Key clinical point: Treatment of irradiated peripheral blood mononuclear cells (PBMCs) with filgotinib in particular correlated with enhanced foci in vitro; the study was a rare comparison of all four JAKis approved for RA: tofacitinib, baricitinib, and upadacitinib, and filgotinib.

Major finding: Lymphocyte proliferation was similar for tofacitinib, baricitinib, and upadacitinib, while dosage of filgotinib was two orders of magnitude higher when these JAKis were added to peripheral blood mononuclear cells from healthy donors.

Study details: The data come from an in vitro study of four JAK inhibitors currently approved for the treatment of RA: tofacitinib, baricitinib, upadacitinib, and filgotinib, in which increasing concentrations of the JAKis or methotrexate were added to peripheral blood mononuclear cells from healthy volunteers.

Disclosures: The study was supported by the European Union Program Regional Development Fund of the Ministry of Economy, Science and Digitalisation in Saxony-Anhalt. Lead author Dr. Reddig had no financial conflicts to disclose.

Source: Reddig A et al. J Clin Med. 2021 Apr 1. doi: 103390/jcm10071431.

Key clinical point: Treatment of irradiated peripheral blood mononuclear cells (PBMCs) with filgotinib in particular correlated with enhanced foci in vitro; the study was a rare comparison of all four JAKis approved for RA: tofacitinib, baricitinib, and upadacitinib, and filgotinib.

Major finding: Lymphocyte proliferation was similar for tofacitinib, baricitinib, and upadacitinib, while dosage of filgotinib was two orders of magnitude higher when these JAKis were added to peripheral blood mononuclear cells from healthy donors.

Study details: The data come from an in vitro study of four JAK inhibitors currently approved for the treatment of RA: tofacitinib, baricitinib, upadacitinib, and filgotinib, in which increasing concentrations of the JAKis or methotrexate were added to peripheral blood mononuclear cells from healthy volunteers.

Disclosures: The study was supported by the European Union Program Regional Development Fund of the Ministry of Economy, Science and Digitalisation in Saxony-Anhalt. Lead author Dr. Reddig had no financial conflicts to disclose.

Source: Reddig A et al. J Clin Med. 2021 Apr 1. doi: 103390/jcm10071431.

Key clinical point: Treatment of irradiated peripheral blood mononuclear cells (PBMCs) with filgotinib in particular correlated with enhanced foci in vitro; the study was a rare comparison of all four JAKis approved for RA: tofacitinib, baricitinib, and upadacitinib, and filgotinib.

Major finding: Lymphocyte proliferation was similar for tofacitinib, baricitinib, and upadacitinib, while dosage of filgotinib was two orders of magnitude higher when these JAKis were added to peripheral blood mononuclear cells from healthy donors.

Study details: The data come from an in vitro study of four JAK inhibitors currently approved for the treatment of RA: tofacitinib, baricitinib, upadacitinib, and filgotinib, in which increasing concentrations of the JAKis or methotrexate were added to peripheral blood mononuclear cells from healthy volunteers.

Disclosures: The study was supported by the European Union Program Regional Development Fund of the Ministry of Economy, Science and Digitalisation in Saxony-Anhalt. Lead author Dr. Reddig had no financial conflicts to disclose.

Source: Reddig A et al. J Clin Med. 2021 Apr 1. doi: 103390/jcm10071431.

The association of RA and cardiovascular disease has been extensively described. Beta adrenergic receptors are not known to be involved in RA, though Abuhelwa et al. suggest a potential role in “immunologic balance” in their study of beta blocker use and RA remission. In a pooled analysis of five tocilizumab trials, use of beta blockers was associated with lower proportions of CDAI remission. However, without information on beta blocker dose or duration of therapy as well as potential confounding by indication, the significance of this finding is uncertain.

Another known association of RA and its treatment is malignancy, perhaps due to decrease in immunosurveillance; it remains a concern in choice of therapy and long-term effects. Solipuram et al. performed a systematic review of combination JAK inhibitor and methotrexate therapy in RA to evaluate the evidence regarding malignancy risk. Among the 13 trials included for analysis, 40 cases of malignancy were reported for over 3,600 patient-years in patients receiving combination therapy, compared to 7 cases among nearly 1,000 patient-years in patients receiving methotrexate alone; no change in relative risk was seen in non-melanomatous skin cancer or other cancers. While this information is reassuring, it does not eliminate the possibility of increased malignancy given variations in duration of followup in different studies.  There is also a need for longer follow-up because of a potential latency period before the development of cancer. Ideally, long-term extension studies could help better define this risk, though those studies tend to be single-armed and without a control.

Though different JAK inhibitors generally are thought to have similar efficacy and class-associated side effects, few studies have compared immunomodulatory effects of the medications. Reddig et al compared the effects of baricitinib, upadicitinib, filgotinib, tofacitinib, and methotrexate on cell proliferation, cell activation, and apoptosis, as well as induction of DNA damage and repair in an in vitro study. The study authors used human peripheral blood monocytes treated with phytohemagglutinin to activate T cells and induce proliferation. Tofacitinib, baricitinib, and upadicitinib were associated with comparable dose-dependent inhibition of lymphocyte activation and proliferation. Higher doses of filgotinib were required to obtain the same effect. Filgotinib at high concentrations also were associated with higher levels of DNA damage markers. These findings are interesting as to the shared mechanism of action of JAK inhibitors, regardless of JAK specificity. However, given the lack of “universal” patterns in vitro, their clinical importance or relevance in distinguishing between the medications is unclear.

Kim et al. investigates the pathogenesis of RA in their in vitro study of mast cells. Though previously identified in RA synovial fluid and tissue and not in OA synovium, their role is not entirely clear. Though normally associated with allergic responses, mast cells have been postulated to have pro- and anti-inflammatory effects, and release inflammatory cytokines and mediators, such as histamine. Synovial fluid and serum samples from RA and OA patients, as well as healthy volunteers, were analyzed for tryptase, chymase, and histamine; serum levels of all three were higher in RA than in OA patients and healthy volunteers. Synovial fluid levels of histamine were higher in RA. Cell culture studies were performed using IL-33 to activate human mast cells, causing an increase in tryptase –positive cells, as well as an increased expression of RANKL and MMP-9. This suggests a role for mast cells in osteoclastogenesis and tissue degradation. In addition to providing more information about the involvement of mast cells in RA pathogenesis, these findings suggest mast cells as a potential therapeutic target.

The association of RA and cardiovascular disease has been extensively described. Beta adrenergic receptors are not known to be involved in RA, though Abuhelwa et al. suggest a potential role in “immunologic balance” in their study of beta blocker use and RA remission. In a pooled analysis of five tocilizumab trials, use of beta blockers was associated with lower proportions of CDAI remission. However, without information on beta blocker dose or duration of therapy as well as potential confounding by indication, the significance of this finding is uncertain.

Another known association of RA and its treatment is malignancy, perhaps due to decrease in immunosurveillance; it remains a concern in choice of therapy and long-term effects. Solipuram et al. performed a systematic review of combination JAK inhibitor and methotrexate therapy in RA to evaluate the evidence regarding malignancy risk. Among the 13 trials included for analysis, 40 cases of malignancy were reported for over 3,600 patient-years in patients receiving combination therapy, compared to 7 cases among nearly 1,000 patient-years in patients receiving methotrexate alone; no change in relative risk was seen in non-melanomatous skin cancer or other cancers. While this information is reassuring, it does not eliminate the possibility of increased malignancy given variations in duration of followup in different studies.  There is also a need for longer follow-up because of a potential latency period before the development of cancer. Ideally, long-term extension studies could help better define this risk, though those studies tend to be single-armed and without a control.

Though different JAK inhibitors generally are thought to have similar efficacy and class-associated side effects, few studies have compared immunomodulatory effects of the medications. Reddig et al compared the effects of baricitinib, upadicitinib, filgotinib, tofacitinib, and methotrexate on cell proliferation, cell activation, and apoptosis, as well as induction of DNA damage and repair in an in vitro study. The study authors used human peripheral blood monocytes treated with phytohemagglutinin to activate T cells and induce proliferation. Tofacitinib, baricitinib, and upadicitinib were associated with comparable dose-dependent inhibition of lymphocyte activation and proliferation. Higher doses of filgotinib were required to obtain the same effect. Filgotinib at high concentrations also were associated with higher levels of DNA damage markers. These findings are interesting as to the shared mechanism of action of JAK inhibitors, regardless of JAK specificity. However, given the lack of “universal” patterns in vitro, their clinical importance or relevance in distinguishing between the medications is unclear.

Kim et al. investigates the pathogenesis of RA in their in vitro study of mast cells. Though previously identified in RA synovial fluid and tissue and not in OA synovium, their role is not entirely clear. Though normally associated with allergic responses, mast cells have been postulated to have pro- and anti-inflammatory effects, and release inflammatory cytokines and mediators, such as histamine. Synovial fluid and serum samples from RA and OA patients, as well as healthy volunteers, were analyzed for tryptase, chymase, and histamine; serum levels of all three were higher in RA than in OA patients and healthy volunteers. Synovial fluid levels of histamine were higher in RA. Cell culture studies were performed using IL-33 to activate human mast cells, causing an increase in tryptase –positive cells, as well as an increased expression of RANKL and MMP-9. This suggests a role for mast cells in osteoclastogenesis and tissue degradation. In addition to providing more information about the involvement of mast cells in RA pathogenesis, these findings suggest mast cells as a potential therapeutic target.

The association of RA and cardiovascular disease has been extensively described. Beta adrenergic receptors are not known to be involved in RA, though Abuhelwa et al. suggest a potential role in “immunologic balance” in their study of beta blocker use and RA remission. In a pooled analysis of five tocilizumab trials, use of beta blockers was associated with lower proportions of CDAI remission. However, without information on beta blocker dose or duration of therapy as well as potential confounding by indication, the significance of this finding is uncertain.

Another known association of RA and its treatment is malignancy, perhaps due to decrease in immunosurveillance; it remains a concern in choice of therapy and long-term effects. Solipuram et al. performed a systematic review of combination JAK inhibitor and methotrexate therapy in RA to evaluate the evidence regarding malignancy risk. Among the 13 trials included for analysis, 40 cases of malignancy were reported for over 3,600 patient-years in patients receiving combination therapy, compared to 7 cases among nearly 1,000 patient-years in patients receiving methotrexate alone; no change in relative risk was seen in non-melanomatous skin cancer or other cancers. While this information is reassuring, it does not eliminate the possibility of increased malignancy given variations in duration of followup in different studies.  There is also a need for longer follow-up because of a potential latency period before the development of cancer. Ideally, long-term extension studies could help better define this risk, though those studies tend to be single-armed and without a control.

Though different JAK inhibitors generally are thought to have similar efficacy and class-associated side effects, few studies have compared immunomodulatory effects of the medications. Reddig et al compared the effects of baricitinib, upadicitinib, filgotinib, tofacitinib, and methotrexate on cell proliferation, cell activation, and apoptosis, as well as induction of DNA damage and repair in an in vitro study. The study authors used human peripheral blood monocytes treated with phytohemagglutinin to activate T cells and induce proliferation. Tofacitinib, baricitinib, and upadicitinib were associated with comparable dose-dependent inhibition of lymphocyte activation and proliferation. Higher doses of filgotinib were required to obtain the same effect. Filgotinib at high concentrations also were associated with higher levels of DNA damage markers. These findings are interesting as to the shared mechanism of action of JAK inhibitors, regardless of JAK specificity. However, given the lack of “universal” patterns in vitro, their clinical importance or relevance in distinguishing between the medications is unclear.

Kim et al. investigates the pathogenesis of RA in their in vitro study of mast cells. Though previously identified in RA synovial fluid and tissue and not in OA synovium, their role is not entirely clear. Though normally associated with allergic responses, mast cells have been postulated to have pro- and anti-inflammatory effects, and release inflammatory cytokines and mediators, such as histamine. Synovial fluid and serum samples from RA and OA patients, as well as healthy volunteers, were analyzed for tryptase, chymase, and histamine; serum levels of all three were higher in RA than in OA patients and healthy volunteers. Synovial fluid levels of histamine were higher in RA. Cell culture studies were performed using IL-33 to activate human mast cells, causing an increase in tryptase –positive cells, as well as an increased expression of RANKL and MMP-9. This suggests a role for mast cells in osteoclastogenesis and tissue degradation. In addition to providing more information about the involvement of mast cells in RA pathogenesis, these findings suggest mast cells as a potential therapeutic target.

The American Heart Association, the American College of Cardiology, and the Obesity Society define overweight as a body mass index (BMI) of 25 to 29.9 and obesity as a BMI ≥ 30. Morbid obesity is defined as a BMI ≥ 35 or 40.^2,3 Based on these BMI cutoffs, the Endocrine Society recommends diet and lifestyle as the foundation of weight management and pharmacotherapy for those with a BMI ≥ 30 without comorbidities. In patients with a BMI ≥ 27, weight management medications may be considered if a patient has comorbid hypertension, T2DM, dyslipidemia, metabolic syndrome, obstructive sleep apnea, or nonalcoholic fatty liver disease. Patients with BMI > 40 are eligible for weight loss surgery.⁴

Lifestyle and dietary interventions are the foundation of current weight management guidelines from the Endocrine Society.⁴ At a minimum, guidelines recommended enrolling motivated patients in a high-intensity lifestyle intervention class of at least 14 sessions in the first 6 months to reach a goal weight loss of 5 to 10% from baseline and to maintain a reduction of 3 to 5% from baseline.³ Medications are recommended as an adjunct to lifestyle and dietary changes. Most weight management medications work in the brain to stimulate satiety signaling, which helps motivated patients adhere to their dietary interventions, assist those who have been unsuccessful in earlier weight loss attempts, and help maintain weight.^3,4

Guidelines recommend 7 weight management medications, including orlistat (both prescription strength and over-the-counter), liraglutide, phentermine, phentermine/topiramate, lorcaserin, and naltrexone/bupropion. Using medications to assist with weight loss increases likelihood that patients will achieve 5 to 10% weight loss from baseline.^5,6 Studies looking at long-term effects of these medications on weight loss have found improvements in blood pressure (BP), biomarkers for cardiovascular disease, and T2DM-related comorbidities.^3,5,7

Positive effects on comorbidities have been found to be related to drug class and mechanism of action (MOA); those that also are approved for T2DM have demonstrated the most favorable cardiovascular effects.⁷ Other medications that work as stimulants or as modulators of serotonin pathways are associated with increased risks, prompting the US Food and Drug Administration (FDA) to remove some medications from the market.^7,8 In January 2020, lorcaserin was taken off the market because of increased risk of cancer found in postmarketing surveillance.⁹ The benefit of weight loss must be weighed against the risk of medication use.

Monthly follow-up is recommended with weight management medications in the beginning to assess safety and efficacy; medications should be discontinued if weight loss is inadequate in the first 3 months.^1,3,4 Limited studies have assessed the long-term use of weight management medications in a real-world setting. Medications are prescribed for weight management at Veteran Health Indiana (VHI) in outpatient clinics, including primary care, endocrinology, and gastrointestinal (GI) specialties. However, prescribing practices, outcomes, and adherence to guideline recommendations have not been studied. Data from this study will be used to better understand how VHI can serve its veterans through diet, lifestyle, and pharmacologic interventions.

Methods

We conducted a single-center, retrospective chart review for patients started on weight management medications at VHI. A patient list was generated based on prescription fills from June 1, 2017 to June 30, 2019. All data were obtained using the Computerized Patient Record System and patients were not contacted. This study was approved by the Indiana University Health Institutional Review Board and the VHI Research and Development Committee.

At the time of study, orlistat, liraglutide, phentermine/topiramate, lorcaserin, and naltrexone/bupropion were available at VHI for patients who met the criteria. All patients must have been enrolled in dietary and lifestyle management to be approved for these medications. The US Department of Veterans Affairs (VA) MOVE! weight management program, designed by the VA National Center for Health Promotion and Disease Promotion, is available at VA sites throughout the country. After MOVE! orientation, patients can participate in group or individual 12-week programs that include weigh ins, goal-setting strategies, meal planning, and habit modification support. If patients are unable to meet in person, phone and other telehealth opportunities are available.

Patients were included in the study if they received a prescription of any 1 of the 5 available medications during the enrollment period. Patients were excluded if they received a prescription from or were treated by a civilian health care provider, if they never used the medication, or if their weight loss was attributed to a cancer diagnosis. These criteria produced 86 patients of whom 96 unique weight loss prescriptions were generated. Data were collected for each instance of medication use so that some patients were included multiple times. In this case, data collection for the failed medication ended when failure was documented, and new data points began when new medication was prescribed; all data collected were per medication, not per patient. This method was used to account for medication failure and provide accurate weight loss results based on medication choice within this institution.

The primary outcomes included total weight loss and weight loss as a percentage of baseline weight at 3, 6, 12, and > 12 months of therapy. Secondary outcomes included weight loss of 5% from baseline, rate of successful weight maintenance after initial weight loss of 5% from baseline, adverse drug reaction (ADR) monitoring, and use of weight management medications across clinics at VHI.

Demographic data included race, age, sex, baseline weight, BMI, and comorbid medical conditions. Comorbidities were collected based on the most recent primary care clinical note before initiating medication. Medication data collected included medications used to manage comorbidities. Data related to weight management medication included prescribing clinic, reason for medication discontinuation, or bariatric surgery intervention if applicable.

Efficacy outcome data included weight and BMI across therapy duration. Safety outcomes data included heart rate, BP, and ADRs that resulted in medication discontinuation as documented in the electronic health record (EHR).

Results

A total of 86 patients were identified based on prescription fills, which produced 99 unique instances of medication use. Of the 99 identified, 3 met exclusion criteria and were not included in the final analysis. Among included veterans, 16 were female and 80 were male (Table 1). Most of those included identified as White race (86%), male (83%), and mean age 53 years. At baseline, mean weight was 130 kg and mean BMI 41.

Comorbidities and Medication Use

Hypertension (66%), hyperlipidemia (64%), and psychiatric diagnoses (50%) were most common comorbid conditions. Substance use (23%) and T2DM (40%) were the most common comorbidities influencing medication choice. Substance use evaluation included amphetamines and cocaine for this analysis.

Phentermine/topiramate is the preferred first-line agent unless patients have contraindications for use, in which case naltrexone/bupropion is recommended, based on guidelines for weight management medications within the VHI system. However, for patients with comorbid T2DM, liraglutide is preferred because of its beneficial effects for both weight loss and blood glucose control.² Most patients at VHI were started on liraglutide (44%) or phentermine/topiramate (42%), which was in line with recommendations. Our sample included ≥ 1 prescription for each medication available at our facility, although the number of patients on each medication was not equal. Of note, the one patient taking lorcaserin at the time of study discontinued therapy in response to recent FDA guidance.⁹

Medications for comorbid conditions could contribute to weight gain. Of the patient sample, β blockers (n = 24) and anticonvulsants, including gabapentin and pregabalin (n = 22) were the most common Other medications that could have contributed to weight gain included sulfonylureas (n = 5), antipsychotics (n = 4), tricyclic antidepressants (n = 2), and hormone replacement therapies (n = 2).

Primary Outcomes

The mean weight of participants dropped from 129.9 to 114.2 kg over the 12 months of weight management medication therapy for a absolute difference of 15.8 kg (Figure 1 and eTable 1 available at doi:10.12788/fp.0117). Weight loss was recorded at 3, 6, 12, and > 12 months of weight management therapy. At each time point, weight loss was statistically significant (P < .001) compared with baseline (Table 2), even though not every patient had weight loss records at each time point.

When classified by medication choice, mean change in weight was orlistat −25.9 kg (n = 5); lorcaserin −22.5 kg (n = 1); liraglutide −10.3 kg (n = 43); phentermine/topiramate −5.0 kg (n = 42); and naltrexone/ bupropion +2.1 kg (n = 5) over the duration of the study (eTable 2 available at doi:10.12788/fp.0117). Patients receiving orlistat and liraglutide had increasing weight loss across the duration of treatment compared with those on lorcaserin who had initial weight gain before weight loss. Phentermine/topiramate showed initial weight loss that tapered off, and naltrexone/bupropion demonstrated initial weight loss with eventual weight gain at study end point.

Secondary Outcomes

More than one-half of the patients analyzed lost 5 to 10% from baseline while taking weight management medication. Fifty-six (59%) patients lost 5% at any point while on therapy (Table 3). Among those patients, 31 (32%) lost ≥ 10% from baseline. When looking at success related to guideline recommendations, 32 (38%) patients lost 5% from baseline in the first 3 months of medication therapy.

