass effect, with superior displacement of the liver and right hemidiaphragm, as well as superomedial deflection of the right kidney, inferior vena cava, and other intraabdominal organs. Subsequent imaging with a CT of the chest, as well as magnetic resonance imaging of the brain, were without evidence of metastatic disease.

Outcome

The patient was treated with external beam radiotherapy (EBRT) delivered simultaneously to both the prostate and high-risk retroperitoneal margins of the DDLPS, as well as concurrent androgen deprivation therapy. Five months after completed radiotherapy, resection of the DDLPS was attempted. However, palliative tumor debulking was instead performed due to extensive locoregional invasion with involvement of the posterior peritoneum and ipsilateral quadratus, iliopsoas, and psoas muscles, as well as the adjacent lumbar nerve roots.

At present, the patient is undergoing surveillance imaging every 3 months to reevaluate his underlying disease burden, which has thus far been radiographically stable. Current management at the primary care level is focused on preserving quality of life, particularly maintaining mobility and functional independence.

Discussion

Although generally a benign entrapment neuropathy, MP bears well-established associations with multiple forms of must-not-miss pathology. Here, we present the case of a veteran in whom MP was the index presentation of a massive retroperitoneal liposarcoma, stressing the importance of a thorough history and physical examination in all patients presenting with MP. The case presented herein highlights many of the red-flag signs and symptoms that primary care physicians might encounter in patients with retroperitoneal pathology, including MP and MP-like syndromes (Figure 4).

In this case, the pretest probability of a spontaneous and uncomplicated MP was high given the patient’s sex, age, body habitus, and DM; however, there important atypia that emerged as the case evolved, including: (1) the progressive course; (2) proximal right lower extremity weakness; (3) asymmetric patellar reflexes; and (4) numerous clinical stigmata of intraabdominal mass effect. The patient exhibited abnormalities on abdominal examination that suggested the presence of an underlying intraabdominal mass, providing key diagnostic insight into this case. Given the slowly progressive nature of liposarcomas, we feel the abnormalities appreciated on abdominal examination were likely apparent during the initial presentation.¹⁸

There are numerous cognitive biases that may explain why an abdominal examination was not prioritized during the initial presentation. Namely, the patient’s numerous risk factors for spontaneous MP, as detailed above, may have contributed to framing bias that limited consideration of alternative diagnoses. In addition, the patient’s physical examination likely contributed to search satisfaction, whereby alternative diagnoses were not further entertained after discovery of findings consistent with spontaneous MP.¹⁹ Finally, it remains conceivable that an abdominal examination was not prioritized as it is often perceived as being distinct from, rather than an integral part of, the neurologic examination.²⁰ Given that numerous neurologic disorders may present with abdominal pathology, we feel a thorough abdominal examination should be considered part of the full neurologic examination, especially in cases presenting with focal neurologic findings involving the lower extremities.²¹

Collectively, this case alludes to the importance of close clinical follow-up, as well as adequate anticipatory patient guidance in cases of suspected MP. In most patients, the clinical course of spontaneous MP is benign and favorable, with up to 85% of patients experiencing resolution within 4 to 6 months of the initial presentation.²² Common conservative measures include weight loss, garment optimization, and nonsteroidal anti-inflammatory drugs as needed for analgesia. In refractory cases, procedural interventions such as with neurolysis or resection of the lateral femoral cutaneous nerve, may be required after the ruling out of alternative diagnoses.^23,24

Importantly, in even prolonged and resistant cases of MP, patient discomfort remains localized to the territory of the LFCN. Additional lower motor neuron signs, such as an expanding territory of sensory involvement, muscle weakness, or diminished reflexes, should prompt additional testing for alternative diagnoses. In addition, clinical findings concerning for intraabdominal mass effect, many of which were observed in this case, should lead to further evaluation and expeditious cross-sectional imaging. Although this patient’s early satiety, polyuria, bilateral lower extremity edema, weight gain, and lumbar plexopathy each may be explained by direct compression, invasion, or displacement, his report of progressive exertional dyspnea merits further discussion.

Exertional dyspnea is an uncommon complication of soft tissue sarcoma, reported almost exclusively in cases with cardiac, mediastinal, or other thoracic involvement.^25-28 In this case, there was no evidence of thoracic involvement, either through direct extension or metastasis. Instead, the patient’s exertional dyspnea may have been attributable to increased intraabdominal pressure leading to compromised diaphragm excursion and reduced pulmonary reserve. In addition, the radiographic findings also raise the possibility of a potential contribution from preload failure due to IVC compression. Overall, dyspnea is a concerning feature that may suggest advanced disease.

Despite the value of a thorough history and physical examination in patients with MP, major clinical guidelines from neurologic, neurosurgical, and orthopedic organizations do not formally address MP evaluation and management. Further, proposed clinical practice algorithms are inconsistent in their recommendations regarding the identification of red-flag features and ruling out of alternative diagnoses.^22,29,30 To supplement the abdominal examination, it would be reasonable to perform a pelvic compression test (PCT) in patients presenting with suspected MP. The PCT is a highly sensitive and specific provocative maneuver shown to enable reliable differentiation between MP and lumbar radiculopathy, and is performed by placing downward force on the anterior superior iliac spine of the affected extremity for 45 seconds with the patient in the lateral recumbent position.³¹ As this maneuver is intended to force relaxation of the inguinal ligament, thereby relieving pressure on the LFCN, improvement in the patient’s symptoms with the PCT is consistent with MP.

Conclusions

Spontaneous MP is a generally benign condition secondary to LFCN entrapment at the level of the inguinal ligament and is encountered frequently in the context of comorbid obesity and DM. However, MP bears known associations with high-risk pathologies that engender specific diagnostic and therapeutic considerations, including retroperitoneal mass lesions. The case presented herein highlights the utility of: (1) a focused history and review of systems to aid in the identification of red-flag symptoms and signs that might suggest a secondary etiology; and (2) a thorough abdominal examination in all patients who present with MP, especially in atypical presentations, cases with additional focal neurologic findings, or in patients who report progressive symptoms. Given the progressively aging population within the United States, coupled with an expanding prevalence of obesity and diabetes mellitus, recognition of the typical and atypical features of MP may be of progressive importance.

Meralgia paresthetica (MP) is a sensory mononeuropathy of the lateral femoral cutaneous nerve (LFCN), clinically characterized by numbness, pain, and paresthesias involving the anterolateral aspect of the thigh. Estimates of MP incidence are derived largely from observational studies and reported to be about 3.2 to 4.3 cases per 10,000 patient-years.^1,2 Although typically arising during midlife and especially in the context of comorbid obesity, diabetes mellitus (DM), and excessive alcohol consumption, MP may occur at any age, and bears a slight predilection for males.^2-4

MP may be divided etiologically into iatrogenic and spontaneous subtypes.⁵ Iatrogenic cases generally are attributable to nerve injury in the setting of direct or indirect trauma (such as with patient malpositioning) arising in the context of multiple forms of procedural or surgical intervention (Table). Spontaneous MP is primarily thought to occur as a result of LFCN compression at the level of the inguinal ligament, wherein internal or external pressures may promote LFCN entrapment and resultant functional disruption (Figure 1).^6,7

Case Presentation

A male Vietnam War veteran aged 69 years presented to a primary care clinic at West Roxbury Veterans Affairs Medical Center (WRVAMC) in Massachusetts with progressive right lower extremity numbness. Three months prior to this visit, he was evaluated in an urgent care clinic at WRVAMC for 6 months of numbness and increasingly painful nocturnal paresthesias involving the same extremity. A targeted physical examination at that visit revealed an obese male wearing tight suspenders, as well as focally diminished sensation to light touch involving the anterolateral aspect of the thigh, extending from just below the right hip to above the knee. Sensation in the medial thigh was spared. Strength and reflexes were normal in the bilateral lower extremities. An abdominal examination was not performed. He received a diagnosis of MP and counseled regarding weight loss, glycemic control, garment optimization, and conservative analgesia with as-needed nonsteroidal anti-inflammatory drugs. He was instructed to follow-up closely with his primary care physician for further monitoring.

During the current visit, the patient reported 2 atraumatic falls the prior 2 months, attributed to escalating right leg weakness. The patient reported that ascending stairs had become difficult, and he was unable to cross his right leg over his left while in a seated position. The territory of numbness expanded to his front and inner thigh. Although previously he was able to hike 4 miles, he now was unable to walk more than half of a mile without developing shortness of breath. He reported frequent urination without hematuria and a recent weight gain of 8 pounds despite early satiety.

His medical history included hypertension, hypercholesterolemia, truncal obesity, noninsulin dependent DM, coronary artery disease, atrial flutter, transient ischemic attack, and benign positional paroxysmal vertigo. He was exposed to Agent Orange during his service in Vietnam. Family history was notable for breast cancer (mother), lung cancer (father), and an unspecified form of lymphoma (brother). He had smoked approximately 2 packs of cigarettes daily for 15 years but quit 38 years prior. He reported consuming on average 3 alcohol-containing drinks per week and no illicit drug use. He was adherent with all medications, including furosemide 40 mg daily, losartan 25 mg daily, metoprolol succinate 50 mg daily, atorvastatin 80 mg daily, metformin 500 mg twice daily, and rivaroxaban 20 mg daily with dinner.

His vital signs included a blood pressure of 123/58 mmHg, a pulse of 74 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 94% on ambient air. His temperature was recorded at 96.7°F, and his weight was 234 pounds with a body mass index (BMI) of 34. He was well groomed and in no acute distress. His cardiopulmonary examination was normal. Carotid, radial, and bilateral dorsalis pedis pulsations were 2+ bilaterally, and no jugular venous distension was observed at 30°. The abdomen was protuberant. Nonshifting dullness to percussion and firmness to palpation was observed throughout right upper and lower quadrants, with hyperactive bowel sounds primarily localized to the left upper and lower quadrants.

Neurologic examination revealed symmetric facies with normal phonation and diction. He was spontaneously moving all extremities, and his gait was normal. Sensation to light touch was severely diminished throughout the anterolateral and medial thigh, extending to the level of the knee, and otherwise reduced in a stocking-type pattern over the bilateral feet and toes. His right hip flexion, adduction, as well as internal and external rotation were focally diminished to 4- out of 5. Right knee extension was 4+ out of 5. Strength was otherwise 5 out of 5. The patient exhibited asymmetric Patellar reflexes—absent on the right and 2+ on the left. Achilles reflexes were absent bilaterally. Straight-leg raise test was negative bilaterally and did not clearly exacerbate his right leg numbness or paresthesias. There were no notable fasciculations. There was 2+ bilateral lower extremity pitting edema appreciated to the level of the midshin (right greater than left), without palpable cords or new skin lesions.

Upon referral to the neurology service, the patient underwent electromyography, which revealed complex repetitive discharges in the right tibialis anterior and pattern of reduced recruitment upon activation of the right vastus medialis, collectively suggestive of an L3-4 plexopathy. The patient was admitted for expedited workup.

A complete blood count and metabolic panel that were taken in the emergency department were normal, save for a serum bicarbonate of 30 mEq/L. His hemoglobin A_1c was 6.6%. Computed tomography (CT) of the abdomen and pelvis with IV contrast was obtained, and notable for a 30 cm fat-containing right-sided retroperitoneal mass with associated solid nodular components and calcification (Figure 2). No enhancement of the lesion was observed. There was significant associated mass effect, with superior displacement of the liver and right hemidiaphragm, as well as superomedial deflection of the right kidney, inferior vena cava, and other intraabdominal organs. Subsequent imaging with a CT of the chest, as well as magnetic resonance imaging of the brain, were without evidence of metastatic disease.

Outcome

The patient was treated with external beam radiotherapy (EBRT) delivered simultaneously to both the prostate and high-risk retroperitoneal margins of the DDLPS, as well as concurrent androgen deprivation therapy. Five months after completed radiotherapy, resection of the DDLPS was attempted. However, palliative tumor debulking was instead performed due to extensive locoregional invasion with involvement of the posterior peritoneum and ipsilateral quadratus, iliopsoas, and psoas muscles, as well as the adjacent lumbar nerve roots.

At present, the patient is undergoing surveillance imaging every 3 months to reevaluate his underlying disease burden, which has thus far been radiographically stable. Current management at the primary care level is focused on preserving quality of life, particularly maintaining mobility and functional independence.

Discussion

Although generally a benign entrapment neuropathy, MP bears well-established associations with multiple forms of must-not-miss pathology. Here, we present the case of a veteran in whom MP was the index presentation of a massive retroperitoneal liposarcoma, stressing the importance of a thorough history and physical examination in all patients presenting with MP. The case presented herein highlights many of the red-flag signs and symptoms that primary care physicians might encounter in patients with retroperitoneal pathology, including MP and MP-like syndromes (Figure 4).

In this case, the pretest probability of a spontaneous and uncomplicated MP was high given the patient’s sex, age, body habitus, and DM; however, there important atypia that emerged as the case evolved, including: (1) the progressive course; (2) proximal right lower extremity weakness; (3) asymmetric patellar reflexes; and (4) numerous clinical stigmata of intraabdominal mass effect. The patient exhibited abnormalities on abdominal examination that suggested the presence of an underlying intraabdominal mass, providing key diagnostic insight into this case. Given the slowly progressive nature of liposarcomas, we feel the abnormalities appreciated on abdominal examination were likely apparent during the initial presentation.¹⁸

There are numerous cognitive biases that may explain why an abdominal examination was not prioritized during the initial presentation. Namely, the patient’s numerous risk factors for spontaneous MP, as detailed above, may have contributed to framing bias that limited consideration of alternative diagnoses. In addition, the patient’s physical examination likely contributed to search satisfaction, whereby alternative diagnoses were not further entertained after discovery of findings consistent with spontaneous MP.¹⁹ Finally, it remains conceivable that an abdominal examination was not prioritized as it is often perceived as being distinct from, rather than an integral part of, the neurologic examination.²⁰ Given that numerous neurologic disorders may present with abdominal pathology, we feel a thorough abdominal examination should be considered part of the full neurologic examination, especially in cases presenting with focal neurologic findings involving the lower extremities.²¹

Collectively, this case alludes to the importance of close clinical follow-up, as well as adequate anticipatory patient guidance in cases of suspected MP. In most patients, the clinical course of spontaneous MP is benign and favorable, with up to 85% of patients experiencing resolution within 4 to 6 months of the initial presentation.²² Common conservative measures include weight loss, garment optimization, and nonsteroidal anti-inflammatory drugs as needed for analgesia. In refractory cases, procedural interventions such as with neurolysis or resection of the lateral femoral cutaneous nerve, may be required after the ruling out of alternative diagnoses.^23,24

Importantly, in even prolonged and resistant cases of MP, patient discomfort remains localized to the territory of the LFCN. Additional lower motor neuron signs, such as an expanding territory of sensory involvement, muscle weakness, or diminished reflexes, should prompt additional testing for alternative diagnoses. In addition, clinical findings concerning for intraabdominal mass effect, many of which were observed in this case, should lead to further evaluation and expeditious cross-sectional imaging. Although this patient’s early satiety, polyuria, bilateral lower extremity edema, weight gain, and lumbar plexopathy each may be explained by direct compression, invasion, or displacement, his report of progressive exertional dyspnea merits further discussion.

Exertional dyspnea is an uncommon complication of soft tissue sarcoma, reported almost exclusively in cases with cardiac, mediastinal, or other thoracic involvement.^25-28 In this case, there was no evidence of thoracic involvement, either through direct extension or metastasis. Instead, the patient’s exertional dyspnea may have been attributable to increased intraabdominal pressure leading to compromised diaphragm excursion and reduced pulmonary reserve. In addition, the radiographic findings also raise the possibility of a potential contribution from preload failure due to IVC compression. Overall, dyspnea is a concerning feature that may suggest advanced disease.

Despite the value of a thorough history and physical examination in patients with MP, major clinical guidelines from neurologic, neurosurgical, and orthopedic organizations do not formally address MP evaluation and management. Further, proposed clinical practice algorithms are inconsistent in their recommendations regarding the identification of red-flag features and ruling out of alternative diagnoses.^22,29,30 To supplement the abdominal examination, it would be reasonable to perform a pelvic compression test (PCT) in patients presenting with suspected MP. The PCT is a highly sensitive and specific provocative maneuver shown to enable reliable differentiation between MP and lumbar radiculopathy, and is performed by placing downward force on the anterior superior iliac spine of the affected extremity for 45 seconds with the patient in the lateral recumbent position.³¹ As this maneuver is intended to force relaxation of the inguinal ligament, thereby relieving pressure on the LFCN, improvement in the patient’s symptoms with the PCT is consistent with MP.

Conclusions

Spontaneous MP is a generally benign condition secondary to LFCN entrapment at the level of the inguinal ligament and is encountered frequently in the context of comorbid obesity and DM. However, MP bears known associations with high-risk pathologies that engender specific diagnostic and therapeutic considerations, including retroperitoneal mass lesions. The case presented herein highlights the utility of: (1) a focused history and review of systems to aid in the identification of red-flag symptoms and signs that might suggest a secondary etiology; and (2) a thorough abdominal examination in all patients who present with MP, especially in atypical presentations, cases with additional focal neurologic findings, or in patients who report progressive symptoms. Given the progressively aging population within the United States, coupled with an expanding prevalence of obesity and diabetes mellitus, recognition of the typical and atypical features of MP may be of progressive importance.

Meralgia paresthetica (MP) is a sensory mononeuropathy of the lateral femoral cutaneous nerve (LFCN), clinically characterized by numbness, pain, and paresthesias involving the anterolateral aspect of the thigh. Estimates of MP incidence are derived largely from observational studies and reported to be about 3.2 to 4.3 cases per 10,000 patient-years.^1,2 Although typically arising during midlife and especially in the context of comorbid obesity, diabetes mellitus (DM), and excessive alcohol consumption, MP may occur at any age, and bears a slight predilection for males.^2-4

MP may be divided etiologically into iatrogenic and spontaneous subtypes.⁵ Iatrogenic cases generally are attributable to nerve injury in the setting of direct or indirect trauma (such as with patient malpositioning) arising in the context of multiple forms of procedural or surgical intervention (Table). Spontaneous MP is primarily thought to occur as a result of LFCN compression at the level of the inguinal ligament, wherein internal or external pressures may promote LFCN entrapment and resultant functional disruption (Figure 1).^6,7

Case Presentation

A male Vietnam War veteran aged 69 years presented to a primary care clinic at West Roxbury Veterans Affairs Medical Center (WRVAMC) in Massachusetts with progressive right lower extremity numbness. Three months prior to this visit, he was evaluated in an urgent care clinic at WRVAMC for 6 months of numbness and increasingly painful nocturnal paresthesias involving the same extremity. A targeted physical examination at that visit revealed an obese male wearing tight suspenders, as well as focally diminished sensation to light touch involving the anterolateral aspect of the thigh, extending from just below the right hip to above the knee. Sensation in the medial thigh was spared. Strength and reflexes were normal in the bilateral lower extremities. An abdominal examination was not performed. He received a diagnosis of MP and counseled regarding weight loss, glycemic control, garment optimization, and conservative analgesia with as-needed nonsteroidal anti-inflammatory drugs. He was instructed to follow-up closely with his primary care physician for further monitoring.

During the current visit, the patient reported 2 atraumatic falls the prior 2 months, attributed to escalating right leg weakness. The patient reported that ascending stairs had become difficult, and he was unable to cross his right leg over his left while in a seated position. The territory of numbness expanded to his front and inner thigh. Although previously he was able to hike 4 miles, he now was unable to walk more than half of a mile without developing shortness of breath. He reported frequent urination without hematuria and a recent weight gain of 8 pounds despite early satiety.

His medical history included hypertension, hypercholesterolemia, truncal obesity, noninsulin dependent DM, coronary artery disease, atrial flutter, transient ischemic attack, and benign positional paroxysmal vertigo. He was exposed to Agent Orange during his service in Vietnam. Family history was notable for breast cancer (mother), lung cancer (father), and an unspecified form of lymphoma (brother). He had smoked approximately 2 packs of cigarettes daily for 15 years but quit 38 years prior. He reported consuming on average 3 alcohol-containing drinks per week and no illicit drug use. He was adherent with all medications, including furosemide 40 mg daily, losartan 25 mg daily, metoprolol succinate 50 mg daily, atorvastatin 80 mg daily, metformin 500 mg twice daily, and rivaroxaban 20 mg daily with dinner.

His vital signs included a blood pressure of 123/58 mmHg, a pulse of 74 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 94% on ambient air. His temperature was recorded at 96.7°F, and his weight was 234 pounds with a body mass index (BMI) of 34. He was well groomed and in no acute distress. His cardiopulmonary examination was normal. Carotid, radial, and bilateral dorsalis pedis pulsations were 2+ bilaterally, and no jugular venous distension was observed at 30°. The abdomen was protuberant. Nonshifting dullness to percussion and firmness to palpation was observed throughout right upper and lower quadrants, with hyperactive bowel sounds primarily localized to the left upper and lower quadrants.

Neurologic examination revealed symmetric facies with normal phonation and diction. He was spontaneously moving all extremities, and his gait was normal. Sensation to light touch was severely diminished throughout the anterolateral and medial thigh, extending to the level of the knee, and otherwise reduced in a stocking-type pattern over the bilateral feet and toes. His right hip flexion, adduction, as well as internal and external rotation were focally diminished to 4- out of 5. Right knee extension was 4+ out of 5. Strength was otherwise 5 out of 5. The patient exhibited asymmetric Patellar reflexes—absent on the right and 2+ on the left. Achilles reflexes were absent bilaterally. Straight-leg raise test was negative bilaterally and did not clearly exacerbate his right leg numbness or paresthesias. There were no notable fasciculations. There was 2+ bilateral lower extremity pitting edema appreciated to the level of the midshin (right greater than left), without palpable cords or new skin lesions.

Upon referral to the neurology service, the patient underwent electromyography, which revealed complex repetitive discharges in the right tibialis anterior and pattern of reduced recruitment upon activation of the right vastus medialis, collectively suggestive of an L3-4 plexopathy. The patient was admitted for expedited workup.

A complete blood count and metabolic panel that were taken in the emergency department were normal, save for a serum bicarbonate of 30 mEq/L. His hemoglobin A_1c was 6.6%. Computed tomography (CT) of the abdomen and pelvis with IV contrast was obtained, and notable for a 30 cm fat-containing right-sided retroperitoneal mass with associated solid nodular components and calcification (Figure 2). No enhancement of the lesion was observed. There was significant associated mass effect, with superior displacement of the liver and right hemidiaphragm, as well as superomedial deflection of the right kidney, inferior vena cava, and other intraabdominal organs. Subsequent imaging with a CT of the chest, as well as magnetic resonance imaging of the brain, were without evidence of metastatic disease.

Outcome

The patient was treated with external beam radiotherapy (EBRT) delivered simultaneously to both the prostate and high-risk retroperitoneal margins of the DDLPS, as well as concurrent androgen deprivation therapy. Five months after completed radiotherapy, resection of the DDLPS was attempted. However, palliative tumor debulking was instead performed due to extensive locoregional invasion with involvement of the posterior peritoneum and ipsilateral quadratus, iliopsoas, and psoas muscles, as well as the adjacent lumbar nerve roots.

At present, the patient is undergoing surveillance imaging every 3 months to reevaluate his underlying disease burden, which has thus far been radiographically stable. Current management at the primary care level is focused on preserving quality of life, particularly maintaining mobility and functional independence.

Discussion

Although generally a benign entrapment neuropathy, MP bears well-established associations with multiple forms of must-not-miss pathology. Here, we present the case of a veteran in whom MP was the index presentation of a massive retroperitoneal liposarcoma, stressing the importance of a thorough history and physical examination in all patients presenting with MP. The case presented herein highlights many of the red-flag signs and symptoms that primary care physicians might encounter in patients with retroperitoneal pathology, including MP and MP-like syndromes (Figure 4).

In this case, the pretest probability of a spontaneous and uncomplicated MP was high given the patient’s sex, age, body habitus, and DM; however, there important atypia that emerged as the case evolved, including: (1) the progressive course; (2) proximal right lower extremity weakness; (3) asymmetric patellar reflexes; and (4) numerous clinical stigmata of intraabdominal mass effect. The patient exhibited abnormalities on abdominal examination that suggested the presence of an underlying intraabdominal mass, providing key diagnostic insight into this case. Given the slowly progressive nature of liposarcomas, we feel the abnormalities appreciated on abdominal examination were likely apparent during the initial presentation.¹⁸

There are numerous cognitive biases that may explain why an abdominal examination was not prioritized during the initial presentation. Namely, the patient’s numerous risk factors for spontaneous MP, as detailed above, may have contributed to framing bias that limited consideration of alternative diagnoses. In addition, the patient’s physical examination likely contributed to search satisfaction, whereby alternative diagnoses were not further entertained after discovery of findings consistent with spontaneous MP.¹⁹ Finally, it remains conceivable that an abdominal examination was not prioritized as it is often perceived as being distinct from, rather than an integral part of, the neurologic examination.²⁰ Given that numerous neurologic disorders may present with abdominal pathology, we feel a thorough abdominal examination should be considered part of the full neurologic examination, especially in cases presenting with focal neurologic findings involving the lower extremities.²¹

Collectively, this case alludes to the importance of close clinical follow-up, as well as adequate anticipatory patient guidance in cases of suspected MP. In most patients, the clinical course of spontaneous MP is benign and favorable, with up to 85% of patients experiencing resolution within 4 to 6 months of the initial presentation.²² Common conservative measures include weight loss, garment optimization, and nonsteroidal anti-inflammatory drugs as needed for analgesia. In refractory cases, procedural interventions such as with neurolysis or resection of the lateral femoral cutaneous nerve, may be required after the ruling out of alternative diagnoses.^23,24

Importantly, in even prolonged and resistant cases of MP, patient discomfort remains localized to the territory of the LFCN. Additional lower motor neuron signs, such as an expanding territory of sensory involvement, muscle weakness, or diminished reflexes, should prompt additional testing for alternative diagnoses. In addition, clinical findings concerning for intraabdominal mass effect, many of which were observed in this case, should lead to further evaluation and expeditious cross-sectional imaging. Although this patient’s early satiety, polyuria, bilateral lower extremity edema, weight gain, and lumbar plexopathy each may be explained by direct compression, invasion, or displacement, his report of progressive exertional dyspnea merits further discussion.