Among patients who lost at least 5% from baseline, we performed further analysis to assess weight maintenance of 3 to 5% from baseline for 12 months. In the 12 months after initial weight loss, the number of patients who were able to maintain their weight loss steadily declined (Figure 2). In the end, 17 (30%) of patients who achieved 5 to 10% weight loss at baseline were able to maintain weight loss. Only 18% of study patients were able to achieve guideline-directed weight loss and maintain that weight for 12 months.

Discussion

This study evaluated the use and outcomes of weight management medication among veterans at VHI. The study aimed to better understand the efficacy and safety of these medications while exposing potential weaknesses in care and to promote avenues to improve weight loss and maintenance.

Clinical trials for weight management medications reported weight loss of 8 to 10 kg over 56 weeks: 21 to 63% of patients losing at least 5% from baseline weight.^10-14 The findings from our study found a higher average weight loss (−15.8 kg) than that reported in trials and a consistent percentage of patients (58.3%) who achieved at least 5% weight loss. It is promising to see that when used in a noncontrolled setting, these medications were able to produce weight loss consistent with results seen in large, controlled trials.

Pi-Sunyer and colleagues found continued weight loss after the initial 5% weight loss to an eventual 10% weight loss in many patients.¹⁰ Additionally, Smith and colleagues found that nearly 68% of their participants who took lorcaserin were able to maintain 3 to 5% weight loss over 12 months.¹³ Sjöström and colleagues acknowledged that many patients taking orlistat for an extended period began to gain weight, although at one-half the rate than that seen in the placebo group.¹² This study found that fewer patients were able to maintain their weight loss over 12 months, with only 30% of patients maintaining 3 to 5% weight loss from baseline. This difference in weight maintenance likely was because of the uncontrolled nature of this study. Once patients reach their initial weight loss goal, even the most motivated patients will have trouble maintaining that weight.⁴ Despite the challenges associated with maintaining weight loss, the quality of life benefits patients gained and potential reductions in health care spending support using resources to improve these outcomes.^2,14,15

Pi-Sunyer and colleagues reported high incidences of nausea (40%), vomiting (16%), diarrhea (21%), and constipation (20%) with liraglutide.¹⁰ Sjöström and colleagues reported 7% of patients experienced GI upset with orlistat.¹² Comparatively, only 17% of our patients reported AEs that required discontinuation, including GI upset. One patient in our study discontinued naltrexone/bupropion because of a significant change in mental status and suicide attempt. Clinical trials did not report a greater risk of depression or suicidality compared with placebo; however, there is a warning on the labeling of naltrexone/bupropion for increased suicidality with the use of antidepressant agents.^16,17 The neurologic AE that required discontinuation of phentermine/topiramate at our institution is unique based on published information.^11,18

The data from this study reinforced the observation that weight maintenance is the most challenging aspect of weight loss. Although our data showed clinically meaningful weight loss from baseline, many patients regained their weight, and some exceeded their baseline weight. Beyond providing these medications, this evidence suggests the need for close, continued follow-up through patients’ weight loss journey.

Limitations

Because this is a retrospective chart review, data collection was influenced by and limited to information that had been recorded in the EHR. AEs that resulted in medication discontinuation were assessed from the patient’s chart, which might not be correct if providers did not update the records. Follow-up was not always scheduled at regular intervals after medication initiation, resulting in varying sample numbers at each time point, potentially interfering with true weight loss averages. Although not included in this analysis, it might be beneficial to evaluate adherence to recommendations for follow-up with laboratory and weight monitoring to better capture where future monitoring can be improved. Second, there was an unbalanced number of patients taking each medication. Specifically, we saw a change in weight with orlistat that exceeded what is consistently seen in larger, more controlled trials. Although this is an effect of the real world, small sample sizes cannot be generalized to the larger population and might result in data reflecting that of an outlier. Last, there is a lack of generalizability because of the veteran population demographic, which is more male and lacks ethnic diversity. This study also was carried out at a single, educational tertiary medical center, which might not apply to all populations.

Conclusions

Despite the limitations discussed, this study shows that the use of weight management medications in a general veteran population produces initial weight loss consistent with previous studies. However, there is room for continued improvement in follow-up strategies to promote greater weight maintenance after initial weight loss. Considering the high health care costs, personal burden, and potential long-term complications associated with obesity, efforts to promote development of programs that support weight management and maintenance are imperative.

Acknowledgment
This material is the result of work supported with resources and the use of facilities at Veteran Health Indiana.

The American Heart Association, the American College of Cardiology, and the Obesity Society define overweight as a body mass index (BMI) of 25 to 29.9 and obesity as a BMI ≥ 30. Morbid obesity is defined as a BMI ≥ 35 or 40.^2,3 Based on these BMI cutoffs, the Endocrine Society recommends diet and lifestyle as the foundation of weight management and pharmacotherapy for those with a BMI ≥ 30 without comorbidities. In patients with a BMI ≥ 27, weight management medications may be considered if a patient has comorbid hypertension, T2DM, dyslipidemia, metabolic syndrome, obstructive sleep apnea, or nonalcoholic fatty liver disease. Patients with BMI > 40 are eligible for weight loss surgery.⁴

Lifestyle and dietary interventions are the foundation of current weight management guidelines from the Endocrine Society.⁴ At a minimum, guidelines recommended enrolling motivated patients in a high-intensity lifestyle intervention class of at least 14 sessions in the first 6 months to reach a goal weight loss of 5 to 10% from baseline and to maintain a reduction of 3 to 5% from baseline.³ Medications are recommended as an adjunct to lifestyle and dietary changes. Most weight management medications work in the brain to stimulate satiety signaling, which helps motivated patients adhere to their dietary interventions, assist those who have been unsuccessful in earlier weight loss attempts, and help maintain weight.^3,4

Guidelines recommend 7 weight management medications, including orlistat (both prescription strength and over-the-counter), liraglutide, phentermine, phentermine/topiramate, lorcaserin, and naltrexone/bupropion. Using medications to assist with weight loss increases likelihood that patients will achieve 5 to 10% weight loss from baseline.^5,6 Studies looking at long-term effects of these medications on weight loss have found improvements in blood pressure (BP), biomarkers for cardiovascular disease, and T2DM-related comorbidities.^3,5,7

Positive effects on comorbidities have been found to be related to drug class and mechanism of action (MOA); those that also are approved for T2DM have demonstrated the most favorable cardiovascular effects.⁷ Other medications that work as stimulants or as modulators of serotonin pathways are associated with increased risks, prompting the US Food and Drug Administration (FDA) to remove some medications from the market.^7,8 In January 2020, lorcaserin was taken off the market because of increased risk of cancer found in postmarketing surveillance.⁹ The benefit of weight loss must be weighed against the risk of medication use.

Monthly follow-up is recommended with weight management medications in the beginning to assess safety and efficacy; medications should be discontinued if weight loss is inadequate in the first 3 months.^1,3,4 Limited studies have assessed the long-term use of weight management medications in a real-world setting. Medications are prescribed for weight management at Veteran Health Indiana (VHI) in outpatient clinics, including primary care, endocrinology, and gastrointestinal (GI) specialties. However, prescribing practices, outcomes, and adherence to guideline recommendations have not been studied. Data from this study will be used to better understand how VHI can serve its veterans through diet, lifestyle, and pharmacologic interventions.

Methods

We conducted a single-center, retrospective chart review for patients started on weight management medications at VHI. A patient list was generated based on prescription fills from June 1, 2017 to June 30, 2019. All data were obtained using the Computerized Patient Record System and patients were not contacted. This study was approved by the Indiana University Health Institutional Review Board and the VHI Research and Development Committee.

At the time of study, orlistat, liraglutide, phentermine/topiramate, lorcaserin, and naltrexone/bupropion were available at VHI for patients who met the criteria. All patients must have been enrolled in dietary and lifestyle management to be approved for these medications. The US Department of Veterans Affairs (VA) MOVE! weight management program, designed by the VA National Center for Health Promotion and Disease Promotion, is available at VA sites throughout the country. After MOVE! orientation, patients can participate in group or individual 12-week programs that include weigh ins, goal-setting strategies, meal planning, and habit modification support. If patients are unable to meet in person, phone and other telehealth opportunities are available.

Patients were included in the study if they received a prescription of any 1 of the 5 available medications during the enrollment period. Patients were excluded if they received a prescription from or were treated by a civilian health care provider, if they never used the medication, or if their weight loss was attributed to a cancer diagnosis. These criteria produced 86 patients of whom 96 unique weight loss prescriptions were generated. Data were collected for each instance of medication use so that some patients were included multiple times. In this case, data collection for the failed medication ended when failure was documented, and new data points began when new medication was prescribed; all data collected were per medication, not per patient. This method was used to account for medication failure and provide accurate weight loss results based on medication choice within this institution.

The primary outcomes included total weight loss and weight loss as a percentage of baseline weight at 3, 6, 12, and > 12 months of therapy. Secondary outcomes included weight loss of 5% from baseline, rate of successful weight maintenance after initial weight loss of 5% from baseline, adverse drug reaction (ADR) monitoring, and use of weight management medications across clinics at VHI.

Demographic data included race, age, sex, baseline weight, BMI, and comorbid medical conditions. Comorbidities were collected based on the most recent primary care clinical note before initiating medication. Medication data collected included medications used to manage comorbidities. Data related to weight management medication included prescribing clinic, reason for medication discontinuation, or bariatric surgery intervention if applicable.

Efficacy outcome data included weight and BMI across therapy duration. Safety outcomes data included heart rate, BP, and ADRs that resulted in medication discontinuation as documented in the electronic health record (EHR).

Results

A total of 86 patients were identified based on prescription fills, which produced 99 unique instances of medication use. Of the 99 identified, 3 met exclusion criteria and were not included in the final analysis. Among included veterans, 16 were female and 80 were male (Table 1). Most of those included identified as White race (86%), male (83%), and mean age 53 years. At baseline, mean weight was 130 kg and mean BMI 41.

Comorbidities and Medication Use

Hypertension (66%), hyperlipidemia (64%), and psychiatric diagnoses (50%) were most common comorbid conditions. Substance use (23%) and T2DM (40%) were the most common comorbidities influencing medication choice. Substance use evaluation included amphetamines and cocaine for this analysis.

Phentermine/topiramate is the preferred first-line agent unless patients have contraindications for use, in which case naltrexone/bupropion is recommended, based on guidelines for weight management medications within the VHI system. However, for patients with comorbid T2DM, liraglutide is preferred because of its beneficial effects for both weight loss and blood glucose control.² Most patients at VHI were started on liraglutide (44%) or phentermine/topiramate (42%), which was in line with recommendations. Our sample included ≥ 1 prescription for each medication available at our facility, although the number of patients on each medication was not equal. Of note, the one patient taking lorcaserin at the time of study discontinued therapy in response to recent FDA guidance.⁹

Medications for comorbid conditions could contribute to weight gain. Of the patient sample, β blockers (n = 24) and anticonvulsants, including gabapentin and pregabalin (n = 22) were the most common Other medications that could have contributed to weight gain included sulfonylureas (n = 5), antipsychotics (n = 4), tricyclic antidepressants (n = 2), and hormone replacement therapies (n = 2).

Primary Outcomes

The mean weight of participants dropped from 129.9 to 114.2 kg over the 12 months of weight management medication therapy for a absolute difference of 15.8 kg (Figure 1 and eTable 1 available at doi:10.12788/fp.0117). Weight loss was recorded at 3, 6, 12, and > 12 months of weight management therapy. At each time point, weight loss was statistically significant (P < .001) compared with baseline (Table 2), even though not every patient had weight loss records at each time point.

When classified by medication choice, mean change in weight was orlistat −25.9 kg (n = 5); lorcaserin −22.5 kg (n = 1); liraglutide −10.3 kg (n = 43); phentermine/topiramate −5.0 kg (n = 42); and naltrexone/ bupropion +2.1 kg (n = 5) over the duration of the study (eTable 2 available at doi:10.12788/fp.0117). Patients receiving orlistat and liraglutide had increasing weight loss across the duration of treatment compared with those on lorcaserin who had initial weight gain before weight loss. Phentermine/topiramate showed initial weight loss that tapered off, and naltrexone/bupropion demonstrated initial weight loss with eventual weight gain at study end point.

Secondary Outcomes

More than one-half of the patients analyzed lost 5 to 10% from baseline while taking weight management medication. Fifty-six (59%) patients lost 5% at any point while on therapy (Table 3). Among those patients, 31 (32%) lost ≥ 10% from baseline. When looking at success related to guideline recommendations, 32 (38%) patients lost 5% from baseline in the first 3 months of medication therapy.

Among patients who lost at least 5% from baseline, we performed further analysis to assess weight maintenance of 3 to 5% from baseline for 12 months. In the 12 months after initial weight loss, the number of patients who were able to maintain their weight loss steadily declined (Figure 2). In the end, 17 (30%) of patients who achieved 5 to 10% weight loss at baseline were able to maintain weight loss. Only 18% of study patients were able to achieve guideline-directed weight loss and maintain that weight for 12 months.

Discussion

This study evaluated the use and outcomes of weight management medication among veterans at VHI. The study aimed to better understand the efficacy and safety of these medications while exposing potential weaknesses in care and to promote avenues to improve weight loss and maintenance.

Clinical trials for weight management medications reported weight loss of 8 to 10 kg over 56 weeks: 21 to 63% of patients losing at least 5% from baseline weight.^10-14 The findings from our study found a higher average weight loss (−15.8 kg) than that reported in trials and a consistent percentage of patients (58.3%) who achieved at least 5% weight loss. It is promising to see that when used in a noncontrolled setting, these medications were able to produce weight loss consistent with results seen in large, controlled trials.

Pi-Sunyer and colleagues found continued weight loss after the initial 5% weight loss to an eventual 10% weight loss in many patients.¹⁰ Additionally, Smith and colleagues found that nearly 68% of their participants who took lorcaserin were able to maintain 3 to 5% weight loss over 12 months.¹³ Sjöström and colleagues acknowledged that many patients taking orlistat for an extended period began to gain weight, although at one-half the rate than that seen in the placebo group.¹² This study found that fewer patients were able to maintain their weight loss over 12 months, with only 30% of patients maintaining 3 to 5% weight loss from baseline. This difference in weight maintenance likely was because of the uncontrolled nature of this study. Once patients reach their initial weight loss goal, even the most motivated patients will have trouble maintaining that weight.⁴ Despite the challenges associated with maintaining weight loss, the quality of life benefits patients gained and potential reductions in health care spending support using resources to improve these outcomes.^2,14,15

Pi-Sunyer and colleagues reported high incidences of nausea (40%), vomiting (16%), diarrhea (21%), and constipation (20%) with liraglutide.¹⁰ Sjöström and colleagues reported 7% of patients experienced GI upset with orlistat.¹² Comparatively, only 17% of our patients reported AEs that required discontinuation, including GI upset. One patient in our study discontinued naltrexone/bupropion because of a significant change in mental status and suicide attempt. Clinical trials did not report a greater risk of depression or suicidality compared with placebo; however, there is a warning on the labeling of naltrexone/bupropion for increased suicidality with the use of antidepressant agents.^16,17 The neurologic AE that required discontinuation of phentermine/topiramate at our institution is unique based on published information.^11,18

The data from this study reinforced the observation that weight maintenance is the most challenging aspect of weight loss. Although our data showed clinically meaningful weight loss from baseline, many patients regained their weight, and some exceeded their baseline weight. Beyond providing these medications, this evidence suggests the need for close, continued follow-up through patients’ weight loss journey.

Limitations

Because this is a retrospective chart review, data collection was influenced by and limited to information that had been recorded in the EHR. AEs that resulted in medication discontinuation were assessed from the patient’s chart, which might not be correct if providers did not update the records. Follow-up was not always scheduled at regular intervals after medication initiation, resulting in varying sample numbers at each time point, potentially interfering with true weight loss averages. Although not included in this analysis, it might be beneficial to evaluate adherence to recommendations for follow-up with laboratory and weight monitoring to better capture where future monitoring can be improved. Second, there was an unbalanced number of patients taking each medication. Specifically, we saw a change in weight with orlistat that exceeded what is consistently seen in larger, more controlled trials. Although this is an effect of the real world, small sample sizes cannot be generalized to the larger population and might result in data reflecting that of an outlier. Last, there is a lack of generalizability because of the veteran population demographic, which is more male and lacks ethnic diversity. This study also was carried out at a single, educational tertiary medical center, which might not apply to all populations.

Conclusions

Despite the limitations discussed, this study shows that the use of weight management medications in a general veteran population produces initial weight loss consistent with previous studies. However, there is room for continued improvement in follow-up strategies to promote greater weight maintenance after initial weight loss. Considering the high health care costs, personal burden, and potential long-term complications associated with obesity, efforts to promote development of programs that support weight management and maintenance are imperative.

Acknowledgment
This material is the result of work supported with resources and the use of facilities at Veteran Health Indiana.

The American Heart Association, the American College of Cardiology, and the Obesity Society define overweight as a body mass index (BMI) of 25 to 29.9 and obesity as a BMI ≥ 30. Morbid obesity is defined as a BMI ≥ 35 or 40.^2,3 Based on these BMI cutoffs, the Endocrine Society recommends diet and lifestyle as the foundation of weight management and pharmacotherapy for those with a BMI ≥ 30 without comorbidities. In patients with a BMI ≥ 27, weight management medications may be considered if a patient has comorbid hypertension, T2DM, dyslipidemia, metabolic syndrome, obstructive sleep apnea, or nonalcoholic fatty liver disease. Patients with BMI > 40 are eligible for weight loss surgery.⁴

Lifestyle and dietary interventions are the foundation of current weight management guidelines from the Endocrine Society.⁴ At a minimum, guidelines recommended enrolling motivated patients in a high-intensity lifestyle intervention class of at least 14 sessions in the first 6 months to reach a goal weight loss of 5 to 10% from baseline and to maintain a reduction of 3 to 5% from baseline.³ Medications are recommended as an adjunct to lifestyle and dietary changes. Most weight management medications work in the brain to stimulate satiety signaling, which helps motivated patients adhere to their dietary interventions, assist those who have been unsuccessful in earlier weight loss attempts, and help maintain weight.^3,4

Guidelines recommend 7 weight management medications, including orlistat (both prescription strength and over-the-counter), liraglutide, phentermine, phentermine/topiramate, lorcaserin, and naltrexone/bupropion. Using medications to assist with weight loss increases likelihood that patients will achieve 5 to 10% weight loss from baseline.^5,6 Studies looking at long-term effects of these medications on weight loss have found improvements in blood pressure (BP), biomarkers for cardiovascular disease, and T2DM-related comorbidities.^3,5,7

Positive effects on comorbidities have been found to be related to drug class and mechanism of action (MOA); those that also are approved for T2DM have demonstrated the most favorable cardiovascular effects.⁷ Other medications that work as stimulants or as modulators of serotonin pathways are associated with increased risks, prompting the US Food and Drug Administration (FDA) to remove some medications from the market.^7,8 In January 2020, lorcaserin was taken off the market because of increased risk of cancer found in postmarketing surveillance.⁹ The benefit of weight loss must be weighed against the risk of medication use.

Monthly follow-up is recommended with weight management medications in the beginning to assess safety and efficacy; medications should be discontinued if weight loss is inadequate in the first 3 months.^1,3,4 Limited studies have assessed the long-term use of weight management medications in a real-world setting. Medications are prescribed for weight management at Veteran Health Indiana (VHI) in outpatient clinics, including primary care, endocrinology, and gastrointestinal (GI) specialties. However, prescribing practices, outcomes, and adherence to guideline recommendations have not been studied. Data from this study will be used to better understand how VHI can serve its veterans through diet, lifestyle, and pharmacologic interventions.

Methods

We conducted a single-center, retrospective chart review for patients started on weight management medications at VHI. A patient list was generated based on prescription fills from June 1, 2017 to June 30, 2019. All data were obtained using the Computerized Patient Record System and patients were not contacted. This study was approved by the Indiana University Health Institutional Review Board and the VHI Research and Development Committee.

At the time of study, orlistat, liraglutide, phentermine/topiramate, lorcaserin, and naltrexone/bupropion were available at VHI for patients who met the criteria. All patients must have been enrolled in dietary and lifestyle management to be approved for these medications. The US Department of Veterans Affairs (VA) MOVE! weight management program, designed by the VA National Center for Health Promotion and Disease Promotion, is available at VA sites throughout the country. After MOVE! orientation, patients can participate in group or individual 12-week programs that include weigh ins, goal-setting strategies, meal planning, and habit modification support. If patients are unable to meet in person, phone and other telehealth opportunities are available.