Exertional dyspnea is an uncommon complication of soft tissue sarcoma, reported almost exclusively in cases with cardiac, mediastinal, or other thoracic involvement.^25-28 In this case, there was no evidence of thoracic involvement, either through direct extension or metastasis. Instead, the patient’s exertional dyspnea may have been attributable to increased intraabdominal pressure leading to compromised diaphragm excursion and reduced pulmonary reserve. In addition, the radiographic findings also raise the possibility of a potential contribution from preload failure due to IVC compression. Overall, dyspnea is a concerning feature that may suggest advanced disease.

Despite the value of a thorough history and physical examination in patients with MP, major clinical guidelines from neurologic, neurosurgical, and orthopedic organizations do not formally address MP evaluation and management. Further, proposed clinical practice algorithms are inconsistent in their recommendations regarding the identification of red-flag features and ruling out of alternative diagnoses.^22,29,30 To supplement the abdominal examination, it would be reasonable to perform a pelvic compression test (PCT) in patients presenting with suspected MP. The PCT is a highly sensitive and specific provocative maneuver shown to enable reliable differentiation between MP and lumbar radiculopathy, and is performed by placing downward force on the anterior superior iliac spine of the affected extremity for 45 seconds with the patient in the lateral recumbent position.³¹ As this maneuver is intended to force relaxation of the inguinal ligament, thereby relieving pressure on the LFCN, improvement in the patient’s symptoms with the PCT is consistent with MP.

Conclusions

Spontaneous MP is a generally benign condition secondary to LFCN entrapment at the level of the inguinal ligament and is encountered frequently in the context of comorbid obesity and DM. However, MP bears known associations with high-risk pathologies that engender specific diagnostic and therapeutic considerations, including retroperitoneal mass lesions. The case presented herein highlights the utility of: (1) a focused history and review of systems to aid in the identification of red-flag symptoms and signs that might suggest a secondary etiology; and (2) a thorough abdominal examination in all patients who present with MP, especially in atypical presentations, cases with additional focal neurologic findings, or in patients who report progressive symptoms. Given the progressively aging population within the United States, coupled with an expanding prevalence of obesity and diabetes mellitus, recognition of the typical and atypical features of MP may be of progressive importance.

An 88-year-old male veteran with a medical history of chronic obstructive pulmonary disease (COPD) on home oxygen, chronic alcohol use, squamous cell carcinoma of the lung status after left upper lobectomy, and a 5.7 cm thoracic aortic aneurysm was admitted to the inpatient medical service for progressive dyspnea and productive cough. The patient was in his usual state of health until 2 days before presentation. A chest computed tomography scan showed a right lower lobe infiltrate, concerning for pneumonia, and stable thoracic aortic aneurysm (Figure). On admission, the patient was started on IV ceftriaxone 2 g daily for pneumonia and nebulizer therapy of combined albuterol 15 mg and ipratropium 1,500 mg every 6 hours for symptomatic treatment of his dyspnea.

The patient responded well to therapy, and his cough and dyspnea improved. However, 72 hours after admission, he developed an asymptomatic acute kidney injury (AKI) and anion-gap metabolic acidosis. His serum creatinine increased from baseline 0.6 mg/dL to 1.2 mg/dL. He also had an anion gap of 21 mmol/L and a decrease in bicarbonate from 23 mmol/L to 17 mmol/L. His condition was further complicated by new-onset hypertension (153/111 mm Hg). His calculated fractional excretion of sodium (FENa) was 0.5%, and his lactate level returned elevated at 3.6 mmol/L. On further investigation, he reported alcohol use the night prior; however, his β-hydroxybutyrate was negative, and serum alcohol level was undetectable. Meanwhile, the patient continued to receive antibiotics and scheduled nebulizer treatments. Although his AKI resolved with initial fluid resuscitation, his repeat lactate levels continued to trend upward to a peak of 4.0 mmol/L.

• What is your diagnosis?
• How would you treat this patient?

Although IV fluids resolved his AKI, prerenal in etiology given the calculated FENa at 0.5%, his lactate levels continued to uptrend to a peak of 4.0 mmol/L complicated by elevated blood pressure (BP) > 150/100 mm Hg. Given his thoracic aneurysm, his BP was treated with metoprolol tartrate and amlodipine 10 mg daily. The patient remained asymptomatic with no evidence of ischemia or sepsis.

We suspected the nebulizer treatments to be the etiology of the patient’s hyperlactatemia and subsequent anion-gap metabolic acidosis. His scheduled albuterol and ipratropium nebulizer treatments were discontinued, and the patient experienced rapid resolution of his anion gap and hyperlactatemia to 1.2 mmol/L over 24 hours. On discontinuation of the nebulization therapy, mild wheezing was noted on physical examination. The patient reported no symptoms and was at his baseline. The patient finished his antibiotic course for his community-acquired pneumonia and was discharged in stable condition with instructions to continue his previously established home COPD medication regimen of umeclidinium/vilanterol 62.5/25 mcg daily and albuterol metered-dose inhaler as needed.

Discussion

Short-acting β-agonists, such as albuterol, are widely used in COPD and are a guideline-recommended treatment in maintenance and exacerbation of asthma and COPD.¹ Short-acting β-agonist adverse effects (AEs) include nausea, vomiting, tremors, headache, and tachycardia; abnormal laboratory results include hypocalcemia, hypokalemia, hypophosphatemia, hypomagnesemia, and hyperglycemia.^2,3 Albuterol-induced hyperlactatemia and lactic acidosis also are known but often overlooked and underreported AEs.

In a randomized control trial, researchers identified a positive correlation between nebulized albuterol use and hyperlactatemia in asthmatics with asthma exacerbation.⁴ One systematic review identified ≤ 20% of patients on either IV or nebulized high-dose treatments with selective β2-agonists may experience hyperlactatemia.⁵ However, aerosolized administration of albuterol as opposed to IV administration is less likely to result in AEs and abnormal laboratory results given decreased systemic absorption.³

Hyperlactatemia and lactic acidosis are associated with increased morbidity and mortality.⁶ Lactic acidosis is classified as either type A or type B. Type A lactic acidosis is characterized by hypoperfusion as subsequent ischemic injuries lead to anaerobic metabolism and elevated lactate. Diseases such as septic, cardiogenic, and hypovolemic shock are often associated with type A lactic acidosis. Type B lactic acidosis, however, encapsulates all nonhypoperfusion-related elevations in lactate, including malignancy, ethanol intoxication, and medication-induced lactic acidosis.^7,8

In this case, the diagnosis was elusive as the patient had multiple comorbidities. His history included COPD, which is associated with elevated lactate levels.⁵ However, his initial laboratory workup did not show an anion gap, confirming a lack of an underlying acidotic process on admission. Because the patient was admitted for pneumonia, a known infectious source, complicated by an acute elevation in lactate, sepsis must be and was effectively ruled out. The patient also reported alcohol use during his admission, which confounded his presentation but was unlikely to impact the etiology of his lactic acidosis, given the unremarkable β-hydroxybutyrate and serum alcohol levels.

Conclusions

We encourage heightened clinical suspicion of albuterol-induced lactic acidosis in acutely ill patients with COPD on albuterol therapy on rule out of life-threatening etiologies and suggest transitioning patients from scheduled to as-needed albuterol treatments on symptomatic improvement in the clinical course. With such, we hope for improved patient outcomes and the prudent use of health care resources.

An 88-year-old male veteran with a medical history of chronic obstructive pulmonary disease (COPD) on home oxygen, chronic alcohol use, squamous cell carcinoma of the lung status after left upper lobectomy, and a 5.7 cm thoracic aortic aneurysm was admitted to the inpatient medical service for progressive dyspnea and productive cough. The patient was in his usual state of health until 2 days before presentation. A chest computed tomography scan showed a right lower lobe infiltrate, concerning for pneumonia, and stable thoracic aortic aneurysm (Figure). On admission, the patient was started on IV ceftriaxone 2 g daily for pneumonia and nebulizer therapy of combined albuterol 15 mg and ipratropium 1,500 mg every 6 hours for symptomatic treatment of his dyspnea.

The patient responded well to therapy, and his cough and dyspnea improved. However, 72 hours after admission, he developed an asymptomatic acute kidney injury (AKI) and anion-gap metabolic acidosis. His serum creatinine increased from baseline 0.6 mg/dL to 1.2 mg/dL. He also had an anion gap of 21 mmol/L and a decrease in bicarbonate from 23 mmol/L to 17 mmol/L. His condition was further complicated by new-onset hypertension (153/111 mm Hg). His calculated fractional excretion of sodium (FENa) was 0.5%, and his lactate level returned elevated at 3.6 mmol/L. On further investigation, he reported alcohol use the night prior; however, his β-hydroxybutyrate was negative, and serum alcohol level was undetectable. Meanwhile, the patient continued to receive antibiotics and scheduled nebulizer treatments. Although his AKI resolved with initial fluid resuscitation, his repeat lactate levels continued to trend upward to a peak of 4.0 mmol/L.

• What is your diagnosis?
• How would you treat this patient?

Although IV fluids resolved his AKI, prerenal in etiology given the calculated FENa at 0.5%, his lactate levels continued to uptrend to a peak of 4.0 mmol/L complicated by elevated blood pressure (BP) > 150/100 mm Hg. Given his thoracic aneurysm, his BP was treated with metoprolol tartrate and amlodipine 10 mg daily. The patient remained asymptomatic with no evidence of ischemia or sepsis.

We suspected the nebulizer treatments to be the etiology of the patient’s hyperlactatemia and subsequent anion-gap metabolic acidosis. His scheduled albuterol and ipratropium nebulizer treatments were discontinued, and the patient experienced rapid resolution of his anion gap and hyperlactatemia to 1.2 mmol/L over 24 hours. On discontinuation of the nebulization therapy, mild wheezing was noted on physical examination. The patient reported no symptoms and was at his baseline. The patient finished his antibiotic course for his community-acquired pneumonia and was discharged in stable condition with instructions to continue his previously established home COPD medication regimen of umeclidinium/vilanterol 62.5/25 mcg daily and albuterol metered-dose inhaler as needed.

Discussion

Short-acting β-agonists, such as albuterol, are widely used in COPD and are a guideline-recommended treatment in maintenance and exacerbation of asthma and COPD.¹ Short-acting β-agonist adverse effects (AEs) include nausea, vomiting, tremors, headache, and tachycardia; abnormal laboratory results include hypocalcemia, hypokalemia, hypophosphatemia, hypomagnesemia, and hyperglycemia.^2,3 Albuterol-induced hyperlactatemia and lactic acidosis also are known but often overlooked and underreported AEs.

In a randomized control trial, researchers identified a positive correlation between nebulized albuterol use and hyperlactatemia in asthmatics with asthma exacerbation.⁴ One systematic review identified ≤ 20% of patients on either IV or nebulized high-dose treatments with selective β2-agonists may experience hyperlactatemia.⁵ However, aerosolized administration of albuterol as opposed to IV administration is less likely to result in AEs and abnormal laboratory results given decreased systemic absorption.³

Hyperlactatemia and lactic acidosis are associated with increased morbidity and mortality.⁶ Lactic acidosis is classified as either type A or type B. Type A lactic acidosis is characterized by hypoperfusion as subsequent ischemic injuries lead to anaerobic metabolism and elevated lactate. Diseases such as septic, cardiogenic, and hypovolemic shock are often associated with type A lactic acidosis. Type B lactic acidosis, however, encapsulates all nonhypoperfusion-related elevations in lactate, including malignancy, ethanol intoxication, and medication-induced lactic acidosis.^7,8

In this case, the diagnosis was elusive as the patient had multiple comorbidities. His history included COPD, which is associated with elevated lactate levels.⁵ However, his initial laboratory workup did not show an anion gap, confirming a lack of an underlying acidotic process on admission. Because the patient was admitted for pneumonia, a known infectious source, complicated by an acute elevation in lactate, sepsis must be and was effectively ruled out. The patient also reported alcohol use during his admission, which confounded his presentation but was unlikely to impact the etiology of his lactic acidosis, given the unremarkable β-hydroxybutyrate and serum alcohol levels.

Conclusions

We encourage heightened clinical suspicion of albuterol-induced lactic acidosis in acutely ill patients with COPD on albuterol therapy on rule out of life-threatening etiologies and suggest transitioning patients from scheduled to as-needed albuterol treatments on symptomatic improvement in the clinical course. With such, we hope for improved patient outcomes and the prudent use of health care resources.