Patients were included in the study if they received a prescription of any 1 of the 5 available medications during the enrollment period. Patients were excluded if they received a prescription from or were treated by a civilian health care provider, if they never used the medication, or if their weight loss was attributed to a cancer diagnosis. These criteria produced 86 patients of whom 96 unique weight loss prescriptions were generated. Data were collected for each instance of medication use so that some patients were included multiple times. In this case, data collection for the failed medication ended when failure was documented, and new data points began when new medication was prescribed; all data collected were per medication, not per patient. This method was used to account for medication failure and provide accurate weight loss results based on medication choice within this institution.

The primary outcomes included total weight loss and weight loss as a percentage of baseline weight at 3, 6, 12, and > 12 months of therapy. Secondary outcomes included weight loss of 5% from baseline, rate of successful weight maintenance after initial weight loss of 5% from baseline, adverse drug reaction (ADR) monitoring, and use of weight management medications across clinics at VHI.

Demographic data included race, age, sex, baseline weight, BMI, and comorbid medical conditions. Comorbidities were collected based on the most recent primary care clinical note before initiating medication. Medication data collected included medications used to manage comorbidities. Data related to weight management medication included prescribing clinic, reason for medication discontinuation, or bariatric surgery intervention if applicable.

Efficacy outcome data included weight and BMI across therapy duration. Safety outcomes data included heart rate, BP, and ADRs that resulted in medication discontinuation as documented in the electronic health record (EHR).

Results

A total of 86 patients were identified based on prescription fills, which produced 99 unique instances of medication use. Of the 99 identified, 3 met exclusion criteria and were not included in the final analysis. Among included veterans, 16 were female and 80 were male (Table 1). Most of those included identified as White race (86%), male (83%), and mean age 53 years. At baseline, mean weight was 130 kg and mean BMI 41.

Comorbidities and Medication Use

Hypertension (66%), hyperlipidemia (64%), and psychiatric diagnoses (50%) were most common comorbid conditions. Substance use (23%) and T2DM (40%) were the most common comorbidities influencing medication choice. Substance use evaluation included amphetamines and cocaine for this analysis.

Phentermine/topiramate is the preferred first-line agent unless patients have contraindications for use, in which case naltrexone/bupropion is recommended, based on guidelines for weight management medications within the VHI system. However, for patients with comorbid T2DM, liraglutide is preferred because of its beneficial effects for both weight loss and blood glucose control.² Most patients at VHI were started on liraglutide (44%) or phentermine/topiramate (42%), which was in line with recommendations. Our sample included ≥ 1 prescription for each medication available at our facility, although the number of patients on each medication was not equal. Of note, the one patient taking lorcaserin at the time of study discontinued therapy in response to recent FDA guidance.⁹

Medications for comorbid conditions could contribute to weight gain. Of the patient sample, β blockers (n = 24) and anticonvulsants, including gabapentin and pregabalin (n = 22) were the most common Other medications that could have contributed to weight gain included sulfonylureas (n = 5), antipsychotics (n = 4), tricyclic antidepressants (n = 2), and hormone replacement therapies (n = 2).

Primary Outcomes

The mean weight of participants dropped from 129.9 to 114.2 kg over the 12 months of weight management medication therapy for a absolute difference of 15.8 kg (Figure 1 and eTable 1 available at doi:10.12788/fp.0117). Weight loss was recorded at 3, 6, 12, and > 12 months of weight management therapy. At each time point, weight loss was statistically significant (P < .001) compared with baseline (Table 2), even though not every patient had weight loss records at each time point.

When classified by medication choice, mean change in weight was orlistat −25.9 kg (n = 5); lorcaserin −22.5 kg (n = 1); liraglutide −10.3 kg (n = 43); phentermine/topiramate −5.0 kg (n = 42); and naltrexone/ bupropion +2.1 kg (n = 5) over the duration of the study (eTable 2 available at doi:10.12788/fp.0117). Patients receiving orlistat and liraglutide had increasing weight loss across the duration of treatment compared with those on lorcaserin who had initial weight gain before weight loss. Phentermine/topiramate showed initial weight loss that tapered off, and naltrexone/bupropion demonstrated initial weight loss with eventual weight gain at study end point.

Secondary Outcomes

More than one-half of the patients analyzed lost 5 to 10% from baseline while taking weight management medication. Fifty-six (59%) patients lost 5% at any point while on therapy (Table 3). Among those patients, 31 (32%) lost ≥ 10% from baseline. When looking at success related to guideline recommendations, 32 (38%) patients lost 5% from baseline in the first 3 months of medication therapy.

Among patients who lost at least 5% from baseline, we performed further analysis to assess weight maintenance of 3 to 5% from baseline for 12 months. In the 12 months after initial weight loss, the number of patients who were able to maintain their weight loss steadily declined (Figure 2). In the end, 17 (30%) of patients who achieved 5 to 10% weight loss at baseline were able to maintain weight loss. Only 18% of study patients were able to achieve guideline-directed weight loss and maintain that weight for 12 months.

Discussion

This study evaluated the use and outcomes of weight management medication among veterans at VHI. The study aimed to better understand the efficacy and safety of these medications while exposing potential weaknesses in care and to promote avenues to improve weight loss and maintenance.

Clinical trials for weight management medications reported weight loss of 8 to 10 kg over 56 weeks: 21 to 63% of patients losing at least 5% from baseline weight.^10-14 The findings from our study found a higher average weight loss (−15.8 kg) than that reported in trials and a consistent percentage of patients (58.3%) who achieved at least 5% weight loss. It is promising to see that when used in a noncontrolled setting, these medications were able to produce weight loss consistent with results seen in large, controlled trials.

Pi-Sunyer and colleagues found continued weight loss after the initial 5% weight loss to an eventual 10% weight loss in many patients.¹⁰ Additionally, Smith and colleagues found that nearly 68% of their participants who took lorcaserin were able to maintain 3 to 5% weight loss over 12 months.¹³ Sjöström and colleagues acknowledged that many patients taking orlistat for an extended period began to gain weight, although at one-half the rate than that seen in the placebo group.¹² This study found that fewer patients were able to maintain their weight loss over 12 months, with only 30% of patients maintaining 3 to 5% weight loss from baseline. This difference in weight maintenance likely was because of the uncontrolled nature of this study. Once patients reach their initial weight loss goal, even the most motivated patients will have trouble maintaining that weight.⁴ Despite the challenges associated with maintaining weight loss, the quality of life benefits patients gained and potential reductions in health care spending support using resources to improve these outcomes.^2,14,15

Pi-Sunyer and colleagues reported high incidences of nausea (40%), vomiting (16%), diarrhea (21%), and constipation (20%) with liraglutide.¹⁰ Sjöström and colleagues reported 7% of patients experienced GI upset with orlistat.¹² Comparatively, only 17% of our patients reported AEs that required discontinuation, including GI upset. One patient in our study discontinued naltrexone/bupropion because of a significant change in mental status and suicide attempt. Clinical trials did not report a greater risk of depression or suicidality compared with placebo; however, there is a warning on the labeling of naltrexone/bupropion for increased suicidality with the use of antidepressant agents.^16,17 The neurologic AE that required discontinuation of phentermine/topiramate at our institution is unique based on published information.^11,18

The data from this study reinforced the observation that weight maintenance is the most challenging aspect of weight loss. Although our data showed clinically meaningful weight loss from baseline, many patients regained their weight, and some exceeded their baseline weight. Beyond providing these medications, this evidence suggests the need for close, continued follow-up through patients’ weight loss journey.

Limitations

Because this is a retrospective chart review, data collection was influenced by and limited to information that had been recorded in the EHR. AEs that resulted in medication discontinuation were assessed from the patient’s chart, which might not be correct if providers did not update the records. Follow-up was not always scheduled at regular intervals after medication initiation, resulting in varying sample numbers at each time point, potentially interfering with true weight loss averages. Although not included in this analysis, it might be beneficial to evaluate adherence to recommendations for follow-up with laboratory and weight monitoring to better capture where future monitoring can be improved. Second, there was an unbalanced number of patients taking each medication. Specifically, we saw a change in weight with orlistat that exceeded what is consistently seen in larger, more controlled trials. Although this is an effect of the real world, small sample sizes cannot be generalized to the larger population and might result in data reflecting that of an outlier. Last, there is a lack of generalizability because of the veteran population demographic, which is more male and lacks ethnic diversity. This study also was carried out at a single, educational tertiary medical center, which might not apply to all populations.

Conclusions

Despite the limitations discussed, this study shows that the use of weight management medications in a general veteran population produces initial weight loss consistent with previous studies. However, there is room for continued improvement in follow-up strategies to promote greater weight maintenance after initial weight loss. Considering the high health care costs, personal burden, and potential long-term complications associated with obesity, efforts to promote development of programs that support weight management and maintenance are imperative.

Acknowledgment
This material is the result of work supported with resources and the use of facilities at Veteran Health Indiana.

Vocational rehabilitation (VR) interventions are offered through Compensated Work Therapy (CWT) as part of clinical care in the Veterans Health Administration (VHA) to improve employment and quality of life outcomes for veterans with life-altering disabilities.^1–5 CWT vocational services range from assessment, vocational counseling, and treatment plan development to job placement, coaching, and follow-along support.¹ However, many veterans receive care in community-based clinics that are not staffed with a VR specialist (VRS) to provide these services.^6–8 Telehealth may increase patient access to VR, especially for rural veterans and those with travel barriers, but it is not known whether veterans and VRS would find this to be a satisfactory service delivery method.^8,9 This paper examines veteran and VRS provider perspectives on VR provided by telehealth (VRtele) as part of a VHA clinical demonstration project. To our knowledge, this is the first report of using real-time, clinic-based VRtele.

Methods

The Rural Veterans Supported Employment Telerehabilitation Initiative (RVSETI) was conducted as a field-initiated demonstration project at 2 US Department of Veterans Affairs (VA) medical centers (VAMCs) in Florida between 2014 and 2016: James A. Haley Veterans’ Hospital & Clinics (Tampa) and Malcom Randall VAMC (Gainesville). This retrospective evaluation of its first year did not require institutional review board approval as it was determined to be a quality improvement project by the local research service.

The patient population for the project was veterans with disabilities who were referred by clinical consults to the CWT service, a recovery-oriented vocational program. During the project years, veterans were offered the option of receiving VR services, such as supported employment, community-based employment services, or vocational assistance, through VRtele rather than traditional face-to-face meetings. The specific interventions delivered included patient orientation, interview assessment, treatment plan development, referral activities, vocational counseling, assessment of workplace for accommodation needs, vocational case management, and other employment supports. VR staff participating in the project included 2 VR supervisors, 1 supported employment mentor trainer, and 5 VRSs.

Each clinic was set up for VRtele, and codes were added to the electronic health record (EHR) to ensure proper documentation. Participating VRSs completed teleconferencing training, including a skills assessment using the equipment for real-time, high-quality video streaming over an encrypted network to provide services in a patient’s home or other remote locations. VRS staff provided veterans with instructions on using a VA-provided tablet or their own device and assisted them with establishing connectivity with the network. Video equipment included speakers, camera, and headphones connected to the desktop computer or laptop of the VRS. A patient’s first VRtelesession was conducted in person at the VAMC to assure veterans were able to use the technology and to identify and resolve any problems.

Demographic data, primary diagnosis, VR usage data, and zip codes of participating veterans were extracted from the EHR. Veterans completed a 2-part satisfaction survey administered 90 days after enrollment and at discharge. Part 1 was composed of 15 items, most with a 5-point Likert scale (higher ratings indicated greater satisfaction), on various aspects of the VRtele experience, such as audio and video quality and wait times.¹⁰ Part 2 addressed VR services and the VRS and consisted of 8 Likert scale items with the option to add a comment for each and 2 open-ended items that asked the participant to list what they liked best and least about VRtele.

Semistructured, in-person 30- to 60-minute interviews were conducted with VRSs at the initiation of VRteleand audio-recorded with permission. An interview guide consisting of 14 questions was used to obtain data on caseload, VRtele set up, use of teleconferencing equipment, and veteran access to VR services.

After ≥ 2 months of VRtele use, researchers observed a session with each participant to obtain qualitative data from all participants on their VRtele experience. Using an observation form with open notes, data were collected on the use of the videoconferencing technology, the quality of the VRtele session, and reactions of veterans and their VRS. Following the observation session, both the VRS and the participating veteran were interviewed separately using a 9-question interview form to obtain data on the use of the technology in general and for VR. Interviews were audio-recorded with the permission of the VRS and veteran and transcribed for analysis.

Analyses

Descriptive statistics were used for EHR data and satisfaction surveys. For qualitative analysis, each transcript was read in full by 2 researchers to get an overview of the data, and a rapid analysis approach was used to identify central themes focused on how technology was used and the experiences of the participants.^11,12 Relevant text for each topic was tabulated, and a summary table was created that highlighted overlapping ideas discussed by the interviewees as well as differences.

Results

Of the 22 veterans who participated in the project, 11 completed satisfaction surveys and 4 participated in qualitative interviews. The rural and nonrural groups did not differ demographically or by diagnosis, which was predominantly mental health related. Only 1 veteran in each group owned a tablet; the majority of both groups required VA-issued devices: 80% (n = 8) rural and 91.7% (n = 11) nonrural. The number of VRtele sessions for the groups also was similar, 53 for rural and 60 for nonrural, as was the mean (SD) number of sessions per veteran: 5.3 (SD, 3.2) rural and 5.0 (SD, 2.5) urban. Overall, 63 miles per session were saved, mostly for rural veterans, and the number of mean (SD) miles saved per veteran was greater for rural than nonrural veterans: 379.2 (243.0) and 256.1 (275.9), respectively. One veteran who moved to a different state during the program continued VRtele at the new location. In a qualitative sampling of 5 VRtele sessions, all the VRSs used office desktop computers.

Level of satisfaction with aspects of VRtele related to the technology rated was consistently > 4 on the Likert scale. The lowest mean (SD) ratings were 4.2 (1.0) for audio quality and 4.4 (0.5) for video quality, and the highest rating was given for equipment operation explanation and privacy was respected, 4.9 (0.3) for both. All questions related to satisfaction with services were also rated high: The mean (SD) lowest ratings were 4.3 (1.0) given to both vocational needs 4.3 (1.0) and tasks effectively helped achieve goals 4.3 (0.7). The highest mean (SD) ratings were 4.6 (0.5) given to VR program service explained and 4.7 (0.5) for appointment timeliness.

Qualitative Results

At first, some VRSs thought the teleconferencing system might be difficult or awkward to use, but they found it easier to set up than expected and seamless to use. VRS staff reported being surprised at how well it worked despite some issues that occurred with loading the software. Once loaded, however, the connection worked well, one VRS noting that following step-by-step instructions solved the problem. Some VRSs indicated they did not invite all the veterans on their caseload to participate in VRtele due to concerns with the patient’s familiarity with technology, but one VRS stated, “I haven’t had anybody that failed to do a [session] that I couldn’t get them up and running within a few minutes.”

When working in the community, VRSs reported using laptops for VRtele but found that these devices were unreliable due to lack of internet access and were slow to start; several VRSs thought tablets would have been more helpful. Some veterans reported technical glitches, lack of comfort with technology, or a problem with sound due to a tablet’s protective case blocking the speakers. To solve the sound issue, a veteran used headphones. This veteran also explained that the log-on process required a new password every time, so he would keep a pen and paper ready to write it down. Because signing in and setting up takes a little time, this veteran and his VRS agreed to start connecting 5 minutes before their meeting time to allow for that set- up time.

Initially, some VRSs expressed concern that transitioning to VRtele would affect the quality of interactions with the veterans. However, VRSs also identified strengths of VRtele, including flexibility, saved time, and increased interaction. One VRS discussed a veteran’s adaptation by saying, “I think he feels even more involved in his plan [and] enjoys the increased interaction.” Veterans reported enjoying using tablets and identified the main strength of VRtele as being able to talk face-to-face with the VRS. Echoing the VRSs, veterans reported teleconferencing saved time by avoiding travel and enabled spontaneous meetings. One of the veterans summed up the benefits of using VRtele: “I’d rather just connect. It’s going to take us 40 to 50 minutes [to meet in person] when we can just connect right here and it takes 15 to 20. We don’t have to go through the driving.… So this right here, doing it ahead of time and having the appointment, it’s a lot easier.”

In their interviews, VRSs talked about enjoying VRtele. A VRS explained: “It makes it a lot easier. It makes me feel less guilty. This way [veterans] don’t have to use their gas money, use their time. I know [the veteran] had something else he needed to do today.” Thus, both veterans and VRSs were satisfied with their VRtele experiences.

Discussion

This first report on the perspective of providers and veterans using VRtele suggests that it is a viable option for service delivery and that is highly satisfactory for serving veterans with disabilities, many of whom live in rural areas or have travel barriers. These findings are consistent with data on telerehabilitation for veterans with cognitive, physical, and mental disabilities.^13-22 Further, the data support the notion of using VRtele to facilitate long-term VR follow-up for persons with disabilities, as illustrated by successful continuation of vocational services after a veteran moved out of state.²³

Similar to other reports, our experience highlighted 2 factors that affect successful VRtele: (1) Troubleshooting technology barriers for both VR providers and clients; and (2) supportive leadership to facilitate implementation.^24-26These areas have been improved with recent telehealth VHA initiatives and upgrades. After the conclusion of this project evaluation, the program was expanded, and local facilities may now receive mentored support to implement similar programs.²⁷ This ongoing telerehabilitation program uses the recently upgraded VHA telehealth platform that enables encrypted sessions to be provided to any mobile or online device, and veterans simply click on a link to connect rather than waiting for a session-specific password.²⁸ By using virtual medical rooms accessed by cameras on tablets, smartphones, or computers, veterans and VR providers now have an easier time scheduling and attending online appointments.²⁹ Improved access to VRtele is important as VHA began providing the majority of appointments via video telemedicine in Spring of 2020 due to the COVID-19 pandemic. The accelerated use of telehealth due to the COVID crisis makes these findings highly relevant to the current practice environment.

Changes to technology and increased usage of VA Video Connect may indicate that the barriers identified from the earlier process described here have been diminished or eliminated. More evaluation is needed to assess whether system upgrades have increased ease of use and access for veterans with disabilities.

Conclusions

Encouragingly, this clinical demonstration project showed that both providers and clients recognize the benefits of VRtele. Patient satisfaction and decreased travel costs were clear advantages to using VRtele for this small group of veterans who had barriers to care due to travel or disability barriers. As this program evaluation was limited by a small sample, absence of a comparison group, and lack of outcome data (eg, employment rates, hours, wages, retention), future research is needed on implementation and outcomes of VRtele.

Acknowledgments
The authors thank Lynn Dirk, MAMC, for substantial editorial assistance. This material was based on work supported by Rural Veterans Supported Employment TeleRehabilitation Initiative (RVSETI), funded by the VA Office of Rural Health (Project # N08-FY14Q3-S2-P01222) and by support of the VA Health Services Research and Development Service. This work was presented in part at the 114th Annual Meeting of the American Anthropological Association at Denver, Colorado, November 21, 2015; a field-based Health Services Research and Development Service meeting, US Department of Veterans Affairs at Washington, DC, September 12, 2016; and the 2016 Annual Conference of the American Congress for Rehabilitation Medicine at Chicago, Illinois, October-November 2016.

Vocational rehabilitation (VR) interventions are offered through Compensated Work Therapy (CWT) as part of clinical care in the Veterans Health Administration (VHA) to improve employment and quality of life outcomes for veterans with life-altering disabilities.^1–5 CWT vocational services range from assessment, vocational counseling, and treatment plan development to job placement, coaching, and follow-along support.¹ However, many veterans receive care in community-based clinics that are not staffed with a VR specialist (VRS) to provide these services.^6–8 Telehealth may increase patient access to VR, especially for rural veterans and those with travel barriers, but it is not known whether veterans and VRS would find this to be a satisfactory service delivery method.^8,9 This paper examines veteran and VRS provider perspectives on VR provided by telehealth (VRtele) as part of a VHA clinical demonstration project. To our knowledge, this is the first report of using real-time, clinic-based VRtele.

Methods

The Rural Veterans Supported Employment Telerehabilitation Initiative (RVSETI) was conducted as a field-initiated demonstration project at 2 US Department of Veterans Affairs (VA) medical centers (VAMCs) in Florida between 2014 and 2016: James A. Haley Veterans’ Hospital & Clinics (Tampa) and Malcom Randall VAMC (Gainesville). This retrospective evaluation of its first year did not require institutional review board approval as it was determined to be a quality improvement project by the local research service.