An 88-year-old male veteran with a medical history of chronic obstructive pulmonary disease (COPD) on home oxygen, chronic alcohol use, squamous cell carcinoma of the lung status after left upper lobectomy, and a 5.7 cm thoracic aortic aneurysm was admitted to the inpatient medical service for progressive dyspnea and productive cough. The patient was in his usual state of health until 2 days before presentation. A chest computed tomography scan showed a right lower lobe infiltrate, concerning for pneumonia, and stable thoracic aortic aneurysm (Figure). On admission, the patient was started on IV ceftriaxone 2 g daily for pneumonia and nebulizer therapy of combined albuterol 15 mg and ipratropium 1,500 mg every 6 hours for symptomatic treatment of his dyspnea.

The patient responded well to therapy, and his cough and dyspnea improved. However, 72 hours after admission, he developed an asymptomatic acute kidney injury (AKI) and anion-gap metabolic acidosis. His serum creatinine increased from baseline 0.6 mg/dL to 1.2 mg/dL. He also had an anion gap of 21 mmol/L and a decrease in bicarbonate from 23 mmol/L to 17 mmol/L. His condition was further complicated by new-onset hypertension (153/111 mm Hg). His calculated fractional excretion of sodium (FENa) was 0.5%, and his lactate level returned elevated at 3.6 mmol/L. On further investigation, he reported alcohol use the night prior; however, his β-hydroxybutyrate was negative, and serum alcohol level was undetectable. Meanwhile, the patient continued to receive antibiotics and scheduled nebulizer treatments. Although his AKI resolved with initial fluid resuscitation, his repeat lactate levels continued to trend upward to a peak of 4.0 mmol/L.

• What is your diagnosis?
• How would you treat this patient?

Although IV fluids resolved his AKI, prerenal in etiology given the calculated FENa at 0.5%, his lactate levels continued to uptrend to a peak of 4.0 mmol/L complicated by elevated blood pressure (BP) > 150/100 mm Hg. Given his thoracic aneurysm, his BP was treated with metoprolol tartrate and amlodipine 10 mg daily. The patient remained asymptomatic with no evidence of ischemia or sepsis.

We suspected the nebulizer treatments to be the etiology of the patient’s hyperlactatemia and subsequent anion-gap metabolic acidosis. His scheduled albuterol and ipratropium nebulizer treatments were discontinued, and the patient experienced rapid resolution of his anion gap and hyperlactatemia to 1.2 mmol/L over 24 hours. On discontinuation of the nebulization therapy, mild wheezing was noted on physical examination. The patient reported no symptoms and was at his baseline. The patient finished his antibiotic course for his community-acquired pneumonia and was discharged in stable condition with instructions to continue his previously established home COPD medication regimen of umeclidinium/vilanterol 62.5/25 mcg daily and albuterol metered-dose inhaler as needed.

Discussion

Short-acting β-agonists, such as albuterol, are widely used in COPD and are a guideline-recommended treatment in maintenance and exacerbation of asthma and COPD.¹ Short-acting β-agonist adverse effects (AEs) include nausea, vomiting, tremors, headache, and tachycardia; abnormal laboratory results include hypocalcemia, hypokalemia, hypophosphatemia, hypomagnesemia, and hyperglycemia.^2,3 Albuterol-induced hyperlactatemia and lactic acidosis also are known but often overlooked and underreported AEs.

In a randomized control trial, researchers identified a positive correlation between nebulized albuterol use and hyperlactatemia in asthmatics with asthma exacerbation.⁴ One systematic review identified ≤ 20% of patients on either IV or nebulized high-dose treatments with selective β2-agonists may experience hyperlactatemia.⁵ However, aerosolized administration of albuterol as opposed to IV administration is less likely to result in AEs and abnormal laboratory results given decreased systemic absorption.³

Hyperlactatemia and lactic acidosis are associated with increased morbidity and mortality.⁶ Lactic acidosis is classified as either type A or type B. Type A lactic acidosis is characterized by hypoperfusion as subsequent ischemic injuries lead to anaerobic metabolism and elevated lactate. Diseases such as septic, cardiogenic, and hypovolemic shock are often associated with type A lactic acidosis. Type B lactic acidosis, however, encapsulates all nonhypoperfusion-related elevations in lactate, including malignancy, ethanol intoxication, and medication-induced lactic acidosis.^7,8

In this case, the diagnosis was elusive as the patient had multiple comorbidities. His history included COPD, which is associated with elevated lactate levels.⁵ However, his initial laboratory workup did not show an anion gap, confirming a lack of an underlying acidotic process on admission. Because the patient was admitted for pneumonia, a known infectious source, complicated by an acute elevation in lactate, sepsis must be and was effectively ruled out. The patient also reported alcohol use during his admission, which confounded his presentation but was unlikely to impact the etiology of his lactic acidosis, given the unremarkable β-hydroxybutyrate and serum alcohol levels.

Conclusions

We encourage heightened clinical suspicion of albuterol-induced lactic acidosis in acutely ill patients with COPD on albuterol therapy on rule out of life-threatening etiologies and suggest transitioning patients from scheduled to as-needed albuterol treatments on symptomatic improvement in the clinical course. With such, we hope for improved patient outcomes and the prudent use of health care resources.

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.

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.

Two different agents showed potential for safely treating patients with hypothalamic obesity in two pilot studies with small numbers of patients.

One study prospectively randomized 21 adults with acquired hypothalamic obesity to treatment with placebo or Tesomet, a compound that combines the novel monoamine reuptake inhibitor tesofensine with metoprolol, a beta-blocker added to protect against adverse effects from tesofensine on heart rate and cardiac contractility. After 24 weeks of treatment, people on tesofensine/metoprolol had significant weight loss, compared with controls, while showing good tolerance with no significant effects on heart rate, blood pressure, or heart rhythm, Ulla Feldt-Rasmussen, MD, DMSc, reported at the annual meeting of the Endocrine Society.

The second report reviewed 18 children and adolescents with either acquired or genetic hypothalamic obesity who received open-label treatment with dextroamphetamine for an average of 20 months, and overall patients safely lost an average of 0.43 in their body mass index (BMI) standard deviation score, reported Jiska van Schaik, MD, in a separate talk at the meeting.



‘A supplement for lost satiety’

Patients with hypothalamic obesity face a dual problem from hypothalamic dysfunction that’s addressed by tesofensine, the weight-loss agent in Tesomet that increases hypothalamic levels of dopamine, serotonin, and noradrenaline by blocking reuptake, and thereby dulls appetite and food craving while also increasing fat metabolism, explained Dr. Feldt-Rasmussen, a professor of medical endocrinology at the University of Denmark and Rigshospitalet in Copenhagen. No treatment currently has regulatory approval for treating any form of hypothalamic obesity.

Tesofensine works as “a supplement for lost satiety, and satiety is what is lost” in patients with hypothalamic obesity as well in patients as Prader-Willi syndrome, the two disorders for which tesofensine/metoprolol is currently undergoing testing. “That’s the rationale, and it seems to work,” she declared during her talk. The formulation contains 0.5 mg tesofensine and 50 mg metoprolol administered orally once daily.

The study, run at Rigshospitalet, randomized 21 patients aged 18-75 years and with a BMI of at least 27 kg/m²who all had acquired hypothalamic obesity secondary to hypothalamic damage following cancer treatment. Patients averaged about 45 years of age, three-quarters were women, and their average BMI was about 37^, with 90% having a BMI of at least 30.

The study’s design calls for 48-week follow-up; Dr. Feldt-Rasmussen presented the interim results after 24 weeks, with 18 of the 21 enrolled patients remaining in the study through 24 weeks. Three patients dropped out because of adverse events: one in the placebo arm, and two who received tesofensine/metoprolol.

Weight dropped by an average of 6.6 kg from baseline among the 11 patients who completed 24 weeks on tesofensine/metoprolol treatment, compared with no average change from baseline among the seven patients who completed the study on placebo, a significant difference. The researchers measured a validated, composite satiety score every 4 weeks, and found significantly more improvement among patients on tesofensine/metoprolol than in those on placebo during the study’s first half, but subsequently average scores among the actively treated patients fell to the same level of modest improvement as in the placebo patients.

Despite this, average weight loss in the patients on tesofensine/metoprolol steadily increased throughout the full 24 weeks.

Safety measures of diastolic blood pressure, heart rate, and corrected QT interval showed no significant between-group difference. Systolic pressure showed a transient average rise of 4 mm Hg above baseline in the tesofensine/metoprolol group, compared with a small dip in the control patients, but by 24 weeks average systolic blood pressure had reverted closer to baseline levels in both subgroups and showed no significant between-group difference. Two patients on tesofensine/metoprolol developed serious adverse events. In one patient these were not treatment related. The other patient developed anxiety after 8 weeks that was possibly treatment related but remained on treatment. Other adverse effects on tesofensine/metoprolol included dizziness, sleep disorder, and dry mouth, but all of these were mild and patients were willing to tolerate them to achieve their weight loss, Dr. Feldt-Rasmussen said.



Repurposing an ADHD treatment

Dextroamphetamine increases satiety and boosts resting energy expenditure, and is a common treatment for attention deficit hyperactivity disorder. Dr. van Schaik and coauthors reviewed 13 children and adolescents with acquired hypothalamic obesity and 5 with genetic hypothalamic obesity who received the treatment at either of two Dutch hospitals during 2014-2020. All 18 patients went on dextroamphetamine after other interventions had failed to produce improvement, said Dr. van Schaik, a researcher at University Medical Center and Wilhelmina Children’s Hospital in Utrecht, the Netherlands. The patients averaged about 13 years of age.

In addition to an overall effect on weight across all 18 subjects, the researchers found they could subdivide the full cohort into 10 responders (56%), 4 (22%) with weight stabilization on treatment, and 4 nonresponders (22%) who continued to gain weight despite treatment. The 10 responding patients had an average drop in their BMI standard deviation score of 0.91. All 10 responders had acquired hypothalamic obesity, and they averaged a 12.5 percentage point rise in their resting energy expenditure level, compared with baseline, while on treatment. The four whose weight stabilized on treatment included three patients with genetic hypothalamic obesity. The four nonresponders split into two with acquired hypothalamic obesity and two with the genetic form.

Thirteen patients (72%) had improvements in hyperphagia, energy, and behavior, and no patient had a serious adverse effect. One patient stopped treatment after 1 month because of elevated blood pressure.

“Dextroamphetamine may be promising, especially for acquired hypothalamic obesity,” Dr. van Schaik concluded, adding that prospective, controlled assessments are needed, and that a healthy lifestyle is the foundation of hypothalamic obesity treatment.

The Tesomet study was sponsored by Saniona, the company developing Tesomet. Dr Feldt-Rasmussen is an advisor to Saniona, and some of the coauthors on the study are Saniona employees. Dr. van Schaik had no disclosures.

[email protected]

Two different agents showed potential for safely treating patients with hypothalamic obesity in two pilot studies with small numbers of patients.

One study prospectively randomized 21 adults with acquired hypothalamic obesity to treatment with placebo or Tesomet, a compound that combines the novel monoamine reuptake inhibitor tesofensine with metoprolol, a beta-blocker added to protect against adverse effects from tesofensine on heart rate and cardiac contractility. After 24 weeks of treatment, people on tesofensine/metoprolol had significant weight loss, compared with controls, while showing good tolerance with no significant effects on heart rate, blood pressure, or heart rhythm, Ulla Feldt-Rasmussen, MD, DMSc, reported at the annual meeting of the Endocrine Society.

The second report reviewed 18 children and adolescents with either acquired or genetic hypothalamic obesity who received open-label treatment with dextroamphetamine for an average of 20 months, and overall patients safely lost an average of 0.43 in their body mass index (BMI) standard deviation score, reported Jiska van Schaik, MD, in a separate talk at the meeting.



‘A supplement for lost satiety’

Patients with hypothalamic obesity face a dual problem from hypothalamic dysfunction that’s addressed by tesofensine, the weight-loss agent in Tesomet that increases hypothalamic levels of dopamine, serotonin, and noradrenaline by blocking reuptake, and thereby dulls appetite and food craving while also increasing fat metabolism, explained Dr. Feldt-Rasmussen, a professor of medical endocrinology at the University of Denmark and Rigshospitalet in Copenhagen. No treatment currently has regulatory approval for treating any form of hypothalamic obesity.

Tesofensine works as “a supplement for lost satiety, and satiety is what is lost” in patients with hypothalamic obesity as well in patients as Prader-Willi syndrome, the two disorders for which tesofensine/metoprolol is currently undergoing testing. “That’s the rationale, and it seems to work,” she declared during her talk. The formulation contains 0.5 mg tesofensine and 50 mg metoprolol administered orally once daily.

The study, run at Rigshospitalet, randomized 21 patients aged 18-75 years and with a BMI of at least 27 kg/m²who all had acquired hypothalamic obesity secondary to hypothalamic damage following cancer treatment. Patients averaged about 45 years of age, three-quarters were women, and their average BMI was about 37^, with 90% having a BMI of at least 30.

The study’s design calls for 48-week follow-up; Dr. Feldt-Rasmussen presented the interim results after 24 weeks, with 18 of the 21 enrolled patients remaining in the study through 24 weeks. Three patients dropped out because of adverse events: one in the placebo arm, and two who received tesofensine/metoprolol.