The patient population for the project was veterans with disabilities who were referred by clinical consults to the CWT service, a recovery-oriented vocational program. During the project years, veterans were offered the option of receiving VR services, such as supported employment, community-based employment services, or vocational assistance, through VRtele rather than traditional face-to-face meetings. The specific interventions delivered included patient orientation, interview assessment, treatment plan development, referral activities, vocational counseling, assessment of workplace for accommodation needs, vocational case management, and other employment supports. VR staff participating in the project included 2 VR supervisors, 1 supported employment mentor trainer, and 5 VRSs.

Each clinic was set up for VRtele, and codes were added to the electronic health record (EHR) to ensure proper documentation. Participating VRSs completed teleconferencing training, including a skills assessment using the equipment for real-time, high-quality video streaming over an encrypted network to provide services in a patient’s home or other remote locations. VRS staff provided veterans with instructions on using a VA-provided tablet or their own device and assisted them with establishing connectivity with the network. Video equipment included speakers, camera, and headphones connected to the desktop computer or laptop of the VRS. A patient’s first VRtelesession was conducted in person at the VAMC to assure veterans were able to use the technology and to identify and resolve any problems.

Demographic data, primary diagnosis, VR usage data, and zip codes of participating veterans were extracted from the EHR. Veterans completed a 2-part satisfaction survey administered 90 days after enrollment and at discharge. Part 1 was composed of 15 items, most with a 5-point Likert scale (higher ratings indicated greater satisfaction), on various aspects of the VRtele experience, such as audio and video quality and wait times.¹⁰ Part 2 addressed VR services and the VRS and consisted of 8 Likert scale items with the option to add a comment for each and 2 open-ended items that asked the participant to list what they liked best and least about VRtele.

Semistructured, in-person 30- to 60-minute interviews were conducted with VRSs at the initiation of VRteleand audio-recorded with permission. An interview guide consisting of 14 questions was used to obtain data on caseload, VRtele set up, use of teleconferencing equipment, and veteran access to VR services.

After ≥ 2 months of VRtele use, researchers observed a session with each participant to obtain qualitative data from all participants on their VRtele experience. Using an observation form with open notes, data were collected on the use of the videoconferencing technology, the quality of the VRtele session, and reactions of veterans and their VRS. Following the observation session, both the VRS and the participating veteran were interviewed separately using a 9-question interview form to obtain data on the use of the technology in general and for VR. Interviews were audio-recorded with the permission of the VRS and veteran and transcribed for analysis.

Analyses

Descriptive statistics were used for EHR data and satisfaction surveys. For qualitative analysis, each transcript was read in full by 2 researchers to get an overview of the data, and a rapid analysis approach was used to identify central themes focused on how technology was used and the experiences of the participants.^11,12 Relevant text for each topic was tabulated, and a summary table was created that highlighted overlapping ideas discussed by the interviewees as well as differences.

Results

Of the 22 veterans who participated in the project, 11 completed satisfaction surveys and 4 participated in qualitative interviews. The rural and nonrural groups did not differ demographically or by diagnosis, which was predominantly mental health related. Only 1 veteran in each group owned a tablet; the majority of both groups required VA-issued devices: 80% (n = 8) rural and 91.7% (n = 11) nonrural. The number of VRtele sessions for the groups also was similar, 53 for rural and 60 for nonrural, as was the mean (SD) number of sessions per veteran: 5.3 (SD, 3.2) rural and 5.0 (SD, 2.5) urban. Overall, 63 miles per session were saved, mostly for rural veterans, and the number of mean (SD) miles saved per veteran was greater for rural than nonrural veterans: 379.2 (243.0) and 256.1 (275.9), respectively. One veteran who moved to a different state during the program continued VRtele at the new location. In a qualitative sampling of 5 VRtele sessions, all the VRSs used office desktop computers.

Level of satisfaction with aspects of VRtele related to the technology rated was consistently > 4 on the Likert scale. The lowest mean (SD) ratings were 4.2 (1.0) for audio quality and 4.4 (0.5) for video quality, and the highest rating was given for equipment operation explanation and privacy was respected, 4.9 (0.3) for both. All questions related to satisfaction with services were also rated high: The mean (SD) lowest ratings were 4.3 (1.0) given to both vocational needs 4.3 (1.0) and tasks effectively helped achieve goals 4.3 (0.7). The highest mean (SD) ratings were 4.6 (0.5) given to VR program service explained and 4.7 (0.5) for appointment timeliness.

Qualitative Results

At first, some VRSs thought the teleconferencing system might be difficult or awkward to use, but they found it easier to set up than expected and seamless to use. VRS staff reported being surprised at how well it worked despite some issues that occurred with loading the software. Once loaded, however, the connection worked well, one VRS noting that following step-by-step instructions solved the problem. Some VRSs indicated they did not invite all the veterans on their caseload to participate in VRtele due to concerns with the patient’s familiarity with technology, but one VRS stated, “I haven’t had anybody that failed to do a [session] that I couldn’t get them up and running within a few minutes.”

When working in the community, VRSs reported using laptops for VRtele but found that these devices were unreliable due to lack of internet access and were slow to start; several VRSs thought tablets would have been more helpful. Some veterans reported technical glitches, lack of comfort with technology, or a problem with sound due to a tablet’s protective case blocking the speakers. To solve the sound issue, a veteran used headphones. This veteran also explained that the log-on process required a new password every time, so he would keep a pen and paper ready to write it down. Because signing in and setting up takes a little time, this veteran and his VRS agreed to start connecting 5 minutes before their meeting time to allow for that set- up time.

Initially, some VRSs expressed concern that transitioning to VRtele would affect the quality of interactions with the veterans. However, VRSs also identified strengths of VRtele, including flexibility, saved time, and increased interaction. One VRS discussed a veteran’s adaptation by saying, “I think he feels even more involved in his plan [and] enjoys the increased interaction.” Veterans reported enjoying using tablets and identified the main strength of VRtele as being able to talk face-to-face with the VRS. Echoing the VRSs, veterans reported teleconferencing saved time by avoiding travel and enabled spontaneous meetings. One of the veterans summed up the benefits of using VRtele: “I’d rather just connect. It’s going to take us 40 to 50 minutes [to meet in person] when we can just connect right here and it takes 15 to 20. We don’t have to go through the driving.… So this right here, doing it ahead of time and having the appointment, it’s a lot easier.”

In their interviews, VRSs talked about enjoying VRtele. A VRS explained: “It makes it a lot easier. It makes me feel less guilty. This way [veterans] don’t have to use their gas money, use their time. I know [the veteran] had something else he needed to do today.” Thus, both veterans and VRSs were satisfied with their VRtele experiences.

Discussion

This first report on the perspective of providers and veterans using VRtele suggests that it is a viable option for service delivery and that is highly satisfactory for serving veterans with disabilities, many of whom live in rural areas or have travel barriers. These findings are consistent with data on telerehabilitation for veterans with cognitive, physical, and mental disabilities.^13-22 Further, the data support the notion of using VRtele to facilitate long-term VR follow-up for persons with disabilities, as illustrated by successful continuation of vocational services after a veteran moved out of state.²³

Similar to other reports, our experience highlighted 2 factors that affect successful VRtele: (1) Troubleshooting technology barriers for both VR providers and clients; and (2) supportive leadership to facilitate implementation.^24-26These areas have been improved with recent telehealth VHA initiatives and upgrades. After the conclusion of this project evaluation, the program was expanded, and local facilities may now receive mentored support to implement similar programs.²⁷ This ongoing telerehabilitation program uses the recently upgraded VHA telehealth platform that enables encrypted sessions to be provided to any mobile or online device, and veterans simply click on a link to connect rather than waiting for a session-specific password.²⁸ By using virtual medical rooms accessed by cameras on tablets, smartphones, or computers, veterans and VR providers now have an easier time scheduling and attending online appointments.²⁹ Improved access to VRtele is important as VHA began providing the majority of appointments via video telemedicine in Spring of 2020 due to the COVID-19 pandemic. The accelerated use of telehealth due to the COVID crisis makes these findings highly relevant to the current practice environment.

Changes to technology and increased usage of VA Video Connect may indicate that the barriers identified from the earlier process described here have been diminished or eliminated. More evaluation is needed to assess whether system upgrades have increased ease of use and access for veterans with disabilities.

Conclusions

Encouragingly, this clinical demonstration project showed that both providers and clients recognize the benefits of VRtele. Patient satisfaction and decreased travel costs were clear advantages to using VRtele for this small group of veterans who had barriers to care due to travel or disability barriers. As this program evaluation was limited by a small sample, absence of a comparison group, and lack of outcome data (eg, employment rates, hours, wages, retention), future research is needed on implementation and outcomes of VRtele.

Acknowledgments
The authors thank Lynn Dirk, MAMC, for substantial editorial assistance. This material was based on work supported by Rural Veterans Supported Employment TeleRehabilitation Initiative (RVSETI), funded by the VA Office of Rural Health (Project # N08-FY14Q3-S2-P01222) and by support of the VA Health Services Research and Development Service. This work was presented in part at the 114th Annual Meeting of the American Anthropological Association at Denver, Colorado, November 21, 2015; a field-based Health Services Research and Development Service meeting, US Department of Veterans Affairs at Washington, DC, September 12, 2016; and the 2016 Annual Conference of the American Congress for Rehabilitation Medicine at Chicago, Illinois, October-November 2016.

Vocational rehabilitation (VR) interventions are offered through Compensated Work Therapy (CWT) as part of clinical care in the Veterans Health Administration (VHA) to improve employment and quality of life outcomes for veterans with life-altering disabilities.^1–5 CWT vocational services range from assessment, vocational counseling, and treatment plan development to job placement, coaching, and follow-along support.¹ However, many veterans receive care in community-based clinics that are not staffed with a VR specialist (VRS) to provide these services.^6–8 Telehealth may increase patient access to VR, especially for rural veterans and those with travel barriers, but it is not known whether veterans and VRS would find this to be a satisfactory service delivery method.^8,9 This paper examines veteran and VRS provider perspectives on VR provided by telehealth (VRtele) as part of a VHA clinical demonstration project. To our knowledge, this is the first report of using real-time, clinic-based VRtele.

Methods

The Rural Veterans Supported Employment Telerehabilitation Initiative (RVSETI) was conducted as a field-initiated demonstration project at 2 US Department of Veterans Affairs (VA) medical centers (VAMCs) in Florida between 2014 and 2016: James A. Haley Veterans’ Hospital & Clinics (Tampa) and Malcom Randall VAMC (Gainesville). This retrospective evaluation of its first year did not require institutional review board approval as it was determined to be a quality improvement project by the local research service.

The patient population for the project was veterans with disabilities who were referred by clinical consults to the CWT service, a recovery-oriented vocational program. During the project years, veterans were offered the option of receiving VR services, such as supported employment, community-based employment services, or vocational assistance, through VRtele rather than traditional face-to-face meetings. The specific interventions delivered included patient orientation, interview assessment, treatment plan development, referral activities, vocational counseling, assessment of workplace for accommodation needs, vocational case management, and other employment supports. VR staff participating in the project included 2 VR supervisors, 1 supported employment mentor trainer, and 5 VRSs.

Each clinic was set up for VRtele, and codes were added to the electronic health record (EHR) to ensure proper documentation. Participating VRSs completed teleconferencing training, including a skills assessment using the equipment for real-time, high-quality video streaming over an encrypted network to provide services in a patient’s home or other remote locations. VRS staff provided veterans with instructions on using a VA-provided tablet or their own device and assisted them with establishing connectivity with the network. Video equipment included speakers, camera, and headphones connected to the desktop computer or laptop of the VRS. A patient’s first VRtelesession was conducted in person at the VAMC to assure veterans were able to use the technology and to identify and resolve any problems.

Demographic data, primary diagnosis, VR usage data, and zip codes of participating veterans were extracted from the EHR. Veterans completed a 2-part satisfaction survey administered 90 days after enrollment and at discharge. Part 1 was composed of 15 items, most with a 5-point Likert scale (higher ratings indicated greater satisfaction), on various aspects of the VRtele experience, such as audio and video quality and wait times.¹⁰ Part 2 addressed VR services and the VRS and consisted of 8 Likert scale items with the option to add a comment for each and 2 open-ended items that asked the participant to list what they liked best and least about VRtele.

Semistructured, in-person 30- to 60-minute interviews were conducted with VRSs at the initiation of VRteleand audio-recorded with permission. An interview guide consisting of 14 questions was used to obtain data on caseload, VRtele set up, use of teleconferencing equipment, and veteran access to VR services.

After ≥ 2 months of VRtele use, researchers observed a session with each participant to obtain qualitative data from all participants on their VRtele experience. Using an observation form with open notes, data were collected on the use of the videoconferencing technology, the quality of the VRtele session, and reactions of veterans and their VRS. Following the observation session, both the VRS and the participating veteran were interviewed separately using a 9-question interview form to obtain data on the use of the technology in general and for VR. Interviews were audio-recorded with the permission of the VRS and veteran and transcribed for analysis.

Analyses

Descriptive statistics were used for EHR data and satisfaction surveys. For qualitative analysis, each transcript was read in full by 2 researchers to get an overview of the data, and a rapid analysis approach was used to identify central themes focused on how technology was used and the experiences of the participants.^11,12 Relevant text for each topic was tabulated, and a summary table was created that highlighted overlapping ideas discussed by the interviewees as well as differences.

Results

Of the 22 veterans who participated in the project, 11 completed satisfaction surveys and 4 participated in qualitative interviews. The rural and nonrural groups did not differ demographically or by diagnosis, which was predominantly mental health related. Only 1 veteran in each group owned a tablet; the majority of both groups required VA-issued devices: 80% (n = 8) rural and 91.7% (n = 11) nonrural. The number of VRtele sessions for the groups also was similar, 53 for rural and 60 for nonrural, as was the mean (SD) number of sessions per veteran: 5.3 (SD, 3.2) rural and 5.0 (SD, 2.5) urban. Overall, 63 miles per session were saved, mostly for rural veterans, and the number of mean (SD) miles saved per veteran was greater for rural than nonrural veterans: 379.2 (243.0) and 256.1 (275.9), respectively. One veteran who moved to a different state during the program continued VRtele at the new location. In a qualitative sampling of 5 VRtele sessions, all the VRSs used office desktop computers.

Level of satisfaction with aspects of VRtele related to the technology rated was consistently > 4 on the Likert scale. The lowest mean (SD) ratings were 4.2 (1.0) for audio quality and 4.4 (0.5) for video quality, and the highest rating was given for equipment operation explanation and privacy was respected, 4.9 (0.3) for both. All questions related to satisfaction with services were also rated high: The mean (SD) lowest ratings were 4.3 (1.0) given to both vocational needs 4.3 (1.0) and tasks effectively helped achieve goals 4.3 (0.7). The highest mean (SD) ratings were 4.6 (0.5) given to VR program service explained and 4.7 (0.5) for appointment timeliness.

Qualitative Results

At first, some VRSs thought the teleconferencing system might be difficult or awkward to use, but they found it easier to set up than expected and seamless to use. VRS staff reported being surprised at how well it worked despite some issues that occurred with loading the software. Once loaded, however, the connection worked well, one VRS noting that following step-by-step instructions solved the problem. Some VRSs indicated they did not invite all the veterans on their caseload to participate in VRtele due to concerns with the patient’s familiarity with technology, but one VRS stated, “I haven’t had anybody that failed to do a [session] that I couldn’t get them up and running within a few minutes.”

When working in the community, VRSs reported using laptops for VRtele but found that these devices were unreliable due to lack of internet access and were slow to start; several VRSs thought tablets would have been more helpful. Some veterans reported technical glitches, lack of comfort with technology, or a problem with sound due to a tablet’s protective case blocking the speakers. To solve the sound issue, a veteran used headphones. This veteran also explained that the log-on process required a new password every time, so he would keep a pen and paper ready to write it down. Because signing in and setting up takes a little time, this veteran and his VRS agreed to start connecting 5 minutes before their meeting time to allow for that set- up time.

Initially, some VRSs expressed concern that transitioning to VRtele would affect the quality of interactions with the veterans. However, VRSs also identified strengths of VRtele, including flexibility, saved time, and increased interaction. One VRS discussed a veteran’s adaptation by saying, “I think he feels even more involved in his plan [and] enjoys the increased interaction.” Veterans reported enjoying using tablets and identified the main strength of VRtele as being able to talk face-to-face with the VRS. Echoing the VRSs, veterans reported teleconferencing saved time by avoiding travel and enabled spontaneous meetings. One of the veterans summed up the benefits of using VRtele: “I’d rather just connect. It’s going to take us 40 to 50 minutes [to meet in person] when we can just connect right here and it takes 15 to 20. We don’t have to go through the driving.… So this right here, doing it ahead of time and having the appointment, it’s a lot easier.”

In their interviews, VRSs talked about enjoying VRtele. A VRS explained: “It makes it a lot easier. It makes me feel less guilty. This way [veterans] don’t have to use their gas money, use their time. I know [the veteran] had something else he needed to do today.” Thus, both veterans and VRSs were satisfied with their VRtele experiences.

Discussion

This first report on the perspective of providers and veterans using VRtele suggests that it is a viable option for service delivery and that is highly satisfactory for serving veterans with disabilities, many of whom live in rural areas or have travel barriers. These findings are consistent with data on telerehabilitation for veterans with cognitive, physical, and mental disabilities.^13-22 Further, the data support the notion of using VRtele to facilitate long-term VR follow-up for persons with disabilities, as illustrated by successful continuation of vocational services after a veteran moved out of state.²³

Similar to other reports, our experience highlighted 2 factors that affect successful VRtele: (1) Troubleshooting technology barriers for both VR providers and clients; and (2) supportive leadership to facilitate implementation.^24-26These areas have been improved with recent telehealth VHA initiatives and upgrades. After the conclusion of this project evaluation, the program was expanded, and local facilities may now receive mentored support to implement similar programs.²⁷ This ongoing telerehabilitation program uses the recently upgraded VHA telehealth platform that enables encrypted sessions to be provided to any mobile or online device, and veterans simply click on a link to connect rather than waiting for a session-specific password.²⁸ By using virtual medical rooms accessed by cameras on tablets, smartphones, or computers, veterans and VR providers now have an easier time scheduling and attending online appointments.²⁹ Improved access to VRtele is important as VHA began providing the majority of appointments via video telemedicine in Spring of 2020 due to the COVID-19 pandemic. The accelerated use of telehealth due to the COVID crisis makes these findings highly relevant to the current practice environment.

Changes to technology and increased usage of VA Video Connect may indicate that the barriers identified from the earlier process described here have been diminished or eliminated. More evaluation is needed to assess whether system upgrades have increased ease of use and access for veterans with disabilities.

Conclusions

Encouragingly, this clinical demonstration project showed that both providers and clients recognize the benefits of VRtele. Patient satisfaction and decreased travel costs were clear advantages to using VRtele for this small group of veterans who had barriers to care due to travel or disability barriers. As this program evaluation was limited by a small sample, absence of a comparison group, and lack of outcome data (eg, employment rates, hours, wages, retention), future research is needed on implementation and outcomes of VRtele.

Acknowledgments
The authors thank Lynn Dirk, MAMC, for substantial editorial assistance. This material was based on work supported by Rural Veterans Supported Employment TeleRehabilitation Initiative (RVSETI), funded by the VA Office of Rural Health (Project # N08-FY14Q3-S2-P01222) and by support of the VA Health Services Research and Development Service. This work was presented in part at the 114th Annual Meeting of the American Anthropological Association at Denver, Colorado, November 21, 2015; a field-based Health Services Research and Development Service meeting, US Department of Veterans Affairs at Washington, DC, September 12, 2016; and the 2016 Annual Conference of the American Congress for Rehabilitation Medicine at Chicago, Illinois, October-November 2016.

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

Opioid Safety Initiative

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

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

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

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

Methods

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

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

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

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

Results

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

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

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

Electronic Consults

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

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

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

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

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

Primary Care Providers

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

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

Discussion

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

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

Guidelines

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

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

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

Limitations

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

Conclusion

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

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

Opioid Safety Initiative

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

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

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

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

Methods

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

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

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

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

Results

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

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

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

Electronic Consults

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

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

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

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

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

Primary Care Providers

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

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

Discussion

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

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

Guidelines

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

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

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

Limitations

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

Conclusion

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

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

Opioid Safety Initiative

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

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

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

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

Methods

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

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

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

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

Results

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

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

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

Electronic Consults

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

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

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

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

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

Primary Care Providers

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

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

Discussion

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

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

Guidelines

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

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

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

Limitations

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

Conclusion

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

Patients who receive the mRNA COVID-19 vaccines are experiencing a variety of skin rashes, a dermatologist told colleagues, and some lesions don’t appear until several days after an injection. The good news is that these side effects tend to be minor and vanish within a few days, Esther Freeman, MD, PhD, said in a presentation at the American Academy of Dermatology Virtual Meeting Experience.

“The reality is actually very reassuring,” Dr. Freeman said, especially in light of what is currently known about when the rashes occur and how anaphylaxis is extremely uncommon. Now, she added, dermatologists can tell patients who had reactions to their initial vaccination that “we know you had this big reaction, and we know that it was upsetting and uncomfortable. But it may not happen the second time around. And if it does, [the reaction is] probably going to be smaller.”

Dr. Freeman, associate professor of dermatology at Harvard Medical School, Boston, highlighted a study published in the Journal of the American Academy of Dermatology that she coauthored with dermatologists across the United States. The researchers tracked 414 cutaneous reactions to the Moderna (83%) and Pfizer (17%) COVID-19 vaccines in a group of patients, which was 90% female, 78% White, and mostly from the United States. Their average age was 44 years. The cases were reported to the AAD–International League of Dermatological Societies registry of COVID-19 cutaneous manifestations.

While most were women, “it’s a little hard to know if this is really going to end up being a true finding,” said Dr. Freeman, the registry’s principal investigator and a member of the AAD’s COVID-19 Ad Hoc Task Force. “If you think about who got vaccinated early, it was health care providers, and the American health care workforce is over 70% female. So I think there’s a little bit of bias here. There may also be a bias because women may be slightly more likely to report or go to their health care provider for a rash.”

Delayed large local reactions were the most common, accounting for 66% (175 cases) of the 267 skin reactions reported after the first Moderna vaccine dose and 30% (31 cases) of the 102 reactions reported after the second dose. These reactions represented 15% (5 cases) of the 34 skin reactions reported after the first Pfizer vaccine dose and 18% (7 cases) of the 40 reactions after the second dose.

There are two peaks with that first dose, Dr. Freeman said. “There’s a peak around day 2 or 3. And there’s another peak around day 7 or 8 with some of these reactions. Only 27% who had a reaction with the first dose had the same reaction with the second.” She added that these reactions “are not cellulitis and don’t require antibiotics.”

Other more common reactions included local injection-site reactions (swelling, erythema, and pain), urticaria (after 24 hours in almost all cases, occurring at a higher rate in patients who received the Pfizer vaccine), and morbilliform eruptions.

Dr. Freeman said that patients may experience redness and swelling in the hands and feet that can be “very uncomfortable.” She described one patient “who was having a hard time actually closing his fist, just because of the amount of swelling and redness in his hand. It did resolve, and it’s important to reassure your patients it will go away.”

According to this study, less common reports of other cutaneous findings with both vaccines included 9 reports of swelling at the site of cosmetic fillers, 8 reports of pernio/chilblains, 10 reports of varicella zoster, 4 reports of herpes simplex flares, 4 pityriasis rosea–like reactions, and 4 rashes in infants of vaccinated breastfeeding mothers.

The study noted that “patients responded well to topical corticosteroids, oral antihistamines, and/or pain-relieving medications. These reactions resolved after a median of 3-4 days.”

It’s important to understand that none of the patients developed anaphylaxis after the second dose even if they’d had a reaction to the first dose, Dr. Freeman said. “But I should point out that we’re talking about reactions that have started more than 4 hours after the vaccine. If a rash such as a urticaria specifically starts within 4 hours of vaccination, that’s in a different category. Those are considered more immediate allergic reactions, and those patients need to be seen by allergy before a second dose.”

Dr. Freeman added that “it’s really interesting to think about how our bodies are really reacting to the vaccine in a way that’s mimicking our body’s reactions to COVID-19.” For example, some patients who got vaccinated developed chilblains similar to the “COVID toes” described in infected patients, apparently as part of the body’s immune response to the virus. “We’ve seen this in patients who actually had COVID and had prior COVID toes and then actually got a flare with their vaccine. And then we’ve also seen it in patients who never had COVID.”

In regard to general advice for patients, she said, “I do still encourage my patients who previously had COVID to go ahead and get the vaccine even if they had a skin manifestation with COVID.”

Shari Lipner, MD, PhD, associate professor of clinical dermatology, Weill Cornell Medicine, New York, said she has have seen only a handful of cases of delayed large local reactions and local injection site reactions after COVID-19 vaccination. “I have seen a significant number of cases of acute urticaria following the first and second doses,” she said in an interview. “However, it is important to keep in mind that we cannot determine cause and effect for the cases of acute urticaria. They may or may not be vaccine related.”

Fortunately, none of the adverse effects she’s seen have been severe. “It is important that dermatologists educate the public and their patients that most people do not develop any skin reaction in response to the vaccine,” she said. In the minority who do, “reactions tend to be mild and are not life-threatening. Many of these skin reactions resolve on their own without treatment.”

She added that “patients with pernio/chilblains or herpes zoster following vaccination should be referred by a board-certified dermatologist for prompt treatment and to avoid sequelae.”


 

‘COVID vaccine arm’

Delayed local reactions to the Moderna vaccine were also described in a report published online on May 12, 2021, in JAMA Dermatology, after the AAD meeting, in 16 patients referred to the Yale New Haven (Conn.) Hospital Dermatology service who experienced delayed localized cutaneous hypersensitivity reactions a median of 7 days after receiving the vaccine (range, 2-12 days), from Jan. 20 to Feb. 12, 2021. No such cases were reported in Pfizer vaccine recipients.

Of the 16 patients, whose median age was 38 years and who were mostly women, 15 developed the reaction after the first dose, described as “pruritic and variably painful erythematous reactions near the injection site,” which lasted a median of 5 days (range, 1-21 days). After the second dose, 12 of the 16 patients developed injection-site reactions (including one patient who had no reaction after dose 1), a median of 2 days after the vaccine was administered (range, 0-5 days). Histologic results of a biopsy in one patient with a reaction to the second dose “ demonstrated mild predominantly perivascular and focal interstitial mixed infiltrate with lymphocytes and eosinophils consistent with a dermal hypersensitivity reaction,” wrote Alicia J. Little, MD, PhD, of the department of dermatology, Yale University, New Haven, and coauthors.

Compared with immediate hypersensitivity reactions, occurring within 4 hours of vaccination, such as anaphylaxis and urticaria, they concluded that “these delayed localized hypersensitivity reactions are not a contraindication to subsequent vaccination,” and they proposed that they be named “COVID vaccine arm.”

Dr. Freeman reported no disclosures. Dr. Lipner also had no relevant disclosures. Dr. Little reported receiving a grant from the National Center for Advancing Translational Science and a Women’s Health Career Development Award from the Dermatology Foundation while the study was conducted; another author reported equity in Johnson & Johnson in his spouse’s retirement fund outside the submitted work.
 

Patients who receive the mRNA COVID-19 vaccines are experiencing a variety of skin rashes, a dermatologist told colleagues, and some lesions don’t appear until several days after an injection. The good news is that these side effects tend to be minor and vanish within a few days, Esther Freeman, MD, PhD, said in a presentation at the American Academy of Dermatology Virtual Meeting Experience.

“The reality is actually very reassuring,” Dr. Freeman said, especially in light of what is currently known about when the rashes occur and how anaphylaxis is extremely uncommon. Now, she added, dermatologists can tell patients who had reactions to their initial vaccination that “we know you had this big reaction, and we know that it was upsetting and uncomfortable. But it may not happen the second time around. And if it does, [the reaction is] probably going to be smaller.”

Dr. Freeman, associate professor of dermatology at Harvard Medical School, Boston, highlighted a study published in the Journal of the American Academy of Dermatology that she coauthored with dermatologists across the United States. The researchers tracked 414 cutaneous reactions to the Moderna (83%) and Pfizer (17%) COVID-19 vaccines in a group of patients, which was 90% female, 78% White, and mostly from the United States. Their average age was 44 years. The cases were reported to the AAD–International League of Dermatological Societies registry of COVID-19 cutaneous manifestations.

While most were women, “it’s a little hard to know if this is really going to end up being a true finding,” said Dr. Freeman, the registry’s principal investigator and a member of the AAD’s COVID-19 Ad Hoc Task Force. “If you think about who got vaccinated early, it was health care providers, and the American health care workforce is over 70% female. So I think there’s a little bit of bias here. There may also be a bias because women may be slightly more likely to report or go to their health care provider for a rash.”

Delayed large local reactions were the most common, accounting for 66% (175 cases) of the 267 skin reactions reported after the first Moderna vaccine dose and 30% (31 cases) of the 102 reactions reported after the second dose. These reactions represented 15% (5 cases) of the 34 skin reactions reported after the first Pfizer vaccine dose and 18% (7 cases) of the 40 reactions after the second dose.

There are two peaks with that first dose, Dr. Freeman said. “There’s a peak around day 2 or 3. And there’s another peak around day 7 or 8 with some of these reactions. Only 27% who had a reaction with the first dose had the same reaction with the second.” She added that these reactions “are not cellulitis and don’t require antibiotics.”

Other more common reactions included local injection-site reactions (swelling, erythema, and pain), urticaria (after 24 hours in almost all cases, occurring at a higher rate in patients who received the Pfizer vaccine), and morbilliform eruptions.

Dr. Freeman said that patients may experience redness and swelling in the hands and feet that can be “very uncomfortable.” She described one patient “who was having a hard time actually closing his fist, just because of the amount of swelling and redness in his hand. It did resolve, and it’s important to reassure your patients it will go away.”

According to this study, less common reports of other cutaneous findings with both vaccines included 9 reports of swelling at the site of cosmetic fillers, 8 reports of pernio/chilblains, 10 reports of varicella zoster, 4 reports of herpes simplex flares, 4 pityriasis rosea–like reactions, and 4 rashes in infants of vaccinated breastfeeding mothers.

The study noted that “patients responded well to topical corticosteroids, oral antihistamines, and/or pain-relieving medications. These reactions resolved after a median of 3-4 days.”

It’s important to understand that none of the patients developed anaphylaxis after the second dose even if they’d had a reaction to the first dose, Dr. Freeman said. “But I should point out that we’re talking about reactions that have started more than 4 hours after the vaccine. If a rash such as a urticaria specifically starts within 4 hours of vaccination, that’s in a different category. Those are considered more immediate allergic reactions, and those patients need to be seen by allergy before a second dose.”

Dr. Freeman added that “it’s really interesting to think about how our bodies are really reacting to the vaccine in a way that’s mimicking our body’s reactions to COVID-19.” For example, some patients who got vaccinated developed chilblains similar to the “COVID toes” described in infected patients, apparently as part of the body’s immune response to the virus. “We’ve seen this in patients who actually had COVID and had prior COVID toes and then actually got a flare with their vaccine. And then we’ve also seen it in patients who never had COVID.”

In regard to general advice for patients, she said, “I do still encourage my patients who previously had COVID to go ahead and get the vaccine even if they had a skin manifestation with COVID.”

Shari Lipner, MD, PhD, associate professor of clinical dermatology, Weill Cornell Medicine, New York, said she has have seen only a handful of cases of delayed large local reactions and local injection site reactions after COVID-19 vaccination. “I have seen a significant number of cases of acute urticaria following the first and second doses,” she said in an interview. “However, it is important to keep in mind that we cannot determine cause and effect for the cases of acute urticaria. They may or may not be vaccine related.”

Fortunately, none of the adverse effects she’s seen have been severe. “It is important that dermatologists educate the public and their patients that most people do not develop any skin reaction in response to the vaccine,” she said. In the minority who do, “reactions tend to be mild and are not life-threatening. Many of these skin reactions resolve on their own without treatment.”

She added that “patients with pernio/chilblains or herpes zoster following vaccination should be referred by a board-certified dermatologist for prompt treatment and to avoid sequelae.”


 

‘COVID vaccine arm’

Delayed local reactions to the Moderna vaccine were also described in a report published online on May 12, 2021, in JAMA Dermatology, after the AAD meeting, in 16 patients referred to the Yale New Haven (Conn.) Hospital Dermatology service who experienced delayed localized cutaneous hypersensitivity reactions a median of 7 days after receiving the vaccine (range, 2-12 days), from Jan. 20 to Feb. 12, 2021. No such cases were reported in Pfizer vaccine recipients.

Of the 16 patients, whose median age was 38 years and who were mostly women, 15 developed the reaction after the first dose, described as “pruritic and variably painful erythematous reactions near the injection site,” which lasted a median of 5 days (range, 1-21 days). After the second dose, 12 of the 16 patients developed injection-site reactions (including one patient who had no reaction after dose 1), a median of 2 days after the vaccine was administered (range, 0-5 days). Histologic results of a biopsy in one patient with a reaction to the second dose “ demonstrated mild predominantly perivascular and focal interstitial mixed infiltrate with lymphocytes and eosinophils consistent with a dermal hypersensitivity reaction,” wrote Alicia J. Little, MD, PhD, of the department of dermatology, Yale University, New Haven, and coauthors.

Compared with immediate hypersensitivity reactions, occurring within 4 hours of vaccination, such as anaphylaxis and urticaria, they concluded that “these delayed localized hypersensitivity reactions are not a contraindication to subsequent vaccination,” and they proposed that they be named “COVID vaccine arm.”

Dr. Freeman reported no disclosures. Dr. Lipner also had no relevant disclosures. Dr. Little reported receiving a grant from the National Center for Advancing Translational Science and a Women’s Health Career Development Award from the Dermatology Foundation while the study was conducted; another author reported equity in Johnson & Johnson in his spouse’s retirement fund outside the submitted work.
 

Patients who receive the mRNA COVID-19 vaccines are experiencing a variety of skin rashes, a dermatologist told colleagues, and some lesions don’t appear until several days after an injection. The good news is that these side effects tend to be minor and vanish within a few days, Esther Freeman, MD, PhD, said in a presentation at the American Academy of Dermatology Virtual Meeting Experience.

“The reality is actually very reassuring,” Dr. Freeman said, especially in light of what is currently known about when the rashes occur and how anaphylaxis is extremely uncommon. Now, she added, dermatologists can tell patients who had reactions to their initial vaccination that “we know you had this big reaction, and we know that it was upsetting and uncomfortable. But it may not happen the second time around. And if it does, [the reaction is] probably going to be smaller.”

Dr. Freeman, associate professor of dermatology at Harvard Medical School, Boston, highlighted a study published in the Journal of the American Academy of Dermatology that she coauthored with dermatologists across the United States. The researchers tracked 414 cutaneous reactions to the Moderna (83%) and Pfizer (17%) COVID-19 vaccines in a group of patients, which was 90% female, 78% White, and mostly from the United States. Their average age was 44 years. The cases were reported to the AAD–International League of Dermatological Societies registry of COVID-19 cutaneous manifestations.

While most were women, “it’s a little hard to know if this is really going to end up being a true finding,” said Dr. Freeman, the registry’s principal investigator and a member of the AAD’s COVID-19 Ad Hoc Task Force. “If you think about who got vaccinated early, it was health care providers, and the American health care workforce is over 70% female. So I think there’s a little bit of bias here. There may also be a bias because women may be slightly more likely to report or go to their health care provider for a rash.”

Delayed large local reactions were the most common, accounting for 66% (175 cases) of the 267 skin reactions reported after the first Moderna vaccine dose and 30% (31 cases) of the 102 reactions reported after the second dose. These reactions represented 15% (5 cases) of the 34 skin reactions reported after the first Pfizer vaccine dose and 18% (7 cases) of the 40 reactions after the second dose.

There are two peaks with that first dose, Dr. Freeman said. “There’s a peak around day 2 or 3. And there’s another peak around day 7 or 8 with some of these reactions. Only 27% who had a reaction with the first dose had the same reaction with the second.” She added that these reactions “are not cellulitis and don’t require antibiotics.”

Other more common reactions included local injection-site reactions (swelling, erythema, and pain), urticaria (after 24 hours in almost all cases, occurring at a higher rate in patients who received the Pfizer vaccine), and morbilliform eruptions.

Dr. Freeman said that patients may experience redness and swelling in the hands and feet that can be “very uncomfortable.” She described one patient “who was having a hard time actually closing his fist, just because of the amount of swelling and redness in his hand. It did resolve, and it’s important to reassure your patients it will go away.”

According to this study, less common reports of other cutaneous findings with both vaccines included 9 reports of swelling at the site of cosmetic fillers, 8 reports of pernio/chilblains, 10 reports of varicella zoster, 4 reports of herpes simplex flares, 4 pityriasis rosea–like reactions, and 4 rashes in infants of vaccinated breastfeeding mothers.

The study noted that “patients responded well to topical corticosteroids, oral antihistamines, and/or pain-relieving medications. These reactions resolved after a median of 3-4 days.”

It’s important to understand that none of the patients developed anaphylaxis after the second dose even if they’d had a reaction to the first dose, Dr. Freeman said. “But I should point out that we’re talking about reactions that have started more than 4 hours after the vaccine. If a rash such as a urticaria specifically starts within 4 hours of vaccination, that’s in a different category. Those are considered more immediate allergic reactions, and those patients need to be seen by allergy before a second dose.”

Dr. Freeman added that “it’s really interesting to think about how our bodies are really reacting to the vaccine in a way that’s mimicking our body’s reactions to COVID-19.” For example, some patients who got vaccinated developed chilblains similar to the “COVID toes” described in infected patients, apparently as part of the body’s immune response to the virus. “We’ve seen this in patients who actually had COVID and had prior COVID toes and then actually got a flare with their vaccine. And then we’ve also seen it in patients who never had COVID.”

In regard to general advice for patients, she said, “I do still encourage my patients who previously had COVID to go ahead and get the vaccine even if they had a skin manifestation with COVID.”

Shari Lipner, MD, PhD, associate professor of clinical dermatology, Weill Cornell Medicine, New York, said she has have seen only a handful of cases of delayed large local reactions and local injection site reactions after COVID-19 vaccination. “I have seen a significant number of cases of acute urticaria following the first and second doses,” she said in an interview. “However, it is important to keep in mind that we cannot determine cause and effect for the cases of acute urticaria. They may or may not be vaccine related.”

Fortunately, none of the adverse effects she’s seen have been severe. “It is important that dermatologists educate the public and their patients that most people do not develop any skin reaction in response to the vaccine,” she said. In the minority who do, “reactions tend to be mild and are not life-threatening. Many of these skin reactions resolve on their own without treatment.”

She added that “patients with pernio/chilblains or herpes zoster following vaccination should be referred by a board-certified dermatologist for prompt treatment and to avoid sequelae.”


 

‘COVID vaccine arm’

Delayed local reactions to the Moderna vaccine were also described in a report published online on May 12, 2021, in JAMA Dermatology, after the AAD meeting, in 16 patients referred to the Yale New Haven (Conn.) Hospital Dermatology service who experienced delayed localized cutaneous hypersensitivity reactions a median of 7 days after receiving the vaccine (range, 2-12 days), from Jan. 20 to Feb. 12, 2021. No such cases were reported in Pfizer vaccine recipients.

Of the 16 patients, whose median age was 38 years and who were mostly women, 15 developed the reaction after the first dose, described as “pruritic and variably painful erythematous reactions near the injection site,” which lasted a median of 5 days (range, 1-21 days). After the second dose, 12 of the 16 patients developed injection-site reactions (including one patient who had no reaction after dose 1), a median of 2 days after the vaccine was administered (range, 0-5 days). Histologic results of a biopsy in one patient with a reaction to the second dose “ demonstrated mild predominantly perivascular and focal interstitial mixed infiltrate with lymphocytes and eosinophils consistent with a dermal hypersensitivity reaction,” wrote Alicia J. Little, MD, PhD, of the department of dermatology, Yale University, New Haven, and coauthors.

Compared with immediate hypersensitivity reactions, occurring within 4 hours of vaccination, such as anaphylaxis and urticaria, they concluded that “these delayed localized hypersensitivity reactions are not a contraindication to subsequent vaccination,” and they proposed that they be named “COVID vaccine arm.”

Dr. Freeman reported no disclosures. Dr. Lipner also had no relevant disclosures. Dr. Little reported receiving a grant from the National Center for Advancing Translational Science and a Women’s Health Career Development Award from the Dermatology Foundation while the study was conducted; another author reported equity in Johnson & Johnson in his spouse’s retirement fund outside the submitted work.
 

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.

Coronary artery vasospasm is a rare but well-known adverse effect of 5-fluorouracil (5-FU) that can be life threatening if unrecognized. Patients typically present with anginal chest pain and ST elevations on electrocardiogram (ECG) without atherosclerotic disease on coronary angiography. This phenomenon typically occurs during or shortly after infusion and resolves within hours to days after cessation of 5-FU.

In this report, we present an unusual case of coronary artery vasospasm that intermittently recurred for 25 days following 5-FU treatment in a 40-year-old male with stage IV gastric adenocarcinoma. We also review the literature on typical presentation and risk factors for 5-FU-induced coronary vasospasm, findings on coronary angiography, and management options.