Weight dropped by an average of 6.6 kg from baseline among the 11 patients who completed 24 weeks on tesofensine/metoprolol treatment, compared with no average change from baseline among the seven patients who completed the study on placebo, a significant difference. The researchers measured a validated, composite satiety score every 4 weeks, and found significantly more improvement among patients on tesofensine/metoprolol than in those on placebo during the study’s first half, but subsequently average scores among the actively treated patients fell to the same level of modest improvement as in the placebo patients.

Despite this, average weight loss in the patients on tesofensine/metoprolol steadily increased throughout the full 24 weeks.

Safety measures of diastolic blood pressure, heart rate, and corrected QT interval showed no significant between-group difference. Systolic pressure showed a transient average rise of 4 mm Hg above baseline in the tesofensine/metoprolol group, compared with a small dip in the control patients, but by 24 weeks average systolic blood pressure had reverted closer to baseline levels in both subgroups and showed no significant between-group difference. Two patients on tesofensine/metoprolol developed serious adverse events. In one patient these were not treatment related. The other patient developed anxiety after 8 weeks that was possibly treatment related but remained on treatment. Other adverse effects on tesofensine/metoprolol included dizziness, sleep disorder, and dry mouth, but all of these were mild and patients were willing to tolerate them to achieve their weight loss, Dr. Feldt-Rasmussen said.



Repurposing an ADHD treatment

Dextroamphetamine increases satiety and boosts resting energy expenditure, and is a common treatment for attention deficit hyperactivity disorder. Dr. van Schaik and coauthors reviewed 13 children and adolescents with acquired hypothalamic obesity and 5 with genetic hypothalamic obesity who received the treatment at either of two Dutch hospitals during 2014-2020. All 18 patients went on dextroamphetamine after other interventions had failed to produce improvement, said Dr. van Schaik, a researcher at University Medical Center and Wilhelmina Children’s Hospital in Utrecht, the Netherlands. The patients averaged about 13 years of age.

In addition to an overall effect on weight across all 18 subjects, the researchers found they could subdivide the full cohort into 10 responders (56%), 4 (22%) with weight stabilization on treatment, and 4 nonresponders (22%) who continued to gain weight despite treatment. The 10 responding patients had an average drop in their BMI standard deviation score of 0.91. All 10 responders had acquired hypothalamic obesity, and they averaged a 12.5 percentage point rise in their resting energy expenditure level, compared with baseline, while on treatment. The four whose weight stabilized on treatment included three patients with genetic hypothalamic obesity. The four nonresponders split into two with acquired hypothalamic obesity and two with the genetic form.

Thirteen patients (72%) had improvements in hyperphagia, energy, and behavior, and no patient had a serious adverse effect. One patient stopped treatment after 1 month because of elevated blood pressure.

“Dextroamphetamine may be promising, especially for acquired hypothalamic obesity,” Dr. van Schaik concluded, adding that prospective, controlled assessments are needed, and that a healthy lifestyle is the foundation of hypothalamic obesity treatment.

The Tesomet study was sponsored by Saniona, the company developing Tesomet. Dr Feldt-Rasmussen is an advisor to Saniona, and some of the coauthors on the study are Saniona employees. Dr. van Schaik had no disclosures.

[email protected]

Two different agents showed potential for safely treating patients with hypothalamic obesity in two pilot studies with small numbers of patients.

One study prospectively randomized 21 adults with acquired hypothalamic obesity to treatment with placebo or Tesomet, a compound that combines the novel monoamine reuptake inhibitor tesofensine with metoprolol, a beta-blocker added to protect against adverse effects from tesofensine on heart rate and cardiac contractility. After 24 weeks of treatment, people on tesofensine/metoprolol had significant weight loss, compared with controls, while showing good tolerance with no significant effects on heart rate, blood pressure, or heart rhythm, Ulla Feldt-Rasmussen, MD, DMSc, reported at the annual meeting of the Endocrine Society.

The second report reviewed 18 children and adolescents with either acquired or genetic hypothalamic obesity who received open-label treatment with dextroamphetamine for an average of 20 months, and overall patients safely lost an average of 0.43 in their body mass index (BMI) standard deviation score, reported Jiska van Schaik, MD, in a separate talk at the meeting.



‘A supplement for lost satiety’

Patients with hypothalamic obesity face a dual problem from hypothalamic dysfunction that’s addressed by tesofensine, the weight-loss agent in Tesomet that increases hypothalamic levels of dopamine, serotonin, and noradrenaline by blocking reuptake, and thereby dulls appetite and food craving while also increasing fat metabolism, explained Dr. Feldt-Rasmussen, a professor of medical endocrinology at the University of Denmark and Rigshospitalet in Copenhagen. No treatment currently has regulatory approval for treating any form of hypothalamic obesity.

Tesofensine works as “a supplement for lost satiety, and satiety is what is lost” in patients with hypothalamic obesity as well in patients as Prader-Willi syndrome, the two disorders for which tesofensine/metoprolol is currently undergoing testing. “That’s the rationale, and it seems to work,” she declared during her talk. The formulation contains 0.5 mg tesofensine and 50 mg metoprolol administered orally once daily.

The study, run at Rigshospitalet, randomized 21 patients aged 18-75 years and with a BMI of at least 27 kg/m²who all had acquired hypothalamic obesity secondary to hypothalamic damage following cancer treatment. Patients averaged about 45 years of age, three-quarters were women, and their average BMI was about 37^, with 90% having a BMI of at least 30.

The study’s design calls for 48-week follow-up; Dr. Feldt-Rasmussen presented the interim results after 24 weeks, with 18 of the 21 enrolled patients remaining in the study through 24 weeks. Three patients dropped out because of adverse events: one in the placebo arm, and two who received tesofensine/metoprolol.

Weight dropped by an average of 6.6 kg from baseline among the 11 patients who completed 24 weeks on tesofensine/metoprolol treatment, compared with no average change from baseline among the seven patients who completed the study on placebo, a significant difference. The researchers measured a validated, composite satiety score every 4 weeks, and found significantly more improvement among patients on tesofensine/metoprolol than in those on placebo during the study’s first half, but subsequently average scores among the actively treated patients fell to the same level of modest improvement as in the placebo patients.

Despite this, average weight loss in the patients on tesofensine/metoprolol steadily increased throughout the full 24 weeks.

Safety measures of diastolic blood pressure, heart rate, and corrected QT interval showed no significant between-group difference. Systolic pressure showed a transient average rise of 4 mm Hg above baseline in the tesofensine/metoprolol group, compared with a small dip in the control patients, but by 24 weeks average systolic blood pressure had reverted closer to baseline levels in both subgroups and showed no significant between-group difference. Two patients on tesofensine/metoprolol developed serious adverse events. In one patient these were not treatment related. The other patient developed anxiety after 8 weeks that was possibly treatment related but remained on treatment. Other adverse effects on tesofensine/metoprolol included dizziness, sleep disorder, and dry mouth, but all of these were mild and patients were willing to tolerate them to achieve their weight loss, Dr. Feldt-Rasmussen said.



Repurposing an ADHD treatment

Dextroamphetamine increases satiety and boosts resting energy expenditure, and is a common treatment for attention deficit hyperactivity disorder. Dr. van Schaik and coauthors reviewed 13 children and adolescents with acquired hypothalamic obesity and 5 with genetic hypothalamic obesity who received the treatment at either of two Dutch hospitals during 2014-2020. All 18 patients went on dextroamphetamine after other interventions had failed to produce improvement, said Dr. van Schaik, a researcher at University Medical Center and Wilhelmina Children’s Hospital in Utrecht, the Netherlands. The patients averaged about 13 years of age.

In addition to an overall effect on weight across all 18 subjects, the researchers found they could subdivide the full cohort into 10 responders (56%), 4 (22%) with weight stabilization on treatment, and 4 nonresponders (22%) who continued to gain weight despite treatment. The 10 responding patients had an average drop in their BMI standard deviation score of 0.91. All 10 responders had acquired hypothalamic obesity, and they averaged a 12.5 percentage point rise in their resting energy expenditure level, compared with baseline, while on treatment. The four whose weight stabilized on treatment included three patients with genetic hypothalamic obesity. The four nonresponders split into two with acquired hypothalamic obesity and two with the genetic form.

Thirteen patients (72%) had improvements in hyperphagia, energy, and behavior, and no patient had a serious adverse effect. One patient stopped treatment after 1 month because of elevated blood pressure.

“Dextroamphetamine may be promising, especially for acquired hypothalamic obesity,” Dr. van Schaik concluded, adding that prospective, controlled assessments are needed, and that a healthy lifestyle is the foundation of hypothalamic obesity treatment.

The Tesomet study was sponsored by Saniona, the company developing Tesomet. Dr Feldt-Rasmussen is an advisor to Saniona, and some of the coauthors on the study are Saniona employees. Dr. van Schaik had no disclosures.

[email protected]

The obesity epidemic in the United States may be slowing improvements in cancer mortality, according to a new analysis of over 50 million cancer and heart disease deaths.

“By integrating 20 years of cancer mortality data, we demonstrated that trends in obesity-associated cancer mortality showed signs of recent deceleration, consistent with recent findings for heart disease mortality,” Christy L. Avery, PhD, and associates wrote in JAMA Network Open.

Improvements in mortality related to heart disease slowed after 2011, a phenomenon that has been associated with rising obesity rates. The age-adjusted mortality rate (AAMR) declined at an average of 3.8 deaths per 100,000 persons from 1999 to 2011 but only 0.7 deaths per 100,000 from 2011 to 2018, based on data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (WONDER).

To understand trends in cancer mortality and their possible connection with obesity, data for 1999-2018 from the WONDER database were divided into obesity-associated and non–obesity-associated categories and compared with heart disease mortality, they explained. The database included more than 50 million deaths that matched inclusion criteria.

The analysis showed there was difference between obesity-associated and non–obesity-associated cancers that was obscured when all cancer deaths were considered together. The average annual change in AAMR for obesity-associated cancers slowed from –1.19 deaths per 100,000 in 1999-2011 to –0.83 in 2011-2018, Dr. Avery and associates reported.

For non–obesity-associated cancers, the annual change in AAMR increased from –1.62 per 100,000 for 1999-2011 to –2.29 for 2011-2018, following the trend for all cancers: –1.48 per 100,000 during 1999-2011 and –1.77 in 2011-2018, they said.

“The largest mortality decreases were observed for melanoma of the skin and lung cancer, two cancers not associated with obesity. For obesity-associated cancers, stable or increasing mortality rates have been observed for liver and pancreatic cancer among both men and women as well as for uterine cancer among women,” the investigators wrote.

Demographically, however, the slowing improvement in mortality for obesity-associated cancers did not follow the trend for heart disease. The deceleration for cancer was more pronounced for women and for non-Hispanic Whites and not seen at all in non-Hispanic Asian/Pacific Islander individuals. “For heart disease, evidence of a deceleration was consistent across sex, race, and ethnicity,” they said.

There are “longstanding disparities in obesity” among various populations in the United States, and the recent trend of obesity occurring earlier in life may be having an effect. “Whether the findings of decelerating mortality rates potentially signal a changing profile of cancer and heart disease mortality as the consequences of the obesity epidemic are realized remains to be seen,” they concluded.

The investigators reported receiving grants from the National Institutes of Health during the conduct of the study, but no other disclosures were reported.

[email protected]

The obesity epidemic in the United States may be slowing improvements in cancer mortality, according to a new analysis of over 50 million cancer and heart disease deaths.

“By integrating 20 years of cancer mortality data, we demonstrated that trends in obesity-associated cancer mortality showed signs of recent deceleration, consistent with recent findings for heart disease mortality,” Christy L. Avery, PhD, and associates wrote in JAMA Network Open.

Improvements in mortality related to heart disease slowed after 2011, a phenomenon that has been associated with rising obesity rates. The age-adjusted mortality rate (AAMR) declined at an average of 3.8 deaths per 100,000 persons from 1999 to 2011 but only 0.7 deaths per 100,000 from 2011 to 2018, based on data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (WONDER).

To understand trends in cancer mortality and their possible connection with obesity, data for 1999-2018 from the WONDER database were divided into obesity-associated and non–obesity-associated categories and compared with heart disease mortality, they explained. The database included more than 50 million deaths that matched inclusion criteria.

The analysis showed there was difference between obesity-associated and non–obesity-associated cancers that was obscured when all cancer deaths were considered together. The average annual change in AAMR for obesity-associated cancers slowed from –1.19 deaths per 100,000 in 1999-2011 to –0.83 in 2011-2018, Dr. Avery and associates reported.

For non–obesity-associated cancers, the annual change in AAMR increased from –1.62 per 100,000 for 1999-2011 to –2.29 for 2011-2018, following the trend for all cancers: –1.48 per 100,000 during 1999-2011 and –1.77 in 2011-2018, they said.

“The largest mortality decreases were observed for melanoma of the skin and lung cancer, two cancers not associated with obesity. For obesity-associated cancers, stable or increasing mortality rates have been observed for liver and pancreatic cancer among both men and women as well as for uterine cancer among women,” the investigators wrote.