5-FU is an IV administered antimetabolite chemotherapy commonly used to treat solid tumors, including gastrointestinal, pancreatic, breast, and head and neck tumors. 5-FU inhibits thymidylate synthase, which reduces levels of thymidine, a key pyrimidine nucleoside required for DNA replication within tumor cells.¹ For several decades, 5-FU has remained one of the first-line drugs for colorectal cancer because it may be curative. It is the third most commonly used chemotherapy in the world and is included on the World Health Organization’s list of essential medicines.²

Cardiotoxicity occurs in 1.2 to 18% of patients who receive 5-FU therapy.³ Although there is variability in presentation for acute cardiotoxicity from 5-FU, including sudden death, angina pectoris, myocardial infarction, and ventricular arrhythmias, the mechanism most commonly implicated is coronary artery vasospasm.³ The direct observation of active coronary artery vasospasm during left heart catheterization is rare due its transient nature; however, several case studies have managed to demonstrate this.^4,5 The pathophysiology of 5-FU-induced cardiotoxicity is unknown, but adverse effects on cardiac microvasculature, myocyte metabolism, platelet aggregation, and coronary vasoconstriction have all been proposed.^3,6In the current case, we present a patient with stage IV gastric adenocarcinoma who complained of chest pain during hospitalization and was found to have coronary artery vasospasm in the setting of recent 5-FU administration. Following coronary angiography that showed a lack of atherosclerotic disease, the patient continued to experience episodes of chest pain with ST elevations on ECG that recurred despite cessation of 5-FU and repeated administration of vasodilatory medications.

Case Presentation 

A male aged 40 years was admitted to the hospital for abdominal pain, with initial imaging concerning for partial small bowel obstruction. His history included recently diagnosed stage IV gastric adenocarcinoma complicated by peritoneal carcinomatosis status post initiation of infusional FOLFOX-4 (5-FU, leucovorin, and oxaliplatin) 11 days prior. The patient was treated for small bowel obstruction. However, several days after admission, he developed nonpleuritic, substernal chest pain unrelated to exertion and unrelieved by rest. The patient reported no known risk factors, family history, or personal history of coronary artery disease. Baseline echocardiography and ECG performed several months prior showed normal left ventricular function without ischemic findings.

Physical examination at the time of chest pain revealed a heart rate of 140 beats/min. The remainder of his vital signs were within normal range. There were no murmurs, rubs, gallops, or additional heart sounds heard on cardiac auscultation. Chest pain was not reproducible to palpation or positional in nature. An ECG demonstrated dynamic inferolateral ST elevations with reciprocal changes in leads I and aVL (Figure 1). A bedside echocardiogram showed hypokinesis of the septal wall. Troponin-I returned below the detectable level.

Treatment

Following catheterization, the patient returned to the medical intensive care unit, where he continued to report intermittent episodes of chest pain with ST elevations. In the following days, he was started on isosorbide mononitrate 150 mg daily and amlodipine 10 mg daily. Although these vasodilatory agents reduced the frequency of his chest pain episodes, intermittent chest pain associated with ST elevations on ECG continued even with maximal doses of isosorbide mononitrate and amlodipine. Administration of sublingual nitroglycerin during chest pain episodes effectively relieved his chest pain. Given the severity and frequency of the patient’s chest pain, the oncology consult team recommended foregoing further chemotherapeutic treatment with 5-FU.

Outcome

Despite holding 5-FU throughout the patient’s hospitalization and treating the patient with antianginal mediations, frequent chest pain episodes associated with ST elevations continued to recur until 25 days after his last treatment with 5-FU (Figure 4). The patient eventually expired during this hospital stay due to cancer-related complications.

Discussion

Coronary artery vasospasm is a well-known complication of 5-FU that can be life threatening if unrecognized.^6-8 As seen in our case, patients typically present with anginal chest pain relieved with nitrates and ST elevations on ECG in the absence of occlusive macrovascular disease on coronary angiography.

A unique aspect of 5-FU is its variability in dose and frequency of administration across chemotherapeutic regimens. Particularly, 5-FU can be administered in daily intravenous bolus doses or as a continuous infusion for a protracted length of time. The spectrum of toxicity from 5-FU differs depending on the dose and frequency of administration. Bolus administration of 5-FU, for example, is thought to be associated with a higher rate of myelosuppression, while infusional administration of 5-FU is thought to be associated with a higher rate of cardiotoxicity and a higher tumor response rate.⁹

Most cases of coronary vasospasm occur either during infusion of 5-FU or within hours to days after completion. The median time of presentation for 5-FU-induced coronary artery vasospasm is about 12 hours postinfusion, while the most delayed presentation reported in the literature is 72 hours postinfusion.^6,8 Delayed presentation of vasospasm may result from the release of potent vasoactive metabolites of 5-FU that accumulate over time; therefore, infusional administration may accentuate this effect.^6,9 Remarkably, our patient’s chest pain episodes persisted for 25 days despite treatment with anti-anginal medications, highlighting the extent to which infusional 5-FU can produce a delay in adverse cardiotoxic effects and the importance of ongoing clinical vigilance after 5-FU exposure.

Vasospasm alone does not completely explain the spectrum of cardiac toxicity attributed to 5-FU administration. As in our case, coronary angiography during symptomatic episodes often fails to demonstrate coronary vasospasm.⁸ Additionally, ergonovine, an alkaloid agent used to assess coronary vasomotor function, failed to induce coronary vasospasm in some patients with suspected 5-FU-induced cardiac toxicity.¹⁰ The lack of vasospasm in some patients with 5-FU-induced cardiac toxicity suggests multiple independent effects of 5-FU on cardiac tissue that are poorly understood.

In the absence of obvious macrovascular effects, there also may be a deleterious effect of 5-FU on the coronary microvasculature that may result in coronary artery vasospasm. Though coronary microvasculature cannot be directly visualized, observation of slowed coronary blood velocity indicates a reduction in microvascular flow.⁸ Thus, the failure to observe epicardial coronary vasospasm in our patient does not preclude a vasospastic pathology.

The heterogeneous presentation of coronary artery vasospasm demands consideration of other disease processes such as atherosclerotic coronary artery disease, pericarditis, myopericarditis, primary arrythmias, and stress-induced cardiomyopathy, all of which have been described in association with 5-FU administration.⁸ A 12-lead ECG should be performed during a suspected attack. An ECG will typically demonstrate ST elevations corresponding to spasm of the involved vessel. Reciprocal ST depressions in the contralateral leads also may be seen. ECG may be useful in the acute setting to identify regional wall motion abnormalities or to rule out pericardial effusion as a cause. Cardiac biomarkers such as troponin-I, -C, and creatine kinase typically are less useful because they are often normal, even in known coronary artery vasospasm.¹¹

Coronary angiography during an episode may show a localized region of vasospasm in an epicardial artery. Diffuse multivessel vasospasm does occur, and the location of vasospasm may change, but these events are rare. Under normal circumstances, provocative testing involving angiography with administration of acetylcholine, ergot agents, or hyperventilation can be performed. However, this type of investigation should be limited to specialized centers and should not be performed in the acute phase of the disease.¹²

Treatment of suspected coronary vasospasm in patients receiving 5-FU involves stopping the infusion and administering calcium channel blockers or oral nitrates to relieve anginal symptoms.¹³ 5-FU-induced coronary artery vasospasm has a 90% rate of recurrence with subsequent infusions.⁸ If possible, alternate chemotherapy regimens should be considered once coronary artery vasospasm has been identified.^14,15 If further 5-FU use is required, or if benefits are deemed to outweigh risks, infusions should be given in an inpatient setting with continuous cardiac monitoring.¹⁶

Calcium channel blockers and oral nitrates have been found to produce benefit in patients in acute settings; however, there is little evidence to attest to their effectiveness as prophylactic agents in those receiving 5-FU. Some reports demonstrate episodes where both calcium channel blockers and oral nitrates failed to prevent subsequent vasospasms.¹⁷ Although this was the case for our patient, short-acting sublingual nitroglycerin seemed to be effective in reducing the frequency of anginal symptoms.

Long-term outcomes have not been well investigated for patients with 5-FU-induced coronary vasospasm. However, many case reports show improvements in left ventricular function between 8 and 15 days after discontinuation of 5-FU.^7,10 Although this would be a valuable topic for further research, the rarity of this phenomenon creates limitations.

Conclusions

5-FU is a first-line chemotherapy for gastrointestinal cancers that is generally well tolerated but may be associated with potentially life-threatening cardiotoxic effects, of which coronary artery vasospasm is the most common. Coronary artery vasospasm presents with anginal chest pain and ST elevations on ECG that can be indistinguishable from acute coronary syndrome. Diagnosis requires cardiac catheterization, which will reveal patent coronary arteries. Infusional administration of 5-FU may be more likely to produce late cardiotoxic effects and a longer period of persistent symptoms, necessitating close monitoring for days or even weeks from last administration of 5-FU. Coronary artery vasospasm should be treated with anti-anginal medications, though varying degrees of effectiveness can be seen; clinicians should remain vigilant for recurrent episodes of chest pain despite treatment.

Coronary artery vasospasm is a rare but well-known adverse effect of 5-fluorouracil (5-FU) that can be life threatening if unrecognized. Patients typically present with anginal chest pain and ST elevations on electrocardiogram (ECG) without atherosclerotic disease on coronary angiography. This phenomenon typically occurs during or shortly after infusion and resolves within hours to days after cessation of 5-FU.

In this report, we present an unusual case of coronary artery vasospasm that intermittently recurred for 25 days following 5-FU treatment in a 40-year-old male with stage IV gastric adenocarcinoma. We also review the literature on typical presentation and risk factors for 5-FU-induced coronary vasospasm, findings on coronary angiography, and management options.

5-FU is an IV administered antimetabolite chemotherapy commonly used to treat solid tumors, including gastrointestinal, pancreatic, breast, and head and neck tumors. 5-FU inhibits thymidylate synthase, which reduces levels of thymidine, a key pyrimidine nucleoside required for DNA replication within tumor cells.¹ For several decades, 5-FU has remained one of the first-line drugs for colorectal cancer because it may be curative. It is the third most commonly used chemotherapy in the world and is included on the World Health Organization’s list of essential medicines.²

Cardiotoxicity occurs in 1.2 to 18% of patients who receive 5-FU therapy.³ Although there is variability in presentation for acute cardiotoxicity from 5-FU, including sudden death, angina pectoris, myocardial infarction, and ventricular arrhythmias, the mechanism most commonly implicated is coronary artery vasospasm.³ The direct observation of active coronary artery vasospasm during left heart catheterization is rare due its transient nature; however, several case studies have managed to demonstrate this.^4,5 The pathophysiology of 5-FU-induced cardiotoxicity is unknown, but adverse effects on cardiac microvasculature, myocyte metabolism, platelet aggregation, and coronary vasoconstriction have all been proposed.^3,6In the current case, we present a patient with stage IV gastric adenocarcinoma who complained of chest pain during hospitalization and was found to have coronary artery vasospasm in the setting of recent 5-FU administration. Following coronary angiography that showed a lack of atherosclerotic disease, the patient continued to experience episodes of chest pain with ST elevations on ECG that recurred despite cessation of 5-FU and repeated administration of vasodilatory medications.

Case Presentation 

A male aged 40 years was admitted to the hospital for abdominal pain, with initial imaging concerning for partial small bowel obstruction. His history included recently diagnosed stage IV gastric adenocarcinoma complicated by peritoneal carcinomatosis status post initiation of infusional FOLFOX-4 (5-FU, leucovorin, and oxaliplatin) 11 days prior. The patient was treated for small bowel obstruction. However, several days after admission, he developed nonpleuritic, substernal chest pain unrelated to exertion and unrelieved by rest. The patient reported no known risk factors, family history, or personal history of coronary artery disease. Baseline echocardiography and ECG performed several months prior showed normal left ventricular function without ischemic findings.

Physical examination at the time of chest pain revealed a heart rate of 140 beats/min. The remainder of his vital signs were within normal range. There were no murmurs, rubs, gallops, or additional heart sounds heard on cardiac auscultation. Chest pain was not reproducible to palpation or positional in nature. An ECG demonstrated dynamic inferolateral ST elevations with reciprocal changes in leads I and aVL (Figure 1). A bedside echocardiogram showed hypokinesis of the septal wall. Troponin-I returned below the detectable level.

Treatment

Following catheterization, the patient returned to the medical intensive care unit, where he continued to report intermittent episodes of chest pain with ST elevations. In the following days, he was started on isosorbide mononitrate 150 mg daily and amlodipine 10 mg daily. Although these vasodilatory agents reduced the frequency of his chest pain episodes, intermittent chest pain associated with ST elevations on ECG continued even with maximal doses of isosorbide mononitrate and amlodipine. Administration of sublingual nitroglycerin during chest pain episodes effectively relieved his chest pain. Given the severity and frequency of the patient’s chest pain, the oncology consult team recommended foregoing further chemotherapeutic treatment with 5-FU.

Outcome

Despite holding 5-FU throughout the patient’s hospitalization and treating the patient with antianginal mediations, frequent chest pain episodes associated with ST elevations continued to recur until 25 days after his last treatment with 5-FU (Figure 4). The patient eventually expired during this hospital stay due to cancer-related complications.

Discussion

Coronary artery vasospasm is a well-known complication of 5-FU that can be life threatening if unrecognized.^6-8 As seen in our case, patients typically present with anginal chest pain relieved with nitrates and ST elevations on ECG in the absence of occlusive macrovascular disease on coronary angiography.

A unique aspect of 5-FU is its variability in dose and frequency of administration across chemotherapeutic regimens. Particularly, 5-FU can be administered in daily intravenous bolus doses or as a continuous infusion for a protracted length of time. The spectrum of toxicity from 5-FU differs depending on the dose and frequency of administration. Bolus administration of 5-FU, for example, is thought to be associated with a higher rate of myelosuppression, while infusional administration of 5-FU is thought to be associated with a higher rate of cardiotoxicity and a higher tumor response rate.⁹

Most cases of coronary vasospasm occur either during infusion of 5-FU or within hours to days after completion. The median time of presentation for 5-FU-induced coronary artery vasospasm is about 12 hours postinfusion, while the most delayed presentation reported in the literature is 72 hours postinfusion.^6,8 Delayed presentation of vasospasm may result from the release of potent vasoactive metabolites of 5-FU that accumulate over time; therefore, infusional administration may accentuate this effect.^6,9 Remarkably, our patient’s chest pain episodes persisted for 25 days despite treatment with anti-anginal medications, highlighting the extent to which infusional 5-FU can produce a delay in adverse cardiotoxic effects and the importance of ongoing clinical vigilance after 5-FU exposure.

Vasospasm alone does not completely explain the spectrum of cardiac toxicity attributed to 5-FU administration. As in our case, coronary angiography during symptomatic episodes often fails to demonstrate coronary vasospasm.⁸ Additionally, ergonovine, an alkaloid agent used to assess coronary vasomotor function, failed to induce coronary vasospasm in some patients with suspected 5-FU-induced cardiac toxicity.¹⁰ The lack of vasospasm in some patients with 5-FU-induced cardiac toxicity suggests multiple independent effects of 5-FU on cardiac tissue that are poorly understood.

In the absence of obvious macrovascular effects, there also may be a deleterious effect of 5-FU on the coronary microvasculature that may result in coronary artery vasospasm. Though coronary microvasculature cannot be directly visualized, observation of slowed coronary blood velocity indicates a reduction in microvascular flow.⁸ Thus, the failure to observe epicardial coronary vasospasm in our patient does not preclude a vasospastic pathology.

The heterogeneous presentation of coronary artery vasospasm demands consideration of other disease processes such as atherosclerotic coronary artery disease, pericarditis, myopericarditis, primary arrythmias, and stress-induced cardiomyopathy, all of which have been described in association with 5-FU administration.⁸ A 12-lead ECG should be performed during a suspected attack. An ECG will typically demonstrate ST elevations corresponding to spasm of the involved vessel. Reciprocal ST depressions in the contralateral leads also may be seen. ECG may be useful in the acute setting to identify regional wall motion abnormalities or to rule out pericardial effusion as a cause. Cardiac biomarkers such as troponin-I, -C, and creatine kinase typically are less useful because they are often normal, even in known coronary artery vasospasm.¹¹

Coronary angiography during an episode may show a localized region of vasospasm in an epicardial artery. Diffuse multivessel vasospasm does occur, and the location of vasospasm may change, but these events are rare. Under normal circumstances, provocative testing involving angiography with administration of acetylcholine, ergot agents, or hyperventilation can be performed. However, this type of investigation should be limited to specialized centers and should not be performed in the acute phase of the disease.¹²

Treatment of suspected coronary vasospasm in patients receiving 5-FU involves stopping the infusion and administering calcium channel blockers or oral nitrates to relieve anginal symptoms.¹³ 5-FU-induced coronary artery vasospasm has a 90% rate of recurrence with subsequent infusions.⁸ If possible, alternate chemotherapy regimens should be considered once coronary artery vasospasm has been identified.^14,15 If further 5-FU use is required, or if benefits are deemed to outweigh risks, infusions should be given in an inpatient setting with continuous cardiac monitoring.¹⁶

Calcium channel blockers and oral nitrates have been found to produce benefit in patients in acute settings; however, there is little evidence to attest to their effectiveness as prophylactic agents in those receiving 5-FU. Some reports demonstrate episodes where both calcium channel blockers and oral nitrates failed to prevent subsequent vasospasms.¹⁷ Although this was the case for our patient, short-acting sublingual nitroglycerin seemed to be effective in reducing the frequency of anginal symptoms.

Long-term outcomes have not been well investigated for patients with 5-FU-induced coronary vasospasm. However, many case reports show improvements in left ventricular function between 8 and 15 days after discontinuation of 5-FU.^7,10 Although this would be a valuable topic for further research, the rarity of this phenomenon creates limitations.

Conclusions

5-FU is a first-line chemotherapy for gastrointestinal cancers that is generally well tolerated but may be associated with potentially life-threatening cardiotoxic effects, of which coronary artery vasospasm is the most common. Coronary artery vasospasm presents with anginal chest pain and ST elevations on ECG that can be indistinguishable from acute coronary syndrome. Diagnosis requires cardiac catheterization, which will reveal patent coronary arteries. Infusional administration of 5-FU may be more likely to produce late cardiotoxic effects and a longer period of persistent symptoms, necessitating close monitoring for days or even weeks from last administration of 5-FU. Coronary artery vasospasm should be treated with anti-anginal medications, though varying degrees of effectiveness can be seen; clinicians should remain vigilant for recurrent episodes of chest pain despite treatment.

Coronary artery vasospasm is a rare but well-known adverse effect of 5-fluorouracil (5-FU) that can be life threatening if unrecognized. Patients typically present with anginal chest pain and ST elevations on electrocardiogram (ECG) without atherosclerotic disease on coronary angiography. This phenomenon typically occurs during or shortly after infusion and resolves within hours to days after cessation of 5-FU.

In this report, we present an unusual case of coronary artery vasospasm that intermittently recurred for 25 days following 5-FU treatment in a 40-year-old male with stage IV gastric adenocarcinoma. We also review the literature on typical presentation and risk factors for 5-FU-induced coronary vasospasm, findings on coronary angiography, and management options.

5-FU is an IV administered antimetabolite chemotherapy commonly used to treat solid tumors, including gastrointestinal, pancreatic, breast, and head and neck tumors. 5-FU inhibits thymidylate synthase, which reduces levels of thymidine, a key pyrimidine nucleoside required for DNA replication within tumor cells.¹ For several decades, 5-FU has remained one of the first-line drugs for colorectal cancer because it may be curative. It is the third most commonly used chemotherapy in the world and is included on the World Health Organization’s list of essential medicines.²

Cardiotoxicity occurs in 1.2 to 18% of patients who receive 5-FU therapy.³ Although there is variability in presentation for acute cardiotoxicity from 5-FU, including sudden death, angina pectoris, myocardial infarction, and ventricular arrhythmias, the mechanism most commonly implicated is coronary artery vasospasm.³ The direct observation of active coronary artery vasospasm during left heart catheterization is rare due its transient nature; however, several case studies have managed to demonstrate this.^4,5 The pathophysiology of 5-FU-induced cardiotoxicity is unknown, but adverse effects on cardiac microvasculature, myocyte metabolism, platelet aggregation, and coronary vasoconstriction have all been proposed.^3,6In the current case, we present a patient with stage IV gastric adenocarcinoma who complained of chest pain during hospitalization and was found to have coronary artery vasospasm in the setting of recent 5-FU administration. Following coronary angiography that showed a lack of atherosclerotic disease, the patient continued to experience episodes of chest pain with ST elevations on ECG that recurred despite cessation of 5-FU and repeated administration of vasodilatory medications.