Demographically, however, the slowing improvement in mortality for obesity-associated cancers did not follow the trend for heart disease. The deceleration for cancer was more pronounced for women and for non-Hispanic Whites and not seen at all in non-Hispanic Asian/Pacific Islander individuals. “For heart disease, evidence of a deceleration was consistent across sex, race, and ethnicity,” they said.

There are “longstanding disparities in obesity” among various populations in the United States, and the recent trend of obesity occurring earlier in life may be having an effect. “Whether the findings of decelerating mortality rates potentially signal a changing profile of cancer and heart disease mortality as the consequences of the obesity epidemic are realized remains to be seen,” they concluded.

The investigators reported receiving grants from the National Institutes of Health during the conduct of the study, but no other disclosures were reported.

[email protected]

The obesity epidemic in the United States may be slowing improvements in cancer mortality, according to a new analysis of over 50 million cancer and heart disease deaths.

“By integrating 20 years of cancer mortality data, we demonstrated that trends in obesity-associated cancer mortality showed signs of recent deceleration, consistent with recent findings for heart disease mortality,” Christy L. Avery, PhD, and associates wrote in JAMA Network Open.

Improvements in mortality related to heart disease slowed after 2011, a phenomenon that has been associated with rising obesity rates. The age-adjusted mortality rate (AAMR) declined at an average of 3.8 deaths per 100,000 persons from 1999 to 2011 but only 0.7 deaths per 100,000 from 2011 to 2018, based on data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (WONDER).

To understand trends in cancer mortality and their possible connection with obesity, data for 1999-2018 from the WONDER database were divided into obesity-associated and non–obesity-associated categories and compared with heart disease mortality, they explained. The database included more than 50 million deaths that matched inclusion criteria.

The analysis showed there was difference between obesity-associated and non–obesity-associated cancers that was obscured when all cancer deaths were considered together. The average annual change in AAMR for obesity-associated cancers slowed from –1.19 deaths per 100,000 in 1999-2011 to –0.83 in 2011-2018, Dr. Avery and associates reported.

For non–obesity-associated cancers, the annual change in AAMR increased from –1.62 per 100,000 for 1999-2011 to –2.29 for 2011-2018, following the trend for all cancers: –1.48 per 100,000 during 1999-2011 and –1.77 in 2011-2018, they said.

“The largest mortality decreases were observed for melanoma of the skin and lung cancer, two cancers not associated with obesity. For obesity-associated cancers, stable or increasing mortality rates have been observed for liver and pancreatic cancer among both men and women as well as for uterine cancer among women,” the investigators wrote.

Demographically, however, the slowing improvement in mortality for obesity-associated cancers did not follow the trend for heart disease. The deceleration for cancer was more pronounced for women and for non-Hispanic Whites and not seen at all in non-Hispanic Asian/Pacific Islander individuals. “For heart disease, evidence of a deceleration was consistent across sex, race, and ethnicity,” they said.

There are “longstanding disparities in obesity” among various populations in the United States, and the recent trend of obesity occurring earlier in life may be having an effect. “Whether the findings of decelerating mortality rates potentially signal a changing profile of cancer and heart disease mortality as the consequences of the obesity epidemic are realized remains to be seen,” they concluded.

The investigators reported receiving grants from the National Institutes of Health during the conduct of the study, but no other disclosures were reported.

[email protected]

Debulking large exophytic basal cell carcinomas prior to hedgehog inhibitor therapy might improve outcomes, according to Allison Vidimos, MD, a Mohs surgeon and chair of the department of dermatology at the Cleveland Clinic.

She and her colleagues have noticed an accelerated and durable response to hedgehog inhibitors after debulking and are studying cell signaling before and after debulking to better understand the issue.

Dr. Vidimos shared a remarkable case to illustrate the point during a clinical pearls talk at the annual meeting of the American College of Mohs Surgery.

An 82-year-old woman presented with a crusted, hemorrhagic, nodular basal cell carcinoma (BCC) that had overgrown over nearly her entire nose and left lower eyelid. A recurrence of a previous BCC, the tumor had been growing for a decade and had invaded her nasal bones but not the periorbital tissue.

An outside surgeon suggested a full rhinectomy and removal of the lower eyelid, but the woman refused.

Dr. Vidimos decided to treat her with vismodegib, but prior to doing so, she debulked the tumor to help with the pain and bleeding. She did not curette the portion of tumor extending through the ala into the nasal vestibule. “I let the vismodegib take care of that,” she said.

After 9 months, the tumor was virtually gone, with no recurrence after 3 years. Surgical debulking prior to hedgehog inhibition “reduces the tumor burden and may increase the efficacy and shorten the course of therapy,” Dr. Vidimos said.

The hedgehog inhibitors vismodegib (Erivedge) and sonidegib Odomzo are both approved for treating locally advanced BCC, with a complete response of 31% of locally advanced disease with vismodegib, according to one report.

But monotherapy is limited by intolerable side effects, most commonly muscle spasms, alopecia, and dysgeusia. To minimize the impact, Dr. Vidimos generally puts patients on treatment with Monday through Friday dosing and gives them the weekends off, a schedule she and her colleagues have reported works as well as daily dosing.

Still, many patients discontinue the drugs because of the side effects. Hedgehog inhibitors are also expensive and responses aren’t always durable. To increase efficacy and shorten the course of therapy, “we need alternative treatment strategies,” Dr. Vidimos said.

Up-front tumor debulking is one such strategy. Altered cell signaling pathways associated with tissue remodeling might improve response, and debulking may reduce the genetic heterogeneity of tumor cells, rendering remaining cells less resistant to hedgehog inhibition, she explained.

“It is exciting to see how tumor debulking may reduce tumor burden and heterogeneity, and thus lead to a durable response in extensive tumors,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington, who heard the presentation. “More investigation is needed to reproduce these results, but this approach may lead to improved outcomes with targeted therapies,” he said in an interview.

Combination therapy with other agents is another option, and there also seems to be a synergistic effect with radiation, with hedgehog inhibitors increasing cellular response to radiation therapy, Dr. Vidimos said.

Hedgehog inhibitors can also be used to shrink tumors before surgery. One small series found a 27% decrease in the area of the tumor after 3 to 6 months of preoperative vismodegib.

Dr. Vidimos shared another case to illustrate the point.

A 64-year-old woman fainted and presented to the ED with a hemoglobin of 3.2 mg/dL because of chronic blood loss from an ulcerated BCC on her upper back. The lesion measured 25 cm by 9 cm, and was 3.5 cm deep with no bone involvement. The woman was addicted to opioids by the time she presented.

She was started on vismodegib; the ulcer shrunk considerably after 6 months, and the woman underwent a resection. Only one small focus of BCC was found across 78 specimens submitted to Dr. Vidimos for Mohs reading.

Resection was followed by a muscle flap repair and radiation. At 5 and a half years, there is no evidence of disease; the only sign that the lesion had been there was a scar running along the woman’s upper spine.

The approach “was very successful for a very aggressive and worrisome tumor,” Dr. Vidimos said.

Dr. Vidimos did not have any relevant disclosures. Dr. Patel had no relevant disclosures.

[email protected]

Debulking large exophytic basal cell carcinomas prior to hedgehog inhibitor therapy might improve outcomes, according to Allison Vidimos, MD, a Mohs surgeon and chair of the department of dermatology at the Cleveland Clinic.

She and her colleagues have noticed an accelerated and durable response to hedgehog inhibitors after debulking and are studying cell signaling before and after debulking to better understand the issue.

Dr. Vidimos shared a remarkable case to illustrate the point during a clinical pearls talk at the annual meeting of the American College of Mohs Surgery.

An 82-year-old woman presented with a crusted, hemorrhagic, nodular basal cell carcinoma (BCC) that had overgrown over nearly her entire nose and left lower eyelid. A recurrence of a previous BCC, the tumor had been growing for a decade and had invaded her nasal bones but not the periorbital tissue.

An outside surgeon suggested a full rhinectomy and removal of the lower eyelid, but the woman refused.

Dr. Vidimos decided to treat her with vismodegib, but prior to doing so, she debulked the tumor to help with the pain and bleeding. She did not curette the portion of tumor extending through the ala into the nasal vestibule. “I let the vismodegib take care of that,” she said.

After 9 months, the tumor was virtually gone, with no recurrence after 3 years. Surgical debulking prior to hedgehog inhibition “reduces the tumor burden and may increase the efficacy and shorten the course of therapy,” Dr. Vidimos said.

The hedgehog inhibitors vismodegib (Erivedge) and sonidegib Odomzo are both approved for treating locally advanced BCC, with a complete response of 31% of locally advanced disease with vismodegib, according to one report.

But monotherapy is limited by intolerable side effects, most commonly muscle spasms, alopecia, and dysgeusia. To minimize the impact, Dr. Vidimos generally puts patients on treatment with Monday through Friday dosing and gives them the weekends off, a schedule she and her colleagues have reported works as well as daily dosing.

Still, many patients discontinue the drugs because of the side effects. Hedgehog inhibitors are also expensive and responses aren’t always durable. To increase efficacy and shorten the course of therapy, “we need alternative treatment strategies,” Dr. Vidimos said.

Up-front tumor debulking is one such strategy. Altered cell signaling pathways associated with tissue remodeling might improve response, and debulking may reduce the genetic heterogeneity of tumor cells, rendering remaining cells less resistant to hedgehog inhibition, she explained.

“It is exciting to see how tumor debulking may reduce tumor burden and heterogeneity, and thus lead to a durable response in extensive tumors,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington, who heard the presentation. “More investigation is needed to reproduce these results, but this approach may lead to improved outcomes with targeted therapies,” he said in an interview.

Combination therapy with other agents is another option, and there also seems to be a synergistic effect with radiation, with hedgehog inhibitors increasing cellular response to radiation therapy, Dr. Vidimos said.

Hedgehog inhibitors can also be used to shrink tumors before surgery. One small series found a 27% decrease in the area of the tumor after 3 to 6 months of preoperative vismodegib.

Dr. Vidimos shared another case to illustrate the point.

A 64-year-old woman fainted and presented to the ED with a hemoglobin of 3.2 mg/dL because of chronic blood loss from an ulcerated BCC on her upper back. The lesion measured 25 cm by 9 cm, and was 3.5 cm deep with no bone involvement. The woman was addicted to opioids by the time she presented.

She was started on vismodegib; the ulcer shrunk considerably after 6 months, and the woman underwent a resection. Only one small focus of BCC was found across 78 specimens submitted to Dr. Vidimos for Mohs reading.

Resection was followed by a muscle flap repair and radiation. At 5 and a half years, there is no evidence of disease; the only sign that the lesion had been there was a scar running along the woman’s upper spine.

The approach “was very successful for a very aggressive and worrisome tumor,” Dr. Vidimos said.

Dr. Vidimos did not have any relevant disclosures. Dr. Patel had no relevant disclosures.

[email protected]

Debulking large exophytic basal cell carcinomas prior to hedgehog inhibitor therapy might improve outcomes, according to Allison Vidimos, MD, a Mohs surgeon and chair of the department of dermatology at the Cleveland Clinic.

She and her colleagues have noticed an accelerated and durable response to hedgehog inhibitors after debulking and are studying cell signaling before and after debulking to better understand the issue.

Dr. Vidimos shared a remarkable case to illustrate the point during a clinical pearls talk at the annual meeting of the American College of Mohs Surgery.

An 82-year-old woman presented with a crusted, hemorrhagic, nodular basal cell carcinoma (BCC) that had overgrown over nearly her entire nose and left lower eyelid. A recurrence of a previous BCC, the tumor had been growing for a decade and had invaded her nasal bones but not the periorbital tissue.

An outside surgeon suggested a full rhinectomy and removal of the lower eyelid, but the woman refused.

Dr. Vidimos decided to treat her with vismodegib, but prior to doing so, she debulked the tumor to help with the pain and bleeding. She did not curette the portion of tumor extending through the ala into the nasal vestibule. “I let the vismodegib take care of that,” she said.

After 9 months, the tumor was virtually gone, with no recurrence after 3 years. Surgical debulking prior to hedgehog inhibition “reduces the tumor burden and may increase the efficacy and shorten the course of therapy,” Dr. Vidimos said.

The hedgehog inhibitors vismodegib (Erivedge) and sonidegib Odomzo are both approved for treating locally advanced BCC, with a complete response of 31% of locally advanced disease with vismodegib, according to one report.

But monotherapy is limited by intolerable side effects, most commonly muscle spasms, alopecia, and dysgeusia. To minimize the impact, Dr. Vidimos generally puts patients on treatment with Monday through Friday dosing and gives them the weekends off, a schedule she and her colleagues have reported works as well as daily dosing.

Still, many patients discontinue the drugs because of the side effects. Hedgehog inhibitors are also expensive and responses aren’t always durable. To increase efficacy and shorten the course of therapy, “we need alternative treatment strategies,” Dr. Vidimos said.