Case Presentation 

A male aged 40 years was admitted to the hospital for abdominal pain, with initial imaging concerning for partial small bowel obstruction. His history included recently diagnosed stage IV gastric adenocarcinoma complicated by peritoneal carcinomatosis status post initiation of infusional FOLFOX-4 (5-FU, leucovorin, and oxaliplatin) 11 days prior. The patient was treated for small bowel obstruction. However, several days after admission, he developed nonpleuritic, substernal chest pain unrelated to exertion and unrelieved by rest. The patient reported no known risk factors, family history, or personal history of coronary artery disease. Baseline echocardiography and ECG performed several months prior showed normal left ventricular function without ischemic findings.

Physical examination at the time of chest pain revealed a heart rate of 140 beats/min. The remainder of his vital signs were within normal range. There were no murmurs, rubs, gallops, or additional heart sounds heard on cardiac auscultation. Chest pain was not reproducible to palpation or positional in nature. An ECG demonstrated dynamic inferolateral ST elevations with reciprocal changes in leads I and aVL (Figure 1). A bedside echocardiogram showed hypokinesis of the septal wall. Troponin-I returned below the detectable level.

Treatment

Following catheterization, the patient returned to the medical intensive care unit, where he continued to report intermittent episodes of chest pain with ST elevations. In the following days, he was started on isosorbide mononitrate 150 mg daily and amlodipine 10 mg daily. Although these vasodilatory agents reduced the frequency of his chest pain episodes, intermittent chest pain associated with ST elevations on ECG continued even with maximal doses of isosorbide mononitrate and amlodipine. Administration of sublingual nitroglycerin during chest pain episodes effectively relieved his chest pain. Given the severity and frequency of the patient’s chest pain, the oncology consult team recommended foregoing further chemotherapeutic treatment with 5-FU.

Outcome

Despite holding 5-FU throughout the patient’s hospitalization and treating the patient with antianginal mediations, frequent chest pain episodes associated with ST elevations continued to recur until 25 days after his last treatment with 5-FU (Figure 4). The patient eventually expired during this hospital stay due to cancer-related complications.

Discussion

Coronary artery vasospasm is a well-known complication of 5-FU that can be life threatening if unrecognized.^6-8 As seen in our case, patients typically present with anginal chest pain relieved with nitrates and ST elevations on ECG in the absence of occlusive macrovascular disease on coronary angiography.

A unique aspect of 5-FU is its variability in dose and frequency of administration across chemotherapeutic regimens. Particularly, 5-FU can be administered in daily intravenous bolus doses or as a continuous infusion for a protracted length of time. The spectrum of toxicity from 5-FU differs depending on the dose and frequency of administration. Bolus administration of 5-FU, for example, is thought to be associated with a higher rate of myelosuppression, while infusional administration of 5-FU is thought to be associated with a higher rate of cardiotoxicity and a higher tumor response rate.⁹

Most cases of coronary vasospasm occur either during infusion of 5-FU or within hours to days after completion. The median time of presentation for 5-FU-induced coronary artery vasospasm is about 12 hours postinfusion, while the most delayed presentation reported in the literature is 72 hours postinfusion.^6,8 Delayed presentation of vasospasm may result from the release of potent vasoactive metabolites of 5-FU that accumulate over time; therefore, infusional administration may accentuate this effect.^6,9 Remarkably, our patient’s chest pain episodes persisted for 25 days despite treatment with anti-anginal medications, highlighting the extent to which infusional 5-FU can produce a delay in adverse cardiotoxic effects and the importance of ongoing clinical vigilance after 5-FU exposure.

Vasospasm alone does not completely explain the spectrum of cardiac toxicity attributed to 5-FU administration. As in our case, coronary angiography during symptomatic episodes often fails to demonstrate coronary vasospasm.⁸ Additionally, ergonovine, an alkaloid agent used to assess coronary vasomotor function, failed to induce coronary vasospasm in some patients with suspected 5-FU-induced cardiac toxicity.¹⁰ The lack of vasospasm in some patients with 5-FU-induced cardiac toxicity suggests multiple independent effects of 5-FU on cardiac tissue that are poorly understood.

In the absence of obvious macrovascular effects, there also may be a deleterious effect of 5-FU on the coronary microvasculature that may result in coronary artery vasospasm. Though coronary microvasculature cannot be directly visualized, observation of slowed coronary blood velocity indicates a reduction in microvascular flow.⁸ Thus, the failure to observe epicardial coronary vasospasm in our patient does not preclude a vasospastic pathology.

The heterogeneous presentation of coronary artery vasospasm demands consideration of other disease processes such as atherosclerotic coronary artery disease, pericarditis, myopericarditis, primary arrythmias, and stress-induced cardiomyopathy, all of which have been described in association with 5-FU administration.⁸ A 12-lead ECG should be performed during a suspected attack. An ECG will typically demonstrate ST elevations corresponding to spasm of the involved vessel. Reciprocal ST depressions in the contralateral leads also may be seen. ECG may be useful in the acute setting to identify regional wall motion abnormalities or to rule out pericardial effusion as a cause. Cardiac biomarkers such as troponin-I, -C, and creatine kinase typically are less useful because they are often normal, even in known coronary artery vasospasm.¹¹

Coronary angiography during an episode may show a localized region of vasospasm in an epicardial artery. Diffuse multivessel vasospasm does occur, and the location of vasospasm may change, but these events are rare. Under normal circumstances, provocative testing involving angiography with administration of acetylcholine, ergot agents, or hyperventilation can be performed. However, this type of investigation should be limited to specialized centers and should not be performed in the acute phase of the disease.¹²

Treatment of suspected coronary vasospasm in patients receiving 5-FU involves stopping the infusion and administering calcium channel blockers or oral nitrates to relieve anginal symptoms.¹³ 5-FU-induced coronary artery vasospasm has a 90% rate of recurrence with subsequent infusions.⁸ If possible, alternate chemotherapy regimens should be considered once coronary artery vasospasm has been identified.^14,15 If further 5-FU use is required, or if benefits are deemed to outweigh risks, infusions should be given in an inpatient setting with continuous cardiac monitoring.¹⁶

Calcium channel blockers and oral nitrates have been found to produce benefit in patients in acute settings; however, there is little evidence to attest to their effectiveness as prophylactic agents in those receiving 5-FU. Some reports demonstrate episodes where both calcium channel blockers and oral nitrates failed to prevent subsequent vasospasms.¹⁷ Although this was the case for our patient, short-acting sublingual nitroglycerin seemed to be effective in reducing the frequency of anginal symptoms.

Long-term outcomes have not been well investigated for patients with 5-FU-induced coronary vasospasm. However, many case reports show improvements in left ventricular function between 8 and 15 days after discontinuation of 5-FU.^7,10 Although this would be a valuable topic for further research, the rarity of this phenomenon creates limitations.

Conclusions

5-FU is a first-line chemotherapy for gastrointestinal cancers that is generally well tolerated but may be associated with potentially life-threatening cardiotoxic effects, of which coronary artery vasospasm is the most common. Coronary artery vasospasm presents with anginal chest pain and ST elevations on ECG that can be indistinguishable from acute coronary syndrome. Diagnosis requires cardiac catheterization, which will reveal patent coronary arteries. Infusional administration of 5-FU may be more likely to produce late cardiotoxic effects and a longer period of persistent symptoms, necessitating close monitoring for days or even weeks from last administration of 5-FU. Coronary artery vasospasm should be treated with anti-anginal medications, though varying degrees of effectiveness can be seen; clinicians should remain vigilant for recurrent episodes of chest pain despite treatment.

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.

Hematology and oncology patients are a complex patient population that requires timely follow-up to prevent clinical decompensation and delays in treatment. Previous reports have demonstrated that outpatient follow-up within 14 days is associated with decreased 30-day readmissions. The magnitude of this effect is greater for higher-risk patients.¹ Therefore, patients being discharged from the hematology and oncology inpatient service should be seen by a hematology and oncology provider within 14 days of discharge. Patients who do not require close oncologic follow-up should be seen by a primary care provider (PCP) within this timeframe.

Background

The Institute of Medicine (IOM) identified the need to focus on quality improvement and patient safety with a 1999 report, To Err Is Human.² Tremendous strides have been made in the areas of quality improvement and patient safety over the past 2 decades. In a 2013 report, the IOM further identified hematology and oncology care as an area of need due to a combination of growing demand, complexity of cancer and cancer treatment, shrinking workforce, and rising costs. The report concluded that cancer care is not as patient-centered, accessible, coordinated, or evidence based as it could be, with detrimental impacts on patients.³ Patients with cancer have been identified as a high-risk population for hospital readmissions.^4,5 Lack of timely follow-up and failed hand-offs have been identified as factors contributing to poor outcomes at time of discharge.^6-10

Upon internal review of baseline performance data, we identified areas needing improvement in the discharge process. These included time to hematology and oncology follow-up appointment, percent of patients with PCP appointments scheduled at time of discharge, and electronically alerts for the outpatient hematologist/oncologist to discharge summaries. It was determined that patients discharged from the inpatient service were seen a mean 17 days later by their outpatient hematology and oncology provider and the time to the follow-up appointment varied substantially, with some patients being seen several weeks to months after discharge. Furthermore, only 68% of patients had a primary care appointment scheduled at the time of discharge. These data along with review of data reported in the medical literature supported our initiative for improvement in the transition from inpatient to outpatient care for our hematology and oncology patients.

Plan-Do-Study-Act (PDSA) quality improvement methodology was used to create and implement several interventions to standardize the discharge process for this patient population, with the primary goal of decreasing the mean time to hematology and oncology follow-up from 17 days by 12% to fewer than 14 days. Patients who do not require close oncologic follow-up should be seen by a PCP within this timeframe. Otherwise, PCP follow-up within at least 6 months should be made. Secondary aims included (1) an increase in scheduled PCP visits at time of discharge from 68% to > 90%; and (2) an increase in communication of the discharge summary via electronic alerting of the outpatient hematology and oncology physician from 20% to > 90%. Herein, we report our experience and results of this quality improvement initiative

Methods

The Institutional Review Board at Edward Hines Veteran Affairs Hospital in Hines, Illinois reviewed this single-center study and deemed it to be exempt from oversight. Using PDSA quality improvement methodology, a multidisciplinary team of hematology and oncology staff developed and implemented a standardized discharge process. The multidisciplinary team included a robust representation of inpatient and outpatient staff caring for the hematology and oncology patient population, including attending physicians, fellows, residents, advanced practice nurses, registered nurses, clinical pharmacists, patient care coordinators, clinic schedulers, clinical applications coordinators, quality support staff, and a systems redesign coach. Hospital leadership including chief of staff, chief of medicine, and chief of nursing participated as the management guidance team. Several interviews and group meetings were conducted and a multidisciplinary team collaboratively developed and implemented the interventions and monitored the results.

Outcome measures were identified, including time to hematology and oncology clinic visit, primary care follow-up scheduling, and communication of discharge to the outpatient hematology and oncology physician. Baseline data were collected and reviewed. The multidisciplinary team developed a process flow map to understand the steps and resources involved with the transition from inpatient to outpatient care. Gap analysis and root cause analysis were performed. A solutions approach was applied to develop interventions. Table 1 shows a summary of the identified problems, symptoms, associated causes, the interventions aimed to address the problems, and expected outcomes. Rotating resident physicians were trained through online and in-person education. The multidisciplinary team met intermittently to monitor outcomes, provide feedback, further refine interventions, and develop additional interventions.

PDSA Cycle 1

A standardized discharge process was developed in the form of guidelines and expectations. These include an explanation of unique features of the hematology and oncology service and expectations of medication reconciliation with emphasis placed on antiemetics, antimicrobial prophylaxis, and bowel regimen when appropriate, outpatient hematology and oncology follow-up within 14 days, primary care follow-up, communication with the outpatient hematology and oncology physician, written discharge instructions, and bedside teaching when appropriate.

PDSA Cycle 2

Based on team member feedback and further discussions, a discharge checklist was developed. This checklist was available online, reviewed in person, and posted in the team room for rotating residents to use for discharge planning and when discharging patients (Figure 1).

PDSA Cycle 3

Based on ongoing user feedback, group discussions, and data monitoring, the discharge checklist was further refined and updated. An electronic clinical decision support tool was developed and integrated into the electronic medical record (EMR) in the form of a discharge checklist note template directly linked to orders. The tool is a computerized patient record system (CPRS) note template that prompts users to select whether medications or return to clinic orders are needed and offers a menu of frequently used medications. If any of the selections are chosen within the note template, an order is generated automatically in the chart that requires only the user’s signature. Furthermore, the patient care coordinator reviews the prescribed follow-up and works with the medical support assistant to make these appointments. The physician is contacted only when an appointment cannot be made. Therefore, this tool allows many additional actions to be bypassed such as generating medication and return to clinic orders individually and calling schedulers to make follow-up appointments (Figure 2).

Data Analysis

All patients discharged during the 2-month period prior to and discharged after the implementation of the standardized process were reviewed. Patients who followed up with hematology and oncology at another facility, enrolled in hospice, or died during admission were excluded. Follow-up appointment scheduling data and communication between inpatient and outpatient providers were reviewed. Data were analyzed using XmR statistical process control chart and Fisher’s Exact Test using GraphPad. Control limits were calculated for each PDSA cycle as the mean ± the average of the moving range multiplied by 2.66. All data were included in the analysis.

Results

A total of 142 consecutive patients were reviewed from May 1, 2018 to August 31, 2018 and January 1, 2019 to April 30, 2019, including 58 patients prior to the intervention and 84 patients during PDSA cycles. There was a gap in data collection between September 1, 2018 and December 31, 2018 due to limited team member availability. All data were collected by 2 reviewers—a postgraduate year (PGY)-4 chief resident and a PGY-2 internal medicine resident. The median age of patients in the preintervention group was 72 years and 69 years in the postintervention group. All patients were men. Baseline data revealed a mean 17 days to hematology and oncology follow-up. Primary care visits were scheduled for 68% of patients at the time of discharge. The outpatient hematology and oncology physician was alerted electronically to the discharge summary for 20% of the patients (Table 2).

The primary endpoint of time to hematology and oncology follow-up appointment improved to 13 days in PDSA cycles 1 and 2 and 10 days in PDSA cycle 3. The target of mean 14 days to follow-up was achieved. The statistical process control chart shows 5 shifts with clusters of ≥ 7 points below the mean revealing a true signal or change in the data and demonstrating that an improvement was seen (Figure 3). Furthermore, the statistical process control chart demonstrates upper control limit decreased from 58 days at baseline to 21 days in PDSA cycle 3, suggesting a decrease in variation.

Discussion

The 2013 IOM report Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis found that that cancer care is not as patient-centered, accessible, coordinated, or evidence-based as it could be, with detrimental impacts on patients.³ The document offered a conceptual framework to improve quality of cancer care that includes the translation of evidence into clinical practice, quality measurement, and performance improvement, as well as using advances in information technology to enhance quality measurement and performance improvement. Our quality initiative uses this framework to work toward the goal as stated by the IOM report: to deliver “comprehensive, patient-centered, evidence-based, high-quality cancer care that is accessible and affordable.”³

Two large studies that evaluated risk factors for 15-day and 30-day hospital readmissions identified cancer diagnosis as a risk factor for increased hospital readmission, highlighting the need to identify strategies to improve the discharge process for these patients.^4,5 Timely outpatient follow-up and better patient hand-off may improve clinical outcomes among this high-risk patient population after hospital discharge. Multiple studies have demonstrated that timely follow-up is associated with fewer readmissions.^1,8-10 A study by Forster and colleagues that evaluated postdischarge adverse events (AEs) revealed a 23% incidence of AEs with 12% of these identified as preventable. Postdischarge monitoring was deemed inadequate among these patients, with closer follow-up and improved hand-offs between inpatient and outpatient medical teams identified as possible interventions to improve postdischarge patient monitoring and to prevent AEs.⁷

The present quality initiative to standardize the discharge process for the hematology and oncology service decreased time to hematology and oncology follow-up appointment, improved communication between inpatient and outpatient teams, and decreased process variation. Timelier follow-up for this complex patient population likely will prevent clinical decompensation, delays in treatment, and directly improve patient access to care.

The multidisciplinary nature of this effort was instrumental to successful completion. In a complex health care system, it is challenging to truly understand a problem and identify possible solutions without the perspective of all members of the care team. The involvement of team members with training in quality improvement methodology was important to evaluate and develop interventions in a systematic way. Furthermore, the support and involvement of leadership is important in order to allocate resources appropriately to achieve system changes that improve care. Using quality improvement methodology, the team was able to map our processes and perform gap and root cause analyses. Strategies were identified to improve our performance using a solutions approach. Changes were implemented with continued intermittent meetings for monitoring of progression and discussion of how interventions could be made more efficient, effective, and user friendly. The primary goal was ultimately achieved.

Integration of intervention into the EMR embodies the IOM’s call to use advances in information technology to enhance the quality and delivery of care, quality measurement, and performance improvement.³ This intervention offered the strongest system changes as an electronic clinical decision support tool was developed and embedded into the EMR in the form of a Discharge Checklist Note that is linked to associated orders. This intervention was the most robust, as it provided objective data regarding utilization of the checklist, offered a more efficient way to communicate with team members regarding discharge needs, and streamlined the workflow for the discharging provider. Furthermore, this electronic tool created the ability to measure other important aspects in the care of this patient population that we previously had no mechanism of measuring: timely nursing appointments for routine care of PICC lines and ports.

Limitations

The absence of clinical endpoints was a limitation of this study. The present study was unable to evaluate the effect of the intervention on readmission rates, emergency department visits, hospital length of stay, cost, or mortality. Coordinating this multidisciplinary effort required much time and planning, and additional resources were not available to evaluate these clinical endpoints. Further studies are needed to evaluate whether the increased patient access and closer follow-up would result in improvement in these clinical endpoints. Another consideration for future improvement projects would be to include patients in the multidisciplinary team. The patient perspective would be invaluable in identifying gaps in care delivery and strategies aimed at improving care delivery.

Conclusions

This quality initiative to standardize the discharge process for the hematology and oncology service decreased time to the initial hematology and oncology follow-up appointment, improved communication between inpatient and outpatient teams, and decreased process variation. Timelier follow-up for this complex patient population likely will prevent clinical decompensation, delays in treatment, and directly improve patient access to care.

Acknowledgments

We thank our patients for whom we hope our process improvement efforts will ultimately benefit. We thank all the hematology and oncology staff at Edward Hines Jr. VA Hospital and Loyola University Medical Center residents and fellows who care for our patients and participated in the multidisciplinary team to improve care for our patients. We thank the following professionals for their uncompensated assistance in the coordination and execution of this initiative: Robert Kutter, MS, and Meghan O’Halloran, MD.

Hematology and oncology patients are a complex patient population that requires timely follow-up to prevent clinical decompensation and delays in treatment. Previous reports have demonstrated that outpatient follow-up within 14 days is associated with decreased 30-day readmissions. The magnitude of this effect is greater for higher-risk patients.¹ Therefore, patients being discharged from the hematology and oncology inpatient service should be seen by a hematology and oncology provider within 14 days of discharge. Patients who do not require close oncologic follow-up should be seen by a primary care provider (PCP) within this timeframe.

Background

The Institute of Medicine (IOM) identified the need to focus on quality improvement and patient safety with a 1999 report, To Err Is Human.² Tremendous strides have been made in the areas of quality improvement and patient safety over the past 2 decades. In a 2013 report, the IOM further identified hematology and oncology care as an area of need due to a combination of growing demand, complexity of cancer and cancer treatment, shrinking workforce, and rising costs. The report concluded that cancer care is not as patient-centered, accessible, coordinated, or evidence based as it could be, with detrimental impacts on patients.³ Patients with cancer have been identified as a high-risk population for hospital readmissions.^4,5 Lack of timely follow-up and failed hand-offs have been identified as factors contributing to poor outcomes at time of discharge.^6-10

Upon internal review of baseline performance data, we identified areas needing improvement in the discharge process. These included time to hematology and oncology follow-up appointment, percent of patients with PCP appointments scheduled at time of discharge, and electronically alerts for the outpatient hematologist/oncologist to discharge summaries. It was determined that patients discharged from the inpatient service were seen a mean 17 days later by their outpatient hematology and oncology provider and the time to the follow-up appointment varied substantially, with some patients being seen several weeks to months after discharge. Furthermore, only 68% of patients had a primary care appointment scheduled at the time of discharge. These data along with review of data reported in the medical literature supported our initiative for improvement in the transition from inpatient to outpatient care for our hematology and oncology patients.