Up-front tumor debulking is one such strategy. Altered cell signaling pathways associated with tissue remodeling might improve response, and debulking may reduce the genetic heterogeneity of tumor cells, rendering remaining cells less resistant to hedgehog inhibition, she explained.

“It is exciting to see how tumor debulking may reduce tumor burden and heterogeneity, and thus lead to a durable response in extensive tumors,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington, who heard the presentation. “More investigation is needed to reproduce these results, but this approach may lead to improved outcomes with targeted therapies,” he said in an interview.

Combination therapy with other agents is another option, and there also seems to be a synergistic effect with radiation, with hedgehog inhibitors increasing cellular response to radiation therapy, Dr. Vidimos said.

Hedgehog inhibitors can also be used to shrink tumors before surgery. One small series found a 27% decrease in the area of the tumor after 3 to 6 months of preoperative vismodegib.

Dr. Vidimos shared another case to illustrate the point.

A 64-year-old woman fainted and presented to the ED with a hemoglobin of 3.2 mg/dL because of chronic blood loss from an ulcerated BCC on her upper back. The lesion measured 25 cm by 9 cm, and was 3.5 cm deep with no bone involvement. The woman was addicted to opioids by the time she presented.

She was started on vismodegib; the ulcer shrunk considerably after 6 months, and the woman underwent a resection. Only one small focus of BCC was found across 78 specimens submitted to Dr. Vidimos for Mohs reading.

Resection was followed by a muscle flap repair and radiation. At 5 and a half years, there is no evidence of disease; the only sign that the lesion had been there was a scar running along the woman’s upper spine.

The approach “was very successful for a very aggressive and worrisome tumor,” Dr. Vidimos said.

Dr. Vidimos did not have any relevant disclosures. Dr. Patel had no relevant disclosures.

[email protected]

Clinicians’ well-being is a “crisis” of grave import to the public health and a top issue that he hopes to get more squarely on the public radar screen, Surgeon General Vivek Murthy, MD, MBA, said May 6 in a “fireside chat” with SHM president Danielle Scheurer, MD, MSRC, SFHM, at SHM Converge, the annual conference of the Society of Hospital Medicine.

“This is a crisis that I don’t know that the country recognizes is fully important,” Dr. Murthy said. “I don’t think that most people in the public recognize just how extraordinarily difficult it is, for many clinicians, to come to practice. And if the clinicians continue to burn out at the rate that they are – in addition to the humanitarian crisis of people who are struggling that we should all feel concern about – it will impact care in a profound way.” He said part of his plan is a “national agenda” for clinician well-being, with a clear pathway for creating an environment more conducive to providing quality patient care.

Dr. Scheurer said that this was “welcome news and wonderful to hear.”

“Fortunately or unfortunately, now I do think it’s more in the front seat,” she said, adding that “this notion of ‘heal thyself,’ we know doesn’t work and these are really systemic ailments that we all have to tackle together.”

Dr. Murthy, a hospitalist by training, recently began his second term as Surgeon General, having served under President Obama and appointed to the post again by President Biden. This second appointment is different in the knowledge he has about the job from the start, in the enormity of the public health challenges posed by the COVID-19 pandemic, and in the political tenor of the country.

He said one of his main priorities is to “recenter our public health response” with scientists and public health leaders regaining their proper role.

“Have them be the voices that are actually speaking directly to the public, not in a way that’s biased by the politics or by politicians, but it’s really guided again by the science and substance of what we know needs to happen,” he said.

The response to COVID goes beyond continuing an aggressive vaccination and testing campaign, he said. The pandemic has given rise to worse mental health issues such as depression and anxiety, substance use disorders, and delays in care for other medical conditions for fear of infection – and these are all priorities, Dr. Murthy said.

One “silver lining” of the pandemic is the expansion of telehealth, but this needs refining and persistence to make it work optimally for all patients, he said.

“We have to ensure that that expansion continues and that it’s even – meaning that there are so many parts of the country where broadband access is a challenge for patients, so they don’t have the benefits of telemedicine,” he said. “We also need to ensure that these systems are integrated across our current systems, across hospitals so that we’re not creating more work for clinicians when it comes to utilizing this technology to reach their patients.”

Clinicians – typically viewed as coming to Capitol Hill only to push for higher payment or changes to medical liability laws – need to use their trusted voices to raise the profile of preventive care and identifying and fixing social barriers related to health, such as transportation issues and unsafe neighborhoods, Dr. Murthy said.

“No one really celebrates the heart attack that was prevented or the asthma that was prevented – we celebrate the illness that took place and was cured,” he said. “We know as clinicians that if you really want to reduce human suffering that you have to focus on the prevention side of the house, and I think that unless our colleagues in medicine and in public health come together and advocate for greater investments in prevention, or a national agenda around prevention, my worry is that it won’t naturally develop.”

On vaccine hesitancy, Dr. Murthy said that the United States needs to work more in increasing confidence that the vaccines will work, and in access to vaccines, but, mostly, in motivation.

“What we’ve learned is that ultimately trusted voices are what make all the difference when it comes to vaccination,” he said. “It’s one of these large, people-powered movements that we have to build in our community.”

Dr. Scheurer noted that, with hospitalists in 90% of U.S. hospitals, they can play a big role. “If we can all do our part then we’ll at least take the ball further down the field.”

Dr. Murthy added that, since residency, when he cared for young cancer patients near his own age, he has focused on “finding meaning now” in his work and life. The pandemic has reinforced this, and he doesn’t necessarily want life to go back to exactly how it was before the pandemic.

“Many of us are thinking – ‘Is there actually a better way for us to live our lives and design our workdays and our choices other than what we were doing prepandemic? Can we center our lives more around the people we love and care about, can we design our work to accommodate our family as opposed to the other way around, to always make our families accommodate our work?’ – These are the kinds of choices that we have to make as a society.”

Clinicians’ well-being is a “crisis” of grave import to the public health and a top issue that he hopes to get more squarely on the public radar screen, Surgeon General Vivek Murthy, MD, MBA, said May 6 in a “fireside chat” with SHM president Danielle Scheurer, MD, MSRC, SFHM, at SHM Converge, the annual conference of the Society of Hospital Medicine.

“This is a crisis that I don’t know that the country recognizes is fully important,” Dr. Murthy said. “I don’t think that most people in the public recognize just how extraordinarily difficult it is, for many clinicians, to come to practice. And if the clinicians continue to burn out at the rate that they are – in addition to the humanitarian crisis of people who are struggling that we should all feel concern about – it will impact care in a profound way.” He said part of his plan is a “national agenda” for clinician well-being, with a clear pathway for creating an environment more conducive to providing quality patient care.

Dr. Scheurer said that this was “welcome news and wonderful to hear.”

“Fortunately or unfortunately, now I do think it’s more in the front seat,” she said, adding that “this notion of ‘heal thyself,’ we know doesn’t work and these are really systemic ailments that we all have to tackle together.”

Dr. Murthy, a hospitalist by training, recently began his second term as Surgeon General, having served under President Obama and appointed to the post again by President Biden. This second appointment is different in the knowledge he has about the job from the start, in the enormity of the public health challenges posed by the COVID-19 pandemic, and in the political tenor of the country.

He said one of his main priorities is to “recenter our public health response” with scientists and public health leaders regaining their proper role.

“Have them be the voices that are actually speaking directly to the public, not in a way that’s biased by the politics or by politicians, but it’s really guided again by the science and substance of what we know needs to happen,” he said.

The response to COVID goes beyond continuing an aggressive vaccination and testing campaign, he said. The pandemic has given rise to worse mental health issues such as depression and anxiety, substance use disorders, and delays in care for other medical conditions for fear of infection – and these are all priorities, Dr. Murthy said.

One “silver lining” of the pandemic is the expansion of telehealth, but this needs refining and persistence to make it work optimally for all patients, he said.

“We have to ensure that that expansion continues and that it’s even – meaning that there are so many parts of the country where broadband access is a challenge for patients, so they don’t have the benefits of telemedicine,” he said. “We also need to ensure that these systems are integrated across our current systems, across hospitals so that we’re not creating more work for clinicians when it comes to utilizing this technology to reach their patients.”

Clinicians – typically viewed as coming to Capitol Hill only to push for higher payment or changes to medical liability laws – need to use their trusted voices to raise the profile of preventive care and identifying and fixing social barriers related to health, such as transportation issues and unsafe neighborhoods, Dr. Murthy said.

“No one really celebrates the heart attack that was prevented or the asthma that was prevented – we celebrate the illness that took place and was cured,” he said. “We know as clinicians that if you really want to reduce human suffering that you have to focus on the prevention side of the house, and I think that unless our colleagues in medicine and in public health come together and advocate for greater investments in prevention, or a national agenda around prevention, my worry is that it won’t naturally develop.”

On vaccine hesitancy, Dr. Murthy said that the United States needs to work more in increasing confidence that the vaccines will work, and in access to vaccines, but, mostly, in motivation.

“What we’ve learned is that ultimately trusted voices are what make all the difference when it comes to vaccination,” he said. “It’s one of these large, people-powered movements that we have to build in our community.”

Dr. Scheurer noted that, with hospitalists in 90% of U.S. hospitals, they can play a big role. “If we can all do our part then we’ll at least take the ball further down the field.”

Dr. Murthy added that, since residency, when he cared for young cancer patients near his own age, he has focused on “finding meaning now” in his work and life. The pandemic has reinforced this, and he doesn’t necessarily want life to go back to exactly how it was before the pandemic.

“Many of us are thinking – ‘Is there actually a better way for us to live our lives and design our workdays and our choices other than what we were doing prepandemic? Can we center our lives more around the people we love and care about, can we design our work to accommodate our family as opposed to the other way around, to always make our families accommodate our work?’ – These are the kinds of choices that we have to make as a society.”

Clinicians’ well-being is a “crisis” of grave import to the public health and a top issue that he hopes to get more squarely on the public radar screen, Surgeon General Vivek Murthy, MD, MBA, said May 6 in a “fireside chat” with SHM president Danielle Scheurer, MD, MSRC, SFHM, at SHM Converge, the annual conference of the Society of Hospital Medicine.

“This is a crisis that I don’t know that the country recognizes is fully important,” Dr. Murthy said. “I don’t think that most people in the public recognize just how extraordinarily difficult it is, for many clinicians, to come to practice. And if the clinicians continue to burn out at the rate that they are – in addition to the humanitarian crisis of people who are struggling that we should all feel concern about – it will impact care in a profound way.” He said part of his plan is a “national agenda” for clinician well-being, with a clear pathway for creating an environment more conducive to providing quality patient care.

Dr. Scheurer said that this was “welcome news and wonderful to hear.”

“Fortunately or unfortunately, now I do think it’s more in the front seat,” she said, adding that “this notion of ‘heal thyself,’ we know doesn’t work and these are really systemic ailments that we all have to tackle together.”

Dr. Murthy, a hospitalist by training, recently began his second term as Surgeon General, having served under President Obama and appointed to the post again by President Biden. This second appointment is different in the knowledge he has about the job from the start, in the enormity of the public health challenges posed by the COVID-19 pandemic, and in the political tenor of the country.

He said one of his main priorities is to “recenter our public health response” with scientists and public health leaders regaining their proper role.

“Have them be the voices that are actually speaking directly to the public, not in a way that’s biased by the politics or by politicians, but it’s really guided again by the science and substance of what we know needs to happen,” he said.

The response to COVID goes beyond continuing an aggressive vaccination and testing campaign, he said. The pandemic has given rise to worse mental health issues such as depression and anxiety, substance use disorders, and delays in care for other medical conditions for fear of infection – and these are all priorities, Dr. Murthy said.

One “silver lining” of the pandemic is the expansion of telehealth, but this needs refining and persistence to make it work optimally for all patients, he said.

“We have to ensure that that expansion continues and that it’s even – meaning that there are so many parts of the country where broadband access is a challenge for patients, so they don’t have the benefits of telemedicine,” he said. “We also need to ensure that these systems are integrated across our current systems, across hospitals so that we’re not creating more work for clinicians when it comes to utilizing this technology to reach their patients.”

Clinicians – typically viewed as coming to Capitol Hill only to push for higher payment or changes to medical liability laws – need to use their trusted voices to raise the profile of preventive care and identifying and fixing social barriers related to health, such as transportation issues and unsafe neighborhoods, Dr. Murthy said.

“No one really celebrates the heart attack that was prevented or the asthma that was prevented – we celebrate the illness that took place and was cured,” he said. “We know as clinicians that if you really want to reduce human suffering that you have to focus on the prevention side of the house, and I think that unless our colleagues in medicine and in public health come together and advocate for greater investments in prevention, or a national agenda around prevention, my worry is that it won’t naturally develop.”

On vaccine hesitancy, Dr. Murthy said that the United States needs to work more in increasing confidence that the vaccines will work, and in access to vaccines, but, mostly, in motivation.

“What we’ve learned is that ultimately trusted voices are what make all the difference when it comes to vaccination,” he said. “It’s one of these large, people-powered movements that we have to build in our community.”

Dr. Scheurer noted that, with hospitalists in 90% of U.S. hospitals, they can play a big role. “If we can all do our part then we’ll at least take the ball further down the field.”

Dr. Murthy added that, since residency, when he cared for young cancer patients near his own age, he has focused on “finding meaning now” in his work and life. The pandemic has reinforced this, and he doesn’t necessarily want life to go back to exactly how it was before the pandemic.

“Many of us are thinking – ‘Is there actually a better way for us to live our lives and design our workdays and our choices other than what we were doing prepandemic? Can we center our lives more around the people we love and care about, can we design our work to accommodate our family as opposed to the other way around, to always make our families accommodate our work?’ – These are the kinds of choices that we have to make as a society.”

Genital skin exams in girls must be conducted with special care and alertness for signs of abuse, a dermatologist told colleagues at the American Academy of Dermatology Virtual Meeting Experience.

“One in four adult women report being childhood victims of sexual abuse, which is just a staggering number. This is an opportunity for us to identify these patients early and give them the terminology to be able to report what is happening to them,” said pediatric dermatologist Kalyani Marathe, MD, MPH, director of the division of dermatology at Cincinnati Children’s Hospital. “We also have the chance to give them a sense of agency over their bodies.”

Dr. Marathe offered the following recommendations when performing a genital skin exam:

• Make sure a “chaperone” is present. “Chaperones are a must when you’re examining children and teens,” she said. “Ask whom they prefer. For prepubertal children, you’re going to usually use the parent who’s there with them. If the parent is their father, they might ask him to step behind the curtain, in which case you can bring over your nurse or medical assistant.” Teens may ask either parent to step out of the room, she said. In that case, a nurse, medical assistant, resident, or trainee can fill in. “If you have male residents or trainees with you and the patient really does not want to be examined by a male, honor their request. Do not force them.”
• Explain why the exam is being performed. Make sure the patient understands why she is being seen, Dr. Marathe advised. For example, say something like “your pediatrician told us that you have an itchy area” or “your mom told us that there’s some loss of color in that area, that you’re having a problem there.” She added that it’s helpful to explain the type of doctor you are, with a comment such as the following: “We’re examining you because we’re doctors who specialize in skin. ... We want to help you feel better and make sure that your skin heals and is healthy.”
• Ask both the child and the parent for permission to perform the exam. While this may seem trivial, “it’s very, very important in setting the right tone for the encounter,” she said. “If the child says yes, we turn to the mom and say: ‘Mom, is it okay for us to do this exam today?’ You can see visible relief on the part of the parent, and as the parent relaxes, the child relaxes. Just saying those few things really makes the encounter so much smoother.” However, “if they say no, you have to honor the response. ... You say: ‘Okay, we’re not going to do the exam today,” and see the patient in a few weeks. If it’s urgent, an exam under anesthesia may be an option, she added.
• Talk to the child about the terms they use for private parts. It can be helpful to ask: “Do you have any terms for your private area?” According to Dr. Marathe, “this is a good chance to educate them on the terms vulva and vagina since they may be using other terminology. Making sure that they have the correct terms will actually help patients identify and report abuse earlier.” Dr. Marathe recalled that a colleague had a patient who’d been calling her private area “pound cake” and had been “reporting to her teacher that someone had been touching her ‘pound cake.’ Her teacher did not know what she meant by that, and this led to a great delay in her childhood abuse being reported.”
• Talk about what will happen during the exam. “I like to show them any instruments that we’re going to be using,” Dr. Marathe said. “If we’re using a flashlight, for example, I like to show them a picture [of a flashlight] or show them that flashlight. If we’re using a camera to do digital photography, show them that. If we’re going to be using a Q-tip or a swab to demonstrate anything or to take a culture, I like to show them that beforehand to make sure that they know what we’re doing.” In regard to photography, “make sure the parent and child know where the photos are going to go, who’s going to see them, what are they going to be used for. If they’re going to be used for educational purposes, make sure they have given explicit permission for that and they know they’ll be deidentified.”
• Make it clear that the exam won’t be painful. It’s important to put both the patient and the parent at ease on this front, Dr. Marathe said. “A lot of parents are concerned that we’re going to do a speculum exam in their prepubertal child. So make sure that it’s clarified ahead of time that we’re not going to be doing a speculum exam.”

Commenting on this topic, Tor Shwayder, MD, a pediatric dermatologist at Henry Ford Health System, Detroit, urged colleagues to take action if they feel suspicious about a possible sign of child abuse, even if they’re far from certain that anything is wrong. “Don’t ignore those feelings in the back of the brain,” he said in an interview.

Most states have child-abuse hotlines for medical professionals, and major hospitals will have child-abuse teams, Dr. Shwayder said. He urged dermatologists to take advantage of these resources when appropriate. “The professionals on the other side of the 800 number or at the hospital will help you. You don’t have to decide immediately whether this is child abuse. You just need to have a suspicion.”

Dr. Marathe and Dr. Shwayder report no disclosures.

Genital skin exams in girls must be conducted with special care and alertness for signs of abuse, a dermatologist told colleagues at the American Academy of Dermatology Virtual Meeting Experience.

“One in four adult women report being childhood victims of sexual abuse, which is just a staggering number. This is an opportunity for us to identify these patients early and give them the terminology to be able to report what is happening to them,” said pediatric dermatologist Kalyani Marathe, MD, MPH, director of the division of dermatology at Cincinnati Children’s Hospital. “We also have the chance to give them a sense of agency over their bodies.”

Dr. Marathe offered the following recommendations when performing a genital skin exam:

• Make sure a “chaperone” is present. “Chaperones are a must when you’re examining children and teens,” she said. “Ask whom they prefer. For prepubertal children, you’re going to usually use the parent who’s there with them. If the parent is their father, they might ask him to step behind the curtain, in which case you can bring over your nurse or medical assistant.” Teens may ask either parent to step out of the room, she said. In that case, a nurse, medical assistant, resident, or trainee can fill in. “If you have male residents or trainees with you and the patient really does not want to be examined by a male, honor their request. Do not force them.”
• Explain why the exam is being performed. Make sure the patient understands why she is being seen, Dr. Marathe advised. For example, say something like “your pediatrician told us that you have an itchy area” or “your mom told us that there’s some loss of color in that area, that you’re having a problem there.” She added that it’s helpful to explain the type of doctor you are, with a comment such as the following: “We’re examining you because we’re doctors who specialize in skin. ... We want to help you feel better and make sure that your skin heals and is healthy.”
• Ask both the child and the parent for permission to perform the exam. While this may seem trivial, “it’s very, very important in setting the right tone for the encounter,” she said. “If the child says yes, we turn to the mom and say: ‘Mom, is it okay for us to do this exam today?’ You can see visible relief on the part of the parent, and as the parent relaxes, the child relaxes. Just saying those few things really makes the encounter so much smoother.” However, “if they say no, you have to honor the response. ... You say: ‘Okay, we’re not going to do the exam today,” and see the patient in a few weeks. If it’s urgent, an exam under anesthesia may be an option, she added.
• Talk to the child about the terms they use for private parts. It can be helpful to ask: “Do you have any terms for your private area?” According to Dr. Marathe, “this is a good chance to educate them on the terms vulva and vagina since they may be using other terminology. Making sure that they have the correct terms will actually help patients identify and report abuse earlier.” Dr. Marathe recalled that a colleague had a patient who’d been calling her private area “pound cake” and had been “reporting to her teacher that someone had been touching her ‘pound cake.’ Her teacher did not know what she meant by that, and this led to a great delay in her childhood abuse being reported.”
• Talk about what will happen during the exam. “I like to show them any instruments that we’re going to be using,” Dr. Marathe said. “If we’re using a flashlight, for example, I like to show them a picture [of a flashlight] or show them that flashlight. If we’re using a camera to do digital photography, show them that. If we’re going to be using a Q-tip or a swab to demonstrate anything or to take a culture, I like to show them that beforehand to make sure that they know what we’re doing.” In regard to photography, “make sure the parent and child know where the photos are going to go, who’s going to see them, what are they going to be used for. If they’re going to be used for educational purposes, make sure they have given explicit permission for that and they know they’ll be deidentified.”
• Make it clear that the exam won’t be painful. It’s important to put both the patient and the parent at ease on this front, Dr. Marathe said. “A lot of parents are concerned that we’re going to do a speculum exam in their prepubertal child. So make sure that it’s clarified ahead of time that we’re not going to be doing a speculum exam.”

Commenting on this topic, Tor Shwayder, MD, a pediatric dermatologist at Henry Ford Health System, Detroit, urged colleagues to take action if they feel suspicious about a possible sign of child abuse, even if they’re far from certain that anything is wrong. “Don’t ignore those feelings in the back of the brain,” he said in an interview.

Most states have child-abuse hotlines for medical professionals, and major hospitals will have child-abuse teams, Dr. Shwayder said. He urged dermatologists to take advantage of these resources when appropriate. “The professionals on the other side of the 800 number or at the hospital will help you. You don’t have to decide immediately whether this is child abuse. You just need to have a suspicion.”

Dr. Marathe and Dr. Shwayder report no disclosures.

Genital skin exams in girls must be conducted with special care and alertness for signs of abuse, a dermatologist told colleagues at the American Academy of Dermatology Virtual Meeting Experience.

“One in four adult women report being childhood victims of sexual abuse, which is just a staggering number. This is an opportunity for us to identify these patients early and give them the terminology to be able to report what is happening to them,” said pediatric dermatologist Kalyani Marathe, MD, MPH, director of the division of dermatology at Cincinnati Children’s Hospital. “We also have the chance to give them a sense of agency over their bodies.”

Dr. Marathe offered the following recommendations when performing a genital skin exam:

• Make sure a “chaperone” is present. “Chaperones are a must when you’re examining children and teens,” she said. “Ask whom they prefer. For prepubertal children, you’re going to usually use the parent who’s there with them. If the parent is their father, they might ask him to step behind the curtain, in which case you can bring over your nurse or medical assistant.” Teens may ask either parent to step out of the room, she said. In that case, a nurse, medical assistant, resident, or trainee can fill in. “If you have male residents or trainees with you and the patient really does not want to be examined by a male, honor their request. Do not force them.”
• Explain why the exam is being performed. Make sure the patient understands why she is being seen, Dr. Marathe advised. For example, say something like “your pediatrician told us that you have an itchy area” or “your mom told us that there’s some loss of color in that area, that you’re having a problem there.” She added that it’s helpful to explain the type of doctor you are, with a comment such as the following: “We’re examining you because we’re doctors who specialize in skin. ... We want to help you feel better and make sure that your skin heals and is healthy.”
• Ask both the child and the parent for permission to perform the exam. While this may seem trivial, “it’s very, very important in setting the right tone for the encounter,” she said. “If the child says yes, we turn to the mom and say: ‘Mom, is it okay for us to do this exam today?’ You can see visible relief on the part of the parent, and as the parent relaxes, the child relaxes. Just saying those few things really makes the encounter so much smoother.” However, “if they say no, you have to honor the response. ... You say: ‘Okay, we’re not going to do the exam today,” and see the patient in a few weeks. If it’s urgent, an exam under anesthesia may be an option, she added.
• Talk to the child about the terms they use for private parts. It can be helpful to ask: “Do you have any terms for your private area?” According to Dr. Marathe, “this is a good chance to educate them on the terms vulva and vagina since they may be using other terminology. Making sure that they have the correct terms will actually help patients identify and report abuse earlier.” Dr. Marathe recalled that a colleague had a patient who’d been calling her private area “pound cake” and had been “reporting to her teacher that someone had been touching her ‘pound cake.’ Her teacher did not know what she meant by that, and this led to a great delay in her childhood abuse being reported.”
• Talk about what will happen during the exam. “I like to show them any instruments that we’re going to be using,” Dr. Marathe said. “If we’re using a flashlight, for example, I like to show them a picture [of a flashlight] or show them that flashlight. If we’re using a camera to do digital photography, show them that. If we’re going to be using a Q-tip or a swab to demonstrate anything or to take a culture, I like to show them that beforehand to make sure that they know what we’re doing.” In regard to photography, “make sure the parent and child know where the photos are going to go, who’s going to see them, what are they going to be used for. If they’re going to be used for educational purposes, make sure they have given explicit permission for that and they know they’ll be deidentified.”
• Make it clear that the exam won’t be painful. It’s important to put both the patient and the parent at ease on this front, Dr. Marathe said. “A lot of parents are concerned that we’re going to do a speculum exam in their prepubertal child. So make sure that it’s clarified ahead of time that we’re not going to be doing a speculum exam.”

Commenting on this topic, Tor Shwayder, MD, a pediatric dermatologist at Henry Ford Health System, Detroit, urged colleagues to take action if they feel suspicious about a possible sign of child abuse, even if they’re far from certain that anything is wrong. “Don’t ignore those feelings in the back of the brain,” he said in an interview.

Most states have child-abuse hotlines for medical professionals, and major hospitals will have child-abuse teams, Dr. Shwayder said. He urged dermatologists to take advantage of these resources when appropriate. “The professionals on the other side of the 800 number or at the hospital will help you. You don’t have to decide immediately whether this is child abuse. You just need to have a suspicion.”

Dr. Marathe and Dr. Shwayder report no disclosures.