Plan-Do-Study-Act (PDSA) quality improvement methodology was used to create and implement several interventions to standardize the discharge process for this patient population, with the primary goal of decreasing the mean time to hematology and oncology follow-up from 17 days by 12% to fewer than 14 days. Patients who do not require close oncologic follow-up should be seen by a PCP within this timeframe. Otherwise, PCP follow-up within at least 6 months should be made. Secondary aims included (1) an increase in scheduled PCP visits at time of discharge from 68% to > 90%; and (2) an increase in communication of the discharge summary via electronic alerting of the outpatient hematology and oncology physician from 20% to > 90%. Herein, we report our experience and results of this quality improvement initiative

Methods

The Institutional Review Board at Edward Hines Veteran Affairs Hospital in Hines, Illinois reviewed this single-center study and deemed it to be exempt from oversight. Using PDSA quality improvement methodology, a multidisciplinary team of hematology and oncology staff developed and implemented a standardized discharge process. The multidisciplinary team included a robust representation of inpatient and outpatient staff caring for the hematology and oncology patient population, including attending physicians, fellows, residents, advanced practice nurses, registered nurses, clinical pharmacists, patient care coordinators, clinic schedulers, clinical applications coordinators, quality support staff, and a systems redesign coach. Hospital leadership including chief of staff, chief of medicine, and chief of nursing participated as the management guidance team. Several interviews and group meetings were conducted and a multidisciplinary team collaboratively developed and implemented the interventions and monitored the results.

Outcome measures were identified, including time to hematology and oncology clinic visit, primary care follow-up scheduling, and communication of discharge to the outpatient hematology and oncology physician. Baseline data were collected and reviewed. The multidisciplinary team developed a process flow map to understand the steps and resources involved with the transition from inpatient to outpatient care. Gap analysis and root cause analysis were performed. A solutions approach was applied to develop interventions. Table 1 shows a summary of the identified problems, symptoms, associated causes, the interventions aimed to address the problems, and expected outcomes. Rotating resident physicians were trained through online and in-person education. The multidisciplinary team met intermittently to monitor outcomes, provide feedback, further refine interventions, and develop additional interventions.

PDSA Cycle 1

A standardized discharge process was developed in the form of guidelines and expectations. These include an explanation of unique features of the hematology and oncology service and expectations of medication reconciliation with emphasis placed on antiemetics, antimicrobial prophylaxis, and bowel regimen when appropriate, outpatient hematology and oncology follow-up within 14 days, primary care follow-up, communication with the outpatient hematology and oncology physician, written discharge instructions, and bedside teaching when appropriate.

PDSA Cycle 2

Based on team member feedback and further discussions, a discharge checklist was developed. This checklist was available online, reviewed in person, and posted in the team room for rotating residents to use for discharge planning and when discharging patients (Figure 1).

PDSA Cycle 3

Based on ongoing user feedback, group discussions, and data monitoring, the discharge checklist was further refined and updated. An electronic clinical decision support tool was developed and integrated into the electronic medical record (EMR) in the form of a discharge checklist note template directly linked to orders. The tool is a computerized patient record system (CPRS) note template that prompts users to select whether medications or return to clinic orders are needed and offers a menu of frequently used medications. If any of the selections are chosen within the note template, an order is generated automatically in the chart that requires only the user’s signature. Furthermore, the patient care coordinator reviews the prescribed follow-up and works with the medical support assistant to make these appointments. The physician is contacted only when an appointment cannot be made. Therefore, this tool allows many additional actions to be bypassed such as generating medication and return to clinic orders individually and calling schedulers to make follow-up appointments (Figure 2).

Data Analysis

All patients discharged during the 2-month period prior to and discharged after the implementation of the standardized process were reviewed. Patients who followed up with hematology and oncology at another facility, enrolled in hospice, or died during admission were excluded. Follow-up appointment scheduling data and communication between inpatient and outpatient providers were reviewed. Data were analyzed using XmR statistical process control chart and Fisher’s Exact Test using GraphPad. Control limits were calculated for each PDSA cycle as the mean ± the average of the moving range multiplied by 2.66. All data were included in the analysis.

Results

A total of 142 consecutive patients were reviewed from May 1, 2018 to August 31, 2018 and January 1, 2019 to April 30, 2019, including 58 patients prior to the intervention and 84 patients during PDSA cycles. There was a gap in data collection between September 1, 2018 and December 31, 2018 due to limited team member availability. All data were collected by 2 reviewers—a postgraduate year (PGY)-4 chief resident and a PGY-2 internal medicine resident. The median age of patients in the preintervention group was 72 years and 69 years in the postintervention group. All patients were men. Baseline data revealed a mean 17 days to hematology and oncology follow-up. Primary care visits were scheduled for 68% of patients at the time of discharge. The outpatient hematology and oncology physician was alerted electronically to the discharge summary for 20% of the patients (Table 2).

The primary endpoint of time to hematology and oncology follow-up appointment improved to 13 days in PDSA cycles 1 and 2 and 10 days in PDSA cycle 3. The target of mean 14 days to follow-up was achieved. The statistical process control chart shows 5 shifts with clusters of ≥ 7 points below the mean revealing a true signal or change in the data and demonstrating that an improvement was seen (Figure 3). Furthermore, the statistical process control chart demonstrates upper control limit decreased from 58 days at baseline to 21 days in PDSA cycle 3, suggesting a decrease in variation.

Discussion

The 2013 IOM report Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis found that that cancer care is not as patient-centered, accessible, coordinated, or evidence-based as it could be, with detrimental impacts on patients.³ The document offered a conceptual framework to improve quality of cancer care that includes the translation of evidence into clinical practice, quality measurement, and performance improvement, as well as using advances in information technology to enhance quality measurement and performance improvement. Our quality initiative uses this framework to work toward the goal as stated by the IOM report: to deliver “comprehensive, patient-centered, evidence-based, high-quality cancer care that is accessible and affordable.”³

Two large studies that evaluated risk factors for 15-day and 30-day hospital readmissions identified cancer diagnosis as a risk factor for increased hospital readmission, highlighting the need to identify strategies to improve the discharge process for these patients.^4,5 Timely outpatient follow-up and better patient hand-off may improve clinical outcomes among this high-risk patient population after hospital discharge. Multiple studies have demonstrated that timely follow-up is associated with fewer readmissions.^1,8-10 A study by Forster and colleagues that evaluated postdischarge adverse events (AEs) revealed a 23% incidence of AEs with 12% of these identified as preventable. Postdischarge monitoring was deemed inadequate among these patients, with closer follow-up and improved hand-offs between inpatient and outpatient medical teams identified as possible interventions to improve postdischarge patient monitoring and to prevent AEs.⁷

The present quality initiative to standardize the discharge process for the hematology and oncology service decreased time to hematology and oncology follow-up appointment, improved communication between inpatient and outpatient teams, and decreased process variation. Timelier follow-up for this complex patient population likely will prevent clinical decompensation, delays in treatment, and directly improve patient access to care.

The multidisciplinary nature of this effort was instrumental to successful completion. In a complex health care system, it is challenging to truly understand a problem and identify possible solutions without the perspective of all members of the care team. The involvement of team members with training in quality improvement methodology was important to evaluate and develop interventions in a systematic way. Furthermore, the support and involvement of leadership is important in order to allocate resources appropriately to achieve system changes that improve care. Using quality improvement methodology, the team was able to map our processes and perform gap and root cause analyses. Strategies were identified to improve our performance using a solutions approach. Changes were implemented with continued intermittent meetings for monitoring of progression and discussion of how interventions could be made more efficient, effective, and user friendly. The primary goal was ultimately achieved.

Integration of intervention into the EMR embodies the IOM’s call to use advances in information technology to enhance the quality and delivery of care, quality measurement, and performance improvement.³ This intervention offered the strongest system changes as an electronic clinical decision support tool was developed and embedded into the EMR in the form of a Discharge Checklist Note that is linked to associated orders. This intervention was the most robust, as it provided objective data regarding utilization of the checklist, offered a more efficient way to communicate with team members regarding discharge needs, and streamlined the workflow for the discharging provider. Furthermore, this electronic tool created the ability to measure other important aspects in the care of this patient population that we previously had no mechanism of measuring: timely nursing appointments for routine care of PICC lines and ports.

Limitations

The absence of clinical endpoints was a limitation of this study. The present study was unable to evaluate the effect of the intervention on readmission rates, emergency department visits, hospital length of stay, cost, or mortality. Coordinating this multidisciplinary effort required much time and planning, and additional resources were not available to evaluate these clinical endpoints. Further studies are needed to evaluate whether the increased patient access and closer follow-up would result in improvement in these clinical endpoints. Another consideration for future improvement projects would be to include patients in the multidisciplinary team. The patient perspective would be invaluable in identifying gaps in care delivery and strategies aimed at improving care delivery.

Conclusions

This quality initiative to standardize the discharge process for the hematology and oncology service decreased time to the initial hematology and oncology follow-up appointment, improved communication between inpatient and outpatient teams, and decreased process variation. Timelier follow-up for this complex patient population likely will prevent clinical decompensation, delays in treatment, and directly improve patient access to care.

Acknowledgments

We thank our patients for whom we hope our process improvement efforts will ultimately benefit. We thank all the hematology and oncology staff at Edward Hines Jr. VA Hospital and Loyola University Medical Center residents and fellows who care for our patients and participated in the multidisciplinary team to improve care for our patients. We thank the following professionals for their uncompensated assistance in the coordination and execution of this initiative: Robert Kutter, MS, and Meghan O’Halloran, MD.

Hematology and oncology patients are a complex patient population that requires timely follow-up to prevent clinical decompensation and delays in treatment. Previous reports have demonstrated that outpatient follow-up within 14 days is associated with decreased 30-day readmissions. The magnitude of this effect is greater for higher-risk patients.¹ Therefore, patients being discharged from the hematology and oncology inpatient service should be seen by a hematology and oncology provider within 14 days of discharge. Patients who do not require close oncologic follow-up should be seen by a primary care provider (PCP) within this timeframe.

Background

The Institute of Medicine (IOM) identified the need to focus on quality improvement and patient safety with a 1999 report, To Err Is Human.² Tremendous strides have been made in the areas of quality improvement and patient safety over the past 2 decades. In a 2013 report, the IOM further identified hematology and oncology care as an area of need due to a combination of growing demand, complexity of cancer and cancer treatment, shrinking workforce, and rising costs. The report concluded that cancer care is not as patient-centered, accessible, coordinated, or evidence based as it could be, with detrimental impacts on patients.³ Patients with cancer have been identified as a high-risk population for hospital readmissions.^4,5 Lack of timely follow-up and failed hand-offs have been identified as factors contributing to poor outcomes at time of discharge.^6-10

Upon internal review of baseline performance data, we identified areas needing improvement in the discharge process. These included time to hematology and oncology follow-up appointment, percent of patients with PCP appointments scheduled at time of discharge, and electronically alerts for the outpatient hematologist/oncologist to discharge summaries. It was determined that patients discharged from the inpatient service were seen a mean 17 days later by their outpatient hematology and oncology provider and the time to the follow-up appointment varied substantially, with some patients being seen several weeks to months after discharge. Furthermore, only 68% of patients had a primary care appointment scheduled at the time of discharge. These data along with review of data reported in the medical literature supported our initiative for improvement in the transition from inpatient to outpatient care for our hematology and oncology patients.

Plan-Do-Study-Act (PDSA) quality improvement methodology was used to create and implement several interventions to standardize the discharge process for this patient population, with the primary goal of decreasing the mean time to hematology and oncology follow-up from 17 days by 12% to fewer than 14 days. Patients who do not require close oncologic follow-up should be seen by a PCP within this timeframe. Otherwise, PCP follow-up within at least 6 months should be made. Secondary aims included (1) an increase in scheduled PCP visits at time of discharge from 68% to > 90%; and (2) an increase in communication of the discharge summary via electronic alerting of the outpatient hematology and oncology physician from 20% to > 90%. Herein, we report our experience and results of this quality improvement initiative

Methods

The Institutional Review Board at Edward Hines Veteran Affairs Hospital in Hines, Illinois reviewed this single-center study and deemed it to be exempt from oversight. Using PDSA quality improvement methodology, a multidisciplinary team of hematology and oncology staff developed and implemented a standardized discharge process. The multidisciplinary team included a robust representation of inpatient and outpatient staff caring for the hematology and oncology patient population, including attending physicians, fellows, residents, advanced practice nurses, registered nurses, clinical pharmacists, patient care coordinators, clinic schedulers, clinical applications coordinators, quality support staff, and a systems redesign coach. Hospital leadership including chief of staff, chief of medicine, and chief of nursing participated as the management guidance team. Several interviews and group meetings were conducted and a multidisciplinary team collaboratively developed and implemented the interventions and monitored the results.

Outcome measures were identified, including time to hematology and oncology clinic visit, primary care follow-up scheduling, and communication of discharge to the outpatient hematology and oncology physician. Baseline data were collected and reviewed. The multidisciplinary team developed a process flow map to understand the steps and resources involved with the transition from inpatient to outpatient care. Gap analysis and root cause analysis were performed. A solutions approach was applied to develop interventions. Table 1 shows a summary of the identified problems, symptoms, associated causes, the interventions aimed to address the problems, and expected outcomes. Rotating resident physicians were trained through online and in-person education. The multidisciplinary team met intermittently to monitor outcomes, provide feedback, further refine interventions, and develop additional interventions.

PDSA Cycle 1

A standardized discharge process was developed in the form of guidelines and expectations. These include an explanation of unique features of the hematology and oncology service and expectations of medication reconciliation with emphasis placed on antiemetics, antimicrobial prophylaxis, and bowel regimen when appropriate, outpatient hematology and oncology follow-up within 14 days, primary care follow-up, communication with the outpatient hematology and oncology physician, written discharge instructions, and bedside teaching when appropriate.

PDSA Cycle 2

Based on team member feedback and further discussions, a discharge checklist was developed. This checklist was available online, reviewed in person, and posted in the team room for rotating residents to use for discharge planning and when discharging patients (Figure 1).

PDSA Cycle 3

Based on ongoing user feedback, group discussions, and data monitoring, the discharge checklist was further refined and updated. An electronic clinical decision support tool was developed and integrated into the electronic medical record (EMR) in the form of a discharge checklist note template directly linked to orders. The tool is a computerized patient record system (CPRS) note template that prompts users to select whether medications or return to clinic orders are needed and offers a menu of frequently used medications. If any of the selections are chosen within the note template, an order is generated automatically in the chart that requires only the user’s signature. Furthermore, the patient care coordinator reviews the prescribed follow-up and works with the medical support assistant to make these appointments. The physician is contacted only when an appointment cannot be made. Therefore, this tool allows many additional actions to be bypassed such as generating medication and return to clinic orders individually and calling schedulers to make follow-up appointments (Figure 2).

Data Analysis

All patients discharged during the 2-month period prior to and discharged after the implementation of the standardized process were reviewed. Patients who followed up with hematology and oncology at another facility, enrolled in hospice, or died during admission were excluded. Follow-up appointment scheduling data and communication between inpatient and outpatient providers were reviewed. Data were analyzed using XmR statistical process control chart and Fisher’s Exact Test using GraphPad. Control limits were calculated for each PDSA cycle as the mean ± the average of the moving range multiplied by 2.66. All data were included in the analysis.

Results

A total of 142 consecutive patients were reviewed from May 1, 2018 to August 31, 2018 and January 1, 2019 to April 30, 2019, including 58 patients prior to the intervention and 84 patients during PDSA cycles. There was a gap in data collection between September 1, 2018 and December 31, 2018 due to limited team member availability. All data were collected by 2 reviewers—a postgraduate year (PGY)-4 chief resident and a PGY-2 internal medicine resident. The median age of patients in the preintervention group was 72 years and 69 years in the postintervention group. All patients were men. Baseline data revealed a mean 17 days to hematology and oncology follow-up. Primary care visits were scheduled for 68% of patients at the time of discharge. The outpatient hematology and oncology physician was alerted electronically to the discharge summary for 20% of the patients (Table 2).

The primary endpoint of time to hematology and oncology follow-up appointment improved to 13 days in PDSA cycles 1 and 2 and 10 days in PDSA cycle 3. The target of mean 14 days to follow-up was achieved. The statistical process control chart shows 5 shifts with clusters of ≥ 7 points below the mean revealing a true signal or change in the data and demonstrating that an improvement was seen (Figure 3). Furthermore, the statistical process control chart demonstrates upper control limit decreased from 58 days at baseline to 21 days in PDSA cycle 3, suggesting a decrease in variation.

Discussion

The 2013 IOM report Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis found that that cancer care is not as patient-centered, accessible, coordinated, or evidence-based as it could be, with detrimental impacts on patients.³ The document offered a conceptual framework to improve quality of cancer care that includes the translation of evidence into clinical practice, quality measurement, and performance improvement, as well as using advances in information technology to enhance quality measurement and performance improvement. Our quality initiative uses this framework to work toward the goal as stated by the IOM report: to deliver “comprehensive, patient-centered, evidence-based, high-quality cancer care that is accessible and affordable.”³

Two large studies that evaluated risk factors for 15-day and 30-day hospital readmissions identified cancer diagnosis as a risk factor for increased hospital readmission, highlighting the need to identify strategies to improve the discharge process for these patients.^4,5 Timely outpatient follow-up and better patient hand-off may improve clinical outcomes among this high-risk patient population after hospital discharge. Multiple studies have demonstrated that timely follow-up is associated with fewer readmissions.^1,8-10 A study by Forster and colleagues that evaluated postdischarge adverse events (AEs) revealed a 23% incidence of AEs with 12% of these identified as preventable. Postdischarge monitoring was deemed inadequate among these patients, with closer follow-up and improved hand-offs between inpatient and outpatient medical teams identified as possible interventions to improve postdischarge patient monitoring and to prevent AEs.⁷

The present quality initiative to standardize the discharge process for the hematology and oncology service decreased time to hematology and oncology follow-up appointment, improved communication between inpatient and outpatient teams, and decreased process variation. Timelier follow-up for this complex patient population likely will prevent clinical decompensation, delays in treatment, and directly improve patient access to care.

The multidisciplinary nature of this effort was instrumental to successful completion. In a complex health care system, it is challenging to truly understand a problem and identify possible solutions without the perspective of all members of the care team. The involvement of team members with training in quality improvement methodology was important to evaluate and develop interventions in a systematic way. Furthermore, the support and involvement of leadership is important in order to allocate resources appropriately to achieve system changes that improve care. Using quality improvement methodology, the team was able to map our processes and perform gap and root cause analyses. Strategies were identified to improve our performance using a solutions approach. Changes were implemented with continued intermittent meetings for monitoring of progression and discussion of how interventions could be made more efficient, effective, and user friendly. The primary goal was ultimately achieved.

Integration of intervention into the EMR embodies the IOM’s call to use advances in information technology to enhance the quality and delivery of care, quality measurement, and performance improvement.³ This intervention offered the strongest system changes as an electronic clinical decision support tool was developed and embedded into the EMR in the form of a Discharge Checklist Note that is linked to associated orders. This intervention was the most robust, as it provided objective data regarding utilization of the checklist, offered a more efficient way to communicate with team members regarding discharge needs, and streamlined the workflow for the discharging provider. Furthermore, this electronic tool created the ability to measure other important aspects in the care of this patient population that we previously had no mechanism of measuring: timely nursing appointments for routine care of PICC lines and ports.

Limitations

The absence of clinical endpoints was a limitation of this study. The present study was unable to evaluate the effect of the intervention on readmission rates, emergency department visits, hospital length of stay, cost, or mortality. Coordinating this multidisciplinary effort required much time and planning, and additional resources were not available to evaluate these clinical endpoints. Further studies are needed to evaluate whether the increased patient access and closer follow-up would result in improvement in these clinical endpoints. Another consideration for future improvement projects would be to include patients in the multidisciplinary team. The patient perspective would be invaluable in identifying gaps in care delivery and strategies aimed at improving care delivery.

Conclusions

This quality initiative to standardize the discharge process for the hematology and oncology service decreased time to the initial hematology and oncology follow-up appointment, improved communication between inpatient and outpatient teams, and decreased process variation. Timelier follow-up for this complex patient population likely will prevent clinical decompensation, delays in treatment, and directly improve patient access to care.

Acknowledgments

We thank our patients for whom we hope our process improvement efforts will ultimately benefit. We thank all the hematology and oncology staff at Edward Hines Jr. VA Hospital and Loyola University Medical Center residents and fellows who care for our patients and participated in the multidisciplinary team to improve care for our patients. We thank the following professionals for their uncompensated assistance in the coordination and execution of this initiative: Robert Kutter, MS, and Meghan O’Halloran, MD.